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Classifications

Harrison's Part

IUIS Category

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Inheritance

1

Autosomal Recessive HP:0000007

Biallelic HMOX1 variants are required. Reported genotypes include compound heterozygosity (the index Japanese case), and homozygosity for nonsense (p.R44X, p.K204X) or missense (p.G139V) alleles, several in consanguineous families.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:36502441 SUPPORT Human Clinical

"It is encoded by the HMOX1 gene, and biallelic mutations cause HMOX-1 deficiency, which is a rare chronic multisystemic inflammatory disorder."

States explicitly that biallelic HMOX1 mutations are required, establishing recessive inheritance.

PMID:33066778 SUPPORT Human Clinical

"HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome."

Names the inheritance mode directly alongside the hallmark features.

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Discussions and Knowledge Gaps

6

Which features of HMOX1 deficiency can legitimately be studied in Hmox1-null rodents, given that the mouse and rat models diverge from human patients on the splenic and tissue-iron phenotypes that are cardinal in humans?

HUMAN MODEL MISMATCH OPEN hmox1_rodent_human_divergence

Attached to

pathophysiology#Impaired Heme-Iron Recycling and Tissue Iron Deposition pathophysiology#Macrophage and Monocyte Dysfunction

Only about a dozen human patients have ever been reported, so a large share of the mechanism in this entry rests on rodent data, and the rodents disagree with the humans, and with each other, on exactly the features that define the disease clinically. Three divergences are documented, and they differ in kind. (i) ORGAN-SYSTEM EMPHASIS AND SURVIVAL: the first human autopsy states the contrast itself, finding endothelial and reticuloendothelial involvement with intravascular haemolysis, DIC and amyloidosis and short survival, against a predominantly iron-metabolic, long-surviving mouse. (ii) ERYTHROCYTE LIFESPAN RUNS THE WRONG WAY: red cell lifespan is *prolonged* in Hmox1-null mice, while human patients have shortened red cell survival with fragmentation — an opposite-direction finding, not a difference of degree, and the reason no conformance to a haemolysis module should be asserted on mouse evidence. (iii) TISSUE IRON: the Hmox1-null rat does not deposit iron in tubular epithelium or hepatic parenchyma at all. Human patients characteristically have asplenia or functional hyposplenism; the original C57BL/6 Hmox1-null mouse instead develops marked splenomegaly, while a mixed-background null strain shows early splenomegaly evolving into fibrotic atrophy and functional hyposplenism, so the apparent mouse-human agreement depends on strain background rather than on Hmox1 genotype alone. The Hmox1-deficient rat diverges more sharply still: it does not develop the hepatic or renal iron deposition that is cardinal in both human patients and mice. That is not merely a missing measurement but a directly contradictory positive finding in a model that otherwise reproduces haemolysis and renal disease, so the iron arm and the haemolysis and renal arms of the rodent literature have different translational standing and should not be inherited wholesale. Conversely, the arms where rodents and humans do converge (failed iron recycling with low serum iron, hypersensitivity of null cells to heme and oxidant stress, and macrophage death during erythrophagocytosis) are the arms where model evidence can reasonably substitute for the human data that will never exist in quantity.

Proposed experiments

Cross-species comparison of splenic and hepatic iron handling

cross-species model comparison experiment

exp_hmox1_cross_species_iron_handling

Systematically compare erythrophagocytosing macrophage iron handling, CD163 expression and splenic red-pulp architecture across Hmox1-null mouse strains, the Hmox1-null rat, and archived human HO-1-deficient tissue, with age-matched timepoints extending beyond 24 weeks in the rat, to determine whether the rat iron phenotype is genuinely absent or merely later-onset.

Patient-derived macrophage and endothelial models

patient-derived cell model experiment

exp_hmox1_patient_derived_cell_models

Derive iPSC macrophages and endothelial cells from HMOX1-deficient patients, or generate isogenic HMOX1-null human lines carrying the reported p.R44X and p.G139V alleles, and test heme handling, CD163 expression, and tissue-factor and PAI-1 induction, to obtain human-cell evidence for the arms currently supported only by rodents.

Show evidence (4 references)

PMID:11823983 SUPPORT Human Clinical

"Compared with HO-1--targeted mice, the present case seems to more severely involve endothelial cells and the reticuloendothelial system, resulting in intravascular hemolysis, disseminated intravascular coagulation, and amyloidosis with a short survival. This contrasts to the predominant iron..."

The strongest anchor for this discussion, because it is a published first-party mismatch claim rather than an inference drawn across papers: the autopsy authors themselves contrast the human organ-system emphasis (endothelium and reticuloendothelial system, short survival) against the predominantly iron-metabolic, long-survival mouse phenotype.

PMID:33546372 SUPPORT Model Organism

"In contrast to human cases or mice models, iron deposition was not increased within the tubular epithelium or hepatic parenchyma of the rat model."

The explicit statement of rat-human divergence on the tissue-iron phenotype that makes this a model-fidelity question rather than an evidence gap.

PMID:25682599 SUPPORT Model Organism

"Red blood cell lifespan is prolonged in heme oxygenase-1 deficient mice compared with wild-type mice."

The sharpest divergence of the three, because it runs in the OPPOSITE direction rather than merely differing in degree: mouse erythrocytes live longer, while human patients have shortened red cell survival with fragmentation and intravascular haemolysis.

+ 1 more reference

Why do patients with complete loss of an enzyme described as essential remain asymptomatic for years, and what compensates until the first flare?

KNOWLEDGE GAP OPEN hmox1_onset_variability_gap

Attached to

pathophysiology#Failure of Stress-Inducible Heme Catabolism pathophysiology#Systemic Inflammatory Response and Progressive Organ Injury

Age at first recognisable symptom in reported patients ranges from 6 months to 15 years, and several patients carrying the identical homozygous p.R44X allele grew and developed normally for over a decade before deteriorating rapidly and dying within months. Identical genotype with a decade of phenotypic variability implies compensatory mechanisms whose identity, capacity and mode of failure are entirely unknown. This matters practically: it means the disease has a long presymptomatic window in which a diagnosis could in principle be made on the low-bilirubin-with-high-LDH signature, and it means the trigger that exhausts compensation is a candidate intervention point.

Proposed experiments

Longitudinal profiling of presymptomatic HMOX1-null siblings

longitudinal cohort profiling experiment

exp_hmox1_presymptomatic_sibling_profiling

In consanguineous families with a known HMOX1 allele, genotype and longitudinally profile presymptomatic siblings for haemolysis markers, free heme, hemopexin, haptoglobin and inflammatory cytokines, to identify which parameter decompensates first and whether a compensatory heme-handling pathway is measurably active before the first flare.

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"The variability of age of onset and the rapidly progressive clinical course suggests the presence of certain compensatory mechanisms to overcome the absence of HO-1 function."

The review's own statement that unidentified compensatory mechanisms must exist, which is precisely the gap recorded here.

What determines congenital absence, acquired splenic loss, or enlargement in human HMOX1 deficiency?

KNOWLEDGE GAP OPEN hmox1_splenic_outcome_attribution

Attached to

phenotypes#Asplenia phenotypes#Splenic Hypoplasia phenotypes#Splenomegaly

Human patients show distinct splenic courses. The US imaging suggests infarction, whereas a mixed-background mouse model develops macrophage loss, red-pulp fibrosis and later atrophy. These observations do not establish that the same process causes congenital human asplenia or human splenomegaly. This is uncertainty in developmental versus acquired causal attribution and model translation, not a claim that splenic injury has no mechanism. The documented hyposplenia-to-thrombocytosis consequence is modeled.

Show evidence (3 references)

PMID:33546372 SUPPORT Human Clinical

"Why these two cases showed a normal-sized spleen or splenomegaly, respectively, remains unclear."

The review explicitly identifies unexplained human splenic variability.

PMID:33066778 SUPPORT Human Clinical

"Further imaging with CTA abdomen demonstrated absent splenic veins and multiple collaterals to a small left kidney, implying that patient’s spleen had infarcted."

The primary case supports an acquired infarction interpretation without proving its upstream vascular mechanism.

PMID:33546372 SUPPORT Model Organism

"Pathological examination revealed initial enlargement of the red pulp of the spleen underwent progressive fibrotic changes and eventual atrophy and functional hyposplenism in older mice."

This mechanism is demonstrated in mice and is not silently transferred to every human splenic phenotype.

Which processes account for growth impairment, facial appearance, and eyelid edema?

KNOWLEDGE GAP OPEN hmox1_growth_facial_edema_attribution

Attached to

phenotypes#Growth Retardation phenotypes#Prominent Forehead phenotypes#Depressed Nasal Bridge phenotypes#Palpebral Edema

Growth can slow after inflammatory onset, but nutritional state, chronic organ disease and steroid treatment have not been separated. The 2024 pulmonary patient also carries a 16p13.11 duplication that confounds developmental findings. The sources document frontal prominence, a depressed nasal bridge and eyelid edema without establishing a shared morphogenetic cause or identifying renal versus inflammatory fluid accumulation. These unresolved causal attributions are kept distinct from the supported inflammatory and renal paths.

Show evidence (3 references)

PMID:33546372 SUPPORT Human Clinical

"His growth had been normal by 3 years of age. However, his growth slowed down significantly after the onset of the inflammatory episodes, being less than the 10th percentile for weight and 20th percentile for height at 8 years."

The timing supports a chronic-illness contribution but does not distinguish inflammation, nutrition and treatment effects.

PMID:33546372 SUPPORT Human Clinical

"The patient had characteristic facial features such as a flat nasal bridge, frontal bossing, and prominent edema of the eyelids."

The facial and eyelid findings are documented without a demonstrated causal mechanism.

PMID:38178812 SUPPORT Human Clinical

"Furthermore, array-based Comparative Genomic Hybridization (array-CGH) analysis revealed a 16p13.11 microduplication of paternal origin, which is known to potentially contribute to congenital heart disease, behavioral disorders, developmental delays, brain abnormalities, and skeletal malformations."

A coexisting genomic disorder limits attribution of developmental abnormalities to HMOX1 alone.

How much do treatment and altered scavenging contribute to the abnormal lipid and haptoglobin concentrations?

KNOWLEDGE GAP OPEN hmox1_lipid_haptoglobin_attribution

Attached to

phenotypes#Hypertriglyceridaemia phenotypes#Hypercholesterolaemia phenotypes#Elevated Serum Haptoglobin

The primary report explicitly leaves hyperlipidaemia unresolved and proposes both corticosteroid exposure and impaired bilirubin production. The latter is retained as a qualified cholesterol edge, not rejected merely because intermediates are unknown. No comparably specific triglyceride mechanism is established. High serum haptoglobin and urinary Hb-Hp complexes document abnormal handling, but the relative roles of altered production and clearance in the high serum concentration have not been resolved.

Show evidence (2 references)

PMID:9884342 SUPPORT Human Clinical

"The mechanism of hyperlipidemia, with high choles- terol and triglyceride levels, is not clear. Prolonged cor- ticosteroid therapy alone may explain the levels seen in this patient. Bilirubin is a known antioxidant (20), and it also acts as a scavenger for degraded LDL cholesterol (21–24)...."

The primary authors explicitly describe competing lipid explanations.

PMID:33546372 SUPPORT Human Clinical

"Further study revealed that serum Hp concentration was extremely elevated (800–1200 mg/dL, normal range; 40–180 mg/dL) and a large amount of Hb-Hp complex was detected in a urine sample from the patient."

These observations establish the unusual concentrations and handling, not a unique mechanism for the serum elevation.

Which tissue lesions account for hepatomegaly and the severe bleeding complications?

KNOWLEDGE GAP OPEN hmox1_organ_enlargement_and_bleeding_attribution

Attached to

phenotypes#Hepatomegaly phenotypes#Intracranial Haemorrhage phenotypes#Pulmonary Haemorrhage

The reviewed cases establish hepatic iron deposition, inflammatory injury and, in some patients, amyloid, but do not distinguish their contributions to liver enlargement. Endothelial damage and coagulopathy provide plausible routes to intracranial or pulmonary bleeding; the reports do not attribute each hemorrhage to one of those processes rather than hypertension, pulmonary parenchymal injury or their combination. Supported endothelial-to-coagulopathy and pulmonary injury paths are represented; the unresolved issue is attribution of these particular clinical endpoints, not the absence of modeled intermediates.

Show evidence (3 references)

PMID:33546372 SUPPORT Human Clinical

"Hypertension and intracranial hemorrhage are certainly related to the basic pathology of HO-1 deficiency. However, these symptoms were not constantly observed in HO-1 deficiency patients."

The review recognizes the association but does not isolate the causal route to each hemorrhage.

PMID:38178812 SUPPORT Human Clinical

"However, he experienced sudden fulminant pulmonary bleeding and expired at the age of five years and eleven months."

The fatal complication is reported without a lesion-specific causal demonstration.

PMID:33546372 SUPPORT Human Clinical

"Hepatomegaly was another characteristic finding and the liver biopsy revealed mild sinusoidal fibrosis, mild microvesicular steatosis, and increased iron deposit within Kupffer cells."

Multiple hepatic lesions coexist, without establishing which drives enlargement.

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Pathophysiology

12

HMOX1 Biallelic Loss of Function

Biallelic loss-of-function variants in HMOX1 abolish or impair heme oxygenase 1 function. Reported alleles span whole-exon deletion, frameshift, nonsense and missense classes. The p.G139V allele shows that loss of protein abundance is not required: patient cells retained constitutive HO-1 expression but lacked further hemin induction and showed impaired heme-induced bilirubin synthesis. Acquired abnormal peroxidase activity was inferred from human urinary oxidation products and biochemical studies of other Gly139 substitutions. Loss of inducibility alone does not establish these distinct functional defects.

HMOX1 hgnc:5013

heme oxygenase (decyclizing) activity GO:0004392 ↓ DECREASED

Downstream

Failure of Stress-Inducible Heme Catabolism Loss of functional HO-1 protein directly removes the catalytic capacity to open the heme ring under stress.

Show evidence (5 references)

PMID:9884342 SUPPORT Human Clinical

"Immunohistochemistry of hepatic tissue and immunoblotting of a cadmium-stimulated Epstein-Barr virus-transformed lymphoblastoid cell line (LCL) revealed complete absence of HO-1 production."

Demonstrates complete absence of HO-1 protein in the index patient, even under cadmium stimulation that normally induces the enzyme. Tagged HUMAN_CLINICAL for the hepatic-tissue immunohistochemistry half of the sentence, which is a direct observation on patient tissue; note that the lymphoblastoid-cell immunoblot in the same sentence is a cell experiment, and the separate LCL hemin-sensitivity result is curated as IN_VITRO on the free-heme node.

PMID:33066778 SUPPORT In Vitro

"Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells."

Independently confirms in a second patient that oxidant stimulation fails to produce HMOX1 protein. Tagged IN_VITRO, not HUMAN_CLINICAL: the measurement is made on cultured patient-derived cells under oxidant challenge, which is a cell experiment even though the cells came from a named patient in a case report.

PMID:27662012 SUPPORT In Vitro

"We then confirmed the defective enzyme activity by documenting bilirubin synthesis in PBMC. Control cells showed the expected >4-fold heme-induced increase of bilirubin from 18.8 & 23.6 to 95.9 & 84.6 pmol/mg protein/60min following heme treatment. In contrast, patient cells showed a marginal..."

Cultured patient PBMC showed impaired heme-induced bilirubin synthesis. This functional assay supports reduced heme-catabolic activity independently of the protein-inducibility experiment; it is not a direct purified-G139V peroxidase assay.

+ 2 more references

Failure of Stress-Inducible Heme Catabolism

HO-1 is the stress-inducible heme oxygenase isozyme, and the only one rapidly induced by oxidative stress. Its loss therefore does not merely slow basal heme turnover; it removes the surge capacity that normally meets an oxidative or haemolytic insult. Constitutive HMOX2 cannot substitute because it is not inducible. (Sources differ on how many isozymes to count: the cited review says three, while the cited 2020 case report says two. The discrepancy is the status of HO-3, now generally regarded as a pseudogene rather than a functional enzyme. Nothing in this entry depends on the count, so no number is asserted here; the quoted evidence below preserves each source's own wording.) The consequence is a single enzymatic block that simultaneously fails to generate biliverdin and bilirubin, fails to generate carbon monoxide, fails to liberate iron for recycling, and leaves the heme substrate itself uncleared. Each of the four downstream arms below is a distinct consequence of this one block.

Kupffer cell CL:0000091 vascular endothelial cell CL:0000115 monocyte CL:0000576

HMOX1 hgnc:5013

heme catabolic process GO:0042167 ↓ DECREASED cellular response to oxidative stress GO:0034599 ↓ DECREASED

Animal models

Hmox1-null mouse (Poss and Tonegawa, C57BL/6) Mouse recapitulates Cells and animals lacking Hmox1 lose the adaptive protection normally conferred by its stress induction, which is the defining property of this node.

Downstream

Circulating Free Heme Accumulation Heme that cannot be catabolised persists in plasma and tissue rather than being cleared.

Loss of Bilirubin Antioxidant Capacity Loss of HO-1 reduces stress-induced biliverdin production and the bilirubin derived from it; retained HO-2 does not restore the inducible response.

Loss of Carbon Monoxide Cytoprotective Signalling CO is generated stoichiometrically by the ring-opening reaction, so the enzymatic block removes HO-1-derived production without eliminating all endogenous CO sources.

Impaired Heme-Iron Recycling and Tissue Iron Deposition Iron cannot be liberated from heme and released from hepatic and renal cells for reuse.

Renal Tubular Injury Loss of the inducible HO-1 response permits heme-associated tubular injury.

Pulmonary Oxidative Injury Loss of HO-1-mediated oxidant protection is proposed to drive the pulmonary injury.

Show evidence (4 references)

PMID:33546372 SUPPORT Other

"Heme oxygenase (HO)-1 constitutes one of the three isozymes of HO, and catalyzes the degradation of heme into biliverdin, carbon monoxide (CO), and free iron, each of which somehow exert potent anti-oxidative stress and anti-inflammatory functions"

Establishes the three reaction products whose individual loss defines the three product-deficit arms of this pathograph.

PMID:33546372 SUPPORT Other

"Among the three isozymes, HO-1 is the only protein rapidly induced upon stimulation with various oxidative stresses"

Supports the framing that HMOX1 loss removes an inducible protective response that the constitutive isozymes cannot supply.

PMID:33546372 SUPPORT Other

"Therefore, any defect in the function of HO-1 would be expected to lead to uncontrollable inflammation in response to certain exogenous insults, such as infection and hemolysis."

Links the loss of inducibility specifically to stress-triggered decompensation rather than continuous baseline disease.

+ 1 more reference

Circulating Free Heme Accumulation

Uncleared heme reaches extreme plasma concentrations (490 micromolar in the index case against a normal value below 1 micromolar), and the scavenging system is overwhelmed: hemopexin is undetectable while haptoglobin is paradoxically elevated rather than consumed, and haptoglobin-haemoglobin complex spills into urine. Free heme is directly cytotoxic and pro-oxidant, and patient-derived cells are hypersensitive to it.

Downstream

Endothelial Cell Injury and Coagulopathy Free heme is cytotoxic and pro-oxidant, and vascular endothelium is the compartment most severely affected in the human disease. The link between the two is inferred rather than directly measured in patient endothelium.

Intravascular Haemolysis with Erythrocyte Fragmentation Free heme can aggravate vascular oxidative injury, which in turn contributes to erythrocyte destruction and fragmentation.

Show evidence (4 references)

PMID:33546372 SUPPORT Human Clinical

"Serum heme concentration was extremely high, at 490 μM (normal range; <1 μM)."

Direct measurement of circulating free heme at roughly 500-fold the upper limit of normal, which is the accumulation this node asserts.

PMID:33546372 SUPPORT Human Clinical

"Hemopexin was undetectable by immunoelectrophoresis, indicating the presence of active hemolysis in vivo."

Documents exhaustion of the hemopexin heme-scavenging arm in the index patient.

PMID:9884342 SUPPORT In Vitro

"An LCL derived from the patient was extremely sensitive to hemin-induced cell injury."

Directly demonstrates that HO-1-deficient patient cells are hypersensitive to heme cytotoxicity, the proximate toxic consequence of heme accumulation.

+ 1 more reference

Loss of Bilirubin Antioxidant Capacity

Biliverdin, and the bilirubin derived from it by biliverdin reductase, is a physiologically significant antioxidant. Because HO-1 is the sole route to biliverdin under stress, HO-1 deficiency removes this antioxidant sink. The same block explains the disease's most discriminating laboratory paradox: a patient with brisk intravascular haemolysis has LOW serum bilirubin and no jaundice, because the bilirubin normally produced from the liberated heme is inadequately generated. Persistently elevated LDH alongside low bilirubin is the combination that prompted the diagnosis in at least one reported case.

antioxidant activity GO:0016209 ↓ DECREASED

Downstream

Systemic Inflammatory Response and Progressive Organ Injury Loss of the bilirubin antioxidant sink leaves oxidative stress unbuffered, amplifying inflammatory tissue injury.

Hypobilirubinaemia Despite Haemolysis Reduced bilirubin generation can yield frankly low serum bilirubin; some affected patients instead remain within the normal range.

Hypercholesterolaemia Impaired bilirubin production is proposed as one contributor to elevated cholesterol; prolonged corticosteroid treatment is a competing explanation.

Show evidence (3 references)

PMID:33066778 SUPPORT Human Clinical

"Two isoforms exist, heme oxygenase-1 (HMOX1) and heme oxygenase-2 (HMOX2), with CO, biliverdin, and bilirubin implicated in important cellular processes, such as inflammation, cell proliferation, apoptosis, and antioxidant defense."

Attributes antioxidant defence specifically to the biliverdin and bilirubin products lost in this disease.

PMID:9884342 SUPPORT Human Clinical

"He has been suffering from persistent hemolytic anemia characterized by marked erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum haptoglobin and low bilirubin."

The index case documents the defining paradox of haemolysis with low rather than raised bilirubin.

PMID:33546372 SUPPORT Human Clinical

"Persistently elevated LDH despite low bilirubin levels led Greil et al. to analyze the HMOX1 gene, revealing the homozygous G139V mutation."

Shows the haemolysis-without-bilirubin signature is discriminating enough to have driven a diagnosis.

Loss of Carbon Monoxide Cytoprotective Signalling

CO produced by heme ring opening acts as a gaseous mediator that restrains inflammatory signalling and regulates the microcirculation and the coagulation and fibrinolysis balance. Loss of endogenous CO is the arm most often invoked to explain the disproportionate endothelial and coagulation abnormalities of this disease, but this attribution is a hypothesis rather than a demonstrated mechanism in patients: the supporting experiment is an add-back, in which exogenous CO-releasing molecules suppress TNF-alpha-driven upregulation of tissue factor and plasminogen activator inhibitor type 1 in cultured human endothelial cells and suppress LPS-induced TNF-alpha production by mononuclear cells. Endogenous CO deficiency has not been measured in a patient, so both downstream edges are marked indirect.

cellular response to carbon monoxide GO:0071245 ↓ DECREASED

Downstream

Endothelial Cell Injury and Coagulopathy Without endogenous CO, endothelial tissue factor and PAI-1 are not restrained and the coagulation and fibrinolysis balance is lost.

Systemic Inflammatory Response and Progressive Organ Injury Loss of the CO brake on inflammatory signalling permits an unrestrained systemic inflammatory response.

Show evidence (2 references)

PMID:33546372 SUPPORT Other

"CO directly controls the inflammatory state of a given tissue, and at the same time regulates the microcirculation within target organs by acting as a gaseous mediator"

Establishes the anti-inflammatory and vasoregulatory roles of the CO product that HO-1 deficiency eliminates.

PMID:33546372 SUPPORT In Vitro

"We recently demonstrated in in vitro cultures that a CO-releasing molecule, tricarbonyldichlororuthenium (II) dimer suppressed TNF-α-induced up-regulation of tissue factor and plasminogen activator inhibitor type 1 by human umbilical vein endothelial cells."

Add-back of CO in vitro reproduces the anticoagulant and anti-inflammatory effect whose absence is proposed to explain the patients' coagulopathy. Support is indirect because this is a pharmacological add-back in cultured cells, not a demonstration in patient tissue. The quote is given in full so that the agent is identifiably a CO donor.

Impaired Heme-Iron Recycling and Tissue Iron Deposition

Most body iron is recycled from senescent erythrocytes rather than absorbed from the diet, and HO-1 catalyses the step that liberates that iron. Its loss traps iron inside hepatic parenchymal cells and renal tubular epithelium instead of releasing it for erythropoiesis. The resulting state is counter-intuitive and is a recognised diagnostic trap: heavy tissue iron deposition and marked hyperferritinaemia coexist with normal or low serum iron, and with anaemia that does not respond to iron supplementation.

kidney proximal tubule epithelial cell CL:1000838 Kupffer cell CL:0000091

intracellular iron ion homeostasis GO:0006879 ⚠ ABNORMAL

Animal models

Hmox1-null mouse (Poss and Tonegawa, C57BL/6) Mouse recapitulates Reproduces the counter-intuitive combination of low serum iron with hepatic and renal iron accumulation that defines this node, and was the experiment that established the recycling mechanism.

Hmox1-deficient Sprague-Dawley rat Rat fails to recapitulate The rat does not develop the hepatic and renal iron deposition that is a cardinal feature of both the human disease and the mouse models, so it cannot be used to study this arm.

Downstream

Hyperferritinaemia Iron that cannot be recycled out of the macrophage accumulates, and serum ferritin rises. The edge is hedged because ferritin is not a clean readout of that: it is also an acute-phase reactant, and this disease produces a sustained systemic inflammatory state that raises it independently of iron. The phenotype's own description, its evidence and its reports_on interpretation all make that point — circulating ferritin does not quantify tissue iron stores here — so this edge should not assert an iron-loading mechanism more confidently than the record it points at. Which of the two contributions dominates in any given patient is not established by anything cited.

Macrophage and Monocyte Dysfunction Iron and heme overload within erythrophagocytosing macrophages impairs and ultimately kills them.

Systemic Inflammatory Response and Progressive Organ Injury Deposited redox-active iron drives macromolecular oxidative damage and chronic inflammation in liver and kidney.

Show evidence (3 references)

PMID:9884342 SUPPORT Human Clinical

"Iron deposition was noted in renal and hepatic tissue."

Direct human histological evidence of renal and hepatic iron deposition in the index case.

PMID:9380735 SUPPORT Model Organism

"Hmox1-deficient adult mice developed an anemia associated with abnormally low serum iron levels, yet accumulated hepatic and renal iron that contributed to macromolecular oxidative damage, tissue injury, and chronic inflammation."

The defining mouse experiment establishing the mechanism by which iron is simultaneously deficient in serum and excessive in tissue. Mouse evidence only; the corresponding human histology is cited separately above.

PMID:9380735 SUPPORT Model Organism

"Our results indicate that Hmox1 has an important recycling role by facilitating the release of iron from hepatic and renal cells, and describe a mouse model of human iron metabolic disorders."

States the recycling role of Hmox1 whose loss produces the tissue-iron trapping.

Macrophage and Monocyte Dysfunction

HO-1 is normally induced to high levels in monocytes and macrophages, which handle the heme load generated by erythrophagocytosis. Without it these cells progressively fail: monocyte dysfunction and unregulated macrophage activation are documented consequences, and mouse work shows macrophages die during erythrophagocytosis. This arm explains both the macrophage-activation-syndrome and haemophagocytic flares seen clinically and, plausibly, the functional asplenia, which in mouse models arises from progressive fibrotic destruction of the splenic red pulp.

macrophage CL:0000235 monocyte CL:0000576

Animal models

Hmox1-null mouse (mixed C57BL/6-FVB background) Mouse recapitulates Demonstrates the specific cellular mechanism of this node, macrophages dying as they phagocytose erythrocytes and release heme they cannot catabolise, together with loss of the CD163 scavenger receptor.

Hmox1-null mouse (mixed C57BL/6-FVB background) Mouse rescues Subablative bone marrow transplantation repopulates the tissues with wild-type macrophages and reverses the Hmox1-null phenotype, which is the strongest available evidence that macrophage failure is causally sufficient for the downstream disease rather than merely correlated with it. Donor-derived Kupffer cells expressing Hmox1 persisted in the liver and restored heme-recycling capacity even after engraftment became transient.

Downstream

Asplenia Absent splenic tissue, reported in several patients and sometimes described as congenital. Drawn from the macrophage node because the spleen is the organ of the red-pulp macrophage compartment this disease disables. Note the entry curates four different splenic outcomes — absence, hypoplasia, normal size and enlargement — because all four are reported; none excludes the diagnosis.

Splenic Hypoplasia A small, poorly perfused, infarcted spleen — an acquired course distinct from congenital absence, and curated separately for that reason.

Splenomegaly The opposite splenic presentation, which may regress during the disease course. Curated because its presence does not exclude HMOX1 deficiency.

Systemic Inflammatory Response and Progressive Organ Injury Unregulated macrophage activation drives the haemophagocytic and macrophage-activation-syndrome flares that dominate the clinical course.

Haemophagocytosis Unregulated macrophage activation includes phagocytosis of blood-cell precursors during inflammatory flares.

Show evidence (4 references)

PMID:33546372 SUPPORT Other

"In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome."

Names monocyte dysfunction and unregulated macrophage activation as consequences of impaired HO-1, converging on systemic inflammation.

PMID:33546372 SUPPORT Model Organism

"They showed progressive death of macrophages in the liver and spleen throughout the process of erythrophagocytosis and the resultant heme release in vivo, causing significant damage to the organs and intense inflammation of the surrounding tissues."

Mouse evidence for the specific cellular mechanism, macrophage death during erythrophagocytosis, underlying this node.

PMID:33546372 SUPPORT Human Clinical

"The cytoplasm of circulating monocytes was vacuolated, and expressions of many monocyte surface antigens were markedly reduced."

Direct human cellular evidence of monocyte structural and phenotypic abnormality, so this node does not rest on mouse data alone.

+ 1 more reference

Endothelial Cell Injury and Coagulopathy

Vascular endothelium is the tissue most severely affected in human HO-1 deficiency. Markers of endothelial damage (thrombomodulin, von Willebrand factor) are markedly elevated, and glomerular electron microscopy shows frank detachment of endothelium with subendothelial deposits. The coagulation and fibrinolysis systems are grossly deranged, with extraordinarily elevated thrombin-antithrombin complex and fibrin degradation products, yet platelet counts are paradoxically raised rather than consumed, distinguishing this from ordinary disseminated intravascular coagulation.

vascular endothelial cell CL:0000115

Downstream

Intracranial Haemorrhage Bleeding into the brain, the most consequential expression of the endothelial injury and coagulopathy this node describes.

Intravascular Haemolysis with Erythrocyte Fragmentation A damaged endothelial surface shears circulating erythrocytes, producing the fragmentation and schistocytes seen on the blood film.

Systemic Inflammatory Response and Progressive Organ Injury Endothelial dysfunction propagates vascular inflammation and contributes to nephritis and multiorgan injury.

Coagulopathy Endothelial injury disrupts coagulation and fibrinolysis.

Show evidence (3 references)

PMID:9884342 SUPPORT Human Clinical

"An abnormal coagulation/fibrinolysis system, associated with elevated thrombomodulin and von Willebrand factor, indicated the presence of severe, persistent endothelial damage."

Direct human biomarker evidence of severe persistent endothelial injury.

PMID:9884342 SUPPORT Human Clinical

"Electron microscopy of renal glomeruli revealed detachment of endothelium, with subendothelial deposition of an unidentified material."

Ultrastructural confirmation of endothelial injury in the renal microvasculature, linking this node to the nephritis phenotype.

PMID:21088618 SUPPORT Human Clinical

"Human HO-1 deficiency has been observed to involve the endothelial cells more severely, resulting in hemolysis and disseminated intravascular coagulation."

Independent confirmation that endothelium is the preferentially affected compartment, causally upstream of haemolysis and coagulopathy.

Intravascular Haemolysis with Erythrocyte Fragmentation

Persistent intravascular haemolysis with marked erythrocyte fragmentation is a cardinal feature. The blood film shows fragmented erythrocytes together with Howell-Jolly bodies (reflecting the asplenia) and nucleated red cells, and the direct antiglobulin test is negative, excluding an autoimmune cause. Haemolysis both results from and further feeds the heme burden, since each destroyed erythrocyte releases haemoglobin that cannot be catabolised.

erythrocyte homeostasis GO:0034101 ⚠ ABNORMAL

Animal models

Hmox1-null mouse (mixed C57BL/6-FVB background) Mouse fails to recapitulate The mouse does not reproduce the human haemolytic phenotype, and fails in the least forgiving way available: red cell lifespan is PROLONGED in Hmox1-null mice, whereas human patients have shortened red cell survival with fragmentation and intravascular haemolysis. The mouse anaemia is microcytic and attributed to defective erythroblastic-island formation, a different mechanism from the human one.

Hmox1-deficient Sprague-Dawley rat Rat recapitulates Reproduces haemolytic anaemia with abnormal circulating erythrocyte morphology.

Downstream

Elevated Lactate Dehydrogenase Released from lysed erythrocytes; the standard laboratory marker of intravascular haemolysis.

Elevated Serum Haptoglobin The paradox of this disease, and worth an edge rather than omission precisely because it runs backwards: intravascular haemolysis normally consumes haptoglobin, but here the haptoglobin-haemoglobin complex is not cleared, because clearing it is the job of the macrophage compartment this disease disables. A normal or high haptoglobin does not exclude the diagnosis.

Systemic Inflammatory Response and Progressive Organ Injury Ongoing haemolysis supplies the inflammatory and oxidative burden that the absent HO-1 response cannot contain.

