Schimke immuno-osseous dysplasia

Genetic MONDO:0009458 Pathograph 20 Show in embeddings browser immuno-osseous dysplasia spondyloepiphyseal dysplasia osteochondrodysplasia autosomal recessive disease

Schimke immuno-osseous dysplasia (SIOD) is an ultra-rare autosomal recessive pleiotropic disorder caused by biallelic loss-of-function variants in SMARCAL1, which encodes an ATP-driven annealing helicase that stabilizes and restarts stalled replication forks. Loss of this genome-maintenance activity produces replication stress and DNA-damage accumulation that preferentially injures highly proliferative and replication-stress-sensitive compartments: growth-plate chondrocytes (spondyloepiphyseal dysplasia with disproportionate short-trunk short stature), podocytes (steroid-resistant nephrotic syndrome from focal segmental glomerulosclerosis progressing to end-stage renal disease), thymocytes and T cells (T-cell lymphopenia with IL7R promoter hypermethylation and recurrent, sometimes opportunistic, infections), and the vasculature (defective elastogenesis with premature arteriosclerosis and cerebral ischemic events). Additional features include hyperpigmented macules, an unusual facies, hypothyroidism, cytopenias and bone marrow failure, migraine-like headaches, and a predisposition to non-Hodgkin lymphoma. The disease spans a spectrum from a severe infantile-onset form that is usually lethal in childhood to a milder later-onset form compatible with survival into adulthood when renal disease is treated; disease severity correlates inversely with residual SMARCAL1 activity. Kidney transplantation (FSGS does not recur in the graft) with minimized immunosuppression is the mainstay for renal failure; conventional myeloablative HSCT has carried very high mortality, attributed to the hypersensitivity of SMARCAL1-deficient cells to genotoxic agents, while sequential reduced-intensity haploidentical HSCT and kidney transplantation from the same donor has achieved immunosuppression-free renal function in early reports.

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1
Inheritance
6
Pathophys.
19
Phenotypes
20
Pathograph
1
Genes
5
Medical Actions
1
References
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE KIDNEY URINARY TRACT
IUIS Category
combined immunodeficiency with syndromic features
ISDS Skeletal Nosology
spondylo epi metaphyseal dysplasias
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Inheritance

1
Autosomal recessive HP:0000007
SIOD is inherited in an autosomal recessive manner; affected individuals carry biallelic SMARCAL1 pathogenic variants and each sib of an affected individual has a 25% recurrence risk at conception.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:11799392 SUPPORT Human Clinical
"Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency."
States the autosomal recessive inheritance of SIOD.
PMID:20301550 SUPPORT Human Clinical
"SIOD is inherited in an autosomal recessive manner."
GeneReviews states the inheritance pattern directly.
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Pathophysiology

6
SMARCAL1 Annealing Helicase Deficiency
Biallelic loss-of-function SMARCAL1 variants abolish or reduce the SMARCAL1 (HARP) protein, an SNF2-family ATP-driven annealing helicase that rewinds RPA-stabilized single-stranded DNA bubbles at replication forks. Disease-associated mutations impair SMARCAL1 expression, stability, chromatin binding, and ATPase/annealing activity, and residual overall SMARCAL1 activity is inversely proportional to disease severity.
Genetic context SMARCAL1 hgnc:11102 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SMARCAL1 (hgnc:11102). hgnc:11102 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Biallelic germline loss-of-function variants; nonsense/frameshift/splice genotypes cause severe disease, whereas biallelic missense variants retaining partial function cause milder disease.
annealing helicase activity GO:0036310 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased annealing helicase activity, annotated with ATP-dependent DNA/DNA annealing activity (GO:0036310). GO:0036310 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Replication Stress and Genome Instability Loss of the annealing helicase removes a replication stress response protein that maintains genome integrity at stalled replication forks, producing replication-associated DNA damage.
Defective Elastogenesis and Premature Arteriosclerosis SMARCAL1 is expressed in arterial and lung tissue, and SMARCAL1-deficient aorta and lung show reduced elastin expression with altered expression of elastin-gene regulators; the intermediate steps from SMARCAL1 loss to the transcriptional deficit are not established.
Show evidence (5 references)
PMID:11799392 SUPPORT Human Clinical
"Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD."
Identifies SMARCAL1 mutations as the cause of SIOD.
PMID:18974355 SUPPORT In Vitro
"We found that HARP is an ATP-dependent annealing helicase that rewinds single-stranded DNA bubbles that are stably bound by replication protein A."
Defines the molecular activity of SMARCAL1/HARP that is lost in SIOD.
PMID:18974355 SUPPORT In Vitro
"Analysis of mutant HARP proteins suggests that SIOD is caused by a deficiency in annealing helicase activity."
Attributes SIOD to deficient annealing helicase activity of the mutant proteins.
+ 2 more references
Replication Stress and Genome Instability
SMARCAL1-deficient cells activate the DNA damage response during S phase without exogenous genotoxins, show slower replication fork recovery and delayed mitotic entry after S-phase arrest, and are hypersensitive to replication stress and DNA-damaging agents in vitro and in vivo. This replication stress preferentially compromises highly proliferative compartments (growth plate, glomerulus, thymus/lymphocytes, marrow) and underlies the hypersensitivity to genotoxic therapies observed clinically.
replication fork processing GO:0031297 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased replication fork processing (GO:0031297). GO:0031297 is a biological process from the Gene Ontology. ↓ DECREASED DNA damage response GO:0006974 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Impaired Chondrogenesis Replication stress compromises proliferating growth-plate chondrocytes; genotoxic agents reproduce growth-plate chondrocyte loss in Smarcal1-deficient mice.
Podocyte Injury and Glomerulosclerosis Genomic instability in the developing and mature kidney, evidenced by markedly increased DNA fragmentation in patient renal biopsies, is proposed to drive the podocytopathy.
Thymic T-cell Development Failure Replication and DNA-damage stress in thymocytes and T cells, together with epigenetic silencing of IL7R, restricts T-cell production; patient T cells show markedly increased apoptosis after DNA damage.
Non-Hodgkin lymphoma Genome instability predisposes to malignancy; NHL is the most commonly reported cancer in SIOD cohorts.
Show evidence (4 references)
PMID:19793861 SUPPORT In Vitro
"Furthermore, SMARCAL1-deficient cells are hypersensitive to replication stress agents."
Documents replication-stress hypersensitivity of SMARCAL1-deficient cells.
PMID:19793862 SUPPORT In Vitro
"SMARCAL1-depleted cells display sensitivity to DNA-damaging agents that induce replication fork collapse, and exhibit slower fork recovery and delayed entry into mitosis following S-phase arrest."
Documents defective replication fork recovery in SMARCAL1-deficient cells.
PMID:22888040 SUPPORT Model Organism
"We did not find evidence of defective NER or NHEJ; however, Smarcal1-deficient mice were hypersensitive to several genotoxic agents."
Confirms in vivo hypersensitivity of Smarcal1-deficient mice to genotoxic agents.
+ 1 more reference
Impaired Chondrogenesis
Defective chondrogenesis with loss of proliferating growth-plate chondrocytes underlies the spondyloepiphyseal dysplasia. Autopsy studies identify defective chondrogenesis and suggest a regulatory role for SMARCAL1 in chondrocyte proliferation; the resulting dysplasia predominantly involves the vertebrae, pelvis, and capital femoral epiphyses, producing short-trunk disproportionate growth failure.
growth plate chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves growth plate chondrocyte, annotated with chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
chondrocyte proliferation GO:0035988 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chondrocyte proliferation (GO:0035988). GO:0035988 is a biological process from the Gene Ontology. ↓ DECREASED cartilage development GO:0051216 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cartilage development (GO:0051216). GO:0051216 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Spondyloepiphyseal dysplasia Defective chondrogenesis of vertebral and proximal epiphyseal growth centers produces the characteristic spondyloepiphyseal dysplasia.
Disproportionate short stature The spondyloepiphyseal dysplasia, with primary involvement of vertebrae and proximal epiphyses, results in short-trunk disproportionate growth failure.
Show evidence (2 references)
PMID:16840568 SUPPORT Human Clinical