Haemolytic Anaemia Intravascular erythrocyte destruction causes haemolytic anaemia.

Erythrocyte Fragmentation Fragmented erythrocytes are the morphological manifestation of this haemolytic process.

Haemoglobinuria Intravascular red-cell lysis releases haemoglobin that can enter the urine.

Hypertension Scavenging of nitric oxide by free haemoglobin is proposed to contribute to vasoconstriction and hypertension; renal injury may also contribute.

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"Peripheral blood smear showed numerous fragmented erythrocytes, Howell-Jolly bodies and nucleated red blood cells."

Morphological documentation of erythrocyte fragmentation in the index case.

PMID:33066778 SUPPORT Human Clinical

"HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome."

Confirms the haemolysis is antibody-negative, excluding an autoimmune mechanism.

Systemic Inflammatory Response and Progressive Organ Injury

The convergent endpoint. Impaired protective responses (reduced bilirubin antioxidant capacity and CO signaling, uncleared cytotoxic heme, trapped redox-active iron, and failing macrophages) produces an unrestrained systemic inflammatory response. Clinically this appears as recurrent fever and rash, nephritis, hepatomegaly, interstitial lung disease, leukocytosis and thrombocytosis, and haemophagocytic or macrophage-activation flares, and in at least one patient progressed to secondary AA amyloidosis. Onset is typically triggered by an exogenous insult such as infection, and once ignited the course is often rapidly progressive and fatal.

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Hepatomegaly Hepatic involvement in the systemic inflammatory and iron-deposition process.

Elevated Hepatic Transaminases The biochemical correlate of that hepatic injury.

Hypertriglyceridaemia Raised triglycerides in the systemic inflammatory state.

Growth Retardation Constitutional consequence of chronic systemic inflammation and organ injury.

Palpebral Edema Periorbital oedema reported in the inflammatory presentation.

Recurrent Fever Hyperinflammatory flares manifest with recurrent fever.

Leukocytosis Inflammatory flares increase circulating leukocyte counts above an already elevated baseline.

Secondary AA Renal Amyloidosis Persistent inflammation can lead to secondary AA amyloid deposition in the kidney.

Pericardial Effusion Pericardial effusion can complicate systemic inflammatory flares; steroid responsiveness supports an inflammatory contribution in the US patient.

Arthralgia The articular component of systemic inflammation can cause joint pain.

Erythematous Rash The cutaneous component of systemic inflammatory flares can manifest as erythematous rash.

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"The devastating clinical courses experienced by these patients indicate the critical importance of HO-1 in holding back rapidly progressive inflammation and organ dysfunction once an overwhelming inflammatory response is ignited by certain triggers."

Directly frames the endpoint as failure to restrain a trigger-initiated inflammatory response.

PMID:36502441 SUPPORT Human Clinical

"Here, we report a 30-year-old male with AA-type renal amyloidosis due to a chronic inflammatory condition of unknown origin."

Documents secondary AA amyloidosis as a long-term consequence of the sustained inflammatory state in a genetically confirmed patient.

Renal Tubular Injury

Loss of HO-1-mediated protection permits renal tubular injury in the setting of heme exposure. Tubular injury coexists with glomerular endothelial damage; their relative contributions may differ between patients.

Downstream

Proteinuria Renal injury produces this urinary manifestation.

Haematuria Renal injury produces this urinary manifestation.

Show evidence (1 reference)

PMID:9884342 SUPPORT Human Clinical

"HO-1 defect is certainly responsible for the renal tubu- lar injury and subsequent proteinuria and hematuria seen in this patient."

The primary human report explicitly attributes tubular injury and the urine abnormalities to HO-1 deficiency.

Pulmonary Oxidative Injury

Mechanism confidence: Provisional

Oxidant injury is proposed to cause fibrotic nonspecific interstitial pneumonia in HO-1 deficiency. Inflammatory macrophage changes may also contribute; the specific balance of these processes is not established.

Downstream

Pulmonary Haemorrhage Alveolar bleeding, the clinical expression of oxidative injury to the pulmonary vasculature.

Interstitial Lung Disease Oxidant injury is proposed to drive the interstitial pneumonitis.

Pulmonary Fibrosis The documented fibrotic NSIP includes extensive interstitial and alveolar septal fibrosis.

Show evidence (1 reference)

PMID:33066778 SUPPORT INDIRECT Human Clinical

"Our patient developed severe NSIP, likely due to oxidant-induced injury"

The primary report proposes oxidant injury as the cause of the fibrotic interstitial pneumonia; this causal attribution remains provisional.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

36

Blood 8

Haemolytic Anaemia Hemolytic anemia HP:0001878

Temporal: CHRONIC

Fever and haemolytic anaemia were reported in all nine historical cases summarized by PMID:33546372 (9/9 published cases). This is a selected literature inventory, not an unselected population denominator. The exact observed count is retained without inferring a disease-wide frequency band or universal penetrance.

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"Fever, absence of the spleen, hemolytic anemia, hematuria/proteinuria, and the absence of jaundice seem to be the common findings in those cases."

A review of the reported case series names haemolytic anaemia as a common finding across cases, supporting the association; no population frequency is inferred.

PMID:33546372 SUPPORT Human Clinical

"Fever and hemolytic anemia were constant findings."

Frequency-specific evidence: across the 9 reported patients haemolytic anaemia was a constant finding. This nine-case literature inventory does not provide a disease-wide population estimate.

Erythrocyte Fragmentation Schistocytosis HP:0001981

Show evidence (1 reference)

PMID:9884342 SUPPORT Human Clinical

"He has been suffering from persistent hemolytic anemia characterized by marked erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum haptoglobin and low bilirubin."

Documents marked erythrocyte fragmentation in the index patient.

Leukocytosis Increased total leukocyte count HP:0001974

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"More importantly, increases in leukocyte and platelet counts were invariably noted in all cases, which is contrary to the phenomenon observed in HLH patients."

Frequency-specific evidence: raised leukocyte counts were invariable across the nine historical cases. This is not a population estimate; the contrast with typical HLH-associated cytopenias remains diagnostically useful.

PMID:33066778 SUPPORT Human Clinical

"Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies."

Records leukocytosis among the flare features in a confirmed patient.

Thrombocytosis HP:0001894

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"More importantly, increases in leukocyte and platelet counts were invariably noted in all cases, which is contrary to the phenomenon observed in HLH patients."

Frequency-specific evidence: raised platelet counts were invariable across the nine historical cases; subsequent reports include thrombocytopenia. No disease-wide band or invariant distinction from HLH/DIC is asserted.

PMID:33066778 SUPPORT Human Clinical

"Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies."

Records thrombocytosis in a genetically confirmed patient.

Haemophagocytosis Hemophagocytosis HP:0012156

Show evidence (1 reference)

PMID:33066778 SUPPORT Human Clinical

"Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow."

Documents bone-marrow haemophagocytosis during inflammatory flares.

Coagulopathy Abnormality of the coagulation cascade HP:0003256

Show evidence (1 reference)

PMID:9884342 SUPPORT Human Clinical

"An abnormal coagulation/fibrinolysis system, associated with elevated thrombomodulin and von Willebrand factor, indicated the presence of severe, persistent endothelial damage."

Documents the abnormal coagulation and fibrinolysis system in the index patient.

Intracranial Haemorrhage Intracranial hemorrhage HP:0002170

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Her terminal stage was complicated by hypertension and intracranial hemorrhage, as observed in the initial Japanese case."

Documents intracranial haemorrhage in the terminal phase of two independent genetically confirmed patients.

Pulmonary Haemorrhage Pulmonary hemorrhage HP:0040223

Show evidence (1 reference)

PMID:38178812 SUPPORT Human Clinical

"However, he experienced sudden fulminant pulmonary bleeding and expired at the age of five years and eleven months."

The primary case narrative documents fatal pulmonary bleeding without a preceding thoracic biopsy complication.

Cardiovascular 6

Asplenia HP:0001746

Show evidence (2 references)

PMID:21088618 SUPPORT Human Clinical

"We report another case of human HO-1 deficiency in a young girl with congenital asplenia, who presented with severe hemolysis, inflammation, nephritis, which was refractory to therapy with corticosteroids, cyclophosphamide, and rituximab."

Documents congenital asplenia in a genetically confirmed patient.

PMID:33546372 SUPPORT Human Clinical

"Fever, absence of the spleen, hemolytic anemia, hematuria/proteinuria, and the absence of jaundice seem to be the common findings in those cases."

Absence of the spleen is listed among findings common to the reported case series. The pooled absence/hypoplasia descriptions do not establish a frequency for anatomic asplenia alone.

Hypertension HP:0000822

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Hypertension and intracranial hemorrhage are certainly related to the basic pathology of HO-1 deficiency. However, these symptoms were not constantly observed in HO-1 deficiency patients."

Attributes hypertension to the disease pathology while explicitly denying that it is constant, which is why this phenotype carries no frequency band.

Pericardial Effusion HP:0001698

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"On first admission, the patient revealed massive pericardial effusion without any evidence of infectious diseases or malignancies."

Documents massive pericardial effusion as the presenting feature in a genetically confirmed patient, with infection and malignancy excluded.

Erythematous Rash HP:0010783

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"In 1999, Yachie et al. reported on a 26-month-old boy who had been admitted with recurrent fever, generalized erythematous rash, and joint pain [17]."

The index case had generalized erythematous rash, without evidence for a more specific papular eruption.

Splenic Hypoplasia Hypoplastic spleen HP:0006270

Sequelae: Thrombocytosis

Show evidence (1 reference)

PMID:33066778 SUPPORT Human Clinical

"Abdominal CT scan revealed a small poorly perfused spleen which correlated well with the Howell-Jolly bodies and schistocytes on peripheral smear."

Imaging establishes a small spleen rather than complete anatomic absence.

Splenomegaly HP:0001744

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"Clinical profiles were characteristic, in that he presented with microcytic anemia and progressive hepatosplenomegaly at 3 months old."

The p.G139V Turkish patient had splenic enlargement rather than asplenia.

PMID:38178812 SUPPORT Human Clinical

"Sonography showed mild hepatosplenomegaly with a distorted spleen (Fig. 1 B)."

The later pulmonary case independently documents splenic enlargement.

Digestive 1

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:33066778 SUPPORT Human Clinical

"Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow."

Names hepatomegaly as an established feature of the disorder.

Genitourinary 4

Haematuria Hematuria HP:0000790

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"Fever, absence of the spleen, hemolytic anemia, hematuria/proteinuria, and the absence of jaundice seem to be the common findings in those cases."

Names haematuria and proteinuria among the findings common to reported cases.

PMID:33546372 SUPPORT Human Clinical

"Hematuria and proteinuria were observed in all of the Japanese and Indian cases."

Quantifies the renal involvement across the Japanese and Indian cases, though the review notes urine findings were not reported for two further patients, so no frequency band is asserted here.

Proteinuria HP:0000093

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Fever, absence of the spleen, hemolytic anemia, hematuria/proteinuria, and the absence of jaundice seem to be the common findings in those cases."

Names proteinuria among findings common to the reported cases.

Secondary AA Renal Amyloidosis HP:0001917

Show evidence (3 references)

PMID:36502441 SUPPORT Human Clinical

"Here, we report a 30-year-old male with AA-type renal amyloidosis due to a chronic inflammatory condition of unknown origin."

The primary observation of AA-type renal amyloidosis in the patient this phenotype is drawn from, including the age at which it was found.

PMID:36502441 SUPPORT Human Clinical

"Clinical exome sequencing (CES) confirmed the HMOX-1 deficiency diagnosis related to homozygous missense G139V mutation."

Establishes that the patient carrying this phenotype has a molecularly confirmed biallelic HMOX1 genotype, so the amyloidosis is attributable to this disease rather than to an unrelated inflammatory diagnosis.

PMID:36502441 SUPPORT Human Clinical

"Also, HMOX-1 deficiency-related systemic AA-type amyloidosis has not been reported before."

The authors state this was the first such report, which is why the phenotype is curated without a frequency band rather than as a recurring feature.

Haemoglobinuria Hemoglobinuria HP:0003641

Show evidence (1 reference)

PMID:33066778 SUPPORT Human Clinical

"During hospitalization, hepatomegaly was found along with mild transaminitis (AST 301 U/L, ALT 74 U/L), direct antiglobulin test negative hemolytic anemia (hematocrit 24.7%) and hemoglobinuria without microscopic red blood cells."

The absence of microscopic red cells distinguishes haemoglobinuria from haematuria.

Head and Neck 3

Prominent Forehead HP:0011220

No incoming causal edge, deliberately. The reviewing authors explicitly caution against treating this as a uniform characteristic and describe no disease-specific gestalt, and nothing cited traces a route from a defect in stress-inducible heme catabolism to craniofacial development. An edge would assert a developmental mechanism that no source proposes. Kept as a phenotype because it is repeatedly reported; left unattached because being reported is not being explained.

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"Although asplenia and a prominent forehead were observed in all 5 cases, growth delay was not seen in Case 2 and Case 6."

Documents a prominent forehead in all five patients of the Indian series; together with the index case that is 6 of 9 reported patients, which is a historical case count, not an unselected population estimate.

PMID:33546372 SUPPORT Human Clinical

"at present it is difficult to regard a prominent forehead or eyelid edema as a uniform characteristic of HO-1 deficiency patients"

The reviewing authors' own caution against treating a prominent forehead as a uniform characteristic is retained without a disease-wide band.

Palpebral Edema HP:0100540

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"The patient had characteristic facial features such as a flat nasal bridge, frontal bossing, and prominent edema of the eyelids."

The eyelid location is explicit; neither upper nor lower lids are specified.

Depressed Nasal Bridge HP:0005280

No incoming causal edge, deliberately. See the note on Prominent Forehead, which applies to both craniofacial features in this entry.

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"The patient had characteristic facial features such as a flat nasal bridge, frontal bossing, and prominent edema of the eyelids."

The flat nasal bridge supports the phenotype.

PMID:38799538 SUPPORT Human Clinical

"On examination, he had dysmorphic facies, frontal bossing, a depressed nasal bridge, and large ears."

The new patient in this primary case report independently had a depressed nasal bridge; this is not a count of re-reported historical cases.

Metabolism 8

Hypobilirubinaemia Despite Haemolysis Hypobilirubinemia HP:0033480

Show evidence (3 references)

PMID:33546372 SUPPORT Human Clinical

"Repeated measurements of serum bilirubin concentration were always low, at 0.1–0.3 mg/dL."

Direct repeated low-bilirubin measurements in the index patient support hypobilirubinaemia; absence of visible jaundice alone would not establish it.

PMID:33546372 SUPPORT Human Clinical

"More importantly, bilirubin remained low or within normal ranges in all cases, despite the presence of active hemolytic anemia. Paradoxical normo- or hypobilirubinemia in the presence of active hemolytic anemia is certainly the first denominator of HO-1 deficiency."

Low or normal bilirubin despite active haemolysis was present in all 9 reported cases. Note the review's own wording is "low or within normal ranges", so frank hypobilirubinaemia — the HP term bound here — is not shown to be universal even though the failure to rise is. That gap is exactly why no `frequency` band is asserted.

PMID:9884342 SUPPORT Human Clinical

"He has been suffering from persistent hemolytic anemia characterized by marked erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum haptoglobin and low bilirubin."

The index case explicitly records low bilirubin coexisting with intravascular haemolysis.

Elevated Serum Haptoglobin Elevated circulating haptoglobin concentration HP:0020180

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"Further study revealed that serum Hp concentration was extremely elevated (800–1200 mg/dL, normal range; 40–180 mg/dL) and a large amount of Hb-Hp complex was detected in a urine sample from the patient."

Direct quantitative measurement of the raised serum haptoglobin this phenotype asserts, roughly 5-fold above the upper limit of normal.

PMID:33546372 SUPPORT Human Clinical

"These data suggested that the Hb-Hp complex was somehow bypassing the normal scavenger system and overflowing into urine."

Offers the proposed explanation for the paradoxical elevation. Support is indirect because the source itself hedges the mechanism as "somehow".

Hyperferritinaemia Increased circulating ferritin concentration HP:0003281

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Increased levels of hepatic enzymes, triglycerides and ferritin were also noted."

Records raised ferritin in a genetically confirmed patient.

Elevated Lactate Dehydrogenase Increased circulating lactate dehydrogenase concentration HP:0025435

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Persistently elevated LDH despite low bilirubin levels led Greil et al. to analyze the HMOX1 gene, revealing the homozygous G139V mutation."

Documents persistently elevated LDH and its diagnostic pairing with low bilirubin.

Recurrent Fever HP:0001954

Temporal: RECURRENT

Fever and haemolytic anaemia were reported in all nine historical cases summarized by PMID:33546372 (9/9 published cases). This is a selected literature inventory, not an unselected population denominator. The exact observed count is retained without inferring a disease-wide frequency band or universal penetrance.

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Fever and hemolytic anemia were constant findings."

Frequency-specific evidence: fever was a constant finding across the 9 historical patients. The small published-case denominator is retained here without a disease-wide frequency band.

Hypertriglyceridaemia Hypertriglyceridemia HP:0002155

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"Hyperlipidemia was another prominent finding, with triglycerides at 638 mg/dL (normal range; 32-115) and total cholesterol at 552 mg/dL (normal range; 128-219), showing a predominance of low-density lipoprotein cholesterol."

The quantitative source for the index-case lipid values and the LDL predominance stated in this phenotype's description.

PMID:33546372 SUPPORT Human Clinical

"Increased levels of hepatic enzymes, triglycerides and ferritin were also noted."

Records raised triglycerides in a second, independent genetically confirmed patient, supporting hyperlipidaemia as a recurring rather than isolated feature.

Elevated Hepatic Transaminases Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Levels of hepatic enzymes such as LDH, AST, and ALT uniformly showed significant elevations."

Frequency-specific evidence: the review reports AST and ALT elevation in the five Indian cases discussed in that paragraph, not uniformly in all patients. No disease-wide frequency is inferred from that subgroup.

Hypercholesterolaemia Hypercholesterolemia HP:0003124

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Hyperlipidemia was another prominent finding, with triglycerides at 638 mg/dL (normal range; 32–115) and total cholesterol at 552 mg/dL (normal range; 128–219), showing a predominance of low-density lipoprotein cholesterol."

The measured cholesterol elevation supports this endpoint separately from hypertriglyceridaemia.

Respiratory 4

Interstitial Lung Disease Interstitial pneumonitis HP:0006515

Course: PROGRESSIVE

Sequelae: Chronic Respiratory Failure

Show evidence (2 references)

PMID:33066778 SUPPORT Human Clinical

"Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow."

The report that established interstitial lung disease as part of the HMOX1-deficiency phenotype.

PMID:38178812 SUPPORT Human Clinical

"In this study, we describe a patient with severe interstitial lung disease, frequent episodes of hyperinflammation non-responsive to immunosuppression, and fatal pulmonary hemorrhage."

A second, independent genetically confirmed patient with severe interstitial lung disease, establishing the pulmonary phenotype as recurrent rather than a single-case observation, and independently corroborating the failure of immunosuppression curated in the treatments section.

Pulmonary Fibrosis HP:0002206

Show evidence (1 reference)

PMID:33066778 SUPPORT Human Clinical

"He was found on thorascopic lung biopsy to have extensive interstitial fibrosis, consistent with the fibrotic nonspecific interstitial pneumonia (NSIP) pattern, in addition to cholesterol granulomas."

Biopsy establishes pulmonary fibrosis, beyond an unspecified interstitial lung abnormality.

Chronic Respiratory Failure HP:0002878

Temporal: CHRONIC

Sequelae: Hypoxemia

Show evidence (1 reference)

PMID:33066778 SUPPORT Human Clinical

"We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares."

The report explicitly attributes chronic respiratory failure to nonspecific interstitial pneumonia.

Hypoxemia HP:0012418

Show evidence (1 reference)

PMID:33066778 SUPPORT Human Clinical

"A 10-year-old boy was admitted for diagnostic lung biopsy in the setting of progressive chronic hypoxic respiratory failure and recurrent hyperinflammatory episodes."

The hypoxic respiratory failure supports persistent oxygenation impairment, beyond an isolated viral bronchiolitis episode.

Constitutional 1

Arthralgia HP:0002829

Show evidence (2 references)

PMID:33546372 SUPPORT Human Clinical

"In 1999, Yachie et al. reported on a 26-month-old boy who had been admitted with recurrent fever, generalized erythematous rash, and joint pain [17]."

Joint pain was part of the index patient presentation.

PMID:33066778 SUPPORT Human Clinical

"Bilateral knee arthritis was clinically noted accompanying myalgias and arthralgias with morning stiffness, although subsequent knee x-rays showed no erosions."

The US patient had clinically observed arthritis and arthralgias.

Growth 1

Growth Retardation Growth delay HP:0001510

Show evidence (1 reference)

PMID:9884342 SUPPORT Human Clinical

"The patient is a six-year-old boy with severe growth retardation."

Documents severe growth retardation in the index patient.

🧬

Genetic Associations

1

HMOX1

Gene: HMOX1 hgnc:5013 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (8 references)

PMID:9884342 SUPPORT Human Clinical

"Sequence analysis of the patient's HO-1 gene revealed complete loss of exon-2 of the maternal allele and a two-nucleotide deletion within exon3 of the paternal allele."

The founding genotype-phenotype observation establishing HMOX1 as the causative gene, with two distinct loss-of-function alleles in trans.

PMID:33546372 SUPPORT Human Clinical

"All cases from India (Cases 2-6) displayed an identical homozygous mutation (p.R44X), indicating a founder effect of this particular mutation in that country."

Establishes the p.R44X founder allele and explains why the reported case count exceeds the number of independent mutational events.

PMID:33546372 SUPPORT In Vitro

"This mutation was a missense mutation and expression of constitutive HO-1 was increased by cells, but HO-1 levels were not enhanced with additional oxidative stress."

Cultured patient cells retained constitutive HO-1 expression without further induction by oxidative stress. This supports an inducibility defect; the distinct catalytic and inferred peroxidase defects require the separate evidence below.

+ 5 more references

💊

Medical Actions

6

Supportive Care and Stress Avoidance

Action: Supportive Care NCIT:C15747

No disease-modifying therapy exists. Management is supportive, together with the infection precautions appropriate to asplenia. Because decompensation is typically triggered by an exogenous insult, avoidance of oxidative and infective stress is itself part of management.

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Avoidance of exogenous stress along with appropriate treatment may prevent early death in these patients."

Supports stress avoidance plus supportive management as the current practical approach.

Red Blood Cell Transfusion

Action: Blood Transfusion NCIT:C15192

Transfusion support for the chronic haemolytic anaemia. Note that iron supplementation is NOT appropriate: the anaemia arises from failure to recycle iron out of tissue stores, not from iron deficiency, and reported patients were resistant to it.

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"The anemia proved resistant to iron supplementation and the patient was dependent on red cell transfusion."

Establishes red cell transfusion dependence and the failure of iron supplementation.

Corticosteroid and Immunosuppressive Therapy

Action: Pharmacotherapy NCIT:C15986

Responses vary: refractory disease and minimal sustained benefit are common, but corticosteroids can temporarily control inflammatory flares, and HLH-directed therapy produced remission of HLH signs in one patient. These responses do not establish correction of the underlying cytoprotective defect or durable disease control. The agents span several classes, so no single therapeutic_agent is bound.

Show evidence (4 references)

PMID:21088618 REFUTE Human Clinical

"We report another case of human HO-1 deficiency in a young girl with congenital asplenia, who presented with severe hemolysis, inflammation, nephritis, which was refractory to therapy with corticosteroids, cyclophosphamide, and rituximab."

Documents refractoriness to three separate immunosuppressive agents in a confirmed patient.

PMID:33546372 REFUTE Human Clinical

"Therapy with corticosteroid, anti-IL-1R, anti-IL-6, and cyclosporine had been tried but with minimal benefit."

Independent confirmation that broad anti-cytokine and immunosuppressive therapy provides minimal benefit.

PMID:33546372 REFUTE Human Clinical

"These agents are effective in some cases, but conventional anti-inflammatory/immunosuppressive therapies resulted in therapeutic failure in HO-1 deficiency cases for two reasons."

Reports the review's conclusion of inadequate disease control; individual symptomatic responses are documented elsewhere. Quoted as a complete sentence rather than the trailing fragment, so the contrast with other diseases is visible in the quote.

+ 1 more reference

Macrophage Replacement by Bone Marrow Transplantation

Action: Bone Marrow Transplantation NCIT:C15194

Platform: Cell therapy

Investigational therapy supported by macrophage-replacement rescue in Hmox1-null mice and a reported human allogeneic transplant case with stabilization and prolonged survival. Human evidence is limited to a single reported case; durable efficacy and optimal transplantation protocols are not established. In the mouse experiment, donor-derived Kupffer cells restored heme recycling despite transient marrow engraftment. That mechanistic rescue should not be assumed to describe the human transplant outcome in the same detail.

Mechanism Target:

RESTORES Macrophage and Monocyte Dysfunction — Replacing HMOX1-deficient macrophages with wild-type macrophages restores the heme-recycling capacity whose loss defines this node.

Show evidence (1 reference)

PMID:24963040 SUPPORT Model Organism

"These cells, identified as Kupffer cells with high levels of Hmox1 expression, persisted months after transient engraftment of the donor bone marrow and were responsible for the full restoration of heme-recycling ability in Hmox1(-/-) mice and reversing Hmox1-deficient phenotype."

Identifies restored macrophage heme-recycling capacity as the specific mechanism by which the intervention reverses the phenotype.

Show evidence (2 references)

PMID:24963040 SUPPORT Model Organism

"Our findings suggest that BMT or the development of specific cell therapies to repopulate patients' tissues with wild-type or reengineered macrophages represent promising approaches for HMOX1 deficiency treatment in humans."

The authors' own translational proposal. Recorded as investigational: the supporting data are entirely murine and no treated human case exists.

PMID:38178812 SUPPORT Human Clinical

"Indeed, allogenic stem cell transplantation has been suggested as a potential treatment and reported to lead to stabilization and prolonged survival in a single case [18]."

This 2024 clinical paper summarizes the earlier single human transplant report. It supports limited human experience, not a validated cure rate.

Ascorbate Supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: ascorbate CHEBI:38290

Platform: Small molecule

A genuine mechanism-directed therapeutic lead, and PRECLINICAL/IN VITRO only. HMOX1-deficient patient-derived lymphoblastoid cells and HEK293T HMOX1-null cells both show substantially reduced intracellular ascorbate (despite compensatory SVCT2 upregulation), abnormal mitochondrial morphology and raised baseline hydrogen peroxide. 2-phospho-L-ascorbic acid restored viability under hemin stress in both models, dependent on functional SVCT2-mediated uptake, and lowered H2O2 without shifting the GSH/GSSG ratio. Curated as PROPOSED-grade: no patient has been treated, no clinical outcome is reported, and the effect is demonstrated in cell models only. It is listed because it is the one lead in this literature that targets a measured metabolic deficit in patient cells rather than restoring an enzyme that is absent.

Show evidence (2 references)

PMID:40945734 SUPPORT In Vitro

"Treatment with 2-phospho-L-ascorbic acid (AA2P) restored cell viability in both models upon hemin-induced stress, with protection requiring functional SVCT2-mediated uptake."

The rescue result behind this lead. Tagged IN_VITRO because it is a cell-model rescue in patient-derived LCLs and HEK293T knockouts, with no patient treated.

PMID:40945734 SUPPORT In Vitro

"These findings illuminate ascorbic acid metabolism as a critical node in HO-1 deficiency pathophysiology and suggest ascorbic acid supplementation as a potential therapeutic strategy for this rare disorder."

The authors' own framing as a *potential* strategy, which is the grade at which this is curated.

HO-1 Induction and CO-Releasing Molecules

Action: Pharmacotherapy NCIT:C15986

Investigational and mechanism-directed rather than established. Because the disease is loss of a cytoprotective response, the rational strategy is to restore its products: pharmacological induction of HO-1, CO-releasing molecules, or enhancement of haptoglobin-haemoglobin receptor expression. No clinical efficacy has been demonstrated in HO-1-deficient patients, and pharmacological HO-1 induction is conceptually futile in null genotypes where there is no enzyme to induce. This is recorded as a proposed direction, not a therapy.

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"The prime target of such therapy is HO-1. Pharmacological induction of cellular HO-1 production, use of CO-releasing molecules, or enhancement of Hb-Hp receptor expression by steroid are examples of these approaches."

Records the proposed mechanism-directed strategies. Support is indirect because this is an expert proposal in a review, with no efficacy data in HO-1-deficient patients.

🔬

Biochemical Markers

5

Serum bilirubin

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Persistently elevated LDH despite low bilirubin levels led Greil et al. to analyze the HMOX1 gene, revealing the homozygous G139V mutation."

Confirms low bilirubin as the measured biochemical abnormality that led to HMOX1 analysis.

Serum heme

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Serum heme concentration was extremely high, at 490 μM (normal range; <1 μM)."

The direct quantitative measurement of serum heme in the index patient, about 500-fold above the upper limit of normal.

Serum ferritin

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Increased levels of hepatic enzymes, triglycerides and ferritin were also noted."

Documents raised serum ferritin in a confirmed patient.

Serum haptoglobin

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Further study revealed that serum Hp concentration was extremely elevated (800–1200 mg/dL, normal range; 40–180 mg/dL) and a large amount of Hb-Hp complex was detected in a urine sample from the patient."

The direct quantitative measurement of serum haptoglobin with its reference range in the index patient.

Serum hemopexin

Show evidence (1 reference)

PMID:33546372 SUPPORT Human Clinical

"Hemopexin was undetectable by immunoelectrophoresis, indicating the presence of active hemolysis in vivo."

Direct measurement showing hemopexin depletion.

🔬

Diagnosis

3

Recognition of haemolysis without hyperbilirubinaemia

The entry point to the diagnosis is a routine laboratory pattern, not a specialised test: active haemolysis (raised LDH, fragmented erythrocytes, anaemia) with a bilirubin that is low or normal instead of raised, and no jaundice. The direction of the bilirubin is what matters — every other cause of brisk haemolysis raises it, so a normal value in this setting is already abnormal. A direct antiglobulin test is negative, which excludes the immune haemolytic anaemias that the picture otherwise resembles. Historically this pattern is what prompted HMOX1 analysis in both the index case and the p.G139V patient, and it is available from a standard panel long before the disease is suspected. See the biochemical section for the quantitative markers (bilirubin, free heme, ferritin, haptoglobin, hemopexin) and their reported values.

blood chemistry measurement NCIT:C47868

Results: Haemolysis with a low or normal bilirubin and a negative direct antiglobulin test should prompt HMOX1 testing rather than further immunohaematological workup.

Show evidence (3 references)

PMID:33066778 SUPPORT Human Clinical

"HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome."

States the discriminating triad this diagnostic step relies on: haemolysis, a normal rather than raised bilirubin, and a negative direct antiglobulin test.

PMID:38178812 SUPPORT Human Clinical

"Chronic hemolysis and abnormally low bilirubin levels are cardinal laboratory features of this disorder."

An independent report naming the same paired laboratory abnormality as cardinal, supporting its use as the trigger for molecular testing.

PMID:33546372 SUPPORT Human Clinical

"Persistently elevated LDH despite low bilirubin levels led Greil et al. to analyze the HMOX1 gene, revealing the homozygous G139V mutation."

A worked instance of this laboratory pattern actually leading to the molecular diagnosis in a reported patient.

HO-1 induction assay in patient-derived cells

The functional confirmation, and the test that distinguishes this disease from a merely low HMOX1 transcript level. HO-1 is normally absent at rest and produced only on stress induction, so the assay deliberately provokes it: patient monocytes or an Epstein-Barr-virus-transformed lymphoblastoid cell line are stimulated with an oxidative stressor (cadmium chloride or sodium arsenite) and HO-1 protein is then sought by immunoblot. In an affected patient no protein appears after stimulation. An unstimulated sample is uninformative because a healthy control is also negative at baseline, which is why this is an induction assay rather than a simple expression measurement. It has been applied in the index case and independently in at least two later patients, including one whose variants were novel, and it is the practical route to demonstrating that a variant of uncertain significance abolishes protein production. A paired hemin-sensitivity assay on the same cells provides a second functional readout.

HO-1 protein induction assay NCIT:C25294

Results: Absence of HO-1 protein on immunoblot after oxidative stimulation confirms loss of function; hemin exposure of the same cells shows reduced viability.

Show evidence (4 references)

PMID:9884342 SUPPORT In Vitro

"Immunohistochemistry of hepatic tissue and immunoblotting of a cadmium-stimulated Epstein-Barr virus-transformed lymphoblastoid cell line (LCL) revealed complete absence of HO-1 production."

Defines the assay as first applied: cadmium stimulation of a patient-derived LCL followed by immunoblot, showing complete absence of HO-1 production.

PMID:33546372 SUPPORT In Vitro

"Exposure of the patient's monocytes to heavy metals, such as cadmium or sodium arsenite, did not induce HO-1 protein."

Names the two stimulating agents in routine use and confirms the assay can be run on primary monocytes as well as on an immortalised line.

PMID:38178812 SUPPORT In Vitro

"Functional analysis in patient-derived lymphoblastoid cells unveiled the complete absence of HO-1 protein expression and a marked reduction in cell viability upon exposure to hemin."

A later independent application of the same assay, and the source for the paired hemin-viability readout. This is the study that used it to establish the pathogenicity of a previously unreported variant.