"As predicted by the clinical course, T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis, cerebral ischaemic lesions and premature atherosclerosis were identified."
Autopsy confirmation of defective chondrogenesis in SIOD.
PMID:16840568 SUPPORT Human Clinical
"A regulatory role for the SMARCAL1 protein in the proliferation of chondrocytes, lymphocytes and spermatozoa, as well as in the development or maintenance of cardiomyocytes and in vascular homoeostasis, is suggested."
Implicates SMARCAL1 in chondrocyte proliferation, the cellular basis of the impaired chondrogenesis.
Podocyte Injury and Glomerulosclerosis
The nephropathy of SIOD is a podocytopathy. SMARCAL1 is expressed in podocytes and glomerular endothelial cells; patient biopsies show the tip and collapsing variants of focal segmental glomerulosclerosis with ultrastructural podocyte and Bowman's-capsule abnormalities, and the podocytopathy usually progresses through FSGS to end-stage kidney disease.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
Downstream
Focal segmental glomerulosclerosis Podocyte injury and loss produce segmental scarring of glomeruli — the tip and collapsing FSGS variants seen on biopsy.
Steroid-resistant nephrotic syndrome The podocytopathy manifests clinically as proteinuria and nephrotic syndrome that does not respond to corticosteroids.
End-stage renal disease The steroid-resistant nephropathy progresses through FSGS to end-stage renal disease, usually within five years of the diagnosis of growth failure.
Show evidence (3 references)
PMID:25319549 SUPPORT Human Clinical
"Our analysis of SIOD patient renal biopsies demonstrates the tip and collapsing variants of focal segmental glomerulosclerosis (FSGS)."
Histological characterization of the SIOD renal lesion.
PMID:25319549 SUPPORT Human Clinical
"Additionally, electron microscopy revealed numerous glomerular abnormalities most notably in the podocyte and Bowman's capsule."
Ultrastructural localization of the injury to the podocyte.
PMID:35704481 SUPPORT Human Clinical
"The nephrotic syndrome in SIOD is a podocytopathy that usually progresses to focal segmental glomerulosclerosis and end-stage kidney disease."
Frames the SIOD nephropathy as a podocytopathy progressing through FSGS to end-stage kidney disease.
Thymic T-cell Development Failure
T-cell production fails at the level of the thymus. SIOD patient T cells have undetectable IL-7 receptor alpha chain (IL7Rα) protein and mRNA with hypermethylation of the IL7R promoter and are unresponsive to IL-7, restricting T-cell development; residual peripheral T cells are skewed to mature/memory phenotypes with exhaustion features. B-cell numbers and immunoglobulins are comparatively preserved early, though hypogammaglobulinemia — aggravated by nephrotic protein loss — is a hallmark of the combined immunodeficiency.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. thymocyte CL:0000893 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves thymocyte (CL:0000893). CL:0000893 is a cell type from the Cell Ontology.
T cell differentiation in thymus GO:0033077 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell differentiation in thymus (GO:0033077). GO:0033077 is a biological process from the Gene Ontology. ↓ DECREASED T cell homeostasis GO:0043029 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell homeostasis (GO:0043029). GO:0043029 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
T-cell lymphopenia Restricted thymic T-cell development produces the characteristic progressive T-cell lymphopenia.
Recurrent infections T-cell deficiency, aggravated by antibody loss from nephrotic syndrome and immunosuppressive treatment, causes recurrent and opportunistic infections — the leading cause of death.
Show evidence (3 references)
PMID:26499378 SUPPORT Human Clinical
"Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor."
Documents the loss of functional IL-7 receptor on SIOD T cells.
PMID:26499378 SUPPORT Human Clinical
"We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients."
Proposes epigenetic IL7R silencing as the mechanism restricting T-cell development.
PMID:39153074 SUPPORT Human Clinical
"Its hallmarks are severe hypogammaglobulinemia requiring immunoglobulin substitution, as well as impaired function of the thymus resulting in overall T cell lymphopenia"
Attributes the T-cell lymphopenia to impaired thymic function and notes the accompanying humoral deficiency.
Defective Elastogenesis and Premature Arteriosclerosis
Reduced elastin expression in aorta and lung, with altered expression of regulators of elastin gene expression, produces an arteriosclerosis characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented, disorganized elastin fibers, and an emphysema-like panlobular enlargement of air spaces. Vascular disease — including premature atherosclerosis and cerebral vaso-occlusion — is a major cause of morbidity and mortality.
vascular smooth muscle cell CL:0000192 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular smooth muscle cell, annotated with smooth muscle cell (CL:0000192). CL:0000192 is a cell type from the Cell Ontology.
elastic fiber assembly GO:0048251 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased elastic fiber assembly (GO:0048251). GO:0048251 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Premature atherosclerosis The elastin-deficient arteriopathy manifests as premature atherosclerosis/arteriosclerosis, present in about half of evaluable patients.
Cerebral ischemic events Cerebral vaso-occlusive disease on the background of the arteriopathy produces transient ischemic attacks and strokes.
Show evidence (2 references)
PMID:22998683 SUPPORT Human Clinical
"The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces."
Histopathological definition of the vascular and pulmonary lesions.
PMID:22998683 SUPPORT Human Clinical
"Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression."
Attributes the lesions to reduced elastogenesis in SMARCAL1-deficient tissue.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Schimke immuno-osseous dysplasia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

19
Blood 4
T-cell lymphopenia FREQUENT Decreased total T cell count HP:0005403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is T-cell lymphopenia, annotated with Decreased total T cell count (HP:0005403). HP:0005403 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301550 SUPPORT Human Clinical
"The majority of tested individuals have T cell deficiency and an associated risk for opportunistic infection, a common cause of death."
"The majority of tested individuals" supports the frequent band for T-cell deficiency.
PMID:39153074 SUPPORT Human Clinical
"Its hallmarks are severe hypogammaglobulinemia requiring immunoglobulin substitution, as well as impaired function of the thymus resulting in overall T cell lymphopenia"
Documents the overall T-cell lymphopenia.
Bone marrow failure Bone marrow hypocellularity HP:0005528 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone marrow failure, annotated with Bone marrow hypocellularity (HP:0005528). HP:0005528 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23950031 SUPPORT Human Clinical
"Two features of SIOD causing much morbidity and mortality are bone marrow failure and T-cell deficiency with the consequent opportunistic infections."
Names bone marrow failure as a major cause of morbidity.
PMID:10653321 SUPPORT Human Clinical
"We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies."
Documents the high incidence of blood cytopenias.
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Transient thrombocytopenia, annotated with Thrombocytopenia (HP:0001873), qualified as temporality transient. HP:0001873 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (1 reference)
PMID:39153074 SUPPORT Human Clinical
"Other symptoms may be present, including skin hyperpigmentations, refractory migraines, hypothyroidism or autoimmune diseases, mainly transient anemia or thrombocytopenia."
Documents transient thrombocytopenia (and anemia) among the autoimmune manifestations.
Non-Hodgkin lymphoma VERY_RARE HP:0012539 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-Hodgkin lymphoma (HP:0012539). HP:0012539 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22888040 SUPPORT Human Clinical
"Among 71 SIOD patients, three had non-Hodgkin lymphoma (NHL) and one had osteosarcoma."
3 of 71 patients (4%) had NHL, supporting the very-rare (1-4%) band while documenting the predisposition.
Cardiovascular 2
Cerebral ischemic events FREQUENT Cerebral ischemia HP:0002637 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral ischemic events (TIA/stroke), annotated with Cerebral ischemia (HP:0002637). HP:0002637 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:10653321 SUPPORT Human Clinical
"We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies."
Reports a high incidence of cerebral ischemia, supporting the frequent band.
PMID:23950031 SUPPORT Human Clinical
"Individuals affected with SIOD usually die within the first two decades of life from infections (23%), stroke (17%), renal failure (15%), pulmonary hypertension and congestive heart failure (15%), complications of organ transplantation (9%), complications of lymphoproliferative disease (9%),..."
Stroke accounts for 17% of deaths in SIOD.
Premature atherosclerosis FREQUENT HP:0002621 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature atherosclerosis, annotated with Atherosclerosis (HP:0002621). HP:0002621 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22998683 SUPPORT Human Clinical
"Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema."
32 of 63 patients (51%) had arteriosclerosis, supporting the frequent band.
PMID:16840568 SUPPORT Human Clinical
"As predicted by the clinical course, T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis, cerebral ischaemic lesions and premature atherosclerosis were identified."
Autopsy confirmation of premature atherosclerosis.
Endocrine 1
Hypothyroidism FREQUENT HP:0000821 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:10653321 SUPPORT Human Clinical
"We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies."
Reports a high incidence of thyroid dysfunction, supporting the frequent band.
PMID:20301550 SUPPORT Human Clinical
"agents that improve blood flow or decrease coagulability to treat transient ischemic attacks or strokes; blood pressure control; levothyroxine for hypothyroidism"
GeneReviews management includes levothyroxine for the hypothyroidism of SIOD.
Genitourinary 4
Steroid-resistant nephrotic syndrome VERY_FREQUENT HP:0012588 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Steroid-resistant nephrotic syndrome (HP:0012588). HP:0012588 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301550 SUPPORT Human Clinical
"Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease."
"Nearly all" supports the very-frequent band for steroid-resistant nephropathy.
PMID:18785907 SUPPORT Human Clinical
"The main clinical findings are spondyloepiphyseal dysplasia with disproportionate growth restriction, defective cellular immunity, and steroid-resistant nephrotic syndrome secondary to biopsy proven FSGS leading to ESRF."
Names steroid-resistant nephrotic syndrome as a main finding.
Focal segmental glomerulosclerosis HP:0000097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal segmental glomerulosclerosis (HP:0000097). HP:0000097 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25319549 SUPPORT Human Clinical
"Our analysis of SIOD patient renal biopsies demonstrates the tip and collapsing variants of focal segmental glomerulosclerosis (FSGS)."
Biopsy demonstration of FSGS variants in SIOD.
PMID:16840568 SUPPORT Human Clinical
"As predicted by the clinical course, T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis, cerebral ischaemic lesions and premature atherosclerosis were identified."
Autopsy confirmation of FSGS.
Proteinuria FREQUENT HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:10653321 SUPPORT Human Clinical
"The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia."
Proteinuria is one of the four characteristic features.
PMID:40004207 SUPPORT Human Clinical
"Proteinuria of varying severity was observed in 16 cases."
16 of 21 patients (76%) had proteinuria, supporting the frequent band.
End-stage renal disease VERY_FREQUENT Stage 5 chronic kidney disease HP:0003774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is End-stage renal disease, annotated with Stage 5 chronic kidney disease (HP:0003774). HP:0003774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301550 SUPPORT Human Clinical
"Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease."
"Nearly all" individuals progress to end-stage renal disease, supporting the very-frequent band.
Head and Neck 1
Characteristic facies Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Unusual facies, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10653321 SUPPORT Human Clinical
"The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia."
An unusual facies is a characteristic feature.
Immune 1
Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:10653321 SUPPORT Human Clinical
"The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia."
Recurrent infections are one of the characteristic features.
PMID:20301550 SUPPORT Human Clinical
"The majority of tested individuals have T cell deficiency and an associated risk for opportunistic infection, a common cause of death."
Documents the associated opportunistic-infection risk and its contribution to mortality.
Integument 2
Hyperpigmented macules Hypermelanotic macule HP:0001034 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperpigmented macules, annotated with Hypermelanotic macule (HP:0001034). HP:0001034 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:10653321 SUPPORT Human Clinical
"The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia."
Hyperpigmented macules are a characteristic feature.
PMID:2066860 SUPPORT Human Clinical
"we describe a disorder characterized by skeletal dysplasia, rapidly progressive nephropathy, episodes of lymphopenia, and pigmentary skin changes"
Pigmentary skin changes were part of the original disease description.
Sparse hair HP:0008070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse hair (HP:0008070). HP:0008070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22888040 SUPPORT Human Clinical
"Additional less prominent features include hyperpigmented macules, sparse hair, migraine-like headaches, atherosclerosis with cerebral ischemia, deficiency of other blood cell lineages, hypothyroidism, opportunistic infections, dental anomalies, corneal opacities, autoimmune enteropathy, and..."
Lists sparse hair among the recognized features of SIOD.
Musculoskeletal 1
Spondyloepiphyseal dysplasia VERY_FREQUENT HP:0002655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spondyloepiphyseal dysplasia (HP:0002655). HP:0002655 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:20301550 SUPPORT Human Clinical
"Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses."
GeneReviews radiographic definition of the SED.
PMID:20301550 SUPPORT Human Clinical
"Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T cell deficiency."
SED is a defining feature of the disease, supporting the very-frequent band.
PMID:20013129 SUPPORT Human Clinical
"We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal."
Defines the anatomical distribution of the SED.
Nervous System 1
Migraine-like headaches HP:0002076 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Migraine-like headaches, annotated with Migraine (HP:0002076). HP:0002076 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22888040 SUPPORT Human Clinical
"Additional less prominent features include hyperpigmented macules, sparse hair, migraine-like headaches, atherosclerosis with cerebral ischemia, deficiency of other blood cell lineages, hypothyroidism, opportunistic infections, dental anomalies, corneal opacities, autoimmune enteropathy, and..."
Lists migraine-like headaches among recognized features.
PMID:39153074 SUPPORT Human Clinical
"Other symptoms may be present, including skin hyperpigmentations, refractory migraines, hypothyroidism or autoimmune diseases, mainly transient anemia or thrombocytopenia."
Documents refractory migraines among the symptoms.
Growth 2
Disproportionate short stature VERY_FREQUENT Disproportionate short-trunk short stature HP:0003521 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disproportionate short-trunk short stature (HP:0003521). HP:0003521 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301550 SUPPORT Human Clinical
"Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T cell deficiency."
GeneReviews names SED-related short stature as a defining (characterizing) feature, supporting the very-frequent band.
PMID:18785907 SUPPORT Human Clinical
"The main clinical findings are spondyloepiphyseal dysplasia with disproportionate growth restriction, defective cellular immunity, and steroid-resistant nephrotic syndrome secondary to biopsy proven FSGS leading to ESRF."
Documents the disproportionate growth restriction.
Intrauterine growth retardation FREQUENT HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40004207 SUPPORT Human Clinical
"Many SIOD patients have intrauterine growth retardation, and they are usually intellectually intact"
"Many" patients supports the frequent band for intrauterine growth retardation.
🧬