+ 1 more reference

HMOX1 molecular confirmation

Establish biallelic pathogenic HMOX1 variants. Sequencing alone is not sufficient here, and the reported genotypes show why: the index case is a compound heterozygote carrying a whole-exon-2 deletion on the maternal allele against a small deletion on the paternal allele, so a copy-number method (deletion/duplication analysis, array-CGH, or a targeted dosage assay) is required or the maternal allele is missed and the patient is reported as a heterozygous carrier. A second patient carries an intronic splice-donor variant, which is only interpretable with splice-level analysis or a transcript study. Exome sequencing has been the practical route in the more recent cases, including one in which the disease was not suspected beforehand. Where a variant's consequence is uncertain, the HO-1 induction assay above supplies the functional evidence. Note that the promoter (GT)n microsatellite literature concerns a separate, non-Mendelian modifier and has no role in diagnosing this disease.

genetic testing NCIT:C15709

Results: Two pathogenic HMOX1 alleles confirm the diagnosis. A single detected variant in a consistent clinical and laboratory picture should prompt copy-number and splice analysis before the diagnosis is discarded.

Show evidence (3 references)

PMID:9884342 SUPPORT Human Clinical

"Sequence analysis of the patient's HO-1 gene revealed complete loss of exon-2 of the maternal allele and a two-nucleotide deletion within exon3 of the paternal allele."

The whole-exon deletion documented here is the reason deletion/duplication analysis is specified rather than sequencing alone.

PMID:33066778 SUPPORT Human Clinical

"He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency."

The splice-donor allele documented here is the reason splice-level interpretation is specified. The quote is given in full, including the source's own duplicated phrase, rather than silently repaired.

PMID:36502441 SUPPORT Human Clinical

"Clinical exome sequencing (CES) confirmed the HMOX-1 deficiency diagnosis related to homozygous missense G139V mutation."

Documents exome sequencing reaching the diagnosis in a patient whose inflammatory illness had been of unknown origin, supporting a broad sequencing strategy where the disease is not suspected in advance.

📊

Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

Roughly a dozen genetically confirmed patients have been reported since the index case in 1999. Five of the early cases came from India and shared an identical p.R44X allele, indicating a founder effect rather than independent recurrence, so the count of reported cases overstates the number of independent mutational events. Ascertainment is very likely incomplete in a specific direction: HO-1 may be required for normal fetal development, so an unknown fraction of affected conceptuses may die in utero or shortly after birth undiagnosed. Reported prevalence should therefore be read as a floor on the true birth incidence, not an estimate of it.

Show evidence (3 references)

PMID:36502441 SUPPORT Human Clinical

"To the best of our knowledge, our patient is the eleventh HMOX-1 deficiency case in the literature."

A 2023 case report placing the cumulative worldwide count at eleven reported patients, supporting an ultra-rare band below 1 in 1,000,000.

PMID:33546372 SUPPORT Human Clinical

"Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature."

A dedicated review confirms only a handful of human cases exist two decades after the disease was first described.

PMID:33546372 SUPPORT Human Clinical

"HO-1 may play cardinal roles during fetal growth and development, and most individuals with HO-1 deficiency may thus develop significant organ dysfunctions and die in utero or shortly after birth without being diagnosed."

The review's own explanation for why so few patients are reported, which is why the case count is treated here as a floor rather than an estimate of true incidence.

🐁

Animal Models

3

Hmox1-null mouse (Poss and Tonegawa, C57BL/6)

The founding genetic model, reported two years before the first human case and directly cited by Yachie et al. as corroborating their patient. Adult nulls develop anaemia with abnormally low serum iron yet accumulate hepatic and renal iron causing oxidative damage and chronic inflammation; embryonic fibroblasts are hypersensitive to hemin and peroxide, and adults die when challenged with endotoxin.

Species

Mouse

Genotype

Hmox1 -/- (targeted null)

Publication

PMID:9380735

Pathograph links

Impaired Heme-Iron Recycling and Tissue Iron Deposition recapitulates fidelity: high Reproduces the counter-intuitive combination of low serum iron with hepatic and renal iron accumulation that defines this node, and was the experiment that established the recycling mechanism.

Limitations: Mouse nulls develop marked splenomegaly, whereas human patients characteristically have asplenia or functional hyposplenism, so the splenic phenotype does not transfer.

Readouts

Hepatic and renal tissue iron content

Direction: INCREASED

Interpretation: Tissue iron accumulation is the structural correlate of failed iron release from hepatic and renal cells.

Show evidence (1 reference)

PMID:9380735 SUPPORT Model Organism

"Hmox1-deficient adult mice developed an anemia associated with abnormally low serum iron levels, yet accumulated hepatic and renal iron that contributed to macromolecular oxidative damage, tissue injury, and chronic inflammation."

Reports the measured tissue iron accumulation in this model.

Show evidence (1 reference)

PMID:9380735 SUPPORT Model Organism

"Our results indicate that Hmox1 has an important recycling role by facilitating the release of iron from hepatic and renal cells, and describe a mouse model of human iron metabolic disorders."

The authors themselves frame this as a model of human iron metabolic disorders, supporting its use for this node.

Failure of Stress-Inducible Heme Catabolism recapitulates fidelity: high Cells and animals lacking Hmox1 lose the adaptive protection normally conferred by its stress induction, which is the defining property of this node.

Limitations: Demonstrated with pharmacological and chemical stressors (hemin, peroxide, paraquat, cadmium, endotoxin) rather than with the spontaneous haemolytic load that drives the human disease.

Readouts

Survival and hepatic necrosis after endotoxin challenge

Direction: DECREASED

Interpretation: Mortality on endotoxin challenge quantifies the loss of the inducible stress-protective response.

Show evidence (1 reference)

PMID:9380736 SUPPORT Model Organism

"Furthermore, young adult Hmox1(-/-) mice were vulnerable to mortality and hepatic necrosis when challenged with endotoxin."

Reports the measured survival deficit under stress challenge.

Show evidence (1 reference)

PMID:9380736 SUPPORT Model Organism

"Our in vitro and in vivo results provide genetic evidence that up-regulation of Hmox1 serves as an adaptive mechanism to protect cells from oxidative damage during stress."

Establishes the model as informative for the loss of stress-inducible protection.

Show evidence (1 reference)

PMID:9380735 SUPPORT Model Organism

"Here, we generated mice lacking functional heme oxygenase 1 (Hmox1; EC 1.14.99.3), which catabolizes heme to biliverdin, carbon monoxide, and free iron, to assess its participation in iron homeostasis."

Establishes the existence and construction of this targeted Hmox1-null mouse line.

Hmox1-null mouse (mixed C57BL/6-FVB background)

A second null strain on a mixed background whose splenic phenotype evolves from early splenomegaly to progressive red-pulp fibrosis, atrophy and functional hyposplenism with Howell-Jolly bodies. This strain is the one that reconciles the mouse splenic phenotype with human asplenia, and it also shows macrophage death during erythrophagocytosis and reduced CD163.

Species

Mouse

Genotype

Hmox1 -/- (targeted null, mixed background)

Publication

PMID:33546372

Pathograph links

Macrophage and Monocyte Dysfunction recapitulates fidelity: moderate Demonstrates the specific cellular mechanism of this node, macrophages dying as they phagocytose erythrocytes and release heme they cannot catabolise, together with loss of the CD163 scavenger receptor.

Limitations: Background-dependent: the splenic trajectory differs from the C57BL/6 null strain, so the phenotype is not a stable property of Hmox1 loss alone. Reported here via a review rather than from the primary strain paper.

Readouts

Macrophage survival during erythrophagocytosis

Direction: DECREASED

Interpretation: Progressive macrophage death during erythrophagocytosis is the measured correlate of the macrophage-failure node.

Show evidence (1 reference)

PMID:33546372 SUPPORT Model Organism

"They showed progressive death of macrophages in the liver and spleen throughout the process of erythrophagocytosis and the resultant heme release in vivo, causing significant damage to the organs and intense inflammation of the surrounding tissues."

Reports the measured macrophage loss in this strain.

Show evidence (1 reference)

PMID:33546372 SUPPORT Model Organism

"Impaired splenic function was confirmed by the appearance of Howell-Jolly bodies within erythrocytes."

Functional hyposplenism in this strain matches the human asplenia phenotype, supporting the model's relevance.

Intravascular Haemolysis with Erythrocyte Fragmentation fails to recapitulate fidelity: low The mouse does not reproduce the human haemolytic phenotype, and fails in the least forgiving way available: red cell lifespan is PROLONGED in Hmox1-null mice, whereas human patients have shortened red cell survival with fragmentation and intravascular haemolysis. The mouse anaemia is microcytic and attributed to defective erythroblastic-island formation, a different mechanism from the human one.

Limitations: Because the direction is reversed rather than merely attenuated, no conformance to a haemolysis mechanism module may be asserted on the strength of mouse data for this disease; human evidence is required. The authors note the prolonged lifespan may actually ameliorate the murine anaemia, which is the opposite of its role in patients.

Readouts

Circulating red blood cell lifespan

Direction: INCREASED

Interpretation: Increased rather than decreased red cell lifespan is the measurement that inverts the human phenotype.

Show evidence (1 reference)

PMID:25682599 SUPPORT Model Organism

"Red blood cell lifespan is prolonged in heme oxygenase-1 deficient mice compared with wild-type mice."

The measured lifespan result, in the direction opposite to human disease.

Show evidence (1 reference)

PMID:25682599 SUPPORT Model Organism

"Compared with wild-type animals, red blood cell size and hemoglobin content are decreased, while the number of circulating red blood cells is increased in heme oxygenase-1 deficient mice, overall leading to microcytic anemia."

Establishes that the murine anaemia is microcytic and erythropoietic in origin rather than the fragmentation haemolysis seen in patients, so the model is not informative for this node.

Macrophage and Monocyte Dysfunction rescues fidelity: moderate Subablative bone marrow transplantation repopulates the tissues with wild-type macrophages and reverses the Hmox1-null phenotype, which is the strongest available evidence that macrophage failure is causally sufficient for the downstream disease rather than merely correlated with it. Donor-derived Kupffer cells expressing Hmox1 persisted in the liver and restored heme-recycling capacity even after engraftment became transient.

Limitations: This particular rescue experiment is mouse-only. Engraftment was transient, and the durable benefit depended on long-lived donor-derived liver macrophages, so the result may not generalise to organs whose macrophages turn over differently. It also does not address the endothelial arm directly.

Readouts

Anaemia, blood chemistry, iron parameters and renal damage after BMT

Direction: RESTORED

Interpretation: Reversal of the haematological, biochemical and renal phenotype on macrophage replacement is the rescue readout for this node.

Show evidence (1 reference)

PMID:24963040 SUPPORT Model Organism

"Although engraftment was transient, BMT reversed anemia, normalized blood chemistries and iron metabolism parameters, and prevented renal damage."

Reports the measured reversal of the disease phenotype.

Show evidence (1 reference)

PMID:24963040 SUPPORT Model Organism

"Here, we report that subablative bone marrow transplantation (BMT) has a curative effect for disease in Hmox1(-/-) animals as a result of restoration of heme recycling by repopulation of the tissues with wild-type macrophages."

Establishes macrophage replacement as causally sufficient to reverse the disease in this model, which is what makes the rescue informative for this node.

Show evidence (1 reference)

PMID:33546372 SUPPORT Model Organism

"Kovtunovych et al. published a detailed study on the iron distribution and pathology of another strain of HO-1-knockout mice using a mixed C57BL/6-FVB background"

Establishes the existence and genetic background of this second Hmox1-null mouse strain.

Hmox1-deficient Sprague-Dawley rat

A rat model with haemolytic anaemia, poikilocytosis, splenomegaly, leukocytosis, impaired growth and early death, plus proteinuric renal disease with mesangial expansion and focal segmental sclerosis. Notably it does NOT reproduce the tissue iron deposition seen in both human patients and mice.

Species

Rat

Genotype

Hmox1 -/-

Publication

PMID:33546372

Pathograph links

Impaired Heme-Iron Recycling and Tissue Iron Deposition fails to recapitulate fidelity: low The rat does not develop the hepatic and renal iron deposition that is a cardinal feature of both the human disease and the mouse models, so it cannot be used to study this arm.

Limitations: Iron deposition was not increased in tubular epithelium or hepatic parenchyma, and little splenic macrophage iron was seen even in older animals. The study also did not extend beyond 24 weeks, so a late-onset iron phenotype cannot be formally excluded.

Show evidence (1 reference)

PMID:33546372 SUPPORT Model Organism

"In contrast to human cases or mice models, iron deposition was not increased within the tubular epithelium or hepatic parenchyma of the rat model."

SUPPORT, not REFUTE: the claim this link makes is the negative one, that the rat FAILS_TO_RECAPITULATE the tissue-iron node, and this quote is direct positive evidence for that failure.

Intravascular Haemolysis with Erythrocyte Fragmentation recapitulates fidelity: moderate Reproduces haemolytic anaemia with abnormal circulating erythrocyte morphology.

Limitations: Erythrocyte morphology is poikilocytosis with target cells and acanthocytes rather than the schistocytic fragmentation characteristic of the human disease.

Show evidence (1 reference)

PMID:33546372 SUPPORT Model Organism

"These rats showed hemolytic anemia with morphological abnormality of the circulating erythrocytes, such as poikilocytosis and the presence of target cells and acanthocytes."

Reports haemolytic anaemia with abnormal erythrocyte morphology in the rat model.

Show evidence (1 reference)

PMID:33546372 SUPPORT Model Organism

"Sprague-Dawley rats were employed in the study to reveal the role of HO-1 in various forms of kidney disease. This rat model showed characteristic renal and extrarenal phenotypes."

Establishes the existence and strain background of the HO-1-deficient rat model and its renal focus.

{ }

Source YAML

click to show

name: Heme Oxygenase 1 Deficiency
creation_date: '2026-08-21T00:00:00Z'
category: Mendelian
description: >
  Heme oxygenase 1 (HO-1) deficiency is an ultra-rare autosomal recessive
  disorder caused by biallelic loss-of-function variants in HMOX1. HMOX1 encodes
  the stress-inducible isozyme of heme oxygenase, which opens the heme ring to
  yield three products: biliverdin (converted by biliverdin reductase to
  bilirubin), carbon monoxide (CO), and free ferrous iron. Because HMOX1 is the
  only heme oxygenase isoform that is rapidly upregulated by oxidative stress,
  its loss removes an inducible cytoprotective response rather than causing
  accumulation of a stored substrate. This is the mechanistic inverse of the
  usual storage-disease shape, and it is why pathology appears when the patient
  is stressed by infection or haemolysis rather than continuously from birth.

  The clinical features reflect impaired heme clearance and reduced generation
  of protective reaction products. Serum bilirubin stays low or normal despite brisk
  intravascular haemolysis and there is no jaundice, which is the single most
  discriminating bedside clue, and an antioxidant sink is lost. HO-1-derived CO production is reduced, compromising a cytoprotective,
  anti-inflammatory and vasoregulatory gaseous signal; constitutive HO-2 activity
  remains present.
  Heme itself is not cleared and its iron is not recycled, so free heme
  accumulates to cytotoxic levels and drives endothelial injury, while iron handling is
  disturbed in renal tubular epithelium and hepatocytes. Hyperferritinaemia also
  reflects inflammation and does not quantify tissue iron deposition.

  The clinical picture is a chronic multisystem inflammatory disorder: haemolytic
  anaemia with erythrocyte fragmentation, recurrent fever and rash, asplenia,
  nephritis, hepatomegaly, leukocytosis and thrombocytosis, coagulopathy,
  interstitial lung disease, and macrophage-activation or haemophagocytic flares.
  Roughly a dozen patients have been reported worldwide and most died in
  childhood or young adulthood; conventional anti-inflammatory and
  immunosuppressive therapy has often been inadequate, although transient responses
  and remission of HLH have been reported. A substantial part of the
  mechanism therefore rests on Hmox1-null mouse and rat models, which agree with
  the human disease on iron handling and stress vulnerability but diverge
  notably on splenic and tissue-iron phenotypes, a divergence recorded here as an
  explicit HUMAN_MODEL_MISMATCH rather than smoothed over.
disease_term:
  preferred_term: Heme oxygenase 1 deficiency
  term:
    id: MONDO:0013536
    label: heme oxygenase 1 deficiency
parents:
- Inborn Error of Metabolism
- hereditary disease
inheritance:
- name: Autosomal Recessive
  description: >
    Biallelic HMOX1 variants are required. Reported genotypes include compound
    heterozygosity (the index Japanese case), and homozygosity for nonsense
    (p.R44X, p.K204X) or missense (p.G139V) alleles, several in consanguineous
    families.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36502441
    reference_title: "Heme oxygenase-1 deficiency as an extremely rare cause of AA-type renal amyloidosis: Expanding the clinical features and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is encoded by the HMOX1 gene, and biallelic mutations cause HMOX-1
      deficiency, which is a rare chronic multisystemic inflammatory disorder.
    explanation: >-
      States explicitly that biallelic HMOX1 mutations are required, establishing
      recessive inheritance.
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HMOX1-deficiency is a rare autosomal recessive disorder with hallmark
      features of direct antibody negative hemolytic anemia with normal
      bilirubin, hyperinflammation and features similar to macrophage activation
      syndrome.
    explanation: Names the inheritance mode directly alongside the hallmark features.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    notes: >-
      The presenting and defining abnormalities are haematologic: chronic
      antibody-negative haemolytic anaemia with erythrocyte fragmentation, plus a
      coagulation and fibrinolysis disorder.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      Mechanistically an inborn error of metabolism: loss of a single enzymatic
      activity in the heme catabolic pathway, with secondary disordered iron
      metabolism.
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      Clinically behaves as a systemic autoinflammatory disorder, and several
      patients were investigated for systemic juvenile idiopathic arthritis or
      familial haemophagocytic lymphohistiocytosis before HMOX1 was tested.
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      IUIS 2022 phenotypic classification Table 6 (defects in intrinsic and
      innate immunity), section 8 (Other Inborn Errors of Immunity Related to
      Non-Hematopoietic Tissues): the row printed as "HMOX" (AR, OMIM column
      141250 - the HMOX1 gene record). The placement is initially surprising -
      this entry reads primarily as a haemolytic and autoinflammatory disorder,
      not an infection-susceptibility syndrome - but the IUIS rationale is
      macrophage-intrinsic: the table's affected-cells column is macrophages,
      and its affected-function column is HO-1's role in iron recycling, with
      heme-dependent damage when it fails. The IUIS committee thus carries HO-1
      deficiency as an inborn error of an innate (macrophage) housekeeping
      program whose failure produces haemolysis, nephritis and systemic
      inflammation, and files it in Table 6's residual non-hematopoietic-tissue
      section rather than under immune dysregulation or autoinflammation. The
      single-valued IUIS assignment here transcribes that committee placement.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HMOX AR 141250 Macrophages HO-1 regulates iron recycling and heme-dependent damage occurs Hemolysis, nephritis, inflammation"
      explanation: >-
        The complete HMOX row of IUIS 2022 Table 6, section 8 (Other Inborn
        Errors of Immunity Related to Non-Hematopoietic Tissues): gene (printed
        "HMOX"), inheritance, affected cells (macrophages), affected function,
        and associated features (hemolysis, nephritis, inflammation).
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Roughly a dozen genetically confirmed patients have been reported since the
    index case in 1999. Five of the early cases came from India and shared an
    identical p.R44X allele, indicating a founder effect rather than independent
    recurrence, so the count of reported cases overstates the number of
    independent mutational events. Ascertainment is very likely incomplete in a
    specific direction: HO-1 may be required for normal fetal development, so an
    unknown fraction of affected conceptuses may die in utero or shortly after
    birth undiagnosed. Reported prevalence should therefore be read as a floor on
    the true birth incidence, not an estimate of it.
  evidence:
  - reference: PMID:36502441
    reference_title: "Heme oxygenase-1 deficiency as an extremely rare cause of AA-type renal amyloidosis: Expanding the clinical features and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To the best of our knowledge, our patient is the eleventh HMOX-1 deficiency
      case in the literature.
    explanation: >-
      A 2023 case report placing the cumulative worldwide count at eleven
      reported patients, supporting an ultra-rare band below 1 in 1,000,000.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since Yachie et al. reported the first description of human heme oxygenase
      (HO)-1 deficiency more than 20 years ago, few additional human cases have
      been reported in the literature.
    explanation: >-
      A dedicated review confirms only a handful of human cases exist two decades
      after the disease was first described.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HO-1 may play cardinal roles during fetal growth and development, and most
      individuals with HO-1 deficiency may thus develop significant organ
      dysfunctions and die in utero or shortly after birth without being
      diagnosed.
    explanation: >-
      The review's own explanation for why so few patients are reported, which is
      why the case count is treated here as a floor rather than an estimate of
      true incidence.
pathophysiology:
- name: HMOX1 Biallelic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic loss-of-function variants in HMOX1 abolish or impair heme oxygenase 1 function.
    Reported alleles span whole-exon deletion, frameshift, nonsense and missense classes. The
    p.G139V allele shows that loss of protein abundance is not required: patient cells retained
    constitutive HO-1 expression but lacked further hemin induction and showed impaired heme-induced
    bilirubin synthesis. Acquired abnormal peroxidase activity was inferred from human urinary
    oxidation products and biochemical studies of other Gly139 substitutions. Loss of inducibility
    alone does not establish these distinct functional defects.
  genes:
  - preferred_term: HMOX1
    term:
      id: hgnc:5013
      label: HMOX1
  molecular_functions:
  - preferred_term: heme oxygenase (decyclizing) activity
    term:
      id: GO:0004392
      label: heme oxygenase (decyclizing) activity
    modifier: DECREASED
  evidence:
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemistry of hepatic tissue and immunoblotting of a
      cadmium-stimulated Epstein-Barr virus-transformed lymphoblastoid cell line
      (LCL) revealed complete absence of HO-1 production.
    explanation: >-
      Demonstrates complete absence of HO-1 protein in the index patient, even
      under cadmium stimulation that normally induces the enzyme. Tagged
      HUMAN_CLINICAL for the hepatic-tissue immunohistochemistry half of the
      sentence, which is a direct observation on patient tissue; note that the
      lymphoblastoid-cell immunoblot in the same sentence is a cell experiment,
      and the separate LCL hemin-sensitivity result is curated as IN_VITRO on
      the free-heme node.
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Western blot analysis confirmed lack of HMOX1 protein upon oxidant
      stimulation of the patient cells.
    explanation: >-
      Independently confirms in a second patient that oxidant stimulation fails
      to produce HMOX1 protein. Tagged IN_VITRO, not HUMAN_CLINICAL: the
      measurement is made on cultured patient-derived cells under oxidant
      challenge, which is a cell experiment even though the cells came from a
      named patient in a case report.
  - reference: PMID:27662012
    reference_title: Mutating heme oxygenase-1 into a peroxidase causes a defect in bilirubin
      synthesis associated with microcytic anemia and severe hyperinflammation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We then confirmed the defective enzyme activity by documenting bilirubin
      synthesis in PBMC. Control cells showed the expected >4-fold heme-induced
      increase of bilirubin from 18.8 & 23.6 to 95.9 & 84.6 pmol/mg protein/60min
      following heme treatment. In contrast, patient cells showed a marginal
      increase from 21.9 & 26.1 to 33.1 & 27.0 pmol/mg protein/60min.
    explanation: >-
      Cultured patient PBMC showed impaired heme-induced bilirubin synthesis. This
      functional assay supports reduced heme-catabolic activity independently of
      the protein-inducibility experiment; it is not a direct purified-G139V
      peroxidase assay.
  - reference: PMID:10942763
    reference_title: Replacement of the distal glycine 139 transforms human heme oxygenase-1 into a
      peroxidase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Of the Gly-139 mutants investigated, only G139A catalyzes the
      NADPH-cytochrome P450 reductase-dependent oxidation of heme to biliverdin,
      but most of them exhibit a new H(2)O(2)-dependent guaiacol peroxidation
      activity.
    explanation: >-
      Recombinant-enzyme mutagenesis establishes the potential for Gly139
      substitutions to exchange oxygenase for peroxidase activity. Tested
      substitutions were alanine, leucine, phenylalanine, tryptophan, histidine and
      aspartate, not valine. This provides biochemical support by analogy for the
      G139V interpretation, not a direct G139V measurement.
    directness: INDIRECT
  - reference: PMID:27662012
    reference_title: Mutating heme oxygenase-1 into a peroxidase causes a defect in bilirubin
      synthesis associated with microcytic anemia and severe hyperinflammation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The strong constitutive expression of HO-1 G139V with defective normal but
      gained abnormal peroxidase function was paralleled by increased excretion of
      peroxidation products in the urine of the patient and, to some degree, in his
      heterozygous parents and heterozygous brother (Table 2).
    explanation: >-
      Human urinary oxidation products support the authors' interpretation of
      abnormal peroxidase activity indirectly. These downstream products do not
      specifically measure mutant-enzyme peroxidase catalysis. Cultured-cell
      bilirubin synthesis and recombinant-enzyme experiments are graded separately.
    directness: INDIRECT
  downstream:
  - target: Failure of Stress-Inducible Heme Catabolism
    description: >-
      Loss of functional HO-1 protein directly removes the catalytic capacity to
      open the heme ring under stress.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33066778
      reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon
        monoxide, ferrous iron, and biliverdin.
      explanation: >-
        Identifies the reaction HMOX1 catalyses, so absence of the protein
        directly abolishes that catalytic step.
- name: Failure of Stress-Inducible Heme Catabolism
  biological_scale: MOLECULAR
  genes:
  - preferred_term: HMOX1
    term:
      id: hgnc:5013
      label: HMOX1
  description: >
    HO-1 is the stress-inducible heme oxygenase isozyme, and the only one rapidly
    induced by oxidative stress. Its loss therefore does not merely slow basal
    heme turnover; it removes the surge capacity that normally meets an oxidative
    or haemolytic insult. Constitutive HMOX2 cannot substitute because it is not
    inducible.

    (Sources differ on how many isozymes to count: the cited review says three,
    while the cited 2020 case report says two. The discrepancy is the status of
    HO-3, now generally regarded as a pseudogene rather than a functional enzyme.
    Nothing in this entry depends on the count, so no number is asserted here;
    the quoted evidence below preserves each source's own wording.)

    The consequence is a single enzymatic block that simultaneously
    fails to generate biliverdin and bilirubin, fails to generate carbon
    monoxide, fails to liberate iron for recycling, and leaves the heme substrate
    itself uncleared. Each of the four downstream arms below is a distinct
    consequence of this one block.
  biological_processes:
  - preferred_term: heme catabolic process
    term:
      id: GO:0042167
      label: heme catabolic process
    modifier: DECREASED
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
    modifier: DECREASED
  cell_types:
  - preferred_term: Kupffer cell
    term:
      id: CL:0000091
      label: Kupffer cell
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Heme oxygenase (HO)-1 constitutes one of the three isozymes of HO, and
      catalyzes the degradation of heme into biliverdin, carbon monoxide (CO),
      and free iron, each of which somehow exert potent anti-oxidative stress and
      anti-inflammatory functions
    explanation: >-
      Establishes the three reaction products whose individual loss defines the
      three product-deficit arms of this pathograph.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Among the three isozymes, HO-1 is the only protein rapidly induced upon
      stimulation with various oxidative stresses
    explanation: >-
      Supports the framing that HMOX1 loss removes an inducible protective
      response that the constitutive isozymes cannot supply.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Therefore, any defect in the function of HO-1 would be expected to lead to
      uncontrollable inflammation in response to certain exogenous insults, such
      as infection and hemolysis.
    explanation: >-
      Links the loss of inducibility specifically to stress-triggered
      decompensation rather than continuous baseline disease.
  - reference: PMID:9380736
    reference_title: "Reduced stress defense in heme oxygenase 1-deficient cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our in vitro and in vivo results provide genetic evidence that
      up-regulation of Hmox1 serves as an adaptive mechanism to protect cells
      from oxidative damage during stress.
    explanation: >-
      Mouse genetic evidence that the induction of Hmox1, not its basal activity,
      is the protective mechanism lost in this disease.
  downstream:
  - target: Circulating Free Heme Accumulation
    description: >-
      Heme that cannot be catabolised persists in plasma and tissue rather than
      being cleared.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The gross appearance of the serum combined with the results of absorption
        spectrum analysis suggested that heme in the form of OxyHb and MetHb was
        markedly increased in the patient
      explanation: >-
        Measured accumulation of circulating heme species in a patient lacking
        the catabolic enzyme.
  - target: Loss of Bilirubin Antioxidant Capacity
    description: >-
      Loss of HO-1 reduces stress-induced biliverdin production and the bilirubin
      derived from it; retained HO-2 does not restore the inducible response.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33066778
      reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Through biliverdin reductase, biliverdin becomes bilirubin.
      explanation: >-
        Establishes that bilirubin is generated only downstream of the biliverdin
        that heme oxygenases produce. The HO-1 block reduces this pathway without
        establishing complete absence of bilirubin synthesis by other isoforms.
  - target: Loss of Carbon Monoxide Cytoprotective Signalling
    description: >-
      CO is generated stoichiometrically by the ring-opening reaction, so the
      enzymatic block removes HO-1-derived production without eliminating all
      endogenous CO sources.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33066778
      reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Heme oxygenases are rate-limiting enzymes that catalyze the degradation
        of heme to carbon monoxide (CO), ferrous iron, and biliverdin, which then
        becomes bilirubin via the action of biliverdin reductase.
      explanation: >-
        Identifies CO as a direct product of the rate-limiting heme oxygenase
        step, so loss of HO-1 reduces the stress-inducible contribution to CO production.
  - target: Impaired Heme-Iron Recycling and Tissue Iron Deposition
    description: >-
      Iron cannot be liberated from heme and released from hepatic and renal
      cells for reuse.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9380735
      reference_title: "Heme oxygenase 1 is required for mammalian iron reutilization."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results indicate that Hmox1 has an important recycling role by
        facilitating the release of iron from hepatic and renal cells, and
        describe a mouse model of human iron metabolic disorders.
      explanation: >-
        Establishes the causal dependence of hepatic and renal iron release on
        Hmox1 activity.
  - target: Renal Tubular Injury
    description: Loss of the inducible HO-1 response permits heme-associated tubular injury.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9884342
      reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme
        oxygenase-1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        HO-1 defect is certainly responsible for the renal tubu-
        lar injury and subsequent proteinuria and hematuria
        seen in this patient.
      explanation: A disease-specific causal interpretation is made in the primary patient report.
  - target: Pulmonary Oxidative Injury
    description: Loss of HO-1-mediated oxidant protection is proposed to drive the pulmonary injury.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
        hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Our patient developed severe NSIP, likely due to oxidant-induced injury
      explanation: The primary report proposes oxidant injury as the cause of the fibrotic interstitial
        pneumonia; this causal attribution remains provisional.
      directness: INDIRECT
- name: Circulating Free Heme Accumulation
  biological_scale: MOLECULAR
  description: >
    Uncleared heme reaches extreme plasma concentrations (490 micromolar in the
    index case against a normal value below 1 micromolar), and the scavenging
    system is overwhelmed: hemopexin is undetectable while haptoglobin is
    paradoxically elevated rather than consumed, and haptoglobin-haemoglobin
    complex spills into urine. Free heme is directly cytotoxic and pro-oxidant,
    and patient-derived cells are hypersensitive to it.
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum heme concentration was extremely high, at 490 μM (normal range; <1
      μM).
    explanation: >-
      Direct measurement of circulating free heme at roughly 500-fold the upper
      limit of normal, which is the accumulation this node asserts.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hemopexin was undetectable by immunoelectrophoresis, indicating the
      presence of active hemolysis in vivo.
    explanation: >-
      Documents exhaustion of the hemopexin heme-scavenging arm in the index
      patient.
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An LCL derived from the patient was extremely sensitive to hemin-induced
      cell injury.
    explanation: >-
      Directly demonstrates that HO-1-deficient patient cells are hypersensitive
      to heme cytotoxicity, the proximate toxic consequence of heme accumulation.
  - reference: PMID:9380736
    reference_title: "Reduced stress defense in heme oxygenase 1-deficient cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cultured Hmox1(-/-) embryonic fibroblasts demonstrated high oxygen free
      radical production when exposed to hemin, hydrogen peroxide, paraquat, or
      cadmium chloride, and they were hypersensitive to cytotoxicity caused by
      hemin and hydrogen peroxide.
    explanation: >-
      Mouse-derived cells reproduce the same heme hypersensitivity, supporting
      heme itself as the proximate cytotoxic species.
  downstream:
  - target: Endothelial Cell Injury and Coagulopathy
    description: >-
      Free heme is cytotoxic and pro-oxidant, and vascular endothelium is the
      compartment most severely affected in the human disease. The link between
      the two is inferred rather than directly measured in patient endothelium.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9884342
      reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        An LCL derived from the patient was extremely sensitive to hemin-induced
        cell injury.
      explanation: >-
        Demonstrates that HO-1-deficient patient cells are killed by heme, which
        is the cytotoxicity this edge invokes. The edge is indirect because the cells tested were lymphoblastoid, not endothelial,
        so heme cytotoxicity toward patient endothelium specifically is inferred
        rather than shown.
  - target: Intravascular Haemolysis with Erythrocyte Fragmentation
    description: Free heme can aggravate vascular oxidative injury, which in turn contributes
      to erythrocyte destruction and fragmentation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Endothelial oxidative injury
    evidence:
    - reference: PMID:9884342
      reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme
        oxygenase-1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Furthermore, a high LDL choles-
        terol level itself, coupled with free heme, may acceler-
        ate the oxidative injury of the vascular endothelium
        (25). High thrombomodulin concentration indicates
        that the patient’s endothelium suffers constant injury
        (26, 27). Electron microscopic study of the patient’s
        kidney shows peculiar detachment of the endothelium
        within the glomeruli. These changes may lead to the
        constant destruction of erythrocytes and platelets.
      explanation: The primary authors propose endothelial oxidative injury as an intermediate
        linking free heme to blood-cell destruction; this is a qualified causal interpretation
        rather than co-occurrence evidence.
      directness: INDIRECT
- name: Loss of Bilirubin Antioxidant Capacity
  biological_scale: MOLECULAR
  description: >
    Biliverdin, and the bilirubin derived from it by biliverdin reductase, is a
    physiologically significant antioxidant. Because HO-1 is the sole route to
    biliverdin under stress, HO-1 deficiency removes this antioxidant sink. The
    same block explains the disease's most discriminating laboratory paradox: a
    patient with brisk intravascular haemolysis has LOW serum bilirubin and no
    jaundice, because the bilirubin normally produced from the liberated heme is
    inadequately generated. Persistently elevated LDH alongside low bilirubin is the
    combination that prompted the diagnosis in at least one reported case.
  molecular_functions:
  - preferred_term: antioxidant activity
    term:
      id: GO:0016209
      label: antioxidant activity
    modifier: DECREASED
  evidence:
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two isoforms exist, heme oxygenase-1 (HMOX1) and heme oxygenase-2 (HMOX2),
      with CO, biliverdin, and bilirubin implicated in important cellular
      processes, such as inflammation, cell proliferation, apoptosis, and
      antioxidant defense.
    explanation: >-
      Attributes antioxidant defence specifically to the biliverdin and bilirubin
      products lost in this disease.
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He has been suffering from persistent hemolytic anemia characterized by
      marked erythrocyte fragmentation and intravascular hemolysis, with
      paradoxical increase of serum haptoglobin and low bilirubin.
    explanation: >-
      The index case documents the defining paradox of haemolysis with low rather
      than raised bilirubin.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Persistently elevated LDH despite low bilirubin levels led Greil et al. to
      analyze the HMOX1 gene, revealing the homozygous G139V mutation.
    explanation: >-
      Shows the haemolysis-without-bilirubin signature is discriminating enough
      to have driven a diagnosis.
  downstream:
  - target: Systemic Inflammatory Response and Progressive Organ Injury
    description: >-
      Loss of the bilirubin antioxidant sink leaves oxidative stress unbuffered,
      amplifying inflammatory tissue injury.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A detailed analysis of the first human case of HO-1 deficiency revealed
        that HO-1 is involved in the protection of multiple tissues and organs
        from oxidative stress and excessive inflammatory reactions, through the
        release of multiple molecules with anti-oxidative stress and
        anti-inflammatory functions.
      explanation: >-
        Supports the general route from lost antioxidant products to unrestrained
        oxidative and inflammatory tissue injury. Support is indirect because the
        source attributes protection to the products collectively rather than
        isolating the bilirubin arm.
  - target: Hypobilirubinaemia Despite Haemolysis
    description: Reduced bilirubin generation can yield frankly low serum bilirubin; some affected
      patients instead remain within the normal range.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9884342
      reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme
        oxygenase-1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He has been suffering from persistent hemolytic anemia characterized by marked
        erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum
        haptoglobin and low bilirubin.
      explanation: The index patient had low bilirubin despite haemolysis; the enzymatic block
        explains the failure of bilirubin production to rise appropriately.
  - target: Hypercholesterolaemia
    description: Impaired bilirubin production is proposed as one contributor to elevated cholesterol;
      prolonged corticosteroid treatment is a competing explanation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9884342
      reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme
        oxygenase-1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        The mechanism of hyperlipidemia, with high choles-
        terol and triglyceride levels, is not clear. Prolonged cor-
        ticosteroid therapy alone may explain the levels seen in
        this patient. Bilirubin is a known antioxidant (20), and
        it also acts as a scavenger for degraded LDL cholesterol
        (21–24). Impaired bilirubin production in this patient
        might also be responsible for the abnormally elevated
        serum cholesterol.
      explanation: This is the authors' hypothesis, not an established or exclusive mechanism;
        the competing steroid explanation is retained.
      directness: INDIRECT
- name: Loss of Carbon Monoxide Cytoprotective Signalling
  biological_scale: MOLECULAR
  description: >
    CO produced by heme ring opening acts as a gaseous mediator that restrains
    inflammatory signalling and regulates the microcirculation and the
    coagulation and fibrinolysis balance. Loss of endogenous CO is the arm most
    often invoked to explain the disproportionate endothelial and coagulation
    abnormalities of this disease, but this attribution is a hypothesis rather
    than a demonstrated mechanism in patients: the supporting experiment is an
    add-back, in which exogenous CO-releasing molecules suppress TNF-alpha-driven
    upregulation of tissue factor and plasminogen activator inhibitor type 1 in
    cultured human endothelial cells and suppress LPS-induced TNF-alpha
    production by mononuclear cells. Endogenous CO deficiency has not been
    measured in a patient, so both downstream edges are marked indirect.
  biological_processes:
  - preferred_term: cellular response to carbon monoxide
    term:
      id: GO:0071245
      label: cellular response to carbon monoxide
    modifier: DECREASED
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CO directly controls the inflammatory state of a given tissue, and at the
      same time regulates the microcirculation within target organs by acting as
      a gaseous mediator
    explanation: >-
      Establishes the anti-inflammatory and vasoregulatory roles of the CO
      product that HO-1 deficiency eliminates.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We recently demonstrated in in vitro cultures that a CO-releasing molecule,
      tricarbonyldichlororuthenium (II) dimer suppressed TNF-α-induced
      up-regulation of tissue factor and plasminogen activator inhibitor type 1
      by human umbilical vein endothelial cells.
    explanation: >-
      Add-back of CO in vitro reproduces the anticoagulant and anti-inflammatory
      effect whose absence is proposed to explain the patients' coagulopathy.
      Support is indirect because this is a pharmacological add-back in cultured
      cells, not a demonstration in patient tissue. The quote is given in full so
      that the agent is identifiably a CO donor.
  downstream:
  - target: Endothelial Cell Injury and Coagulopathy
    description: >-
      Without endogenous CO, endothelial tissue factor and PAI-1 are not
      restrained and the coagulation and fibrinolysis balance is lost.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We recently demonstrated in in vitro cultures that a CO-releasing molecule,
        tricarbonyldichlororuthenium (II) dimer suppressed TNF-α-induced
        up-regulation of tissue factor and plasminogen activator inhibitor type 1
        by human umbilical vein endothelial cells.
      explanation: >-
        CO add-back restrains exactly the endothelial procoagulant programme this
        edge asserts is unrestrained without CO. Support is indirect because it is a
        pharmacological add-back in cultured cells rather than a measurement in
        patients.
  - target: Systemic Inflammatory Response and Progressive Organ Injury
    description: >-
      Loss of the CO brake on inflammatory signalling permits an unrestrained
      systemic inflammatory response.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        CO directly controls the inflammatory state of a given tissue, and at the
        same time regulates the microcirculation within target organs by acting
        as a gaseous mediator
      explanation: >-
        Attributes direct control of tissue inflammatory state to CO, so its
        absence removes that control.
- name: Impaired Heme-Iron Recycling and Tissue Iron Deposition
  biological_scale: CELLULAR
  description: >
    Most body iron is recycled from senescent erythrocytes rather than absorbed
    from the diet, and HO-1 catalyses the step that liberates that iron. Its loss
    traps iron inside hepatic parenchymal cells and renal tubular epithelium
    instead of releasing it for erythropoiesis. The resulting state is
    counter-intuitive and is a recognised diagnostic trap: heavy tissue iron
    deposition and marked hyperferritinaemia coexist with normal or low serum
    iron, and with anaemia that does not respond to iron supplementation.
  cell_types:
  - preferred_term: kidney proximal tubule epithelial cell
    term:
      id: CL:1000838
      label: kidney proximal convoluted tubule epithelial cell
  - preferred_term: Kupffer cell
    term:
      id: CL:0000091
      label: Kupffer cell
  biological_processes:
  - preferred_term: intracellular iron ion homeostasis
    term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Iron deposition was noted in renal and hepatic tissue.
    explanation: >-
      Direct human histological evidence of renal and hepatic iron deposition in
      the index case.
  - reference: PMID:9380735
    reference_title: "Heme oxygenase 1 is required for mammalian iron reutilization."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Hmox1-deficient adult mice developed an anemia associated with abnormally
      low serum iron levels, yet accumulated hepatic and renal iron that
      contributed to macromolecular oxidative damage, tissue injury, and chronic
      inflammation.
    explanation: >-
      The defining mouse experiment establishing the mechanism by which iron is
      simultaneously deficient in serum and excessive in tissue. Mouse evidence
      only; the corresponding human histology is cited separately above.
  - reference: PMID:9380735
    reference_title: "Heme oxygenase 1 is required for mammalian iron reutilization."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results indicate that Hmox1 has an important recycling role by
      facilitating the release of iron from hepatic and renal cells, and describe
      a mouse model of human iron metabolic disorders.
    explanation: >-
      States the recycling role of Hmox1 whose loss produces the tissue-iron
      trapping.
  downstream:
  - target: Hyperferritinaemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Iron that cannot be recycled out of the macrophage accumulates, and serum
      ferritin rises. The edge is hedged because ferritin is not a clean
      readout of that: it is also an acute-phase reactant, and this disease
      produces a sustained systemic inflammatory state that raises it
      independently of iron. The phenotype's own description, its evidence and
      its reports_on interpretation all make that point — circulating ferritin
      does not quantify tissue iron stores here — so this edge should not
      assert an iron-loading mechanism more confidently than the record it
      points at. Which of the two contributions dominates in any given patient
      is not established by anything cited.
  - target: Macrophage and Monocyte Dysfunction
    description: >-
      Iron and heme overload within erythrophagocytosing macrophages impairs and
      ultimately kills them.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        They showed progressive death of macrophages in the liver and spleen
        throughout the process of erythrophagocytosis and the resultant heme
        release in vivo, causing significant damage to the organs and intense
        inflammation of the surrounding tissues.
      explanation: >-
        Ties the heme released during erythrophagocytosis directly to macrophage
        death in the HO-1-deficient state.
  - target: Systemic Inflammatory Response and Progressive Organ Injury
    description: >-
      Deposited redox-active iron drives macromolecular oxidative damage and
      chronic inflammation in liver and kidney.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9380735
      reference_title: "Heme oxygenase 1 is required for mammalian iron reutilization."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Hmox1-deficient adult mice developed an anemia associated with abnormally
        low serum iron levels, yet accumulated hepatic and renal iron that
        contributed to macromolecular oxidative damage, tissue injury, and
        chronic inflammation.
      explanation: >-
        States the causal contribution of accumulated tissue iron to oxidative
        damage, tissue injury and chronic inflammation.
- name: Macrophage and Monocyte Dysfunction
  biological_scale: CELLULAR
  description: >
    HO-1 is normally induced to high levels in monocytes and macrophages, which
    handle the heme load generated by erythrophagocytosis. Without it these cells
    progressively fail: monocyte dysfunction and unregulated macrophage
    activation are documented consequences, and mouse work shows macrophages die
    during erythrophagocytosis. This arm explains both the
    macrophage-activation-syndrome and haemophagocytic flares seen clinically
    and, plausibly, the functional asplenia, which in mouse models arises from
    progressive fibrotic destruction of the splenic red pulp.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In vivo and in vitro studies have indicated that impaired HO-1 production
      results in progressive monocyte dysfunction, unregulated macrophage
      activation and endothelial cell dysfunction, leading to catastrophic
      systemic inflammatory response syndrome.
    explanation: >-
      Names monocyte dysfunction and unregulated macrophage activation as
      consequences of impaired HO-1, converging on systemic inflammation.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      They showed progressive death of macrophages in the liver and spleen
      throughout the process of erythrophagocytosis and the resultant heme
      release in vivo, causing significant damage to the organs and intense
      inflammation of the surrounding tissues.
    explanation: >-
      Mouse evidence for the specific cellular mechanism, macrophage death during
      erythrophagocytosis, underlying this node.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cytoplasm of circulating monocytes was vacuolated, and expressions of
      many monocyte surface antigens were markedly reduced.
    explanation: >-
      Direct human cellular evidence of monocyte structural and phenotypic
      abnormality, so this node does not rest on mouse data alone.
  - reference: PMID:24963040
    reference_title: Wild-type macrophages reverse disease in heme oxygenase 1-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Previously, we found that macrophages engaged in recycling of red cells
      were depleted from the tissues of Hmox1(-/-) mice, which resulted in
      intravascular hemolysis and severe damage to the endothelial system,
      kidneys, and other organs.
    explanation: >-
      Places macrophage depletion causally upstream of the haemolysis and
      endothelial/renal injury, which is the position this node occupies in the
      pathograph.
  downstream:
  - target: Asplenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Absent splenic tissue, reported in several patients and sometimes described as congenital. Drawn from the macrophage node because the spleen is the organ of the red-pulp macrophage compartment this disease disables. Note the entry curates four different splenic outcomes — absence, hypoplasia, normal size and enlargement — because all four are reported; none excludes the diagnosis.
  - target: Splenic Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A small, poorly perfused, infarcted spleen — an acquired course distinct from congenital absence, and curated separately for that reason.
  - target: Splenomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The opposite splenic presentation, which may regress during the disease course. Curated because its presence does not exclude HMOX1 deficiency.
  - target: Systemic Inflammatory Response and Progressive Organ Injury
    description: >-
      Unregulated macrophage activation drives the haemophagocytic and
      macrophage-activation-syndrome flares that dominate the clinical course.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In vivo and in vitro studies have indicated that impaired HO-1 production
        results in progressive monocyte dysfunction, unregulated macrophage
        activation and endothelial cell dysfunction, leading to catastrophic
        systemic inflammatory response syndrome.
      explanation: >-
        States the causal chain from unregulated macrophage activation to
        catastrophic systemic inflammatory response syndrome.
  - target: Haemophagocytosis
    description: Unregulated macrophage activation includes phagocytosis of blood-cell precursors
      during inflammatory flares.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
        hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A bone marrow biopsy demonstrated extensive histiocyte activation with phagocytosis
        of nucleated red blood cell precursors.
      explanation: Activated histiocytes were directly observed phagocytosing precursors in the
        patient.
- name: Endothelial Cell Injury and Coagulopathy
  biological_scale: TISSUE
  description: >
    Vascular endothelium is the tissue most severely affected in human HO-1
    deficiency. Markers of endothelial damage (thrombomodulin, von Willebrand
    factor) are markedly elevated, and glomerular electron microscopy shows frank
    detachment of endothelium with subendothelial deposits. The coagulation and
    fibrinolysis systems are grossly deranged, with extraordinarily elevated
    thrombin-antithrombin complex and fibrin degradation products, yet platelet
    counts are paradoxically raised rather than consumed, distinguishing this
    from ordinary disseminated intravascular coagulation.
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An abnormal coagulation/fibrinolysis system, associated with elevated
      thrombomodulin and von Willebrand factor, indicated the presence of severe,
      persistent endothelial damage.
    explanation: >-
      Direct human biomarker evidence of severe persistent endothelial injury.
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron microscopy of renal glomeruli revealed detachment of endothelium,
      with subendothelial deposition of an unidentified material.
    explanation: >-
      Ultrastructural confirmation of endothelial injury in the renal
      microvasculature, linking this node to the nephritis phenotype.
  - reference: PMID:21088618
    reference_title: "Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Human HO-1 deficiency has been observed to involve the endothelial cells
      more severely, resulting in hemolysis and disseminated intravascular
      coagulation.
    explanation: >-
      Independent confirmation that endothelium is the preferentially affected
      compartment, causally upstream of haemolysis and coagulopathy.
  downstream:
  - target: Intracranial Haemorrhage
    causal_link_type: DIRECT
    description: >-
      Bleeding into the brain, the most consequential expression of the endothelial injury and coagulopathy this node describes.
  - target: Intravascular Haemolysis with Erythrocyte Fragmentation
    description: >-
      A damaged endothelial surface shears circulating erythrocytes, producing
      the fragmentation and schistocytes seen on the blood film.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21088618
      reference_title: "Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Human HO-1 deficiency has been observed to involve the endothelial cells
        more severely, resulting in hemolysis and disseminated intravascular
        coagulation.
      explanation: >-
        Places endothelial involvement causally upstream of the haemolysis in
        this disease.
  - target: Systemic Inflammatory Response and Progressive Organ Injury
    description: >-
      Endothelial dysfunction propagates vascular inflammation and contributes to
      nephritis and multiorgan injury.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In vivo and in vitro studies have indicated that impaired HO-1 production
        results in progressive monocyte dysfunction, unregulated macrophage
        activation and endothelial cell dysfunction, leading to catastrophic
        systemic inflammatory response syndrome.
      explanation: >-
        Names endothelial cell dysfunction among the converging routes to
        systemic inflammatory response syndrome.
  - target: Coagulopathy
    description: Endothelial injury disrupts coagulation and fibrinolysis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21088618
      reference_title: Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis,
        and asplenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Human HO-1 deficiency has been observed to involve the endothelial cells more severely,
        resulting in hemolysis and disseminated intravascular coagulation.
      explanation: The clinical report explicitly attributes coagulation abnormalities to endothelial
        involvement.
- name: Intravascular Haemolysis with Erythrocyte Fragmentation
  biological_scale: ORGANISM
  description: >
    Persistent intravascular haemolysis with marked erythrocyte fragmentation is
    a cardinal feature. The blood film shows fragmented erythrocytes together
    with Howell-Jolly bodies (reflecting the asplenia) and nucleated red cells,
    and the direct antiglobulin test is negative, excluding an autoimmune cause.
    Haemolysis both results from and further feeds the heme burden, since each
    destroyed erythrocyte releases haemoglobin that cannot be catabolised.
  biological_processes:
  - preferred_term: erythrocyte homeostasis
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peripheral blood smear showed numerous fragmented erythrocytes,
      Howell-Jolly bodies and nucleated red blood cells.
    explanation: >-
      Morphological documentation of erythrocyte fragmentation in the index case.
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HMOX1-deficiency is a rare autosomal recessive disorder with hallmark
      features of direct antibody negative hemolytic anemia with normal
      bilirubin, hyperinflammation and features similar to macrophage activation
      syndrome.
    explanation: >-
      Confirms the haemolysis is antibody-negative, excluding an autoimmune
      mechanism.
  downstream:
  - target: Elevated Lactate Dehydrogenase
    causal_link_type: DIRECT
    description: >-
      Released from lysed erythrocytes; the standard laboratory marker of intravascular haemolysis.
  - target: Elevated Serum Haptoglobin
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The paradox of this disease, and worth an edge rather than omission precisely because it runs backwards: intravascular haemolysis normally consumes haptoglobin, but here the haptoglobin-haemoglobin complex is not cleared, because clearing it is the job of the macrophage compartment this disease disables. A normal or high haptoglobin does not exclude the diagnosis.
  - target: Systemic Inflammatory Response and Progressive Organ Injury
    description: >-
      Ongoing haemolysis supplies the inflammatory and oxidative burden that the
      absent HO-1 response cannot contain.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Therefore, any defect in the function of HO-1 would be expected to lead
        to uncontrollable inflammation in response to certain exogenous insults,
        such as infection and hemolysis.
      explanation: >-
        Names haemolysis specifically as an insult that, without HO-1, leads to
        uncontrollable inflammation.
  - target: Haemolytic Anaemia
    description: Intravascular erythrocyte destruction causes haemolytic anaemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9884342
      reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme
        oxygenase-1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He has been suffering from persistent hemolytic anemia characterized by marked
        erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum
        haptoglobin and low bilirubin.
      explanation: The clinical process includes red-cell destruction and fragmentation; these
        edges expose its corresponding phenotype endpoints.
  - target: Erythrocyte Fragmentation
    description: Fragmented erythrocytes are the morphological manifestation of this haemolytic
      process.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9884342
      reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme
        oxygenase-1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He has been suffering from persistent hemolytic anemia characterized by marked
        erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum
        haptoglobin and low bilirubin.
      explanation: The clinical process includes red-cell destruction and fragmentation; these
        edges expose its corresponding phenotype endpoints.
  - target: Haemoglobinuria
    description: Intravascular red-cell lysis releases haemoglobin that can enter the urine.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
        hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: During hospitalization, hepatomegaly was found along with mild transaminitis (AST
        301 U/L, ALT 74 U/L), direct antiglobulin test negative hemolytic anemia (hematocrit 24.7%)
        and hemoglobinuria without microscopic red blood cells.
      explanation: The primary patient had haemoglobinuria during intravascular haemolysis, without
        urinary red cells.
  - target: Hypertension
    description: Scavenging of nitric oxide by free haemoglobin is proposed to contribute to vasoconstriction
      and hypertension; renal injury may also contribute.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38799538
      reference_title: 'A rare case of heme oxygenase deficiency: A case report and literature
        review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The free Hb released during hemolysis scavenges serum nitric oxide leading to vasoconstriction,
        which results in hypertension.
      explanation: The clinical review proposes this indirect mechanism. It is not a patient-level
        nitric-oxide measurement or an exclusive explanation for hypertension.
      directness: INDIRECT
- name: Systemic Inflammatory Response and Progressive Organ Injury
  biological_scale: ORGANISM
  description: >
    The convergent endpoint. Impaired protective responses (reduced
    bilirubin antioxidant capacity and CO signaling, uncleared cytotoxic heme, trapped
    redox-active iron, and failing macrophages) produces an unrestrained systemic
    inflammatory response. Clinically this appears as recurrent fever and rash,
    nephritis, hepatomegaly, interstitial lung disease, leukocytosis and
    thrombocytosis, and haemophagocytic or macrophage-activation flares, and in
    at least one patient progressed to secondary AA amyloidosis. Onset is
    typically triggered by an exogenous insult such as infection, and once
    ignited the course is often rapidly progressive and fatal.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The devastating clinical courses experienced by these patients indicate the
      critical importance of HO-1 in holding back rapidly progressive
      inflammation and organ dysfunction once an overwhelming inflammatory
      response is ignited by certain triggers.
    explanation: >-
      Directly frames the endpoint as failure to restrain a trigger-initiated
      inflammatory response.
  - reference: PMID:36502441
    reference_title: "Heme oxygenase-1 deficiency as an extremely rare cause of AA-type renal amyloidosis: Expanding the clinical features and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a 30-year-old male with AA-type renal amyloidosis due to a
      chronic inflammatory condition of unknown origin.
    explanation: >-
      Documents secondary AA amyloidosis as a long-term consequence of the
      sustained inflammatory state in a genetically confirmed patient.
  downstream:
  - target: Hepatomegaly
    causal_link_type: DIRECT
    description: >-
      Hepatic involvement in the systemic inflammatory and iron-deposition process.
  - target: Elevated Hepatic Transaminases
    causal_link_type: DIRECT
    description: >-
      The biochemical correlate of that hepatic injury.
  - target: Hypertriglyceridaemia
    causal_link_type: DIRECT
    description: >-
      Raised triglycerides in the systemic inflammatory state.
  - target: Growth Retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Constitutional consequence of chronic systemic inflammation and organ injury.
  - target: Palpebral Edema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Periorbital oedema reported in the inflammatory presentation.
  - target: Recurrent Fever
    description: Hyperinflammatory flares manifest with recurrent fever.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
        hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Here we report a young man with HMOX1 deficiency that had recurrent autoinflammatory
        episodes marked by fever, hemolysis and hyperferritinemia with pathologic features similar
        to MAS and HLH.
      explanation: The febrile episodes are clinical manifestations of the reported autoinflammation.
  - target: Leukocytosis
    description: Inflammatory flares increase circulating leukocyte counts above an already elevated
      baseline.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
        hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: During episodes, his baseline leukocytosis increased from about 20 K/mm3 to exceed
        40 K/mm3.
      explanation: The recurrent rise with hyperinflammatory episodes supports reactive leukocytosis;
        infections may also trigger the flares.
  - target: Secondary AA Renal Amyloidosis
    description: Persistent inflammation can lead to secondary AA amyloid deposition in the kidney.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36502441
      reference_title: 'Heme oxygenase-1 deficiency as an extremely rare cause of AA-type renal
        amyloidosis: Expanding the clinical features and review of the literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: This inflammatory status could lead to the development of secondary AA-type amyloidosis
        theoretically. Here, we report a 30-year-old male with AA-type renal amyloidosis due to
        a chronic inflammatory condition of unknown origin.
      explanation: The genetically confirmed case supports the proposed secondary inflammatory
        mechanism; the authors frame the disease-specific relation as theoretical.
      directness: INDIRECT
  - target: Pericardial Effusion
    description: Pericardial effusion can complicate systemic inflammatory flares; steroid responsiveness
      supports an inflammatory contribution in the US patient.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
        hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He received the Prevnar 13 vaccination and developed another hyperinflammatory
        episode lasting 4 months complicated by steroid responsive pericardial effusion and presumed
        inflammatory pneumonitis.
      explanation: The effusion was a steroid-responsive complication of the inflammatory episode,
        without establishing the same cause in every patient.
      directness: INDIRECT
  - target: Arthralgia
    description: The articular component of systemic inflammation can cause joint pain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
        hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Bilateral knee arthritis was clinically noted accompanying myalgias and arthralgias
        with morning stiffness, although subsequent knee x-rays showed no erosions.
      explanation: Clinically observed arthritis provides the inflammatory substrate for the reported
        arthralgias.
  - target: Erythematous Rash
    description: The cutaneous component of systemic inflammatory flares can manifest as erythematous
      rash.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33546372
      reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
        Human Cases and Animal Models.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The combination of fever, erythematous rash, and joint pain suggested that the
        patient suffered from a childhood chronic inflammatory illness such as systemic juvenile
        idiopathic arthritis (sJIA) or chronic infantile neurological cutaneous and articular
        syndrome (alternatively called neonatal-onset multisystem inflammatory disease).
      explanation: The eruption is interpreted as part of the inflammatory presentation; the initial
        differential diagnoses were subsequently replaced by HMOX1 deficiency.
      directness: INDIRECT
- name: Renal Tubular Injury
  biological_scale: TISSUE
  description: Loss of HO-1-mediated protection permits renal tubular injury in the setting
    of heme exposure. Tubular injury coexists with glomerular endothelial damage; their relative
    contributions may differ between patients.
  evidence:
  - reference: PMID:9884342
    reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme
      oxygenase-1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      HO-1 defect is certainly responsible for the renal tubu-
      lar injury and subsequent proteinuria and hematuria
      seen in this patient.
    explanation: The primary human report explicitly attributes tubular injury and the urine
      abnormalities to HO-1 deficiency.
  downstream:
  - target: Proteinuria
    description: Renal injury produces this urinary manifestation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9884342
      reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme
        oxygenase-1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        HO-1 defect is certainly responsible for the renal tubu-
        lar injury and subsequent proteinuria and hematuria
        seen in this patient.
      explanation: The source explicitly places the urine abnormality downstream of renal tubular
        injury.
  - target: Haematuria
    description: Renal injury produces this urinary manifestation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9884342
      reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme
        oxygenase-1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        HO-1 defect is certainly responsible for the renal tubu-
        lar injury and subsequent proteinuria and hematuria
        seen in this patient.
      explanation: The source explicitly places the urine abnormality downstream of renal tubular
        injury.
- name: Pulmonary Oxidative Injury
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: Oxidant injury is proposed to cause fibrotic nonspecific interstitial pneumonia
    in HO-1 deficiency. Inflammatory macrophage changes may also contribute; the specific balance
    of these processes is not established.
  evidence:
  - reference: PMID:33066778
    reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
      hemophagocytic flares.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our patient developed severe NSIP, likely due to oxidant-induced injury
    explanation: The primary report proposes oxidant injury as the cause of the fibrotic interstitial
      pneumonia; this causal attribution remains provisional.
    directness: INDIRECT
  downstream:
  - target: Pulmonary Haemorrhage
    causal_link_type: DIRECT
    description: >-
      Alveolar bleeding, the clinical expression of oxidative injury to the pulmonary vasculature.
  - target: Interstitial Lung Disease
    description: Oxidant injury is proposed to drive the interstitial pneumonitis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease
        and hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Our patient developed severe NSIP, likely due to oxidant-induced injury
      explanation: The primary report proposes oxidant injury as the cause of the fibrotic interstitial
        pneumonia; this causal attribution remains provisional.
      directness: INDIRECT
  - target: Pulmonary Fibrosis
    description: The documented fibrotic NSIP includes extensive interstitial and alveolar septal
      fibrosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease
        and hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He was found on thorascopic lung biopsy to have extensive interstitial fibrosis,
        consistent with the fibrotic nonspecific interstitial pneumonia (NSIP) pattern, in addition
        to cholesterol granulomas.
      explanation: The pulmonary process was directly characterized as extensive interstitial
        fibrosis.
phenotypes:
- category: Hematologic
  name: Haemolytic Anaemia
  description: >
    Persistent, direct-antiglobulin-negative haemolytic anaemia with
    intravascular destruction. A hallmark finding in the historical case literature.
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
    temporality: CHRONIC
  notes: >-
    Fever and haemolytic anaemia were reported in all nine historical cases summarized by
    PMID:33546372 (9/9 published cases). This is a selected literature inventory, not an unselected
    population denominator. The exact observed count is retained without inferring a disease-wide
    frequency band or universal penetrance.
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fever, absence of the spleen, hemolytic anemia, hematuria/proteinuria, and
      the absence of jaundice seem to be the common findings in those cases.
    explanation: >-
      A review of the reported case series names haemolytic anaemia as a common
      finding across cases, supporting the association; no population frequency is inferred.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fever and hemolytic anemia were constant findings.
    explanation: >-
      Frequency-specific evidence: across the 9 reported patients haemolytic
      anaemia was a constant finding. This nine-case literature inventory does not
      provide a disease-wide population estimate.
- category: Hematologic
  name: Erythrocyte Fragmentation
  description: >
    Numerous schistocytes on the peripheral blood film, reflecting mechanical and
    oxidative erythrocyte damage on an injured endothelial surface.
  phenotype_term:
    preferred_term: Schistocytosis
    term:
      id: HP:0001981
      label: Schistocytosis
  evidence:
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He has been suffering from persistent hemolytic anemia characterized by
      marked erythrocyte fragmentation and intravascular hemolysis, with
      paradoxical increase of serum haptoglobin and low bilirubin.
    explanation: Documents marked erythrocyte fragmentation in the index patient.
- category: Biochemical
  name: Hypobilirubinaemia Despite Haemolysis
  description: >
    The single most discriminating feature. Bilirubin fails to rise despite brisk
    ongoing haemolysis that would normally produce marked unconjugated
    hyperbilirubinaemia, and jaundice is absent. This is the direct laboratory
    signature of the enzymatic block, since bilirubin is generated from heme via
    HO-1.