Genetic Associations

1
SMARCAL1 (Biallelic germline loss-of-function variants in SMARCAL1 cause SIOD; genotype tracks with severity — biallelic nonsense/frameshift/splicing genotypes cause severe disease, biallelic missense variants retaining partial function cause milder disease.)
Gene: SMARCAL1 hgnc:11102 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SMARCAL1 (hgnc:11102). hgnc:11102 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:11799392 SUPPORT Human Clinical
"Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD."
Establishes SMARCAL1 as the causative gene.
PMID:11799392 SUPPORT Human Clinical
"affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele"
Documents the genotype-severity correlation.
PMID:40004207 SUPPORT Human Clinical
"the most common was c.2542G>T, resulting in premature translation termination (p.E848*), and it was found in 14 patients either in a homozygous (four patients) or compound-heterozygous (10 patients) state"
Documents the recurrent founder truncating variant.
+ 1 more reference
💊

Medical Actions

5
Kidney transplantation
Action: kidney transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is kidney transplantation (NCIT:C15265). NCIT:C15265 is a clinical intervention from the NCI Thesaurus. Ontology label: Kidney Transplantation NCIT:C15265
Platform: Surgery
Kidney transplantation is the therapy of choice for the end-stage renal failure of SIOD because FSGS does not recur in the graft; GeneReviews recommends transplantation with mild immunosuppressive therapy given the underlying immunodeficiency.
Mechanism Target:
BYPASSES Podocyte Injury and Glomerulosclerosis — Transplantation replaces the sclerosed kidney rather than correcting the SMARCAL1 defect; because the podocytopathy is cell-autonomous, FSGS does not recur in the donor graft.
Show evidence (1 reference)
PMID:18785907 SUPPORT Human Clinical
"Concerning ESRF, kidney transplantation is the therapy of choice since FSGS does not recur in the graft."
Transplantation bypasses the intrinsic podocytopathy, and the disease does not recur in donor tissue.
Show evidence (2 references)
PMID:18785907 SUPPORT Human Clinical
"Concerning ESRF, kidney transplantation is the therapy of choice since FSGS does not recur in the graft."
Establishes kidney transplantation as the therapy of choice.
PMID:20301550 SUPPORT Human Clinical
"renal transplantation as indicated using mild immunosuppressive therapy"
GeneReviews management recommendation for renal transplantation.
Minimized post-transplant immunosuppression
Action: immunosuppressive therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunosuppressive therapy (NCIT:C15261). NCIT:C15261 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunosuppressive Therapy NCIT:C15261
Because of the underlying T-cell immunodeficiency, conventional combination immunosuppression after renal transplantation has led to severe disseminated cutaneous papillomavirus infections and EBV-associated lymphoproliferative disease; immunosuppressive monotherapy maintenance gives good graft outcomes with fewer severe infections, and limited immunosuppression appears possible without increased rejection risk.
Show evidence (2 references)
PMID:18785907 SUPPORT Human Clinical
"We have found that post-renal transplantation immunosuppressive monotherapy results in a good outcome with a reduced number of severe infections."
Supports monotherapy maintenance immunosuppression in SIOD.
PMID:18785907 SUPPORT Human Clinical
"Under conventional immunosuppressive regimens some SIOD patients have developed severe disseminated cutaneous papilloma virus infections or EBV associated lymphoproliferative disease."
Documents the infectious complications of conventional-intensity immunosuppression that motivate minimization.
Hematopoietic stem cell transplantation
Action: hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
HSCT is a potential definitive therapy for the T-cell immunodeficiency and bone marrow failure, but the historical experience is poor: only one of the first five transplanted patients survived, with the four deaths following myeloablative conditioning — a toxicity plausibly linked to the hypersensitivity of SMARCAL1-deficient cells to DNA-damaging agents. Reduced-intensity conditioning with alpha-beta T-cell-depleted haploidentical grafts underlies the more recent successes.
Mechanism Target:
RESTORES Thymic T-cell Development Failure — Successful engraftment replaces the SMARCAL1-deficient hematopoietic compartment, restoring T-cell immunity; full donor chimerism has been achieved with reduced-intensity haploidentical protocols.
Show evidence (1 reference)
PMID:35704481 SUPPORT Human Clinical
"Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation."
Demonstrates full donor hematopoietic reconstitution in SIOD patients after reduced-intensity haploidentical HSCT.
Show evidence (3 references)
PMID:23950031 SUPPORT Human Clinical
"We find that only one patient survived the transplantation procedure and that the existing indicators of a good prognosis for bone marrow transplantation were not predictive in this small cohort."
Documents the very high procedure-related mortality of early BMT in SIOD, the stated caveat for this treatment.
PMID:35704481 SUPPORT Human Clinical
"Previously, four of five patients with SIOD who underwent HSCT after myeloablative conditioning died from HSCT-related causes, including infections and GVHD"
Attributes the historical HSCT deaths to myeloablative-conditioning-era protocols.
PMID:20301550 SUPPORT Human Clinical
"hematopoietic stem cell transplantation as indicated"
GeneReviews lists HSCT among management options as indicated.
Sequential haploidentical HSCT and kidney transplantation
Action: sequential stem cell and kidney transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is sequential stem cell and kidney transplantation, annotated with Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Sequential transplantation of alpha-beta T-cell-depleted, CD19 B-cell-depleted haploidentical hematopoietic stem cells followed by a kidney from the same donor established full donor chimerism and immune tolerance in three children with SIOD, who maintained normal renal function without any immunosuppression at 22 to 34 months — addressing the immunodeficiency and the renal failure with a single donor while eliminating post-transplant immunosuppression.
Mechanism Target:
RESTORES Thymic T-cell Development Failure — The haploidentical HSCT arm replaces the defective hematopoietic and immune compartment.
Show evidence (1 reference)
PMID:35704481 SUPPORT Human Clinical
"Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation."
Documents immune reconstitution with donor chimerism and tolerance.
BYPASSES Podocyte Injury and Glomerulosclerosis — The same-donor kidney replaces the failed organ, and the induced tolerance removes the need for maintenance immunosuppression.
Show evidence (1 reference)
PMID:35704481 SUPPORT Human Clinical
"Each patient received sequential transplants of αβ T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor."
Describes the sequential same-donor stem cell and kidney transplantation strategy.
Show evidence (1 reference)
PMID:35704481 SUPPORT Human Clinical
"Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation."
Reports the immunosuppression-free outcome of sequential stem cell-kidney transplantation in three SIOD patients.
Supportive and preventive management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Multidisciplinary supportive care includes acyclovir for recurrent herpetic infections, imiquimod and cidofovir for severe disseminated cutaneous papillomavirus infections, G-CSF or GM-CSF for neutropenia, levothyroxine for hypothyroidism, agents that improve blood flow or reduce coagulability for ischemic events, and blood-pressure control. Live-attenuated vaccines should be avoided in T-cell-deficient patients; hypertension, heat, stress, and sleep deprivation can precipitate neurovascular events; and DNA-damaging anti-cancer therapies must be used with caution given the genotoxic hypersensitivity.
Show evidence (2 references)
PMID:20301550 SUPPORT Human Clinical
"acyclovir for recurrent herpetic infections and/or shingles; imiquimod and cidofovir for severe disseminated cutaneous papilloma virus infections"
GeneReviews anti-infective supportive measures.
PMID:20301550 SUPPORT Human Clinical
"Avoid hypertension; heat, stress, and lack of sleep; and live attenuated immunizations in those who are T cell deficient. Use DNA-damaging anti-cancer therapies with caution due to evidence of susceptibility to genotoxic agents."
GeneReviews agents/circumstances to avoid, including the genotoxic caution that follows from the replication-stress mechanism.
🔬