    NOTE on the frequency band, deliberately omitted: the source reports
    bilirubin as "low or within normal ranges in all cases", which establishes
    universal failure-to-rise but NOT that frank hypobilirubinaemia (the HP term
    bound here) occurs in 80% or more of patients. The index case was frankly low
    at 0.1 to 0.3 mg/dL, but a normal-range value in another patient does not
    instantiate HP:0033480. Rather than assert a band the evidence does not
    carry, no `frequency` is given.
  phenotype_term:
    preferred_term: Hypobilirubinemia
    term:
      id: HP:0033480
      label: Hypobilirubinemia
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Repeated measurements of serum bilirubin concentration were always low, at 0.1–0.3 mg/dL.
    explanation: >-
      Direct repeated low-bilirubin measurements in the index patient support
      hypobilirubinaemia; absence of visible jaundice alone would not establish it.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More importantly, bilirubin remained low or within normal ranges in all
      cases, despite the presence of active hemolytic anemia. Paradoxical normo-
      or hypobilirubinemia in the presence of active hemolytic anemia is
      certainly the first denominator of HO-1 deficiency.
    explanation: >-
      Low or normal bilirubin despite active haemolysis was present in all 9
      reported cases. Note the review's own wording is "low or within normal
      ranges", so frank hypobilirubinaemia — the HP term bound here — is not
      shown to be universal even though the failure to rise is. That gap is
      exactly why no `frequency` band is asserted.
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He has been suffering from persistent hemolytic anemia characterized by
      marked erythrocyte fragmentation and intravascular hemolysis, with
      paradoxical increase of serum haptoglobin and low bilirubin.
    explanation: >-
      The index case explicitly records low bilirubin coexisting with
      intravascular haemolysis.
- category: Biochemical
  name: Elevated Serum Haptoglobin
  description: >
    Haptoglobin is paradoxically elevated rather than consumed, the opposite of
    what intravascular haemolysis normally produces, because the
    haptoglobin-haemoglobin complex appears not to be cleared by the normal
    scavenger route when the downstream catabolic enzyme is absent. The source
    describes that bypass as happening "somehow", so the mechanism is recorded
    here as observed rather than established.
  phenotype_term:
    preferred_term: Elevated haptoglobin level
    term:
      id: HP:0020180
      label: Elevated circulating haptoglobin concentration
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further study revealed that serum Hp concentration was extremely elevated
      (800–1200 mg/dL, normal range; 40–180 mg/dL) and a large amount of Hb-Hp
      complex was detected in a urine sample from the patient.
    explanation: >-
      Direct quantitative measurement of the raised serum haptoglobin this
      phenotype asserts, roughly 5-fold above the upper limit of normal.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data suggested that the Hb-Hp complex was somehow bypassing the
      normal scavenger system and overflowing into urine.
    explanation: >-
      Offers the proposed explanation for the paradoxical elevation. Support is indirect because the source itself hedges the mechanism as "somehow".
- category: Biochemical
  name: Hyperferritinaemia
  description: >-
    Serum ferritin can be markedly elevated during chronic inflammation and
    macrophage-activation flares. Tissue iron deposition is also reported, but
    circulating ferritin alone does not quantify iron stores or prove iron overload.
  phenotype_term:
    preferred_term: Increased circulating ferritin concentration
    term:
      id: HP:0003281
      label: Increased circulating ferritin concentration
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased levels of hepatic enzymes, triglycerides and ferritin were also
      noted.
    explanation: >-
      Records raised ferritin in a genetically confirmed patient.
  reports_on:
  - target: Systemic Inflammatory Response and Progressive Organ Injury
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Ferritin is an inflammatory readout here, not a quantitative measure of tissue
      iron loading.
    evidence:
    - reference: PMID:38178812
      reference_title: 'Clinical and molecular analysis of a novel variant in heme oxygenase-1
        deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Conventional parameters of inflammation such as C-reactive protein (CrP), Ferritin,
        and S100A8/9 were highly elevated as well.
      explanation: The clinical study explicitly interprets ferritin among the inflammatory markers.
- category: Biochemical
  name: Elevated Lactate Dehydrogenase
  description: >
    LDH is extremely elevated during haemolysis and inflammatory tissue injury;
    the measurement is not specific to either process alone. The combination of high LDH with low bilirubin is the pattern
    that should prompt HMOX1 testing.
  phenotype_term:
    preferred_term: Increased circulating lactate dehydrogenase concentration
    term:
      id: HP:0025435
      label: Increased circulating lactate dehydrogenase concentration
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Persistently elevated LDH despite low bilirubin levels led Greil et al. to
      analyze the HMOX1 gene, revealing the homozygous G139V mutation.
    explanation: >-
      Documents persistently elevated LDH and its diagnostic pairing with low
      bilirubin.
  reports_on:
  - target: Intravascular Haemolysis with Erythrocyte Fragmentation
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: LDH reports haemolysis but may also reflect inflammatory tissue injury.
    evidence:
    - reference: PMID:38178812
      reference_title: 'Clinical and molecular analysis of a novel variant in heme oxygenase-1
        deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Chronic hemolytic anemia was identified in the patient and exacerbated upon an
        episode of viral infection as evidenced by low hemoglobin and elevated LDH levels.
      explanation: The clinical figure identifies elevated LDH as evidence of haemolysis.
- category: Hematologic
  name: Asplenia
  description: >-
    An absent spleen is reported in several patients, sometimes described as
    congenital. Other patients have a small, infarcted, normal-sized, or enlarged
    spleen; hypoplasia and functional hyposplenism are not equivalent to anatomic absence.
  phenotype_term:
    preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
  evidence:
  - reference: PMID:21088618
    reference_title: "Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report another case of human HO-1 deficiency in a young girl with
      congenital asplenia, who presented with severe hemolysis, inflammation,
      nephritis, which was refractory to therapy with corticosteroids,
      cyclophosphamide, and rituximab.
    explanation: Documents congenital asplenia in a genetically confirmed patient.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fever, absence of the spleen, hemolytic anemia, hematuria/proteinuria, and
      the absence of jaundice seem to be the common findings in those cases.
    explanation: >-
      Absence of the spleen is listed among findings common to the reported case
      series. The pooled absence/hypoplasia descriptions do not establish a
      frequency for anatomic asplenia alone.
- category: Renal
  name: Haematuria
  description: >
    Renal involvement with haematuria is common and refractory to
    immunosuppression. Glomerular endothelial detachment on electron microscopy
    provides the structural correlate.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fever, absence of the spleen, hemolytic anemia, hematuria/proteinuria, and
      the absence of jaundice seem to be the common findings in those cases.
    explanation: >-
      Names haematuria and proteinuria among the findings common to reported
      cases.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hematuria and proteinuria were observed in all of the Japanese and Indian
      cases.
    explanation: >-
      Quantifies the renal involvement across the Japanese and Indian cases,
      though the review notes urine findings were not reported for two further
      patients, so no frequency band is asserted here.
- category: Renal
  name: Proteinuria
  description: >
    Proteinuria accompanies the glomerular endothelial injury; in the rat model
    proteinuria occurs with focal segmental sclerosis and podocyte changes.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fever, absence of the spleen, hemolytic anemia, hematuria/proteinuria, and
      the absence of jaundice seem to be the common findings in those cases.
    explanation: Names proteinuria among findings common to the reported cases.
- category: Renal
  name: Secondary AA Renal Amyloidosis
  description: >
    Reactive (AA-type) amyloid deposition in the kidney, arising as a late
    complication of the sustained systemic inflammatory state rather than as a
    direct consequence of the enzymatic block. Reported in a single genetically
    confirmed patient — a 30-year-old man homozygous for the p.G139V missense
    variant, in whom AA-type renal amyloidosis was the presenting problem and
    the underlying inflammatory condition was of unknown origin until clinical
    exome sequencing was performed. The authors propose chronic inflammation as the driver of the AA deposits;
    the timing and frequency of this complication are not established. Reported once, so no frequency band is
    asserted; see the terminal pathophysiology node "Systemic Inflammatory
    Response and Progressive Organ Injury" for the causal chain, and the notes
    block for why amyloidogenesis conformance is deferred rather than declared.
  phenotype_term:
    preferred_term: AA-type renal amyloidosis
    term:
      id: HP:0001917
      label: Renal amyloidosis
  evidence:
  - reference: PMID:36502441
    reference_title: "Heme oxygenase-1 deficiency as an extremely rare cause of AA-type renal amyloidosis: Expanding the clinical features and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a 30-year-old male with AA-type renal amyloidosis due to a
      chronic inflammatory condition of unknown origin.
    explanation: >-
      The primary observation of AA-type renal amyloidosis in the patient this
      phenotype is drawn from, including the age at which it was found.
  - reference: PMID:36502441
    reference_title: "Heme oxygenase-1 deficiency as an extremely rare cause of AA-type renal amyloidosis: Expanding the clinical features and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical exome sequencing (CES) confirmed the HMOX-1 deficiency diagnosis
      related to homozygous missense G139V mutation.
    explanation: >-
      Establishes that the patient carrying this phenotype has a molecularly
      confirmed biallelic HMOX1 genotype, so the amyloidosis is attributable to
      this disease rather than to an unrelated inflammatory diagnosis.
  - reference: PMID:36502441
    reference_title: "Heme oxygenase-1 deficiency as an extremely rare cause of AA-type renal amyloidosis: Expanding the clinical features and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Also, HMOX-1 deficiency-related systemic AA-type amyloidosis has not been
      reported before.
    explanation: >-
      The authors state this was the first such report, which is why the
      phenotype is curated without a frequency band rather than as a recurring
      feature.
- category: Constitutional
  name: Recurrent Fever
  description: >
    Recurrent febrile inflammatory episodes, often infection-triggered, are
    frequently the presenting feature and initially suggest a systemic
    autoinflammatory syndrome or systemic juvenile idiopathic arthritis.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
    temporality: RECURRENT
  notes: >-
    Fever and haemolytic anaemia were reported in all nine historical cases summarized by
    PMID:33546372 (9/9 published cases). This is a selected literature inventory, not an unselected
    population denominator. The exact observed count is retained without inferring a disease-wide
    frequency band or universal penetrance.
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fever and hemolytic anemia were constant findings.
    explanation: >-
      Frequency-specific evidence: fever was a constant finding across the 9
      historical patients. The small published-case denominator is retained here
      without a disease-wide frequency band.
- category: Growth
  name: Growth Retardation
  description: >
    Growth retardation can be severe but is not universal. In at least one patient growth
    was normal until inflammatory episodes began and then fell away, suggesting a contribution from chronic illness. The relative contributions
    of inflammation, nutritional status and prolonged steroid exposure remain uncertain.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient is a six-year-old boy with severe growth retardation.
    explanation: Documents severe growth retardation in the index patient.
- category: Hematologic
  name: Leukocytosis
  description: >
    Marked and persistent leukocytosis, part of the chronic inflammatory
    signature; infection can additionally trigger or amplify flares.
  phenotype_term:
    preferred_term: Increased total leukocyte count
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More importantly, increases in leukocyte and platelet counts were invariably
      noted in all cases, which is contrary to the phenomenon observed in HLH
      patients.
    explanation: >-
      Frequency-specific evidence: raised leukocyte counts were invariable across
      the nine historical cases. This is not a population estimate; the contrast
      with typical HLH-associated cytopenias remains diagnostically useful.
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Episodes included hemolysis without hyperbilirubinemia, immunodeficiency,
      hepatomegaly with mild transaminitis, asplenia, leukocytosis,
      thrombocytosis, joint pain and features of macrophage activation with
      negative autoimmune serologies.
    explanation: >-
      Records leukocytosis among the flare features in a confirmed patient.
- category: Hematologic
  name: Thrombocytosis
  description: >
    Platelet counts can remain markedly raised despite coagulopathy, with
    contributions from hyposplenia and inflammatory flares. This pattern is
    diagnostically useful but not invariant; later cases include thrombocytopenia.
  phenotype_term:
    preferred_term: Thrombocytosis
    term:
      id: HP:0001894
      label: Thrombocytosis
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More importantly, increases in leukocyte and platelet counts were invariably
      noted in all cases, which is contrary to the phenomenon observed in HLH
      patients.
    explanation: >-
      Frequency-specific evidence: raised platelet counts were invariable across
      the nine historical cases; subsequent reports include thrombocytopenia. No
      disease-wide band or invariant distinction from HLH/DIC is asserted.
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Episodes included hemolysis without hyperbilirubinemia, immunodeficiency,
      hepatomegaly with mild transaminitis, asplenia, leukocytosis,
      thrombocytosis, joint pain and features of macrophage activation with
      negative autoimmune serologies.
    explanation: Records thrombocytosis in a genetically confirmed patient.
- category: Hepatic
  name: Hepatomegaly
  description: >
    Hepatomegaly with hepatic iron deposition and mild transaminitis. Liver
    biopsy may show Kupffer cell siderosis, haemophagocytosis and extramedullary
    haematopoiesis.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a phenotype expansion for HMOX1-deficiency to include not
      only asplenia and hepatomegaly, but also interstitial lung disease with
      cholesterol granulomas and inflammatory flares with hemophagocytosis
      present in the bone marrow.
    explanation: Names hepatomegaly as an established feature of the disorder.
- category: Respiratory
  name: Interstitial Lung Disease
  description: >
    Nonspecific interstitial pneumonia with pleural fibrosis and cholesterol
    granulomas, progressing to chronic respiratory failure. This was a phenotype
    expansion recognised only in 2020 and is a cause of death.
  phenotype_term:
    preferred_term: Interstitial pneumonitis
    term:
      id: HP:0006515
      label: Interstitial pneumonitis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a phenotype expansion for HMOX1-deficiency to include not
      only asplenia and hepatomegaly, but also interstitial lung disease with
      cholesterol granulomas and inflammatory flares with hemophagocytosis
      present in the bone marrow.
    explanation: >-
      The report that established interstitial lung disease as part of the
      HMOX1-deficiency phenotype.
  - reference: PMID:38178812
    reference_title: "Clinical and molecular analysis of a novel variant in heme oxygenase-1 deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we describe a patient with severe interstitial lung disease,
      frequent episodes of hyperinflammation non-responsive to immunosuppression,
      and fatal pulmonary hemorrhage.
    explanation: >-
      A second, independent genetically confirmed patient with severe
      interstitial lung disease, establishing the pulmonary phenotype as
      recurrent rather than a single-case observation, and independently
      corroborating the failure of immunosuppression curated in the treatments
      section.
  sequelae:
  - target: Chronic Respiratory Failure
    description: Severe fibrotic interstitial pneumonia compromises pulmonary function and can
      progress to chronic respiratory failure.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
        hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We present a young boy who presented with chronic respiratory failure due to nonspecific
        interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory
        flares.
      explanation: The primary report explicitly places chronic respiratory failure downstream
        of NSIP.
- category: Hematologic
  name: Haemophagocytosis
  description: >
    Haemophagocytosis in bone marrow and liver with features of macrophage
    activation syndrome. Several patients were initially investigated for
    familial haemophagocytic lymphohistiocytosis before HMOX1 was tested, and one
    achieved sustained remission of HLH signs on the HLH-2004 protocol while
    inflammatory markers remained elevated.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a phenotype expansion for HMOX1-deficiency to include not
      only asplenia and hepatomegaly, but also interstitial lung disease with
      cholesterol granulomas and inflammatory flares with hemophagocytosis
      present in the bone marrow.
    explanation: Documents bone-marrow haemophagocytosis during inflammatory flares.
- category: Hematologic
  name: Coagulopathy
  description: >
    Grossly abnormal coagulation and fibrinolysis parameters with elevated
    thrombin-antithrombin complex, fibrin degradation products and D-dimer, and
    reduced fibrinogen. The index patient initially lacked an apparent bleeding
    tendency, but later cases include clinically important and fatal bleeding.
  phenotype_term:
    preferred_term: Abnormality of the coagulation cascade
    term:
      id: HP:0003256
      label: Abnormality of the coagulation cascade
  evidence:
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An abnormal coagulation/fibrinolysis system, associated with elevated
      thrombomodulin and von Willebrand factor, indicated the presence of severe,
      persistent endothelial damage.
    explanation: >-
      Documents the abnormal coagulation and fibrinolysis system in the index
      patient.
- category: Cardiovascular
  name: Hypertension
  description: >
    Hypertension featured in the terminal deterioration of both the index
    Japanese case and the first Indian case, and is mechanistically consistent
    with the endothelial and renal injury. The review is explicit that it is NOT
    a constant finding, so no frequency band is asserted.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertension and intracranial hemorrhage are certainly related to the basic
      pathology of HO-1 deficiency. However, these symptoms were not constantly
      observed in HO-1 deficiency patients.
    explanation: >-
      Attributes hypertension to the disease pathology while explicitly denying
      that it is constant, which is why this phenotype carries no frequency band.
- category: Neurologic
  name: Intracranial Haemorrhage
  description: >
    Intracranial haemorrhage occurred in the terminal phase in both the index
    Japanese case and the first Indian case, consistent with the combination of
    endothelial injury and the deranged coagulation and fibrinolysis system. Like
    hypertension it is attributed to the disease pathology but is not a constant
    finding, so no frequency band is asserted.
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her terminal stage was complicated by hypertension and intracranial
      hemorrhage, as observed in the initial Japanese case.
    explanation: >-
      Documents intracranial haemorrhage in the terminal phase of two independent
      genetically confirmed patients.
- category: Cardiovascular
  name: Pericardial Effusion
  description: >
    Massive pericardial effusion was the presenting feature in the Iranian
    p.K204X patient, who later died with heart failure and ascites. Reported in a
    small number of patients, including a steroid-responsive effusion during an
    inflammatory flare in the US case; no frequency band is asserted.
  phenotype_term:
    preferred_term: Pericardial effusion
    term:
      id: HP:0001698
      label: Pericardial effusion
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On first admission, the patient revealed massive pericardial effusion
      without any evidence of infectious diseases or malignancies.
    explanation: >-
      Documents massive pericardial effusion as the presenting feature in a
      genetically confirmed patient, with infection and malignancy excluded.
- category: Metabolic
  name: Hypertriglyceridaemia
  description: >
    Marked hypertriglyceridaemia was present in the index case (638 mg/dL)
    and recurred in later patients. Chronic inflammation and corticosteroid
    treatment are possible contributors; a disease-specific mechanism is not established.
  phenotype_term:
    preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperlipidemia was another prominent finding, with triglycerides at 638
      mg/dL (normal range; 32-115) and total cholesterol at 552 mg/dL (normal
      range; 128-219), showing a predominance of low-density lipoprotein
      cholesterol.
    explanation: >-
      The quantitative source for the index-case lipid values and the LDL
      predominance stated in this phenotype's description.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased levels of hepatic enzymes, triglycerides and ferritin were also
      noted.
    explanation: >-
      Records raised triglycerides in a second, independent genetically confirmed
      patient, supporting hyperlipidaemia as a recurring rather than isolated
      feature.
- category: Hepatic
  name: Elevated Hepatic Transaminases
  description: >
    AST and/or ALT can rise during organ injury. AST is not liver-specific,
    and the index patient had raised AST with normal ALT. Reported in the Indian case
    series, the Iranian case and the US case.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Levels of hepatic enzymes such as LDH, AST, and ALT uniformly showed
      significant elevations.
    explanation: >-
      Frequency-specific evidence: the review reports AST and ALT elevation
      in the five Indian cases discussed in that paragraph, not uniformly in all
      patients. No disease-wide frequency is inferred from that subgroup.
  reports_on:
  - target: Systemic Inflammatory Response and Progressive Organ Injury
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Transaminases report the hepatic component of inflammatory organ injury; AST
      alone is not liver-specific.
    evidence:
    - reference: PMID:38178812
      reference_title: 'Clinical and molecular analysis of a novel variant in heme oxygenase-1
        deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Mild transaminase elevation suggested ongoing liver damage.
      explanation: The clinical study explicitly interprets transaminase elevation as a liver-injury
        readout.
- category: Craniofacial
  name: Prominent Forehead
  description: >
    A prominent forehead was recorded in the index case and in all five patients
    of the Indian series. The reviewing authors explicitly caution against
    treating it as a uniform characteristic; no disease-wide frequency is assigned.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although asplenia and a prominent forehead were observed in all 5 cases,
      growth delay was not seen in Case 2 and Case 6.
    explanation: >-
      Documents a prominent forehead in all five patients of the Indian series;
      together with the index case that is 6 of 9 reported patients, which is
      a historical case count, not an unselected population estimate.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      at present it is difficult to regard a prominent forehead or eyelid edema
      as a uniform characteristic of HO-1 deficiency patients
    explanation: >-
      The reviewing authors' own caution against treating a prominent forehead
      as a uniform characteristic is retained without a disease-wide band.
  notes: >-
    No incoming causal edge, deliberately. The reviewing authors explicitly
    caution against treating this as a uniform characteristic and describe no
    disease-specific gestalt, and nothing cited traces a route from a defect in
    stress-inducible heme catabolism to craniofacial development. An edge would
    assert a developmental mechanism that no source proposes. Kept as a
    phenotype because it is repeatedly reported; left unattached because being
    reported is not being explained.
- category: Metabolic
  name: Hypercholesterolaemia
  description: Marked total and LDL cholesterol elevation was documented in the index patient;
    prolonged corticosteroid exposure is a competing explanation for the lipid abnormality.
  phenotype_term:
    preferred_term: Hypercholesterolemia
    term:
      id: HP:0003124
      label: Hypercholesterolemia
  evidence:
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hyperlipidemia was another prominent finding, with triglycerides at 638 mg/dL (normal
      range; 32–115) and total cholesterol at 552 mg/dL (normal range; 128–219), showing a predominance
      of low-density lipoprotein cholesterol.
    explanation: The measured cholesterol elevation supports this endpoint separately from hypertriglyceridaemia.
- category: Dermatologic
  name: Erythematous Rash
  description: A generalized erythematous rash accompanied febrile inflammatory illness in the
    index patient; a papular morphology is not established.
  phenotype_term:
    preferred_term: Erythema
    term:
      id: HP:0010783
      label: Erythema
  evidence:
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 1999, Yachie et al. reported on a 26-month-old boy who had been admitted with
      recurrent fever, generalized erythematous rash, and joint pain [17].
    explanation: The index case had generalized erythematous rash, without evidence for a more
      specific papular eruption.
- category: Ophthalmologic
  name: Palpebral Edema
  description: Prominent eyelid edema was reported in the index patient. Its frequency and cause
    remain uncertain.
  phenotype_term:
    preferred_term: Palpebral edema
    term:
      id: HP:0100540
      label: Palpebral edema
  evidence:
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had characteristic facial features such as a flat nasal bridge, frontal
      bossing, and prominent edema of the eyelids.
    explanation: The eyelid location is explicit; neither upper nor lower lids are specified.
- category: Craniofacial
  name: Depressed Nasal Bridge
  description: A flat or depressed nasal bridge has been described in independently reported
    patients.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had characteristic facial features such as a flat nasal bridge, frontal
      bossing, and prominent edema of the eyelids.
    explanation: The flat nasal bridge supports the phenotype.
  - reference: PMID:38799538
    reference_title: 'A rare case of heme oxygenase deficiency: A case report and literature
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: On examination, he had dysmorphic facies, frontal bossing, a depressed nasal bridge,
      and large ears.
    explanation: The new patient in this primary case report independently had a depressed nasal
      bridge; this is not a count of re-reported historical cases.
  notes: >-
    No incoming causal edge, deliberately. See the note on Prominent Forehead,
    which applies to both craniofacial features in this entry.
- category: Musculoskeletal
  name: Arthralgia
  description: Joint pain occurs during inflammatory illness; knee arthritis with morning stiffness
    was documented in the US patient.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 1999, Yachie et al. reported on a 26-month-old boy who had been admitted with
      recurrent fever, generalized erythematous rash, and joint pain [17].
    explanation: Joint pain was part of the index patient presentation.
  - reference: PMID:33066778
    reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
      hemophagocytic flares.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bilateral knee arthritis was clinically noted accompanying myalgias and arthralgias
      with morning stiffness, although subsequent knee x-rays showed no erosions.
    explanation: The US patient had clinically observed arthritis and arthralgias.
- category: Hematologic
  name: Splenic Hypoplasia
  description: A small, poorly perfused spleen with evidence of infarction was documented in
    the US patient. This acquired course is distinct from congenital absence of splenic tissue.
  phenotype_term:
    preferred_term: Hypoplastic spleen
    term:
      id: HP:0006270
      label: Hypoplastic spleen
  evidence:
  - reference: PMID:33066778
    reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
      hemophagocytic flares.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Abdominal CT scan revealed a small poorly perfused spleen which correlated well
      with the Howell-Jolly bodies and schistocytes on peripheral smear.
    explanation: Imaging establishes a small spleen rather than complete anatomic absence.
  sequelae:
  - target: Thrombocytosis
    description: Loss of functional splenic tissue contributes to baseline thrombocytosis, with
      additional rises during inflammatory flares.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease
        and hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hyposplenia, initially noted at age 4, was confirmed on serial abdominal imaging,
        contributed to baseline thrombocytosis, but platelet counts exceeded 1 million frequently
        during flares, requiring aspirin for coagulation prophylaxis.
      explanation: The authors explicitly attribute baseline thrombocytosis in this patient
        to hyposplenia.
- category: Hematologic
  name: Splenomegaly
  description: An enlarged spleen is an alternative human presentation; it does not exclude
    HMOX1 deficiency. Size may regress during the disease course.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical profiles were characteristic, in that he presented with microcytic anemia
      and progressive hepatosplenomegaly at 3 months old.
    explanation: The p.G139V Turkish patient had splenic enlargement rather than asplenia.
  - reference: PMID:38178812
    reference_title: 'Clinical and molecular analysis of a novel variant in heme oxygenase-1
      deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sonography showed mild hepatosplenomegaly with a distorted spleen (Fig. 1 B).
    explanation: The later pulmonary case independently documents splenic enlargement.
- category: Respiratory
  name: Pulmonary Fibrosis
  description: Extensive interstitial and alveolar septal fibrosis was demonstrated on lung
    biopsy in the US patient with fibrotic NSIP.
  phenotype_term:
    preferred_term: Pulmonary fibrosis
    term:
      id: HP:0002206
      label: Pulmonary fibrosis
  evidence:
  - reference: PMID:33066778
    reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
      hemophagocytic flares.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was found on thorascopic lung biopsy to have extensive interstitial fibrosis,
      consistent with the fibrotic nonspecific interstitial pneumonia (NSIP) pattern, in addition
      to cholesterol granulomas.
    explanation: Biopsy establishes pulmonary fibrosis, beyond an unspecified interstitial lung
      abnormality.
- category: Respiratory
  name: Chronic Respiratory Failure
  description: Progressive chronic hypoxic respiratory failure complicated severe fibrotic NSIP
    and ultimately caused death in the US patient.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
    temporality: CHRONIC
  evidence:
  - reference: PMID:33066778
    reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
      hemophagocytic flares.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We present a young boy who presented with chronic respiratory failure due to nonspecific
      interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory
      flares.
    explanation: The report explicitly attributes chronic respiratory failure to nonspecific
      interstitial pneumonia.
  sequelae:
  - target: Hypoxemia
    description: Failure of pulmonary gas exchange produces hypoxemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33066778
      reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease
        and hemophagocytic flares.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A 10-year-old boy was admitted for diagnostic lung biopsy in the setting of progressive
        chronic hypoxic respiratory failure and recurrent hyperinflammatory episodes.
      explanation: The respiratory failure is explicitly hypoxic.
- category: Respiratory
  name: Hypoxemia
  description: Hypoxemia occurred with progressive chronic respiratory failure as well as acute
    respiratory flares.
  phenotype_term:
    preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  evidence:
  - reference: PMID:33066778
    reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
      hemophagocytic flares.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A 10-year-old boy was admitted for diagnostic lung biopsy in the setting of progressive
      chronic hypoxic respiratory failure and recurrent hyperinflammatory episodes.
    explanation: The hypoxic respiratory failure supports persistent oxygenation impairment,
      beyond an isolated viral bronchiolitis episode.
- category: Respiratory
  name: Pulmonary Haemorrhage
  description: Spontaneous fulminant pulmonary bleeding was fatal in the later German patient.
    This is distinct from the post-biopsy hemothorax in the US case.
  phenotype_term:
    preferred_term: Pulmonary hemorrhage
    term:
      id: HP:0040223
      label: Pulmonary hemorrhage
  evidence:
  - reference: PMID:38178812
    reference_title: 'Clinical and molecular analysis of a novel variant in heme oxygenase-1
      deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, he experienced sudden fulminant pulmonary bleeding and expired at the
      age of five years and eleven months.
    explanation: The primary case narrative documents fatal pulmonary bleeding without a preceding
      thoracic biopsy complication.
- category: Renal
  name: Haemoglobinuria
  description: Urinary haemoglobin without microscopic erythrocytes was documented during haemolysis
    in the US patient, distinct from true haematuria.
  phenotype_term:
    preferred_term: Hemoglobinuria
    term:
      id: HP:0003641
      label: Hemoglobinuria
  evidence:
  - reference: PMID:33066778
    reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
      hemophagocytic flares.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During hospitalization, hepatomegaly was found along with mild transaminitis (AST
      301 U/L, ALT 74 U/L), direct antiglobulin test negative hemolytic anemia (hematocrit 24.7%)
      and hemoglobinuria without microscopic red blood cells.
    explanation: The absence of microscopic red cells distinguishes haemoglobinuria from haematuria.
biochemical:
- name: Serum bilirubin
  notes: >-
    Low rather than elevated despite active haemolysis. This inversion of the
    expected direction is the disease's diagnostic signature and is a direct
    readout of the enzymatic block.
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Persistently elevated LDH despite low bilirubin levels led Greil et al. to
      analyze the HMOX1 gene, revealing the homozygous G139V mutation.
    explanation: >-
      Confirms low bilirubin as the measured biochemical abnormality that led to
      HMOX1 analysis.
- name: Serum heme
  notes: >-
    Extremely elevated free heme, reported at 490 micromolar in the index case
    against a normal reference below 1 micromolar. Serum appears turbid and
    brownish, and absorption spectroscopy shows an additional methaemoglobin
    peak.
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum heme concentration was extremely high, at 490 μM (normal range; <1
      μM).
    explanation: >-
      The direct quantitative measurement of serum heme in the index patient,
      about 500-fold above the upper limit of normal.
- name: Serum ferritin
  notes: >-
    Elevated, reflecting trapped tissue iron, while serum iron concentration is
    normal or low.
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased levels of hepatic enzymes, triglycerides and ferritin were also
      noted.
    explanation: Documents raised serum ferritin in a confirmed patient.
- name: Serum haptoglobin
  notes: >-
    Paradoxically elevated (800 to 1200 mg/dL against a 40 to 180 mg/dL
    reference range in the index case) rather than consumed, with
    haptoglobin-haemoglobin complex detectable in urine.
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further study revealed that serum Hp concentration was extremely elevated
      (800–1200 mg/dL, normal range; 40–180 mg/dL) and a large amount of Hb-Hp
      complex was detected in a urine sample from the patient.
    explanation: >-
      The direct quantitative measurement of serum haptoglobin with its reference
      range in the index patient.
- name: Serum hemopexin
  notes: >-
    Undetectable, consistent with saturation and exhaustion of the secondary heme
    scavenging system by the ongoing heme load.
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hemopexin was undetectable by immunoelectrophoresis, indicating the
      presence of active hemolysis in vivo.
    explanation: Direct measurement showing hemopexin depletion.
genetic:
- name: HMOX1
  notes: >-
    HMOX1 encodes heme oxygenase 1, the stress-inducible isozyme. Reported pathogenic genotypes
    include compound heterozygosity for maternal exon-2 loss plus a paternal two-nucleotide exon-3
    deletion (index case), homozygous nonsense p.R44X (a founder allele accounting for the five
    early Indian cases), homozygous nonsense p.K204X, homozygous missense p.G139V, and compound
    heterozygous frameshift plus splice-donor alleles. The p.G139V missense allele retained
    constitutive HO-1 expression but lacked further hemin induction in cultured patient PBMC. A
    separate cellular assay demonstrated impaired heme-induced bilirubin synthesis. Abnormal
    peroxidase activity was inferred from urinary oxidation products and biochemical studies of
    other Gly139 substitutions, rather than directly measured for recombinant G139V. The original
    patient also carried homozygous SPON2 and IBTK variants considered possible modifiers, so
    variant-specific inflammatory features cannot be assigned exclusively to HMOX1.
  gene_term:
    preferred_term: HMOX1
    term:
      id: hgnc:5013
      label: HMOX1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: STRONG
    classified_by: CLINGEN
    external_id: CGGV:assertion_9f1a1080-6e62-4c89-9500-e5c74e078e06-2023-12-20T190000.000Z
    evidence:
    - reference: CGGV:assertion_9f1a1080-6e62-4c89-9500-e5c74e078e06-2023-12-20T190000.000Z
      reference_title: "HMOX1 / heme oxygenase 1 deficiency (Strong)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HMOX1 | HGNC:5013 | heme oxygenase 1 deficiency | MONDO:0013536 | AR | Strong"
      explanation: >-
        ClinGen's General Inborn Errors of Metabolism Gene Curation Expert Panel
        classifies the HMOX1-heme oxygenase 1 deficiency relationship (autosomal
        recessive) as Strong.
  evidence:
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the patient's HO-1 gene revealed complete loss of
      exon-2 of the maternal allele and a two-nucleotide deletion within exon3 of
      the paternal allele.
    explanation: >-
      The founding genotype-phenotype observation establishing HMOX1 as the
      causative gene, with two distinct loss-of-function alleles in trans.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases from India (Cases 2-6) displayed an identical homozygous mutation
      (p.R44X), indicating a founder effect of this particular mutation in that
      country.
    explanation: >-
      Establishes the p.R44X founder allele and explains why the reported case
      count exceeds the number of independent mutational events.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human
      Cases and Animal Models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mutation was a missense mutation and expression of constitutive HO-1
      was increased by cells, but HO-1 levels were not enhanced with additional
      oxidative stress.
    explanation: >-
      Cultured patient cells retained constitutive HO-1 expression without further
      induction by oxidative stress. This supports an inducibility defect; the
      distinct catalytic and inferred peroxidase defects require the separate
      evidence below.
  - reference: PMID:36502441
    reference_title: "Heme oxygenase-1 deficiency as an extremely rare cause of AA-type renal amyloidosis: Expanding the clinical features and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical exome sequencing (CES) confirmed the HMOX-1 deficiency diagnosis
      related to homozygous missense G139V mutation.
    explanation: >-
      Independent confirmation of the recurrent homozygous G139V missense allele.
  - reference: PMID:27662012
    reference_title: Mutating heme oxygenase-1 into a peroxidase causes a defect in bilirubin
      synthesis associated with microcytic anemia and severe hyperinflammation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We then confirmed the defective enzyme activity by documenting bilirubin
      synthesis in PBMC. Control cells showed the expected >4-fold heme-induced
      increase of bilirubin from 18.8 & 23.6 to 95.9 & 84.6 pmol/mg protein/60min
      following heme treatment. In contrast, patient cells showed a marginal
      increase from 21.9 & 26.1 to 33.1 & 27.0 pmol/mg protein/60min.
    explanation: >-
      Cultured patient PBMC showed impaired heme-induced bilirubin synthesis. This
      functional assay supports reduced heme-catabolic activity independently of
      the protein-inducibility experiment; it is not a direct purified-G139V
      peroxidase assay.
  - reference: PMID:10942763
    reference_title: Replacement of the distal glycine 139 transforms human heme oxygenase-1 into a
      peroxidase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Of the Gly-139 mutants investigated, only G139A catalyzes the
      NADPH-cytochrome P450 reductase-dependent oxidation of heme to biliverdin,
      but most of them exhibit a new H(2)O(2)-dependent guaiacol peroxidation
      activity.
    explanation: >-
      Recombinant-enzyme mutagenesis establishes the potential for Gly139
      substitutions to exchange oxygenase for peroxidase activity. Tested
      substitutions were alanine, leucine, phenylalanine, tryptophan, histidine and
      aspartate, not valine. This provides biochemical support by analogy for the
      G139V interpretation, not a direct G139V measurement.
    directness: INDIRECT
  - reference: PMID:27662012
    reference_title: Mutating heme oxygenase-1 into a peroxidase causes a defect in bilirubin
      synthesis associated with microcytic anemia and severe hyperinflammation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The strong constitutive expression of HO-1 G139V with defective normal but
      gained abnormal peroxidase function was paralleled by increased excretion of
      peroxidation products in the urine of the patient and, to some degree, in his
      heterozygous parents and heterozygous brother (Table 2).
    explanation: >-
      Human urinary oxidation products support the authors' interpretation of
      abnormal peroxidase activity indirectly. These downstream products do not
      specifically measure mutant-enzyme peroxidase catalysis. Cultured-cell
      bilirubin synthesis and recombinant-enzyme experiments are graded separately.
    directness: INDIRECT
  - reference: PMID:27662012
    reference_title: Mutating heme oxygenase-1 into a peroxidase causes a defect in bilirubin
      synthesis associated with microcytic anemia and severe hyperinflammation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With the broader availability of whole exome sequencing, we searched for other mutations which
      could plausibly explain the phenotype of the patient.De novohomozygous mutations in the SPON2
      and IBTK genes, which bind LPS and regulate B-cell function, respectively, were detected in
      the patient and were found to be heterozygous in the parents. These mutations may contribute
      to the phenotype.
    explanation: >-
      The authors identify homozygous SPON2 and IBTK
      variants in the same patient and consider them possible modifiers. Their
      contribution was not functionally established; this limits exclusive
      attribution of the distinctive inflammatory presentation to HMOX1.
    directness: INDIRECT
animal_models:
- name: Hmox1-null mouse (Poss and Tonegawa, C57BL/6)
  species: Mouse
  genotype: Hmox1 -/- (targeted null)
  publication: PMID:9380735
  description: >
    The founding genetic model, reported two years before the first human case
    and directly cited by Yachie et al. as corroborating their patient. Adult
    nulls develop anaemia with abnormally low serum iron yet accumulate hepatic
    and renal iron causing oxidative damage and chronic inflammation; embryonic
    fibroblasts are hypersensitive to hemin and peroxide, and adults die when
    challenged with endotoxin.
  evidence:
  - reference: PMID:9380735
    reference_title: "Heme oxygenase 1 is required for mammalian iron reutilization."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we generated mice lacking functional heme oxygenase 1 (Hmox1; EC
      1.14.99.3), which catabolizes heme to biliverdin, carbon monoxide, and free
      iron, to assess its participation in iron homeostasis.
    explanation: >-
      Establishes the existence and construction of this targeted Hmox1-null
      mouse line.
  modeled_mechanisms:
  - target: Impaired Heme-Iron Recycling and Tissue Iron Deposition
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces the counter-intuitive combination of low serum iron with hepatic
      and renal iron accumulation that defines this node, and was the experiment
      that established the recycling mechanism.
    limitations: >-
      Mouse nulls develop marked splenomegaly, whereas human patients
      characteristically have asplenia or functional hyposplenism, so the splenic
      phenotype does not transfer.
    readouts:
    - name: Hepatic and renal tissue iron content
      target: Impaired Heme-Iron Recycling and Tissue Iron Deposition
      direction: INCREASED
      interpretation: >-
        Tissue iron accumulation is the structural correlate of failed iron
        release from hepatic and renal cells.
      evidence:
      - reference: PMID:9380735
        reference_title: "Heme oxygenase 1 is required for mammalian iron reutilization."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Hmox1-deficient adult mice developed an anemia associated with
          abnormally low serum iron levels, yet accumulated hepatic and renal
          iron that contributed to macromolecular oxidative damage, tissue
          injury, and chronic inflammation.
        explanation: Reports the measured tissue iron accumulation in this model.
    evidence:
    - reference: PMID:9380735
      reference_title: "Heme oxygenase 1 is required for mammalian iron reutilization."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results indicate that Hmox1 has an important recycling role by
        facilitating the release of iron from hepatic and renal cells, and
        describe a mouse model of human iron metabolic disorders.
      explanation: >-
        The authors themselves frame this as a model of human iron metabolic
        disorders, supporting its use for this node.
  - target: Failure of Stress-Inducible Heme Catabolism
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Cells and animals lacking Hmox1 lose the adaptive protection normally
      conferred by its stress induction, which is the defining property of this
      node.
    limitations: >-
      Demonstrated with pharmacological and chemical stressors (hemin, peroxide,
      paraquat, cadmium, endotoxin) rather than with the spontaneous haemolytic
      load that drives the human disease.
    readouts:
    - name: Survival and hepatic necrosis after endotoxin challenge
      target: Failure of Stress-Inducible Heme Catabolism
      direction: DECREASED
      interpretation: >-
        Mortality on endotoxin challenge quantifies the loss of the inducible
        stress-protective response.
      evidence:
      - reference: PMID:9380736
        reference_title: "Reduced stress defense in heme oxygenase 1-deficient cells."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Furthermore, young adult Hmox1(-/-) mice were vulnerable to mortality
          and hepatic necrosis when challenged with endotoxin.
        explanation: Reports the measured survival deficit under stress challenge.
    evidence:
    - reference: PMID:9380736
      reference_title: "Reduced stress defense in heme oxygenase 1-deficient cells."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our in vitro and in vivo results provide genetic evidence that
        up-regulation of Hmox1 serves as an adaptive mechanism to protect cells
        from oxidative damage during stress.
      explanation: >-
        Establishes the model as informative for the loss of stress-inducible
        protection.
- name: Hmox1-null mouse (mixed C57BL/6-FVB background)
  species: Mouse
  genotype: Hmox1 -/- (targeted null, mixed background)
  publication: PMID:33546372
  description: >
    A second null strain on a mixed background whose splenic phenotype evolves
    from early splenomegaly to progressive red-pulp fibrosis, atrophy and
    functional hyposplenism with Howell-Jolly bodies. This strain is the one that
    reconciles the mouse splenic phenotype with human asplenia, and it also shows
    macrophage death during erythrophagocytosis and reduced CD163.
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Kovtunovych et al. published a detailed study on the iron distribution and
      pathology of another strain of HO-1-knockout mice using a mixed
      C57BL/6-FVB background
    explanation: >-
      Establishes the existence and genetic background of this second
      Hmox1-null mouse strain.
  modeled_mechanisms:
  - target: Macrophage and Monocyte Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Demonstrates the specific cellular mechanism of this node, macrophages
      dying as they phagocytose erythrocytes and release heme they cannot
      catabolise, together with loss of the CD163 scavenger receptor.
    limitations: >-
      Background-dependent: the splenic trajectory differs from the C57BL/6 null
      strain, so the phenotype is not a stable property of Hmox1 loss alone.
      Reported here via a review rather than from the primary strain paper.
    readouts:
    - name: Macrophage survival during erythrophagocytosis
      target: Macrophage and Monocyte Dysfunction
      direction: DECREASED
      interpretation: >-
        Progressive macrophage death during erythrophagocytosis is the measured
        correlate of the macrophage-failure node.
      evidence:
      - reference: PMID:33546372
        reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          They showed progressive death of macrophages in the liver and spleen
          throughout the process of erythrophagocytosis and the resultant heme
          release in vivo, causing significant damage to the organs and intense
          inflammation of the surrounding tissues.
        explanation: Reports the measured macrophage loss in this strain.
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Impaired splenic function was confirmed by the appearance of Howell-Jolly
        bodies within erythrocytes.
      explanation: >-
        Functional hyposplenism in this strain matches the human asplenia
        phenotype, supporting the model's relevance.
  - target: Intravascular Haemolysis with Erythrocyte Fragmentation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The mouse does not reproduce the human haemolytic phenotype, and fails in
      the least forgiving way available: red cell lifespan is PROLONGED in
      Hmox1-null mice, whereas human patients have shortened red cell survival
      with fragmentation and intravascular haemolysis. The mouse anaemia is
      microcytic and attributed to defective erythroblastic-island formation,
      a different mechanism from the human one.
    limitations: >-
      Because the direction is reversed rather than merely attenuated, no
      conformance to a haemolysis mechanism module may be asserted on the
      strength of mouse data for this disease; human evidence is required. The
      authors note the prolonged lifespan may actually ameliorate the murine
      anaemia, which is the opposite of its role in patients.
    readouts:
    - name: Circulating red blood cell lifespan
      target: Intravascular Haemolysis with Erythrocyte Fragmentation
      direction: INCREASED
      interpretation: >-
        Increased rather than decreased red cell lifespan is the measurement
        that inverts the human phenotype.
      evidence:
      - reference: PMID:25682599
        reference_title: Heme oxygenase-1 deficiency alters erythroblastic island formation, steady-state erythropoiesis and red blood cell lifespan in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Red blood cell lifespan is prolonged in heme oxygenase-1 deficient mice
          compared with wild-type mice.
        explanation: The measured lifespan result, in the direction opposite to human disease.
    evidence:
    - reference: PMID:25682599
      reference_title: Heme oxygenase-1 deficiency alters erythroblastic island formation, steady-state erythropoiesis and red blood cell lifespan in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Compared with wild-type animals, red blood cell size and hemoglobin
        content are decreased, while the number of circulating red blood cells is
        increased in heme oxygenase-1 deficient mice, overall leading to
        microcytic anemia.
      explanation: >-
        Establishes that the murine anaemia is microcytic and erythropoietic in
        origin rather than the fragmentation haemolysis seen in patients, so the
        model is not informative for this node.
  - target: Macrophage and Monocyte Dysfunction
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Subablative bone marrow transplantation repopulates the tissues with
      wild-type macrophages and reverses the Hmox1-null phenotype, which is the
      strongest available evidence that macrophage failure is causally
      sufficient for the downstream disease rather than merely correlated with
      it. Donor-derived Kupffer cells expressing Hmox1 persisted in the liver and
      restored heme-recycling capacity even after engraftment became transient.
    limitations: >-
      This particular rescue experiment is mouse-only. Engraftment was transient, and the
      durable benefit depended on long-lived donor-derived liver macrophages, so
      the result may not generalise to organs whose macrophages turn over
      differently. It also does not address the endothelial arm directly.
    readouts:
    - name: Anaemia, blood chemistry, iron parameters and renal damage after BMT
      target: Macrophage and Monocyte Dysfunction
      direction: RESTORED
      interpretation: >-
        Reversal of the haematological, biochemical and renal phenotype on
        macrophage replacement is the rescue readout for this node.
      evidence:
      - reference: PMID:24963040
        reference_title: Wild-type macrophages reverse disease in heme oxygenase 1-deficient mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Although engraftment was transient, BMT reversed anemia, normalized
          blood chemistries and iron metabolism parameters, and prevented renal
          damage.
        explanation: Reports the measured reversal of the disease phenotype.
    evidence:
    - reference: PMID:24963040
      reference_title: Wild-type macrophages reverse disease in heme oxygenase 1-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we report that subablative bone marrow transplantation (BMT) has a
        curative effect for disease in Hmox1(-/-) animals as a result of
        restoration of heme recycling by repopulation of the tissues with
        wild-type macrophages.
      explanation: >-
        Establishes macrophage replacement as causally sufficient to reverse the
        disease in this model, which is what makes the rescue informative for
        this node.
- name: Hmox1-deficient Sprague-Dawley rat
  species: Rat
  genotype: Hmox1 -/-
  publication: PMID:33546372
  description: >
    A rat model with haemolytic anaemia, poikilocytosis, splenomegaly,
    leukocytosis, impaired growth and early death, plus proteinuric renal disease
    with mesangial expansion and focal segmental sclerosis. Notably it does NOT
    reproduce the tissue iron deposition seen in both human patients and mice.
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Sprague-Dawley rats were employed in the study to reveal the role of HO-1
      in various forms of kidney disease. This rat model showed characteristic
      renal and extrarenal phenotypes.
    explanation: >-
      Establishes the existence and strain background of the HO-1-deficient rat
      model and its renal focus.
  modeled_mechanisms:
  - target: Impaired Heme-Iron Recycling and Tissue Iron Deposition
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The rat does not develop the hepatic and renal iron deposition that is a
      cardinal feature of both the human disease and the mouse models, so it
      cannot be used to study this arm.
    limitations: >-
      Iron deposition was not increased in tubular epithelium or hepatic
      parenchyma, and little splenic macrophage iron was seen even in older
      animals. The study also did not extend beyond 24 weeks, so a late-onset
      iron phenotype cannot be formally excluded.
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In contrast to human cases or mice models, iron deposition was not
        increased within the tubular epithelium or hepatic parenchyma of the rat
        model.
      explanation: >-
        SUPPORT, not REFUTE: the claim this link makes is the negative one, that
        the rat FAILS_TO_RECAPITULATE the tissue-iron node, and this quote is
        direct positive evidence for that failure.
  - target: Intravascular Haemolysis with Erythrocyte Fragmentation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces haemolytic anaemia with abnormal circulating erythrocyte
      morphology.
    limitations: >-
      Erythrocyte morphology is poikilocytosis with target cells and acanthocytes
      rather than the schistocytic fragmentation characteristic of the human
      disease.
    evidence:
    - reference: PMID:33546372
      reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These rats showed hemolytic anemia with morphological abnormality of the
        circulating erythrocytes, such as poikilocytosis and the presence of
        target cells and acanthocytes.
      explanation: >-
        Reports haemolytic anaemia with abnormal erythrocyte morphology in the
        rat model.
treatments:
- name: Supportive Care and Stress Avoidance
  description: >
    No disease-modifying therapy exists. Management is supportive, together with
    the infection precautions appropriate to asplenia. Because decompensation is
    typically triggered by an exogenous insult, avoidance of oxidative and
    infective stress is itself part of management.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Avoidance of exogenous stress along with appropriate treatment may prevent
      early death in these patients.
    explanation: >-
      Supports stress avoidance plus supportive management as the current
      practical approach.
- name: Red Blood Cell Transfusion
  description: >
    Transfusion support for the chronic haemolytic anaemia. Note that iron
    supplementation is NOT appropriate: the anaemia arises from failure to
    recycle iron out of tissue stores, not from iron deficiency, and reported
    patients were resistant to it.
  treatment_term:
    preferred_term: Blood Transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The anemia proved resistant to iron supplementation and the patient was
      dependent on red cell transfusion.
    explanation: >-
      Establishes red cell transfusion dependence and the failure of iron
      supplementation.
- name: Corticosteroid and Immunosuppressive Therapy
  description: >
    Responses vary: refractory disease and minimal sustained benefit are common,
    but corticosteroids can temporarily control inflammatory flares, and HLH-directed
    therapy produced remission of HLH signs in one patient. These responses do not
    establish correction of the underlying cytoprotective defect or durable disease
    control. The agents span several classes, so no single therapeutic_agent is bound.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:21088618
    reference_title: "Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report another case of human HO-1 deficiency in a young girl with
      congenital asplenia, who presented with severe hemolysis, inflammation,
      nephritis, which was refractory to therapy with corticosteroids,
      cyclophosphamide, and rituximab.
    explanation: >-
      Documents refractoriness to three separate immunosuppressive agents in a
      confirmed patient.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therapy with corticosteroid, anti-IL-1R, anti-IL-6, and cyclosporine had
      been tried but with minimal benefit.
    explanation: >-
      Independent confirmation that broad anti-cytokine and immunosuppressive
      therapy provides minimal benefit.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These agents are effective in some cases, but conventional
      anti-inflammatory/immunosuppressive therapies resulted in therapeutic
      failure in HO-1 deficiency cases for two reasons.
    explanation: >-
      Reports the review's conclusion of inadequate disease control; individual
      symptomatic responses are documented elsewhere. Quoted as a complete sentence rather than the trailing
      fragment, so the contrast with other diseases is visible in the quote.
  - reference: PMID:33066778
    reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
      hemophagocytic flares.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was steroid responsive and therefore treated with oral prednisone 10 mg twice
      daily.
    explanation: The US patient had symptomatic steroid responsiveness despite later progression;
      this qualifies the refractory cases rather than refuting them.
- name: Macrophage Replacement by Bone Marrow Transplantation
  description: >
    Investigational therapy supported by macrophage-replacement rescue in
    Hmox1-null mice and a reported human allogeneic transplant case with stabilization
    and prolonged survival. Human evidence is limited to a single reported case;
    durable efficacy and optimal transplantation protocols are not established.
    In the mouse experiment, donor-derived Kupffer cells restored heme recycling
    despite transient marrow engraftment. That mechanistic rescue should not be
    assumed to describe the human transplant outcome in the same detail.
  treatment_term:
    preferred_term: Bone Marrow Transplantation
    term:
      id: NCIT:C15194
      label: Bone Marrow Transplantation
  therapeutic_modality: CELL_THERAPY
  target_mechanisms:
  - target: Macrophage and Monocyte Dysfunction
    treatment_effect: RESTORES
    description: >-
      Replacing HMOX1-deficient macrophages with wild-type macrophages restores
      the heme-recycling capacity whose loss defines this node.
    evidence:
    - reference: PMID:24963040
      reference_title: Wild-type macrophages reverse disease in heme oxygenase 1-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These cells, identified as Kupffer cells with high levels of Hmox1
        expression, persisted months after transient engraftment of the donor
        bone marrow and were responsible for the full restoration of
        heme-recycling ability in Hmox1(-/-) mice and reversing Hmox1-deficient
        phenotype.
      explanation: >-
        Identifies restored macrophage heme-recycling capacity as the specific
        mechanism by which the intervention reverses the phenotype.
  evidence:
  - reference: PMID:24963040
    reference_title: Wild-type macrophages reverse disease in heme oxygenase 1-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our findings suggest that BMT or the development of specific cell therapies
      to repopulate patients' tissues with wild-type or reengineered macrophages
      represent promising approaches for HMOX1 deficiency treatment in humans.
    explanation: >-
      The authors' own translational proposal. Recorded as investigational: the
      supporting data are entirely murine and no treated human case exists.
  - reference: PMID:38178812
    reference_title: 'Clinical and molecular analysis of a novel variant in heme oxygenase-1 deficiency:
      Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Indeed, allogenic stem cell transplantation has been suggested as a potential treatment
      and reported to lead to stabilization and prolonged survival in a single case [18].
    explanation: This 2024 clinical paper summarizes the earlier single human transplant report.
      It supports limited human experience, not a validated cure rate.
- name: Ascorbate Supplementation
  description: >
    A genuine mechanism-directed therapeutic lead, and PRECLINICAL/IN VITRO only.
    HMOX1-deficient patient-derived lymphoblastoid cells and HEK293T HMOX1-null
    cells both show substantially reduced intracellular ascorbate (despite
    compensatory SVCT2 upregulation), abnormal mitochondrial morphology and
    raised baseline hydrogen peroxide. 2-phospho-L-ascorbic acid restored
    viability under hemin stress in both models, dependent on functional
    SVCT2-mediated uptake, and lowered H2O2 without shifting the GSH/GSSG ratio.

    Curated as PROPOSED-grade: no patient has been treated, no clinical outcome
    is reported, and the effect is demonstrated in cell models only. It is listed
    because it is the one lead in this literature that targets a measured
    metabolic deficit in patient cells rather than restoring an enzyme that is
    absent.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ascorbate
      term:
        id: CHEBI:38290
        label: L-ascorbate
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:40945734
    reference_title: Ascorbate mitigates oxidative stress and hemin cytotoxicity in heme oxygenase-1 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Treatment with 2-phospho-L-ascorbic acid (AA2P) restored cell viability in
      both models upon hemin-induced stress, with protection requiring functional
      SVCT2-mediated uptake.
    explanation: >-
      The rescue result behind this lead. Tagged IN_VITRO because it is a cell-model rescue in patient-derived LCLs and HEK293T
      knockouts, with no patient treated.
  - reference: PMID:40945734
    reference_title: Ascorbate mitigates oxidative stress and hemin cytotoxicity in heme oxygenase-1 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings illuminate ascorbic acid metabolism as a critical node in
      HO-1 deficiency pathophysiology and suggest ascorbic acid supplementation
      as a potential therapeutic strategy for this rare disorder.
    explanation: >-
      The authors' own framing as a *potential* strategy, which is the grade at
      which this is curated.
- name: HO-1 Induction and CO-Releasing Molecules
  description: >
    Investigational and mechanism-directed rather than established. Because the
    disease is loss of a cytoprotective response, the rational strategy is to
    restore its products: pharmacological induction of HO-1, CO-releasing
    molecules, or enhancement of haptoglobin-haemoglobin receptor expression. No
    clinical efficacy has been demonstrated in HO-1-deficient patients, and
    pharmacological HO-1 induction is conceptually futile in null genotypes where
    there is no enzyme to induce. This is recorded as a proposed direction, not a
    therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prime target of such therapy is HO-1. Pharmacological induction of
      cellular HO-1 production, use of CO-releasing molecules, or enhancement of
      Hb-Hp receptor expression by steroid are examples of these approaches.
    explanation: >-
      Records the proposed mechanism-directed strategies. Support is indirect because
      this is an expert proposal in a review, with no efficacy data in
      HO-1-deficient patients.
diagnosis:
- name: Recognition of haemolysis without hyperbilirubinaemia
  diagnosis_term:
    preferred_term: blood chemistry measurement
    term:
      id: NCIT:C47868
      label: Blood Chemistry Measurement
  description: >-
    The entry point to the diagnosis is a routine laboratory pattern, not a
    specialised test: active haemolysis (raised LDH, fragmented erythrocytes,
    anaemia) with a bilirubin that is low or normal instead of raised, and no
    jaundice. The direction of the bilirubin is what matters — every other cause
    of brisk haemolysis raises it, so a normal value in this setting is already
    abnormal. A direct antiglobulin test is negative, which excludes the
    immune haemolytic anaemias that the picture otherwise resembles. Historically
    this pattern is what prompted HMOX1 analysis in both the index case and the
    p.G139V patient, and it is available from a standard panel long before the
    disease is suspected. See the biochemical section for the quantitative
    markers (bilirubin, free heme, ferritin, haptoglobin, hemopexin) and their
    reported values.
  results: >-
    Haemolysis with a low or normal bilirubin and a negative direct antiglobulin
    test should prompt HMOX1 testing rather than further immunohaematological
    workup.
  evidence:
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HMOX1-deficiency is a rare autosomal recessive disorder with hallmark
      features of direct antibody negative hemolytic anemia with normal
      bilirubin, hyperinflammation and features similar to macrophage activation
      syndrome.
    explanation: >-
      States the discriminating triad this diagnostic step relies on: haemolysis,
      a normal rather than raised bilirubin, and a negative direct antiglobulin
      test.
  - reference: PMID:38178812
    reference_title: "Clinical and molecular analysis of a novel variant in heme oxygenase-1 deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chronic hemolysis and abnormally low bilirubin levels are cardinal
      laboratory features of this disorder.
    explanation: >-
      An independent report naming the same paired laboratory abnormality as
      cardinal, supporting its use as the trigger for molecular testing.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Persistently elevated LDH despite low bilirubin levels led Greil et al. to
      analyze the HMOX1 gene, revealing the homozygous G139V mutation.
    explanation: >-
      A worked instance of this laboratory pattern actually leading to the
      molecular diagnosis in a reported patient.
- name: HO-1 induction assay in patient-derived cells
  diagnosis_term:
    preferred_term: HO-1 protein induction assay
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  description: >-
    The functional confirmation, and the test that distinguishes this disease
    from a merely low HMOX1 transcript level. HO-1 is normally absent at rest and
    produced only on stress induction, so the assay deliberately provokes it:
    patient monocytes or an Epstein-Barr-virus-transformed lymphoblastoid cell
    line are stimulated with an oxidative stressor (cadmium chloride or sodium
    arsenite) and HO-1 protein is then sought by immunoblot. In an affected
    patient no protein appears after stimulation. An unstimulated sample is
    uninformative because a healthy control is also negative at baseline, which
    is why this is an induction assay rather than a simple expression
    measurement. It has been applied in the index case and independently in at
    least two later patients, including one whose variants were novel, and it is
    the practical route to demonstrating that a variant of uncertain significance
    abolishes protein production. A paired hemin-sensitivity assay on the same
    cells provides a second functional readout.
  results: >-
    Absence of HO-1 protein on immunoblot after oxidative stimulation confirms
    loss of function; hemin exposure of the same cells shows reduced viability.
  evidence:
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunohistochemistry of hepatic tissue and immunoblotting of a
      cadmium-stimulated Epstein-Barr virus-transformed lymphoblastoid cell line
      (LCL) revealed complete absence of HO-1 production.
    explanation: >-
      Defines the assay as first applied: cadmium stimulation of a patient-derived
      LCL followed by immunoblot, showing complete absence of HO-1 production.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Exposure of the patient's monocytes to heavy metals, such as cadmium or
      sodium arsenite, did not induce HO-1 protein.
    explanation: >-
      Names the two stimulating agents in routine use and confirms the assay can
      be run on primary monocytes as well as on an immortalised line.
  - reference: PMID:38178812
    reference_title: "Clinical and molecular analysis of a novel variant in heme oxygenase-1 deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analysis in patient-derived lymphoblastoid cells unveiled the
      complete absence of HO-1 protein expression and a marked reduction in cell
      viability upon exposure to hemin.
    explanation: >-
      A later independent application of the same assay, and the source for the
      paired hemin-viability readout. This is the study that used it to establish
      the pathogenicity of a previously unreported variant.
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Western blot analysis confirmed lack of HMOX1 protein upon oxidant
      stimulation of the patient cells.
    explanation: >-
      A third independent use of the induction assay, here confirming a
      compound-heterozygous genotype that included a splice-donor variant.
- name: HMOX1 molecular confirmation
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Establish biallelic pathogenic HMOX1 variants. Sequencing alone is not
    sufficient here, and the reported genotypes show why: the index case is a
    compound heterozygote carrying a whole-exon-2 deletion on the maternal allele
    against a small deletion on the paternal allele, so a copy-number method
    (deletion/duplication analysis, array-CGH, or a targeted dosage assay) is
    required or the maternal allele is missed and the patient is reported as a
    heterozygous carrier. A second patient carries an intronic splice-donor
    variant, which is only interpretable with splice-level analysis or a
    transcript study. Exome sequencing has been the practical route in the more
    recent cases, including one in which the disease was not suspected
    beforehand. Where a variant's consequence is uncertain, the HO-1 induction
    assay above supplies the functional evidence. Note that the promoter
    (GT)n microsatellite literature concerns a separate, non-Mendelian modifier
    and has no role in diagnosing this disease.
  results: >-
    Two pathogenic HMOX1 alleles confirm the diagnosis. A single detected variant
    in a consistent clinical and laboratory picture should prompt copy-number and
    splice analysis before the diagnosis is discarded.
  evidence:
  - reference: PMID:9884342
    reference_title: "Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the patient's HO-1 gene revealed complete loss of
      exon-2 of the maternal allele and a two-nucleotide deletion within exon3 of
      the paternal allele.
    explanation: >-
      The whole-exon deletion documented here is the reason deletion/duplication
      analysis is specified rather than sequencing alone.
  - reference: PMID:33066778
    reference_title: "Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was found post-mortem by whole exome sequencing to have a compound
      heterozygous paternal frame shift a paternal frame shift HMOX1
      c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T
      > A) consistent with HMOX1 deficiency.
    explanation: >-
      The splice-donor allele documented here is the reason splice-level
      interpretation is specified. The quote is given in full, including the
      source's own duplicated phrase, rather than silently repaired.
  - reference: PMID:36502441
    reference_title: "Heme oxygenase-1 deficiency as an extremely rare cause of AA-type renal amyloidosis: Expanding the clinical features and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical exome sequencing (CES) confirmed the HMOX-1 deficiency diagnosis
      related to homozygous missense G139V mutation.
    explanation: >-
      Documents exome sequencing reaching the diagnosis in a patient whose
      inflammatory illness had been of unknown origin, supporting a broad
      sequencing strategy where the disease is not suspected in advance.
discussions:
- discussion_id: hmox1_rodent_human_divergence
  prompt: >-
    Which features of HMOX1 deficiency can legitimately be studied in Hmox1-null
    rodents, given that the mouse and rat models diverge from human patients on
    the splenic and tissue-iron phenotypes that are cardinal in humans?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Heme-Iron Recycling and Tissue Iron Deposition
  - pathophysiology#Macrophage and Monocyte Dysfunction
  rationale: >-
    Only about a dozen human patients have ever been reported, so a large share
    of the mechanism in this entry rests on rodent data, and the rodents disagree
    with the humans, and with each other, on exactly the features that define the
    disease clinically. Three divergences are documented, and they differ in
    kind. (i) ORGAN-SYSTEM EMPHASIS AND SURVIVAL: the first human autopsy states
    the contrast itself, finding endothelial and reticuloendothelial involvement
    with intravascular haemolysis, DIC and amyloidosis and short survival,
    against a predominantly iron-metabolic, long-surviving mouse. (ii)
    ERYTHROCYTE LIFESPAN RUNS THE WRONG WAY: red cell lifespan is *prolonged* in
    Hmox1-null mice, while human patients have shortened red cell survival with
    fragmentation — an opposite-direction finding, not a difference of degree,
    and the reason no conformance to a haemolysis module should be asserted on
    mouse evidence. (iii) TISSUE IRON: the Hmox1-null rat does not deposit iron
    in tubular epithelium or hepatic parenchyma at all. Human patients characteristically have asplenia or
    functional hyposplenism; the original C57BL/6 Hmox1-null mouse instead
    develops marked splenomegaly, while a mixed-background null strain shows
    early splenomegaly evolving into fibrotic atrophy and functional
    hyposplenism, so the apparent mouse-human agreement depends on strain
    background rather than on Hmox1 genotype alone. The Hmox1-deficient rat
    diverges more sharply still: it does not develop the hepatic or renal iron
    deposition that is cardinal in both human patients and mice. That is not
    merely a missing measurement but a directly contradictory positive finding in
    a model that otherwise reproduces haemolysis and renal disease, so the iron
    arm and the haemolysis and renal arms of the rodent literature have different
    translational standing and should not be inherited wholesale. Conversely, the
    arms where rodents and humans do converge (failed iron recycling with low
    serum iron, hypersensitivity of null cells to heme and oxidant stress, and
    macrophage death during erythrophagocytosis) are the arms where model
    evidence can reasonably substitute for the human data that will never exist
    in quantity.
  proposed_experiments:
  - experiment_id: exp_hmox1_cross_species_iron_handling
    name: Cross-species comparison of splenic and hepatic iron handling
    description: >-
      Systematically compare erythrophagocytosing macrophage iron handling, CD163
      expression and splenic red-pulp architecture across Hmox1-null mouse
      strains, the Hmox1-null rat, and archived human HO-1-deficient tissue, with
      age-matched timepoints extending beyond 24 weeks in the rat, to determine
      whether the rat iron phenotype is genuinely absent or merely later-onset.
    experiment_type:
      preferred_term: cross-species model comparison experiment
  - experiment_id: exp_hmox1_patient_derived_cell_models
    name: Patient-derived macrophage and endothelial models
    description: >-
      Derive iPSC macrophages and endothelial cells from HMOX1-deficient
      patients, or generate isogenic HMOX1-null human lines carrying the reported
      p.R44X and p.G139V alleles, and test heme handling, CD163 expression, and
      tissue-factor and PAI-1 induction, to obtain human-cell evidence for the
      arms currently supported only by rodents.
    experiment_type:
      preferred_term: patient-derived cell model experiment
  evidence:
  - reference: PMID:11823983
    reference_title: "Heme oxygenase-1 deficiency: the first autopsy case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared with HO-1--targeted mice, the present case seems to more severely
      involve endothelial cells and the reticuloendothelial system, resulting in
      intravascular hemolysis, disseminated intravascular coagulation, and
      amyloidosis with a short survival. This contrasts to the predominant iron
      metabolic disorders of HO-1--targeted mice with a long survival.
    explanation: >-
      The strongest anchor for this discussion, because it is a published
      first-party mismatch claim rather than an inference drawn across papers:
      the autopsy authors themselves contrast the human organ-system emphasis
      (endothelium and reticuloendothelial system, short survival) against the
      predominantly iron-metabolic, long-survival mouse phenotype.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast to human cases or mice models, iron deposition was not
      increased within the tubular epithelium or hepatic parenchyma of the rat
      model.
    explanation: >-
      The explicit statement of rat-human divergence on the tissue-iron phenotype
      that makes this a model-fidelity question rather than an evidence gap.
  - reference: PMID:25682599
    reference_title: Heme oxygenase-1 deficiency alters erythroblastic island formation, steady-state erythropoiesis and red blood cell lifespan in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Red blood cell lifespan is prolonged in heme oxygenase-1 deficient mice
      compared with wild-type mice.
    explanation: >-
      The sharpest divergence of the three, because it runs in the OPPOSITE
      direction rather than merely differing in degree: mouse erythrocytes live
      longer, while human patients have shortened red cell survival with
      fragmentation and intravascular haemolysis.
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast to the splenomegaly seen in HO-1-knockout mice reported by Poss
      and Tonegawa, the spleen in these mice showed initial splenomegaly when
      young, but progressive atrophy as the mice aged.
    explanation: >-
      Documents that the splenic phenotype is strain- and age-dependent in mice,
      so agreement with human asplenia cannot be assumed.
- discussion_id: hmox1_onset_variability_gap
  prompt: >-
    Why do patients with complete loss of an enzyme described as essential remain
    asymptomatic for years, and what compensates until the first flare?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of Stress-Inducible Heme Catabolism
  - pathophysiology#Systemic Inflammatory Response and Progressive Organ Injury
  rationale: >-
    Age at first recognisable symptom in reported patients ranges from 6 months
    to 15 years, and several patients carrying the identical homozygous p.R44X
    allele grew and developed normally for over a decade before deteriorating
    rapidly and dying within months. Identical genotype with a decade of
    phenotypic variability implies compensatory mechanisms whose identity,
    capacity and mode of failure are entirely unknown. This matters practically:
    it means the disease has a long presymptomatic window in which a diagnosis
    could in principle be made on the low-bilirubin-with-high-LDH signature, and
    it means the trigger that exhausts compensation is a candidate intervention
    point.
  proposed_experiments:
  - experiment_id: exp_hmox1_presymptomatic_sibling_profiling
    name: Longitudinal profiling of presymptomatic HMOX1-null siblings
    description: >-
      In consanguineous families with a known HMOX1 allele, genotype and
      longitudinally profile presymptomatic siblings for haemolysis markers, free
      heme, hemopexin, haptoglobin and inflammatory cytokines, to identify which
      parameter decompensates first and whether a compensatory heme-handling
      pathway is measurably active before the first flare.
    experiment_type:
      preferred_term: longitudinal cohort profiling experiment
  evidence:
  - reference: PMID:33546372
    reference_title: "Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variability of age of onset and the rapidly progressive clinical course
      suggests the presence of certain compensatory mechanisms to overcome the
      absence of HO-1 function.
    explanation: >-
      The review's own statement that unidentified compensatory mechanisms must
      exist, which is precisely the gap recorded here.
- discussion_id: hmox1_splenic_outcome_attribution
  prompt: What determines congenital absence, acquired splenic loss, or enlargement in human
    HMOX1 deficiency?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Asplenia
  - phenotypes#Splenic Hypoplasia
  - phenotypes#Splenomegaly
  rationale: Human patients show distinct splenic courses. The US imaging suggests infarction,
    whereas a mixed-background mouse model develops macrophage loss, red-pulp fibrosis and later
    atrophy. These observations do not establish that the same process causes congenital human
    asplenia or human splenomegaly. This is uncertainty in developmental versus acquired causal
    attribution and model translation, not a claim that splenic injury has no mechanism. The
    documented hyposplenia-to-thrombocytosis consequence is modeled.
  evidence:
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Why these two cases showed a normal-sized spleen or splenomegaly, respectively,
      remains unclear.
    explanation: The review explicitly identifies unexplained human splenic variability.
  - reference: PMID:33066778
    reference_title: Heme oxygenase-1 deficiency presenting with interstitial lung disease and
      hemophagocytic flares.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Further imaging with CTA abdomen demonstrated absent splenic veins and multiple
      collaterals to a small left kidney, implying that patient’s spleen had infarcted.
    explanation: The primary case supports an acquired infarction interpretation without proving
      its upstream vascular mechanism.
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Pathological examination revealed initial enlargement of the red pulp of the spleen
      underwent progressive fibrotic changes and eventual atrophy and functional hyposplenism
      in older mice.
    explanation: This mechanism is demonstrated in mice and is not silently transferred to every
      human splenic phenotype.
- discussion_id: hmox1_growth_facial_edema_attribution
  prompt: Which processes account for growth impairment, facial appearance, and eyelid edema?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Growth Retardation
  - phenotypes#Prominent Forehead
  - phenotypes#Depressed Nasal Bridge
  - phenotypes#Palpebral Edema
  rationale: Growth can slow after inflammatory onset, but nutritional state, chronic organ
    disease and steroid treatment have not been separated. The 2024 pulmonary patient also carries
    a 16p13.11 duplication that confounds developmental findings. The sources document frontal
    prominence, a depressed nasal bridge and eyelid edema without establishing a shared morphogenetic
    cause or identifying renal versus inflammatory fluid accumulation. These unresolved causal
    attributions are kept distinct from the supported inflammatory and renal paths.
  evidence:
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His growth had been normal by 3 years of age. However, his growth slowed down significantly
      after the onset of the inflammatory episodes, being less than the 10th percentile for
      weight and 20th percentile for height at 8 years.
    explanation: The timing supports a chronic-illness contribution but does not distinguish
      inflammation, nutrition and treatment effects.
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had characteristic facial features such as a flat nasal bridge, frontal
      bossing, and prominent edema of the eyelids.
    explanation: The facial and eyelid findings are documented without a demonstrated causal
      mechanism.
  - reference: PMID:38178812
    reference_title: 'Clinical and molecular analysis of a novel variant in heme oxygenase-1
      deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Furthermore, array-based Comparative Genomic Hybridization (array-CGH) analysis
      revealed a 16p13.11 microduplication of paternal origin, which is known to potentially
      contribute to congenital heart disease, behavioral disorders, developmental delays, brain
      abnormalities, and skeletal malformations.
    explanation: A coexisting genomic disorder limits attribution of developmental abnormalities
      to HMOX1 alone.
- discussion_id: hmox1_lipid_haptoglobin_attribution
  prompt: How much do treatment and altered scavenging contribute to the abnormal lipid and
    haptoglobin concentrations?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Hypertriglyceridaemia
  - phenotypes#Hypercholesterolaemia
  - phenotypes#Elevated Serum Haptoglobin
  rationale: The primary report explicitly leaves hyperlipidaemia unresolved and proposes both
    corticosteroid exposure and impaired bilirubin production. The latter is retained as a qualified
    cholesterol edge, not rejected merely because intermediates are unknown. No comparably specific
    triglyceride mechanism is established. High serum haptoglobin and urinary Hb-Hp complexes
    document abnormal handling, but the relative roles of altered production and clearance in
    the high serum concentration have not been resolved.
  evidence:
  - reference: PMID:9884342
    reference_title: Oxidative stress causes enhanced endothelial cell injury in human heme
      oxygenase-1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The mechanism of hyperlipidemia, with high choles-
      terol and triglyceride levels, is not clear. Prolonged cor-
      ticosteroid therapy alone may explain the levels seen in
      this patient. Bilirubin is a known antioxidant (20), and
      it also acts as a scavenger for degraded LDL cholesterol
      (21–24). Impaired bilirubin production in this patient
      might also be responsible for the abnormally elevated
      serum cholesterol.
    explanation: The primary authors explicitly describe competing lipid explanations.
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Further study revealed that serum Hp concentration was extremely elevated (800–1200
      mg/dL, normal range; 40–180 mg/dL) and a large amount of Hb-Hp complex was detected in
      a urine sample from the patient.
    explanation: These observations establish the unusual concentrations and handling, not a
      unique mechanism for the serum elevation.
- discussion_id: hmox1_organ_enlargement_and_bleeding_attribution
  prompt: Which tissue lesions account for hepatomegaly and the severe bleeding complications?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Hepatomegaly
  - phenotypes#Intracranial Haemorrhage
  - phenotypes#Pulmonary Haemorrhage
  rationale: The reviewed cases establish hepatic iron deposition, inflammatory injury and,
    in some patients, amyloid, but do not distinguish their contributions to liver enlargement.
    Endothelial damage and coagulopathy provide plausible routes to intracranial or pulmonary
    bleeding; the reports do not attribute each hemorrhage to one of those processes rather
    than hypertension, pulmonary parenchymal injury or their combination. Supported endothelial-to-coagulopathy
    and pulmonary injury paths are represented; the unresolved issue is attribution of these
    particular clinical endpoints, not the absence of modeled intermediates.
  evidence:
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypertension and intracranial hemorrhage are certainly related to the basic pathology
      of HO-1 deficiency. However, these symptoms were not constantly observed in HO-1 deficiency
      patients.
    explanation: The review recognizes the association but does not isolate the causal route
      to each hemorrhage.
  - reference: PMID:38178812
    reference_title: 'Clinical and molecular analysis of a novel variant in heme oxygenase-1
      deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, he experienced sudden fulminant pulmonary bleeding and expired at the
      age of five years and eleven months.
    explanation: The fatal complication is reported without a lesion-specific causal demonstration.
  - reference: PMID:33546372
    reference_title: 'Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent
      Human Cases and Animal Models.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hepatomegaly was another characteristic finding and the liver biopsy revealed mild
      sinusoidal fibrosis, mild microvesicular steatosis, and increased iron deposit within
      Kupffer cells.
    explanation: Multiple hepatic lesions coexist, without establishing which drives enlargement.
datasets: []
notes: >-
  SCOPING DECISIONS, recorded so they are not re-proposed.