Diagnosis

1
Clinical, laboratory, and radiographic diagnosis with molecular confirmation
The diagnosis is established in a proband with the characteristic combination of spondyloepiphyseal dysplasia, progressive steroid-resistant nephropathy, and T-cell deficiency — clinical, laboratory, and radiographic features — and/or biallelic pathogenic SMARCAL1 variants on molecular genetic testing. Molecular confirmation matters because a fraction of clinically typical cases have no detectable SMARCAL1 variant.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301550 SUPPORT Human Clinical
"The diagnosis of SIOD is established in a proband with the characteristic clinical, laboratory, and radiographic features and/or biallelic pathogenic variants in SMARCAL1 identified on molecular genetic testing."
GeneReviews states the diagnostic criterion: characteristic features and/or biallelic SMARCAL1 variants.
📈

Progression

2
Severe infantile-onset form
Age: In utero / infantile onset; death usually within the first two decades
The severe end of the spectrum presents in utero or in infancy, is usually associated with biallelic nonsense, frameshift, or splicing SMARCAL1 variants, and carries a high risk of death in childhood from infection, stroke, renal failure, or cardiopulmonary complications; the mean age of death across reported patients is about 10.8-11 years.
Show evidence (3 references)
PMID:20301550 SUPPORT Human Clinical
"SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated."
GeneReviews defines the severe early-onset end of the SIOD spectrum.
PMID:23950031 SUPPORT Human Clinical
"Individuals affected with SIOD usually die within the first two decades of life from infections (23%), stroke (17%), renal failure (15%), pulmonary hypertension and congestive heart failure (15%), complications of organ transplantation (9%), complications of lymphoproliferative disease (9%),..."
Documents the early mortality and its cause-of-death distribution in SIOD.
PMID:22888040 SUPPORT Human Clinical
"The mean age of death among SIOD patients is 10.8 years (range: 3-28 years)."
Quantifies the mean age of death across reported patients.
Milder later-onset form
Age: Juvenile onset; survival into adulthood possible
The milder end of the spectrum, typically associated with biallelic missense variants retaining partial SMARCAL1 function, presents later and is compatible with survival into adulthood when the renal disease is appropriately treated; survival beyond 20 years is reported.
Show evidence (3 references)
PMID:20301550 SUPPORT Human Clinical
"SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated."
GeneReviews defines the milder later-onset end of the spectrum.
PMID:40004207 SUPPORT Human Clinical
"whereas some patients develop a severe form of the disease with in utero onset, individuals with mild cases of SIOD might survive into adulthood, and cases of survival for more than 20 years have been reported"
Documents survival into adulthood at the mild end of the spectrum.
PMID:11799392 SUPPORT Human Clinical
"These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease."
Links the milder course to missense alleles retaining partial SMARCAL1 function.
📊

Prevalence

1
Worldwide
Birth Prevalence 0.033–0.1 per 100,000 <1 in 1,000,000 (births)
Estimated incidence of approximately 1 per 1-3 million live births (0.033-0.1 per 100,000). Among genetically determined nephrotic syndrome, SIOD accounts for 2.4-9.4% of cases. The Orphanet code for SIOD is ORPHA:1830 (MONDO xref); a structured Orphadata cache entry was not available at curation time, so the rate is anchored to the literature.
Show evidence (1 reference)
PMID:40004207 SUPPORT Human Clinical
"SIOD is an ultra-rare condition, with an incidence of ~1 per 1-3 million live births"
Direct source for the birth incidence band converted to the rate range here.
{ }