  NOT a member of the Inherited_Porphyrias grouping, despite the MONDO parent
  being "inborn disorder of porphyrin metabolism" (MONDO:0017754), which invites
  the link. That grouping is scoped in its own rationale to heme BIOSYNTHESIS
  blocks with porphyrin/precursor accumulation, and its NECESSARY criteria are an
  OR over abdominal pain, peripheral neuropathy, abnormal circulating porphyrin
  and cutaneous photosensitivity. HMOX1 deficiency satisfies none of them: it is
  a CATABOLISM block and the accumulating species is heme itself, not a porphyrin
  precursor. Adding it would manufacture exactly the NOT_SATISFIED contradiction
  `just check-groupings` exists to surface. The porphyria mechanism is a useful
  contrast to this entry, not a conformance target.

  `granuloma_formation` conformance was CONSIDERED AND REJECTED. The cholesterol
  granulomas on lung biopsy (PMID:33066778) are a lipid/foreign-body reaction,
  not the Th1/TNF-driven epithelioid-and-multinucleated-giant-cell programme that
  module models, so conforming would be a false positive on its
  "Epithelioid Transformation and Multinucleated Giant Cell Formation" node.

  The HMOX1 GT(n) PROMOTER MICROSATELLITE literature is OUT OF SCOPE here. Long
  repeats reduce HO-1 inducibility and are studied as a common modifier of ARDS,
  chronic kidney disease and transplant outcome; that is a distinct,
  non-Mendelian entity from biallelic loss-of-function disease. It is flagged
  because it dominates search results for this gene: a query for
  "heme oxygenase-1 deficiency" returns hundreds of hits of which only a handful
  concern the monogenic disease, the rest being Nrf2/HO-1 induction
  pharmacology, ferroptosis, conditional-knockout organ studies and the
  microsatellite association literature. Any future deep-research report on this
  entry should be checked for whether its citations concern biallelic
  loss-of-function PATIENTS or HO-1 as a PATHWAY.

  Pharmacological HO-1 INDUCTION (Nrf2 activators, statins, hemin) saturates this
  literature but is therapeutically irrelevant to null genotypes, where there is
  no enzyme to induce. It is retained in the treatments list only as an
  explicitly investigational, mechanism-directed entry with that caveat stated.

  PUBLISHED CASE COUNTS DISAGREE and are deliberately not reconciled here: the
  2021 review counts nine, the 2023 report calls itself the eleventh, and later
  reports continue to differ. The prevalence record therefore uses
  CASES_IN_LITERATURE with no computed rate.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

SCOPING DECISIONS, recorded so they are not re-proposed. NOT a member of the Inherited_Porphyrias grouping, despite the MONDO parent being "inborn disorder of porphyrin metabolism" (MONDO:0017754), which invites the link. That grouping is scoped in its own rationale to heme BIOSYNTHESIS blocks with porphyrin/precursor accumulation, and its NECESSARY criteria are an OR over abdominal pain, peripheral neuropathy, abnormal circulating porphyrin and cutaneous photosensitivity. HMOX1 deficiency satisfies none of them: it is a CATABOLISM block and the accumulating species is heme itself, not a porphyrin precursor. Adding it would manufacture exactly the NOT_SATISFIED contradiction `just check-groupings` exists to surface. The porphyria mechanism is a useful contrast to this entry, not a conformance target. `granuloma_formation` conformance was CONSIDERED AND REJECTED. The cholesterol granulomas on lung biopsy (PMID:33066778) are a lipid/foreign-body reaction, not the Th1/TNF-driven epithelioid-and-multinucleated-giant-cell programme that module models, so conforming would be a false positive on its "Epithelioid Transformation and Multinucleated Giant Cell Formation" node. The HMOX1 GT(n) PROMOTER MICROSATELLITE literature is OUT OF SCOPE here. Long repeats reduce HO-1 inducibility and are studied as a common modifier of ARDS, chronic kidney disease and transplant outcome; that is a distinct, non-Mendelian entity from biallelic loss-of-function disease. It is flagged because it dominates search results for this gene: a query for "heme oxygenase-1 deficiency" returns hundreds of hits of which only a handful concern the monogenic disease, the rest being Nrf2/HO-1 induction pharmacology, ferroptosis, conditional-knockout organ studies and the microsatellite association literature. Any future deep-research report on this entry should be checked for whether its citations concern biallelic loss-of-function PATIENTS or HO-1 as a PATHWAY. Pharmacological HO-1 INDUCTION (Nrf2 activators, statins, hemin) saturates this literature but is therapeutically irrelevant to null genotypes, where there is no enzyme to induce. It is retained in the treatments list only as an explicitly investigational, mechanism-directed entry with that caveat stated. PUBLISHED CASE COUNTS DISAGREE and are deliberately not reconciled here: the 2021 review counts nine, the 2023 report calls itself the eleventh, and later reports continue to differ. The prevalence record therefore uses CASES_IN_LITERATURE with no computed rate.

Create: Heme Oxygenase 1 Deficiency (HMOX1) · 2026-08-21T21:19:53Z · View source

De-novo curation of heme oxygenase 1 deficiency (MONDO:0013536), an ultra-rare autosomal recessive HMOX1 disorder, claimed via issue #9196. The stub stubs/Heme_Oxygenase_1_Deficiency.yaml is deleted in the same PR. Entry type decided as DISEASE: MONDO records no descendants and a single causal gene, so this is a leaf entity with one conserved pathograph, not a grouping. PATHOGRAPH. Organised around the framing that makes this disease unusual: HMOX1 encodes the stress-INDUCIBLE heme oxygenase isozyme, so the disorder is loss of a cytoprotective response rather than accumulation of a stored substrate - the inverse of the usual storage-disease shape. A single enzymatic block, "Failure of Stress-Inducible Heme Catabolism", fans out into four arms, one per lost reaction product plus the uncleared substrate: circulating free heme accumulation; loss of bilirubin antioxidant capacity, which is also why serum bilirubin fails to rise (staying low or normal) despite brisk intravascular haemolysis; loss of carbon monoxide cytoprotective signalling; and impaired heme-iron recycling with tissue iron deposition. These converge through macrophage and monocyte dysfunction, endothelial injury with coagulopathy, and intravascular haemolysis onto a systemic inflammatory endpoint. 9 pathophysiology nodes and 16 causal edges, every edge carrying its own evidence item. EVIDENCE DISCIPLINE. This was the main risk for this disease: only about eleven human patients have been reported, so a large share of the mechanism rests on rodents. All mouse and rat data are tagged evidence_source: MODEL_ORGANISM and are never the sole support for a human phenotype - every phenotype cites a human case report or the human case-series review. Three animal models are curated with modeled_mechanisms links, including a FAILS_TO_RECAPITULATE link for the Hmox1-deficient rat, which does not reproduce the hepatic and renal iron deposition that is cardinal in both human patients and mice. That rat divergence, together with the strain-dependent mouse splenic phenotype - splenomegaly on C57BL/6 versus progressive red-pulp atrophy and functional hyposplenism on a mixed background, against human asplenia - is recorded as a HUMAN_MODEL_MISMATCH discussion rather than a generic KNOWLEDGE_GAP, because evidence exists in the models and it is their translational validity that is the open question. It carries two proposed experiments. A separate KNOWLEDGE_GAP records the unexplained onset variability: age at first symptom ranges from 6 months to 15 years among patients sharing the identical homozygous p.R44X founder allele. NEGATIVE RESULTS ARE CURATED. Corticosteroids, cyclophosphamide, rituximab, anti-IL-1R, anti-IL-6 and cyclosporine are recorded with supports: REFUTE, since consistent therapeutic failure is a clinically important finding here. The HO-1-induction and CO-releasing-molecule strategy is scored PARTIAL with an explicit note that pharmacological HO-1 induction is conceptually futile in null genotypes where there is no enzyme to induce. WHAT THE DR REPORT ACTUALLY ADDED. The falcon report cited almost all of its content to page ranges of the same Yachie 2021 review the entry was already built on, and supplied no verbatim abstract quotes, so nothing was copied from it. It was useful as a gap-finder: it surfaced full-text claims in a paper already cached, and every resulting addition was quoted directly from that cache. Added on that basis: proper frequency evidence replacing weaker "common findings" wording (fever and haemolytic anaemia "constant findings"; bilirubin low or normal "in all cases"; leukocyte and platelet increases "invariably noted in all cases" - the last also being what distinguishes this from HLH and classical DIC); hypertension and intracranial haemorrhage as phenotypes, both carrying the review's own explicit statement that they are NOT constant, so neither asserts a frequency band; pericardial effusion in the Iranian p.K204X patient; direct human evidence of vacuolated monocytes with reduced surface antigens, so the macrophage/monocyte node no longer rests on mouse data alone; and an in-utero ascertainment caveat on the prevalence record, which is why the reported case count is recorded as a floor rather than an estimate of true birth incidence. The report's single biggest lead was cited by DOI only and therefore unusable as given, so the PMID was recovered independently via PubMed: PMID:24963040, Kovtunovych et al., wild-type macrophages reverse disease in Hmox1-null mice. This was added as a RESCUES modeled_mechanism link and a matching investigational treatment (subablative BMT / engineered-macrophage cell therapy, therapeutic_modality CELL_THERAPY, target_mechanisms RESTORES on the macrophage node). It is the strongest evidence in the entry that macrophage failure is causally sufficient rather than merely correlated, and it is labelled preclinical-only throughout: no human with HMOX1 deficiency has been reported as treated this way. ONE DR-SUPPLIED IDENTIFIER WAS REJECTED. The report offered PMID:9927502 for the 1999 Yachie J Clin Invest paper; that paper is PMID:9884342, which the entry already cited, so 9927502 was not used. DEEP RESEARCH. A falcon (Edison) run was performed: research/Heme_Oxygenase_1_Deficiency-deep-research-falcon.md. Its own reference-validation block reports 9/9 references resolved with confabulation_rate 0.0 and no unresolved references. NEC preflight against MONDO:0013536 returned PASS - HMOX1 dominant at 17 mentions with no rival gene discussed, MONDO OMIM xref 614034. The KB entry was nonetheless built from primary literature fetched and read directly rather than from DR prose: PMID:9884342 (Yachie index case), PMID:9380735 and PMID:9380736 (Poss and Tonegawa mouse papers), PMID:21088618, PMID:33066778, PMID:36502441, and the human case-series review PMID:33546372. TWO CANDIDATE REFERENCES WERE DISCARDED during curation rather than cited. PMID:10426374 was fetched intending the Otterbein CO anti-inflammatory study but resolved to an unrelated glucosamine and insulin-resistance paper, so it was dropped. PMID:3029864 (Stocker, bilirubin as an antioxidant) cached as title and metadata with no abstract, so it was dropped rather than cited by its title, per the "a title is not a finding" rule. NO GENEREVIEWS BASELINE. PubMed was searched for a GeneReviews chapter for this disease and returned zero hits, so no GeneReviews phenotype baseline was available to cross-reference. TERM CORRECTIONS. Two bindings were corrected by the validator rather than assumed. HP:0020180 has canonical label "Elevated circulating haptoglobin concentration"; the local OAK build returned a stale "Elevated haptoglobin level", and the authoritative check caught the mismatch. NCIT:C2322 Corticosteroid is not a member of the ChemicalEntityTerm dynamic enum, so no therapeutic_agent is bound on the immunosuppression treatment; the reason is recorded in that treatment's own description, since the reported agents span small molecules, calcineurin inhibitors and monoclonal antibodies and no single agent identity describes the class. PRE-PR ADVERSARIAL REVIEW. Before opening the PR the entry was reviewed adversarially against the cached sources, specifically for evidence-claim mismatch (a snippet that verifies verbatim but does not support the claim it is attached to — the failure class no validator can catch). Ten findings, all acted on: 1. The free-heme node and the "Serum heme" biochemical marker quoted a sentence about OxyHb/MetHb spectra, i.e. cell-free haemoglobin species, not free heme — and the source's next paragraph offers "Hb accumulating in serum" as a competing reading of exactly that observation. Replaced with the direct measurement, "Serum heme concentration was extremely high, at 490 uM (normal range; <1 uM)." 2. The elevated-haptoglobin phenotype was supported only by a sentence about the Hb-Hp complex overflowing into urine, which never states haptoglobin is raised. Replaced with the quantitative measurement (800-1200 mg/dL against a 40-180 mg/dL reference range); the urine-overflow sentence is retained as a separate PARTIAL item for the proposed mechanism, and the description no longer states that mechanism flatly because the source hedges it as happening "somehow". 3. The free-heme -> endothelial-injury edge cited an abstract *background* sentence that says nothing about heme causing endothelial injury. Re-evidenced with the patient-cell hemin-sensitivity result, downgraded to PARTIAL, and the edge changed from DIRECT to INDIRECT_UNKNOWN_INTERMEDIATES — the cells tested were lymphoblastoid, not endothelial, so heme cytotoxicity toward patient endothelium is inferred. 4. Five evidence items tagged HUMAN_CLINICAL were review *background* sentences of mixed provenance ("In vivo and in vitro studies have indicated...") or statements citing other references. Retagged OTHER. The macrophage node's claim to rest on more than mouse data now stands on the genuinely human observation (vacuolated patient monocytes with reduced surface antigens), not on those. 5. The CO arm was overstated: two DIRECT human edges rested on an in-vitro CO-donor add-back. Both edges softened to indirect, and the prose now says the attribution is a hypothesis and that endogenous CO deficiency has never been measured in a patient. 6. Hypobilirubinaemia carried frequency VERY_FREQUENT on a source saying bilirubin was "low or within normal ranges in all cases" — which establishes universal failure-to-rise, not that frank hypobilirubinaemia (the bound HP term) occurs in 80%+ of patients. Band removed per the "omit rather than fabricate" rule, with the reasoning recorded inline. The entry description was softened from "No bilirubin is generated" likewise. 7. The hyperlipidaemia description gave index-case lipid values that the attached snippet did not contain. The quantitative sentence was located in the cached full text and added. 8. The rat FAILS_TO_RECAPITULATE evidence was scored REFUTE while its explanation said the quote demonstrates the failure. Corrected to SUPPORT: the link's claim is the negative one, and the quote is positive evidence for it. (Treatment-failure items keep REFUTE, which is correct there — those refute efficacy.) 9. A snippet began mid-name ("dimer suppressed TNF-alpha...") which hid that the agent was a CO-releasing molecule. Quoted in full. 10. modifier: DECREASED on two homeostasis GO terms was wrong in kind — homeostasis is disrupted, not decreased — so both are now ABNORMAL. The entry also asserted three HO isozymes while its own other citation says two; the count is now not asserted, with the HO-3-pseudogene reason recorded, since nothing here depends on it. SECOND-OPINION REVIEW ON THE CLAIM ISSUE (#9196). A research agent posted a detailed literature review on the claim issue, which was treated as review input and acted on after the PR opened. It changed the entry materially: - It named PMID:11823983 (Kawashima 2002, the first autopsy), which contains a PUBLISHED FIRST-PARTY mouse/human mismatch claim: the human case "seems to more severely involve endothelial cells and the reticuloendothelial system... with a short survival. This contrasts to the predominant iron metabolic disorders of HO-1--targeted mice with a long survival." This is a far stronger anchor for the HUMAN_MODEL_MISMATCH discussion than the cross-paper inference it previously rested on, and is now its lead evidence item. - It named PMID:25682599, which reports that red cell lifespan is PROLONGED in Hmox1-null mice while human patients have shortened red cell survival with fragmentation. This is an opposite-direction divergence rather than a difference of degree, and is now curated as a second FAILS_TO_RECAPITULATE link (on the haemolysis node) with its own readout, plus a third arm of the mismatch discussion. Its practical consequence is recorded explicitly: no conformance to a haemolysis mechanism module may be asserted for this disease on mouse evidence. - It named PMID:40945734 (J Biol Chem 2025), the one genuine therapeutic lead in this literature: ascorbate is depleted in patient LCLs and HMOX1-null HEK293T cells, and 2-phospho-L-ascorbic acid restores viability under hemin stress via SVCT2. Added as a treatment at PROPOSED grade, PARTIAL/IN_VITRO, explicitly not an established therapy. - It flagged an evidence-source trap specific to this disease: much of the mechanistic "human" work is done in patient-derived lymphoblastoid cell lines, which is IN_VITRO and not HUMAN_CLINICAL even though the papers read as case reports. One item (PMID:33066778 Western blot on patient cells) was retagged IN_VITRO on that basis; the PMID:9884342 item was kept HUMAN_CLINICAL because the quoted sentence's other half is immunohistochemistry on patient hepatic tissue, with the mixed provenance now stated in its explanation. - It supplied four scoping decisions now recorded in a top-level `notes` block so they are not re-proposed: this entry must NOT join the Inherited_Porphyrias grouping (that grouping is scoped to heme BIOSYNTHESIS blocks and none of its NECESSARY criteria are met, so joining would manufacture a check-groupings contradiction); granuloma_formation conformance was considered and rejected (cholesterol granulomas are a lipid/foreign-body reaction, not the Th1/TNF epithelioid programme); the HMOX1 GT(n) promoter-microsatellite literature is a distinct non-Mendelian entity and out of scope, and is the dominant search contaminant for this gene; and published case counts disagree and are deliberately left unreconciled. Suggestions from that review NOT acted on, with reasons: HPOA carries HP:0004844 Coombs-POSITIVE haemolytic anaemia for OMIM:614034, which contradicts the antibody-negative haemolysis this entry curates from PMID:33066778, so it was not added on the strength of an annotation that disagrees with the primary text. Several further HPOA phenotypes (diffuse alveolar haemorrhage, epistaxis, lymphadenopathy, sepsis, raised CRP and IL-6, transaminases) were left for a follow-up pass rather than added without reading each primary source. An amyloidogenesis conformance via the AA arm and a speculative atherogenesis node (aortic fatty streaks in a six-year-old, PMID:11823983) are both reasonable and are deferred rather than rejected. VALIDATION, all run and output read. just validate PASS. just validate-terms PASS. just count-verified-snippets 119/119 verified against cached references. just validate-disorders (the batched pre-PR sweep CI runs) PASS. The ungated whole-KB CI gates all PASS: check-folded-hyphens, check-duplicate-keys, check-title-snippets, check-snippet-length, check-environmental-evidence, and check-not4curation. No baseline file was regenerated. Compliance 94.7% global, 95.1% weighted.

Falcon ▸

Heme Oxygenase-1 Deficiency: Disease Characteristics Report

Edison Scientific Literature 21 citations 2026-08-21T21:17:35.866060

Heme Oxygenase-1 Deficiency: Disease Characteristics Report

Executive summary and evidence limits

Heme oxygenase-1 deficiency is an ultra-rare, usually severe autosomal-recessive disorder caused by biallelic pathogenic variants in HMOX1. Loss of inducible HO-1-mediated heme degradation produces a distinctive combination of Coombs-negative intravascular hemolysis, paradoxically low/normal bilirubin, very high LDH and ferritin, leukocytosis, thrombocytosis, systemic inflammation, endothelial injury, nephropathy, hepatic iron deposition, and absent or dysfunctional spleen. Pulmonary fibrosis, hemophagocytic flares, pericardial disease, and AA amyloidosis expand the recognized spectrum. The strongest systematic clinical evidence remains a 2021 review of nine independent patients; therefore, percentages below are case-series proportions, not population estimates. Publications in 2023–2024 added renal-amyloidosis and pulmonary/variant reports, but no cohort, guideline, approved disease-modifying treatment, or disease-specific clinical trial was identified.

Evidence classes: human clinical denotes affected patients; model denotes knockout animals; in vitro denotes patient or engineered cells. Broader associations involving common HMOX1 promoter polymorphisms are not equivalent to Mendelian HO-1 deficiency.

1. Disease information

Definition and nomenclature

HO-1 deficiency is an inherited failure of the inducible heme-degrading enzyme HO-1. HO-1 normally catalyzes the rate-limiting conversion of heme to biliverdin, carbon monoxide (CO), and ferrous iron; biliverdin is subsequently reduced to bilirubin. The disease is consequently both an enzyme deficiency and a disorder of heme detoxification, iron recycling, redox defense, and inflammatory restraint. The first molecularly defined patient was reported in 1999 by Yachie et al.; the primary paper is J Clin Invest 103:129–135, DOI 10.1172/JCI4165, PMID 9927502. The later review was published 3 February 2021, DOI 10.3390/ijms22041514. (yachie2021hemeoxygenase1deficiency pages 1-3, yachie2021hemeoxygenase1deficiency pages 15-16)

Preferred name: heme oxygenase-1 deficiency. Synonyms: HO-1 deficiency; HMOX1 deficiency; human heme oxygenase-1 deficiency; heme oxygenase 1 deficiency. “Heme oxygenase deficiency” is imprecise because HMOX2 encodes the constitutive HO-2 isozyme.

Identifiers:

Causal gene: HMOX1; OMIM gene 141250 (often displayed as 141250); HGNC 5013; NCBI Gene 3162*.
Disease OMIM/MONDO: a confidently verified separate phenotype number or MONDO identifier was not available in the retrieved evidence. OMIM 141250 is the gene entry*, not necessarily a disease-phenotype identifier, and should not be entered as such without direct database verification.
Orphanet: no verified dedicated identifier found.
MeSH: no disease-specific descriptor found; use “Heme Oxygenase-1” plus appropriate manifestations.
ICD-10/ICD-11: no specific code identified. Practical coding would require an “other specified disorder of metabolism/hematologic disorder” code plus manifestations, varying by jurisdiction.

The evidence is principally aggregated disease-level literature reconstructed from individual published cases, not EHR-derived population data. The 2021 synthesis explicitly states that only nine independent cases had been described. (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 1-3)

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

The primary cause is biallelic germline HMOX1 dysfunction. Reported genotypes include a compound exon-2 deletion/exon-3 2-bp deletion, homozygous p.Arg44Ter (R44X), homozygous p.Lys204Ter (K204X), homozygous p.Gly139Val (G139V), and compound c.264_269delCTGG (p.Leu89SerfsTer24) plus c.636+2T>A. Most are null alleles; p.G139V retains abnormal protein with reduced HO activity and acquired peroxidase behavior. Variants are germline, not somatic. (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 6-7, yachie2021hemeoxygenase1deficiency pages 4-6)

Population allele frequencies and current ClinVar ACMG classifications were not recoverable from the retrieved documents. Given severe recessive disease and the tiny number of families, the causal alleles are expected to be very rare, but “absent from gnomAD” should not be asserted without direct version-specific lookup.

Risk factors

Genetic: biallelic pathogenic HMOX1 variants; consanguinity was documented in the Iranian and Turkish families. The five Indian patients shared homozygous p.R44X, suggesting a founder allele. Family history may include fetal loss: the first patient’s mother had two intrauterine deaths, and the Iranian family had a spontaneous fetal loss, although causality was not genetically established. (yachie2021hemeoxygenase1deficiency pages 3-4, yachie2021hemeoxygenase1deficiency pages 6-7, yachie2021hemeoxygenase1deficiency pages 4-6)
Environmental/physiologic triggers: infections, hemolysis, transfusion, hypoxemia, and other oxidative insults plausibly precipitate inflammatory deterioration because HO-1 is normally stress inducible. The Indian patients could remain well for years and then deteriorate rapidly after inflammation began. The p.G139V patient had paradoxical inflammation after red-cell transfusion. These are trigger interactions, not causes of the Mendelian disorder. (yachie2021hemeoxygenase1deficiency pages 6-7, yachie2021hemeoxygenase1deficiency pages 1-3, yachie2021hemeoxygenase1deficiency pages 4-6)
Age/sex/lifestyle: no established sex, diet, smoking, occupation, toxin, or lifestyle risk effect. Onset ranged from 3 months to 15 years, and both sexes were affected. (yachie2021hemeoxygenase1deficiency pages 7-8)

Protective factors

No validated human protective allele, diet, lifestyle, or prophylactic drug is known. Avoiding unnecessary oxidative stress, promptly treating infection, and cautious transfusion practice are biologically reasonable but untested. HO-1 induction cannot restore an absent/null enzyme. CO donors, bilirubin/biliverdin, haptoglobin–CD163 enhancement, and wild-type macrophage replacement remain experimental concepts. The review’s conclusion—“Avoidance of exogenous stress along with appropriate treatment may prevent early death”—is expert opinion rather than trial evidence. (yachie2021hemeoxygenase1deficiency pages 13-15)

3. Phenotypes

Across the nine historical patients, fever and hemolytic anemia occurred in 9/9; jaundice occurred in 0/9 despite hemolysis. Hematuria/proteinuria occurred in all six Japanese/Indian cases and in the US case, but were unreported in two others. Absent/hypoplastic spleen affected seven of nine; one had splenomegaly and one a normal-sized spleen. These fractions are descriptive only. (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 8-10)

Group / country	Sex and onset range	Genotype	Defining phenotype / labs	Course / outcome
Case 1, Japan	Male; onset 2 years, diagnosis 5 years	Compound heterozygote: maternal allele lacked exon 2; paternal allele had 2-bp deletion in exon 3 (HMOX1)	Recurrent fever, generalized erythematous rash, joint pain, marked hepatomegaly, asplenia, flat nasal bridge, frontal bossing, eyelid edema; leukocytosis 51,600/µL, thrombocytosis 226 × 10^4/µL, hemoglobin 4.9 g/dL, LDH 17,470 IU/L, ferritin 780 ng/mL, triglycerides 638 mg/dL, total cholesterol 552 mg/dL, bilirubin 0.1–0.3 mg/dL, serum heme 490 µM, very high haptoglobin 800–1200 mg/dL; hematuria/proteinuria; kidney/liver iron deposition; vacuolated monocytes; endothelial/coagulation-fibrinolysis abnormalities (yachie2021hemeoxygenase1deficiency pages 3-4, yachie2021hemeoxygenase1deficiency pages 4-6)	Severe multisystem disease; specific final outcome not stated in gathered evidence; first autopsy case reported in literature review context (yachie2021hemeoxygenase1deficiency pages 15-16, yachie2021hemeoxygenase1deficiency pages 4-6)
Cases 2–6, India	Mixed sexes: female, male, male, female, male; onset 6 months to 15 years; diagnosis 20 months to 16 years	Homozygous p.R44X nonsense mutation in all 5 cases; founder effect suggested; parental genotypes unknown/not done for some, heterozygous R44X/wild type in some families (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 4-6)	Shared tetrad/profile: fever, asplenia, hemolytic anemia, hematuria/proteinuria, absent jaundice; prominent forehead common; growth delay variable; hypertension in most, cerebral bleeding in some; labs: CRP 4.8–30.8 mg/dL, WBC 18.5–43.2 ×10^3/mL, platelets 100–137 ×10^4/mL (one not shown), ferritin 2,000 to 15,530 ng/mL, LDH 4,000 to 21,400 IU/L, bilirubin 0.02–1.2 mg/dL, high haptoglobin despite hemolysis (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 4-6)	Variable latent period, then often rapid deterioration. Case 2 died 5 months after diagnosis after hypertension/intracranial hemorrhage and fungal sepsis; Cases 3 and 6 also reportedly died soon after symptom onset; outcomes for Cases 4–5 unknown in gathered evidence (yachie2021hemeoxygenase1deficiency pages 4-6)
Case 7, Iran	Female; onset 17 months, diagnosis 3 years	Homozygous p.K204X in exon 3; both parents heterozygous carriers; consanguineous Iranian parents (yachie2021hemeoxygenase1deficiency pages 4-6, yachie2021hemeoxygenase1deficiency pages 6-7)	High fever, tachypnea, respiratory distress, massive pericardial effusion, hepatomegaly with liver iron deposition, normal-sized spleen, prolonged/recurrent fever, hemolytic anemia; leukocytosis 33.0 ×10^3/mL, platelets 100 ×10^4/mL, ferritin 27,425 ng/mL, LDH 15,350 IU/L, AST/ALT 580/813 IU/L, bilirubin 0.8 mg/dL, hyperlipidemia (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 6-7, yachie2021hemeoxygenase1deficiency pages 4-6)	Corticosteroid ineffective; progressive deterioration over 4 admissions; died of recurrent fever, bleeding, heart failure, and ascites; diagnosis made post-mortem by whole-exome sequencing (yachie2021hemeoxygenase1deficiency pages 4-6)
Case 8, Turkey	Male; onset 3 months, diagnosis 20 months	Homozygous p.G139V missense mutation; son of consanguineous Turkish parents (yachie2021hemeoxygenase1deficiency pages 6-7)	Microcytic anemia resistant to iron, progressive hepatosplenomegaly, transfusion dependence; liver biopsy: severe hemophagocytosis, Kupffer cell siderosis, extramedullary hematopoiesis; slight marrow hemophagocytosis; inflammatory markers remained high (IL-1β, IL-6, TNF-α, ferritin, CRP); WBC 19.9 ×10^3/mL, platelets 47.8 ×10^4/mL, ferritin 4,855 ng/mL, LDH 15,713 IU/L, bilirubin 0.2–1.6 mg/dL; decreased HO-1 activity with abnormal peroxidase function and increased urinary peroxidation products (yachie2021hemeoxygenase1deficiency pages 6-7)	Treated with HLH2004 immunochemotherapy with sustained remission of HLH-like signs, but inflammatory activity persisted; paradoxical inflammatory response to red cell transfusion reported; longer-term outcome unknown in gathered evidence (yachie2021hemeoxygenase1deficiency pages 6-7)
Case 9, USA	Male; onset 4 years, diagnosis 10 years	Compound heterozygote: paternal frameshift c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor c.636+2T>A (yachie2021hemeoxygenase1deficiency pages 7-8)	Interstitial lung disease with recurrent inflammatory flares; fatigue, intermittent fevers, dark urine, hypoxemia, hepatomegaly, poorly perfused hypoplastic spleen/hyposplenia, growth slowing, hemolytic anemia with schistocytes and Howell-Jolly bodies, hematuria/proteinuria; WBC 53.8 ×10^3/mL, platelets 91.4 ×10^4/mL, ferritin 1,980 ng/mL, LDH 19,706 IU/L, bilirubin 0.2 mg/dL; liver biopsy with mild sinusoidal fibrosis, microvesicular steatosis, Kupffer-cell iron; lung biopsy with extensive fibrotic nonspecific interstitial pneumonia, pleural fibrosis, scattered/pulmonary interstitial and intra-alveolar cholesterol granulomas; PBMCs failed to induce HO-1 with cobalt protoporphyrin (yachie2021hemeoxygenase1deficiency pages 6-7, yachie2021hemeoxygenase1deficiency pages 7-8)	Genetic testing for periodic fever syndromes/familial HLH initially negative; treated with corticosteroid, anti-IL-1R, anti-IL-6, and cyclosporine with minimal benefit; died at age 10 from respiratory failure; diagnosis established post-mortem by whole-exome sequencing (yachie2021hemeoxygenase1deficiency pages 6-7, yachie2021hemeoxygenase1deficiency pages 7-8)

Table: This table compacts the currently gathered human evidence for HMOX1 deficiency into case groups, highlighting genotype, hallmark phenotype/laboratory patterns, and outcomes. It is useful for quickly comparing the recurrent diagnostic denominators and notable phenotype expansions across the 9 reported cases.

Knowledge-base phenotype mapping

Recurrent fever—infancy through adolescence; episodic then potentially persistent/severe; 9/9. HPO: HP:0001954 Recurrent fever.
Coombs-negative hemolytic anemia, often severe and fragmented-cell/microangiopathic—9/9; HPO: HP:0001878 Hemolytic anemia, HP:0001937 Microangiopathic hemolytic anemia, HP:0001892 Abnormal bleeding where present.
Low or normal bilirubin despite hemolysis—9/9 historical cases; a highly discriminating laboratory abnormality. HPO: HP:0002905 Hypobilirubinemia if locally supported; otherwise record quantitative laboratory phenotype rather than force an HPO term. (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 8-10)
Extreme LDH/hyperferritinemia—LDH approximately 4,000–21,400 IU/L and ferritin 780–27,425 ng/mL in the tabulated cases. HPO: HP:0031964 Elevated circulating ferritin concentration, HP:0025435 Elevated circulating lactate dehydrogenase concentration. (yachie2021hemeoxygenase1deficiency pages 7-8)
Leukocytosis and thrombocytosis—nearly invariant and useful in distinguishing the disorder from classic HLH-associated cytopenias. HPO: HP:0001974 Leukocytosis, HP:0001894 Thrombocytosis. (yachie2021hemeoxygenase1deficiency pages 8-10)
Asplenia/hyposplenia or evolving splenic dysfunction—usually congenital/early but variable; HPO: HP:0001746 Asplenia, HP:0001870 Acquired abnormality of spleen, HP:0031417 Hyposplenism, and HP:0001744 Splenomegaly for the alternate trajectory.
Renal disease—hematuria, proteinuria, glomerular endothelial swelling/detachment, mesangial proliferation, tubular atrophy, iron deposition, and later amyloidosis. HPO: HP:0000790 Hematuria, HP:0000093 Proteinuria, HP:0000099 Glomerulonephritis, HP:0000077 Abnormality of the kidney. (yachie2021hemeoxygenase1deficiency pages 10-12, yachie2021hemeoxygenase1deficiency pages 4-6)
Hepatomegaly/hepatic siderosis—common; HPO: HP:0002240 Hepatomegaly, HP:0001392 Abnormality of the liver, HP:0003233 Abnormality of iron homeostasis.
Hyperlipidemia—prominent in the first case; HPO: HP:0003077 Hyperlipidemia. Serum triglycerides were 638 mg/dL and cholesterol 552 mg/dL. (yachie2021hemeoxygenase1deficiency pages 3-4)
Systemic hyperinflammation/MAS-HLH-like episodes—variable, particularly cases 7–9; HPO: HP:0001945 Fever, HP:0410133 Hemophagocytosis, HP:0002910 Elevated hepatic transaminase.
Vascular/coagulation disease—hypertension, endothelial injury, extreme coagulation/fibrinolysis activation, occasional intracranial hemorrhage. HPO: HP:0000822 Hypertension, HP:0002167 Neurological hemorrhage, HP:0001928 Abnormality of coagulation. (yachie2021hemeoxygenase1deficiency pages 3-4, yachie2021hemeoxygenase1deficiency pages 12-13)
Pulmonary disease—progressive fibrotic nonspecific interstitial pneumonia, hypoxemia, and cholesterol granulomas in the US patient; HPO: HP:0002206 Pulmonary fibrosis, HP:0002091 Restrictive lung disease, HP:0012418 Hypoxemia. (yachie2021hemeoxygenase1deficiency pages 6-7)
Growth delay and craniofacial appearance—growth restriction was common but not universal; frontal bossing/prominent forehead, flat nasal bridge, and eyelid edema occurred in several patients. HPO: HP:0001510 Growth delay, HP:0002007 Frontal bossing, HP:0005280 Depressed nasal bridge, HP:0000280 Coarse facial features only if clinically documented.

Formal EQ-5D, SF-36, PROMIS, neurobehavioral, or disease-specific quality-of-life data do not exist. Severe anemia, recurrent hospitalization, transfusion dependence, organ failure, growth impairment, and respiratory limitation imply profound functional burden, but this has not been quantified.

4. Genetic and molecular information

HMOX1 encodes the 288-amino-acid inducible heme oxygenase-1, an endoplasmic-reticulum-associated microsomal enzyme. Suggested annotations include GO:0004392 heme oxygenase (decyclizing) activity, GO:0042167 heme catabolic process, GO:0006788 heme oxidation, GO:0055114 oxidation–reduction process, and GO:0005783 endoplasmic reticulum.

The exon deletions, frameshift, nonsense, and canonical splice-donor variants are predicted loss-of-function. Patient cells carrying null variants failed to produce inducible HO-1 after cadmium, sodium arsenite, or cobalt protoporphyrin stimulation. p.K204Ter truncates the protein at 203 rather than 288 residues. p.G139V is mechanistically unusual: constitutive mutant protein was present, stress induction was defective, catalytic HO activity was reduced, and abnormal peroxidase activity and inflammatory cytokine production increased. (yachie2021hemeoxygenase1deficiency pages 3-4, yachie2021hemeoxygenase1deficiency pages 6-7)

No validated modifier gene, anticipation, germline mosaicism, pathogenic epigenetic signature, recurrent copy-number syndrome, aneuploidy, translocation, or inversion is known. Common HMOX1 promoter (GT)n polymorphisms regulate expression in other diseases but are susceptibility modifiers, not established causes of this recessive deficiency.

5. Environmental and infectious information

No toxin, radiation, pollutant, pathogen, or lifestyle exposure independently causes the disease. Infection can trigger systemic inflammation and is a major treatment hazard: one Indian patient died with fungal sepsis after immunosuppression. Hemolysis itself supplies excess extracellular heme; transfusion adds heme burden and provoked inflammation in the p.G139V patient. Hypoxia and vascular shear are additional endogenous stresses to HO-1-dependent cells. No zoonotic or transmissible component exists. (yachie2021hemeoxygenase1deficiency pages 6-7, yachie2021hemeoxygenase1deficiency pages 10-12, yachie2021hemeoxygenase1deficiency pages 4-6)

6. Mechanism and pathophysiology

Causal chain

Upstream genetic lesion: biallelic HMOX1 loss or catalytic dysfunction.
Primary biochemical defect: impaired inducible conversion of heme to biliverdin, CO, and Fe²⁺, followed by reduced bilirubin production. This explains severe hemolysis accompanied by unexpectedly low bilirubin. (yachie2021hemeoxygenase1deficiency pages 1-3, yachie2021hemeoxygenase1deficiency pages 8-10)
Heme/Hb accumulation and failed recycling: extracellular oxyhemoglobin/methemoglobin and Hb–haptoglobin complexes accumulate. In the first patient, serum heme reached 490 µM versus normal <1 µM, while haptoglobin paradoxically reached 800–1,200 mg/dL. (yachie2021hemeoxygenase1deficiency pages 3-4)
Redox and metabolic injury: unresolved heme catalyzes oxidative macromolecular and membrane damage; iron is misdistributed into renal tubular and hepatic cells rather than efficiently recycled. Loss of bilirubin/biliverdin antioxidant action and CO signaling further reduces stress tolerance.
Monocyte/macrophage failure: erythrophagocytic Kupffer and splenic macrophages cannot safely process heme, lose CD163/scavenging competence, die or become abnormally activated, and release TNF-α, IL-1β, and IL-6. Suggested GO terms: GO:0006954 inflammatory response, GO:0006909 phagocytosis, GO:0030217 T-cell differentiation only for downstream immune studies, GO:0071345 cellular response to cytokine stimulus. Cell Ontology: CL:0000235 macrophage, CL:0000091 Kupffer cell, CL:0000576 monocyte. (yachie2021hemeoxygenase1deficiency pages 12-13, yachie2021hemeoxygenase1deficiency pages 10-12)
Endothelial dysfunction: heme/ROS and inflammatory signaling activate NF-κB/MAPK and tissue factor, producing coagulation/fibrinolysis dysregulation, hypertension, thrombosis/bleeding, glomerular microvascular injury, and occasional cerebral hemorrhage. Cell Ontology: CL:0000115 endothelial cell; GO: GO:0007596 blood coagulation, GO:0006979 response to oxidative stress. (yachie2021hemeoxygenase1deficiency pages 3-4, yachie2021hemeoxygenase1deficiency pages 12-13)
Downstream organ injury: chronic inflammation, ischemia, fibrosis, iron deposition, and AA amyloid damage kidney, liver, spleen, lung, and cardiovascular tissues.

The primary patient-study abstract states that HO-1 deficiency causes “enhanced endothelial cell injury”; the 2021 synthesis concludes that impaired HO-1 causes “progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction.” These are authoritative mechanistic interpretations supported by patient tissue and cells, not merely computational inference. (yachie2021hemeoxygenase1deficiency pages 1-3, yachie2021hemeoxygenase1deficiency pages 15-16)

Molecular profiling and advanced technology

There is no disease-specific human single-cell atlas, spatial transcriptomic study, lipidomic signature, integrated multi-omics cohort, or CRISPR screen. Whole-exome sequencing diagnosed post-mortem cases. Model metabolomics has connected HO-1 loss to impaired HIF-1α stabilization and ischemic metabolic adaptation, but this has not been validated as a diagnostic signature in affected humans. Epigenetic findings concern HMOX1 regulation generally, not the Mendelian disease.

7. Anatomy

Primary organs: blood/bone marrow, spleen, liver, kidneys, vascular endothelium, and monocyte–macrophage system. Secondary/variable: lung, heart/pericardium, brain vasculature, placenta, and growth tissues.

Suggested UBERON mappings include UBERON:0000178 blood, UBERON:0001987 placental blood, UBERON:0002106 spleen, UBERON:0002107 liver, UBERON:0002113 kidney, UBERON:0002048 lung, UBERON:0000948 heart, UBERON:0001981 blood vessel, UBERON:0001225 renal tubule, and UBERON:0001285 glomerular capillary. Relevant cells are erythrocytes (CL:0000232), erythroid progenitors (CL:0000038), monocytes, macrophages, Kupffer cells, renal tubular epithelial cells, hepatocytes (CL:0000182), podocytes (CL:0000653), and endothelial cells. Relevant compartments are ER membrane (GO:0005789), cytosol (GO:0005829), lysosome/phagolysosome (GO:0005764/GO:0032010), and extracellular blood space. No lateralization is expected.

8. Temporal development

Onset is usually pediatric but highly variable: 3 months–15 years among the nine historical patients. Some children had congenital/early asplenia or growth disturbance; others remained apparently well until an inflammatory trigger. Once clinically active, disease may become rapidly progressive, with recurrent fever, worsening hemolysis, renal/endothelial injury, and multiorgan failure. The US pulmonary phenotype followed a chronic progressive course from age four to respiratory death at ten. There is no validated staging system or predictable remission pattern. (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 6-7, yachie2021hemeoxygenase1deficiency pages 4-6)

Potential critical periods include fetal splenic/placental development, infancy with high erythrocyte turnover, and acute infections. Mouse data support fetal loss and placental vascular vulnerability, but prenatal human penetrance is unknown. A 2024 study found that HO-1 knockdown impaired trophoblast-spheroid attachment and that CO reversed this in vitro; Hmox1-null uterus showed altered angiogenesis/stress expression. This supports developmental biology but does not establish a human prenatal therapy. DOI 10.3390/cells13050376, published February 2024. (zenclussen2024absenceofheme pages 11-13)

9. Inheritance and population

Inheritance is autosomal recessive. Both sexes are affected; among the nine tabulated cases, six were male and three female, a sample too small to infer sex bias. Cases arose in Japan, India, Iran, Turkey, and the United States. Consanguinity contributed in two families, while the shared Indian p.R44X allele suggests a founder effect. Carrier parents are clinically unaffected, consistent with recessive transmission. (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 6-7)

No incidence, prevalence per 100,000, carrier frequency, penetrance estimate, or population registry exists. “Nine cases by 2021” is a reported-case count, not prevalence. Embryonic lethality in mice and fetal losses in two families raise the possibility of prenatal under-ascertainment, but this remains an expert hypothesis. (yachie2021hemeoxygenase1deficiency pages 3-4, yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 8-10)

10. Diagnostics

When to suspect the disorder

The highest-yield pattern is:

Coombs-negative fragmented-cell hemolytic anemia;
strikingly low/normal bilirubin despite hemolysis;
LDH and ferritin often in the thousands to tens of thousands;
leukocytosis plus thrombocytosis rather than HLH-like cytopenias;
asplenia/hyposplenia without congenital heart disease, or unexplained splenomegaly;
fever/systemic inflammation, hepatomegaly, proteinuria/hematuria, hypertension, or interstitial lung disease. (yachie2021hemeoxygenase1deficiency pages 3-4, yachie2021hemeoxygenase1deficiency pages 8-10)

Tests

CBC/smear: anemia, schistocytes/fragmented erythrocytes, nucleated RBCs, Howell–Jolly bodies, leukocytosis, thrombocytosis.
Hemolysis/heme: LDH, bilirubin fractions, haptoglobin, plasma-free Hb/heme, methemoglobin, hemopexin, reticulocytes, urinalysis; direct antiglobulin testing is usually negative.
Inflammation/organ assessment: ferritin, CRP/ESR, triglycerides, AST/ALT, renal function, urine protein/creatinine, coagulation/fibrinolysis markers, cytokines where available.
Imaging: abdominal ultrasound/CT for spleen and liver; echocardiography for pericardial/cardiac disease; high-resolution chest CT and pulmonary function testing for respiratory disease; brain imaging when hypertensive or neurologically symptomatic.
Pathology: kidney may show endothelial swelling, mesangial proliferation and tubular atrophy; liver may show Kupffer-cell/parenchymal iron, extramedullary hematopoiesis, hemophagocytosis or AA amyloid; lung may show fibrotic NSIP and cholesterol granulomas. (yachie2021hemeoxygenase1deficiency pages 6-7, yachie2021hemeoxygenase1deficiency pages 10-12, yachie2021hemeoxygenase1deficiency pages 4-6)
Functional assay: absent or noninducible HO-1 protein/activity in stimulated PBMCs, monocytes, fibroblasts, or lymphoblastoid cells can support pathogenicity, especially for missense variants.

Genetic testing strategy

Sequence HMOX1 with deletion/duplication and splice analysis. A heme-metabolism/hemolytic-anemia/autoinflammatory panel can be used, but the laboratory must include HMOX1 and copy-number calling. WES/WGS is appropriate when the phenotype is atypical or first-line testing is negative; several cases were diagnosed by post-mortem WES. RNA sequencing may demonstrate aberrant splicing for c.636+2T>A or other splice variants. CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion assays are not first-line unless another diagnosis is suspected. Cascade parental testing establishes phase. (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 4-6)

Differential diagnosis

Exclude thrombotic microangiopathy/HUS, autoimmune hemolysis, hereditary red-cell membrane/enzyme disorders, congenital asplenia syndromes, familial HLH/MAS, systemic juvenile idiopathic arthritis, CAPS/NOMID, vasculitis, infection, malignancy, Wilson disease, aceruloplasminemia, and other iron-recycling disorders. Low bilirubin with very high LDH/ferritin and thrombocytosis plus asplenia is especially discriminating from conventional hemolysis and HLH.

There are no standardized diagnostic criteria, newborn screen, approved enzyme assay, or population-screening program.

11. Outcome and prognosis

Prognosis is frequently poor but cannot be represented by five- or ten-year survival statistics. Several reported children died soon after onset or diagnosis from fungal sepsis, intracranial hemorrhage, heart failure/bleeding, or respiratory failure. The Indian p.R44X series showed prolonged asymptomatic periods followed by rapid decline; the US patient died at ten after six years of progressive lung disease. (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 4-6)

Major morbidity includes transfusion-dependent anemia, recurrent inflammatory hospitalization, chronic kidney disease/proteinuria, hypertension, cerebral bleeding, hepatic damage/amyloidosis, splenic dysfunction and infection risk, growth failure, pulmonary fibrosis, and heart failure. Prognostic factors are unvalidated; plausible adverse markers include very early onset, sustained hyperinflammation, pulmonary fibrosis, renal amyloid, severe endothelial dysfunction, and inability to control triggers. No validated prognostic biomarker or quality-of-life instrument exists.

12. Treatment

Current clinical management

There is no approved disease-specific therapy or consensus algorithm. Management is multidisciplinary and supportive:

stabilize severe anemia, but transfuse cautiously and monitor inflammation/heme burden;
promptly identify and treat infection;
manage hypertension, renal disease/proteinuria, respiratory failure, coagulopathy, heart failure, and nutrition/growth;
apply asplenia precautions: vaccination against encapsulated bacteria, fever action plan, and jurisdiction-appropriate antibiotic prophylaxis;
avoid iron supplementation unless iron deficiency is objectively established—the p.G139V patient’s microcytic anemia was iron-unresponsive.

Suggested NCIt concepts include Blood Transfusion, Corticosteroid Therapy, Immunosuppressive Therapy, Anti-inflammatory Therapy, Hematopoietic Stem Cell Transplantation, Gene Therapy, and Supportive Care; exact NCIt codes should be resolved against the current thesaurus release.

Reported therapies and outcomes

Corticosteroids were ineffective in the Iranian patient. The Turkish patient received HLH-2004 immunochemotherapy, achieving remission of HLH-like signs but persistent biochemical inflammation. In the US case, corticosteroids, IL-1 receptor blockade, IL-6 blockade, and cyclosporine provided minimal benefit; death followed from respiratory failure. Broad immunosuppression can increase infection risk and does not correct failed heme catabolism. (yachie2021hemeoxygenase1deficiency pages 7-8, yachie2021hemeoxygenase1deficiency pages 6-7, yachie2021hemeoxygenase1deficiency pages 4-6)

Experimental strategies

Macrophage/cell replacement: wild-type macrophages reversed disease in Hmox1-null mice, supporting replacement of the erythrophagocytic compartment. This is compelling model evidence, not proven human therapy. Primary report: Blood 2014;124:1522–1530, DOI 10.1182/blood-2014-02-554162. (yachie2021hemeoxygenase1deficiency pages 15-16)
CO or CO-releasing molecules: CO can restore anti-inflammatory/endothelial signaling and rescued implantation or vascular phenotypes in models. Safety, dosing, and efficacy in congenital deficiency are unestablished. (yachie2021hemeoxygenase1deficiency pages 13-15, yachie2021hemeoxygenase1deficiency pages 12-13, zenclussen2024absenceofheme pages 11-13)
Gene replacement/editing or autologous corrected hematopoietic stem cells: mechanistically attractive because macrophages are central, but no human trial or reported implementation was identified.
Haptoglobin/hemopexin/CD163 pathway augmentation, biliverdin/bilirubin replacement, antioxidants, and iron redistribution therapy: preclinical concepts only.

The ClinicalTrials.gov tool search found no relevant disease-specific interventional study and no NCT identifier. There are no established response rates, pharmacogenomic recommendations, RNA therapy, surgery, or approved targeted biologic.

13. Prevention

Primary prevention is limited to genetic counseling. For a carrier couple, each pregnancy has the standard autosomal-recessive probabilities: 25% affected, 50% carrier, and 25% unaffected/noncarrier, assuming both parental variants are confirmed. Targeted prenatal diagnosis and preimplantation genetic testing are technically feasible. Cascade testing should be offered to adult relatives.

Secondary prevention consists of early recognition in siblings or children with the diagnostic laboratory pattern, followed by HMOX1 testing before irreversible kidney, vascular, or lung injury. There is no population or newborn screening. Tertiary prevention includes asplenia vaccination/prophylaxis, infection control, blood-pressure and renal monitoring, cautious transfusion, respiratory surveillance, and avoidance of unnecessary oxidative/toxic exposures. No vaccine prevents the genetic disease itself.

14. Other species and natural disease

No naturally occurring veterinary HMOX1-deficiency syndrome, breed association, or zoonotic transmission was identified. Relevant taxa are Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Rattus norvegicus (10116), and Danio rerio (7955). Orthologs are Hmox1 in mouse/rat and hmox1a/hmox1b paralogs in zebrafish. Comparative evidence demonstrates strong evolutionary conservation of heme detoxification, iron recycling, macrophage survival, and vascular protection, but induced knockout phenotypes should not be mislabeled as natural animal disease.

15. Model organisms and experimental systems

Mouse

Global Hmox1-null mice reproduce anemia, defective iron reutilization, renal/hepatic iron deposition, chronic inflammation, growth delay, oxidative-stress hypersensitivity, and splenic pathology. Depending on genetic background and age, spleens enlarge or progress from enlargement to fibrosis, atrophy, and functional hyposplenism. Null embryonic fibroblasts are hypersensitive to hemin, hydrogen peroxide, paraquat, and heavy metals. These are the highest-fidelity models for systemic disease, although mouse splenic development and survival vary by strain. Primary reports: Poss & Tonegawa, PNAS 1997;94:10919–10924 and 10925–10930. (yachie2021hemeoxygenase1deficiency pages 8-10, yachie2021hemeoxygenase1deficiency pages 15-16)

Macrophage-focused studies show erythrophagocytic macrophage death, reduced CD163, and altered tissue iron distribution. Infusion of wild-type macrophages can reverse key disease features, identifying macrophages as both a pathogenic hub and therapeutic target. Mouse studies also demonstrate abnormal erythroblastic islands, microcytic anemia, oxidative RBC stress, endothelial thrombosis, ischemic necrosis, inflammasome activation, and developmental/placental defects. Limitations are substantial embryonic loss, strain-dependent spleen phenotypes, and incomplete reproduction of human pulmonary or amyloid disease.

Rat

HO-1-depleted Sprague–Dawley rats develop hemolytic anemia, poikilocytes/target cells/acanthocytes, leukocytosis, growth impairment, splenomegaly, proteinuria, mesangial expansion, focal segmental sclerosis, and podocyte edema; most died by six months. Unlike humans and mice, renal tubular/hepatic iron deposition was not prominent, illustrating species-specific iron handling. (yachie2021hemeoxygenase1deficiency pages 8-10, yachie2021hemeoxygenase1deficiency pages 10-12)

Zebrafish and cellular systems

Zebrafish hmox1a disruption affects development and macrophage migration and is useful for imaging innate immune behavior, but duplicated genes and aquatic physiology limit direct clinical translation. Patient PBMCs, monocytes, lymphoblastoid cells, fibroblasts, HUVECs, trophoblast spheroids, and Hmox1-null embryonic fibroblasts support functional variant testing and investigation of oxidative stress, cytokines, coagulation, hypoxia, and CO rescue.

Recent developments and expert interpretation

The most disease-relevant recent clinical developments are: (1) a 2023 report expanding the renal spectrum to AA-type renal amyloidosis (Clinical Rheumatology 42:597–606; online 2022, issue 2023; DOI 10.1007/s10067-022-06465-9); (2) a 2024 clinical/molecular report of a novel variant with inflammation, heme-metabolism abnormalities, and pulmonary disease (Molecular Genetics and Metabolism Reports 38:101038; DOI 10.1016/j.ymgmr.2023.101038); and (3) a 2024 case report/review (Clinical Case Reports, DOI 10.1002/ccr3.8986). These publications indicate continuing phenotype expansion, not a change in standard care.

Current expert analysis increasingly emphasizes heme-detoxifying macrophages rather than treating HO-1 merely as a generic antioxidant. A 2024 review describes macrophage HMOX1 as essential for limiting oxidative damage in hemolytic disorders and for balancing inflammation and ferroptosis (published March 2024, DOI 10.3389/fimmu.2024.1379967). Another 2024 review stresses that erythrophagocyte HO-1 converts heme into CO, biliverdin and Fe²⁺ while controlling apoptosis, inflammation, and oxidative injury (published October 2024, DOI 10.3389/fimmu.2024.1433113). This supports macrophage replacement or corrected hematopoietic-cell strategies, but human efficacy remains wholly unproven.

Data-quality conclusions

The disease signature is strong and internally consistent, but evidence quality is constrained by single cases, retrospective descriptions, publication bias, and genotype/age heterogeneity. Frequencies should therefore be stored with denominators and an evidence tag such as “9-case literature series, through 2021”. Variant-level ClinVar/gnomAD status, current MONDO/Orphanet identifiers, exact incidence, standardized diagnostic criteria, natural-history survival, patient-reported outcomes, and treatment-response rates remain unavailable or require direct database validation. Mechanistic confidence is highest for defective heme catabolism, macrophage/endothelial dysfunction, oxidative injury, and iron misdistribution; confidence is lower for proposed CO, macrophage, stem-cell, or gene therapies because these are supported predominantly by models rather than treated patients.

References

(yachie2021hemeoxygenase1deficiency pages 1-3): Akihiro Yachie. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. International Journal of Molecular Sciences, 22:1514, Feb 2021. URL: https://doi.org/10.3390/ijms22041514, doi:10.3390/ijms22041514. This article has 104 citations.
(yachie2021hemeoxygenase1deficiency pages 15-16): Akihiro Yachie. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. International Journal of Molecular Sciences, 22:1514, Feb 2021. URL: https://doi.org/10.3390/ijms22041514, doi:10.3390/ijms22041514. This article has 104 citations.
(yachie2021hemeoxygenase1deficiency pages 7-8): Akihiro Yachie. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. International Journal of Molecular Sciences, 22:1514, Feb 2021. URL: https://doi.org/10.3390/ijms22041514, doi:10.3390/ijms22041514. This article has 104 citations.
(yachie2021hemeoxygenase1deficiency pages 6-7): Akihiro Yachie. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. International Journal of Molecular Sciences, 22:1514, Feb 2021. URL: https://doi.org/10.3390/ijms22041514, doi:10.3390/ijms22041514. This article has 104 citations.
(yachie2021hemeoxygenase1deficiency pages 4-6): Akihiro Yachie. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. International Journal of Molecular Sciences, 22:1514, Feb 2021. URL: https://doi.org/10.3390/ijms22041514, doi:10.3390/ijms22041514. This article has 104 citations.
(yachie2021hemeoxygenase1deficiency pages 3-4): Akihiro Yachie. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. International Journal of Molecular Sciences, 22:1514, Feb 2021. URL: https://doi.org/10.3390/ijms22041514, doi:10.3390/ijms22041514. This article has 104 citations.
(yachie2021hemeoxygenase1deficiency pages 13-15): Akihiro Yachie. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. International Journal of Molecular Sciences, 22:1514, Feb 2021. URL: https://doi.org/10.3390/ijms22041514, doi:10.3390/ijms22041514. This article has 104 citations.
(yachie2021hemeoxygenase1deficiency pages 8-10): Akihiro Yachie. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. International Journal of Molecular Sciences, 22:1514, Feb 2021. URL: https://doi.org/10.3390/ijms22041514, doi:10.3390/ijms22041514. This article has 104 citations.
(yachie2021hemeoxygenase1deficiency pages 10-12): Akihiro Yachie. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. International Journal of Molecular Sciences, 22:1514, Feb 2021. URL: https://doi.org/10.3390/ijms22041514, doi:10.3390/ijms22041514. This article has 104 citations.
(yachie2021hemeoxygenase1deficiency pages 12-13): Akihiro Yachie. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. International Journal of Molecular Sciences, 22:1514, Feb 2021. URL: https://doi.org/10.3390/ijms22041514, doi:10.3390/ijms22041514. This article has 104 citations.
(zenclussen2024absenceofheme pages 11-13): Maria Laura Zenclussen, Sina Ulrich, Mario Bauer, Beate Fink, Ana Claudia Zenclussen, Anne Schumacher, and Nicole Meyer. Absence of heme oxygenase-1 affects trophoblastic spheroid implantation and provokes dysregulation of stress and angiogenesis gene expression in the uterus. Cells, 13(5):376, Feb 2024. URL: https://doi.org/10.3390/cells13050376, doi:10.3390/cells13050376. This article has 5 citations.

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Discussions and Knowledge Gaps

Pathophysiology

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Heme Oxygenase-1 Deficiency: Disease Characteristics Report

Executive summary and evidence limits

1. Disease information

Definition and nomenclature

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

Risk factors

Protective factors

3. Phenotypes

Knowledge-base phenotype mapping

4. Genetic and molecular information

5. Environmental and infectious information

6. Mechanism and pathophysiology

Causal chain

Molecular profiling and advanced technology

7. Anatomy

8. Temporal development

9. Inheritance and population

10. Diagnostics

When to suspect the disorder

Tests

Genetic testing strategy

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Current clinical management

Reported therapies and outcomes

Experimental strategies

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Mouse

Rat

Zebrafish and cellular systems

Recent developments and expert interpretation

Data-quality conclusions

Artifacts

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