Source YAML

click to show 
name: Schimke immuno-osseous dysplasia
creation_date: "2026-08-29T00:00:00Z"
category: Genetic
description: >-
  Schimke immuno-osseous dysplasia (SIOD) is an ultra-rare autosomal recessive
  pleiotropic disorder caused by biallelic loss-of-function variants in
  SMARCAL1, which encodes an ATP-driven annealing helicase that stabilizes and
  restarts stalled replication forks. Loss of this genome-maintenance activity
  produces replication stress and DNA-damage accumulation that preferentially
  injures highly proliferative and replication-stress-sensitive compartments:
  growth-plate chondrocytes (spondyloepiphyseal dysplasia with disproportionate
  short-trunk short stature), podocytes (steroid-resistant nephrotic syndrome
  from focal segmental glomerulosclerosis progressing to end-stage renal
  disease), thymocytes and T cells (T-cell lymphopenia with IL7R promoter
  hypermethylation and recurrent, sometimes opportunistic, infections), and the
  vasculature (defective elastogenesis with premature arteriosclerosis and
  cerebral ischemic events). Additional features include hyperpigmented
  macules, an unusual facies, hypothyroidism, cytopenias and bone marrow
  failure, migraine-like headaches, and a predisposition to non-Hodgkin
  lymphoma. The disease spans a spectrum from a severe infantile-onset form
  that is usually lethal in childhood to a milder later-onset form compatible
  with survival into adulthood when renal disease is treated; disease severity
  correlates inversely with residual SMARCAL1 activity. Kidney transplantation
  (FSGS does not recur in the graft) with minimized immunosuppression is the
  mainstay for renal failure; conventional myeloablative HSCT has carried very
  high mortality, attributed to the hypersensitivity of SMARCAL1-deficient
  cells to genotoxic agents, while sequential reduced-intensity haploidentical
  HSCT and kidney transplantation from the same donor has achieved
  immunosuppression-free renal function in early reports.
synonyms:
- SIOD
- Schimke syndrome
- Schimke immunoosseous dysplasia
- immunoosseous dysplasia Schimke type
- spondyloepiphyseal dysplasia-nephrotic syndrome
disease_term:
  preferred_term: Schimke immuno-osseous dysplasia
  term:
    id: MONDO:0009458
    label: Schimke immuno-osseous dysplasia
parents:
- immuno-osseous dysplasia
- spondyloepiphyseal dysplasia
- osteochondrodysplasia
- autosomal recessive disease
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Mendelian (autosomal recessive) multisystem disorder of a single
      chromatin-associated genome-maintenance gene.
    evidence:
    - reference: PMID:11799392
      reference_title: "Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency."
      explanation: >-
        Establishes SIOD as a monogenic autosomal recessive pleiotropic
        disorder, the basis for the hereditary-disease placement.
  - classification_value: KIDNEY_URINARY_TRACT
    notes: >-
      Progressive steroid-resistant nephropathy terminating in end-stage renal
      disease is a near-universal, management-defining axis of the disease.
    evidence:
    - reference: PMID:20301550
      reference_title: "Schimke Immunoosseous Dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease."
      explanation: >-
        GeneReviews documents the progressive nephropathy that anchors the
        kidney/urinary-tract placement.
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    notes: >-
      IUIS 2022 phenotypic classification (Tangye et al., PMID:35748970),
      Table 2 (combined immunodeficiencies with associated or syndromic
      features), immuno-osseous dysplasias: listed as "Schimke Immuno-osseous
      dysplasia" (SMARCAL1, AR, MIM 606622) alongside cartilage-hair
      hypoplasia.
    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: "Schimke Immuno-osseous dysplasia SMARCAL1 AR 606622 Decreased Normal Normal Short stature, spondyloepiphyseal dysplasia, intrauterine growth retardation; nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure"
      explanation: >-
        The IUIS 2022 classification table row for SIOD in the syndromic
        combined immunodeficiency (immuno-osseous dysplasia) group.
    - reference: PMID:39153074
      reference_title: "Profound T Lymphocyte and DNA Repair Defect Characterizes Schimke Immuno-Osseous Dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Immunodeficiency is a prevalent and pronounced symptom of SIOD, affecting both cellular and humoral immunity and leading to the disease being classified as an inborn error of immunity according to the International Union of Immunological Societies (IUIS) classification published in 2022"
      explanation: >-
        Independently documents that SIOD is classified as an inborn error of
        immunity in the IUIS 2022 classification.
  isds_skeletal_category:
  - classification_value: spondylo_epi_metaphyseal_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et
      al., PMID:36779427), group 13 "Spondyloepi(meta)physeal dysplasias
      (SE(M)D)"; listed as immuno-osseous dysplasia (Schimke).
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    SIOD is inherited in an autosomal recessive manner; affected individuals
    carry biallelic SMARCAL1 pathogenic variants and each sib of an affected
    individual has a 25% recurrence risk at conception.
  evidence:
  - reference: PMID:11799392
    reference_title: "Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency."
    explanation: States the autosomal recessive inheritance of SIOD.
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SIOD is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the inheritance pattern directly.
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_low: 0.033
  rate_high: 0.1
  notes: >-
    Estimated incidence of approximately 1 per 1-3 million live births
    (0.033-0.1 per 100,000). Among genetically determined nephrotic syndrome,
    SIOD accounts for 2.4-9.4% of cases. The Orphanet code for SIOD is
    ORPHA:1830 (MONDO xref); a structured Orphadata cache entry was not
    available at curation time, so the rate is anchored to the literature.
  evidence:
  - reference: PMID:40004207
    reference_title: "Genetic and Clinical Features of Schimke Immuno-Osseous Dysplasia: Single-Centre Retrospective Study of 21 Unrelated Paediatric Patients over a Period of 20 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SIOD is an ultra-rare condition, with an incidence of ~1 per 1-3 million live births"
    explanation: >-
      Direct source for the birth incidence band converted to the rate range
      here.
progression:
- phase: Severe infantile-onset form
  age_range: In utero / infantile onset; death usually within the first two decades
  notes: >-
    The severe end of the spectrum presents in utero or in infancy, is usually
    associated with biallelic nonsense, frameshift, or splicing SMARCAL1
    variants, and carries a high risk of death in childhood from infection,
    stroke, renal failure, or cardiopulmonary complications; the mean age of
    death across reported patients is about 10.8-11 years.
  evidence:
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated."
    explanation: >-
      GeneReviews defines the severe early-onset end of the SIOD spectrum.
  - reference: PMID:23950031
    reference_title: "Bone marrow transplantation in Schimke immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with SIOD usually die within the first two decades of life from infections (23%), stroke (17%), renal failure (15%), pulmonary hypertension and congestive heart failure (15%), complications of organ transplantation (9%), complications of lymphoproliferative disease (9%), gastrointestinal bleeding (6%), bone marrow failure (3%), and unspecified acute restrictive lung disease (3%)"
    explanation: >-
      Documents the early mortality and its cause-of-death distribution in
      SIOD.
  - reference: PMID:22888040
    reference_title: "SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean age of death among SIOD patients is 10.8 years (range: 3-28 years)."
    explanation: Quantifies the mean age of death across reported patients.
- phase: Milder later-onset form
  age_range: Juvenile onset; survival into adulthood possible
  notes: >-
    The milder end of the spectrum, typically associated with biallelic
    missense variants retaining partial SMARCAL1 function, presents later and
    is compatible with survival into adulthood when the renal disease is
    appropriately treated; survival beyond 20 years is reported.
  evidence:
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated."
    explanation: GeneReviews defines the milder later-onset end of the spectrum.
  - reference: PMID:40004207
    reference_title: "Genetic and Clinical Features of Schimke Immuno-Osseous Dysplasia: Single-Centre Retrospective Study of 21 Unrelated Paediatric Patients over a Period of 20 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whereas some patients develop a severe form of the disease with in utero onset, individuals with mild cases of SIOD might survive into adulthood, and cases of survival for more than 20 years have been reported"
    explanation: Documents survival into adulthood at the mild end of the spectrum.
  - reference: PMID:11799392
    reference_title: "Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease."
    explanation: >-
      Links the milder course to missense alleles retaining partial SMARCAL1
      function.
pathophysiology:
- name: SMARCAL1 Annealing Helicase Deficiency
  biological_scale: MOLECULAR
  description: >-
    Biallelic loss-of-function SMARCAL1 variants abolish or reduce the
    SMARCAL1 (HARP) protein, an SNF2-family ATP-driven annealing helicase that
    rewinds RPA-stabilized single-stranded DNA bubbles at replication forks.
    Disease-associated mutations impair SMARCAL1 expression, stability,
    chromatin binding, and ATPase/annealing activity, and residual overall
    SMARCAL1 activity is inversely proportional to disease severity.
  genetic_context:
    gene:
      preferred_term: SMARCAL1
      term:
        id: hgnc:11102
        label: SMARCAL1
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline loss-of-function variants; nonsense/frameshift/splice
      genotypes cause severe disease, whereas biallelic missense variants
      retaining partial function cause milder disease.
  molecular_functions:
  - preferred_term: annealing helicase activity
    term:
      id: GO:0036310
      label: ATP-dependent DNA/DNA annealing activity
    modifier: DECREASED
  evidence:
  - reference: PMID:11799392
    reference_title: "Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD."
    explanation: Identifies SMARCAL1 mutations as the cause of SIOD.
  - reference: PMID:18974355
    reference_title: "HARP is an ATP-driven annealing helicase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that HARP is an ATP-dependent annealing helicase that rewinds single-stranded DNA bubbles that are stably bound by replication protein A."
    explanation: >-
      Defines the molecular activity of SMARCAL1/HARP that is lost in SIOD.
  - reference: PMID:18974355
    reference_title: "HARP is an ATP-driven annealing helicase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Analysis of mutant HARP proteins suggests that SIOD is caused by a deficiency in annealing helicase activity."
    explanation: >-
      Attributes SIOD to deficient annealing helicase activity of the mutant
      proteins.
  - reference: PMID:18805831
    reference_title: "Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The SIOD associated SMARCAL1 mutations affected SMARCAL1 protein expression, stability, subcellular localisation, chromatin binding, and enzymatic activity."
    explanation: >-
      Documents the multiple molecular defects produced by SIOD-associated
      SMARCAL1 mutations.
  - reference: PMID:18805831
    reference_title: "Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Further, expressing SMARCAL1 missense mutants in Drosophila melanogaster showed that disease severity was inversely proportionate to overall SMARCAL1 activity."
    explanation: >-
      In vivo Drosophila assay showing residual SMARCAL1 activity tracks
      inversely with disease severity.
  downstream:
  - target: Replication Stress and Genome Instability
    causal_link_type: DIRECT
    description: >-
      Loss of the annealing helicase removes a replication stress response
      protein that maintains genome integrity at stalled replication forks,
      producing replication-associated DNA damage.
    evidence:
    - reference: PMID:19793861
      reference_title: "The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Thus, SMARCAL1 is a replication stress response protein, and the pleiotropic phenotypes of SIOD are at least partly due to defects in genome maintenance during DNA replication."
      explanation: >-
        Directly links SMARCAL1 loss to defective genome maintenance during
        replication as the proximate disease mechanism.
  - target: Defective Elastogenesis and Premature Arteriosclerosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      SMARCAL1 is expressed in arterial and lung tissue, and SMARCAL1-deficient
      aorta and lung show reduced elastin expression with altered expression of
      elastin-gene regulators; the intermediate steps from SMARCAL1 loss to the
      transcriptional deficit are not established.
    evidence:
    - reference: PMID:22998683
      reference_title: "Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression."
      explanation: >-
        Connects SMARCAL1 deficiency in vascular tissue to reduced elastin
        expression.
- name: Replication Stress and Genome Instability
  biological_scale: CELLULAR
  description: >-
    SMARCAL1-deficient cells activate the DNA damage response during S phase
    without exogenous genotoxins, show slower replication fork recovery and
    delayed mitotic entry after S-phase arrest, and are hypersensitive to
    replication stress and DNA-damaging agents in vitro and in vivo. This
    replication stress preferentially compromises highly proliferative
    compartments (growth plate, glomerulus, thymus/lymphocytes, marrow) and
    underlies the hypersensitivity to genotoxic therapies observed clinically.
  biological_processes:
  - preferred_term: replication fork processing
    term:
      id: GO:0031297
      label: replication fork processing
    modifier: DECREASED
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  evidence:
  - reference: PMID:19793861
    reference_title: "The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, SMARCAL1-deficient cells are hypersensitive to replication stress agents."
    explanation: >-
      Documents replication-stress hypersensitivity of SMARCAL1-deficient
      cells.
  - reference: PMID:19793862
    reference_title: "The SIOD disorder protein SMARCAL1 is an RPA-interacting protein involved in replication fork restart."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SMARCAL1-depleted cells display sensitivity to DNA-damaging agents that induce replication fork collapse, and exhibit slower fork recovery and delayed entry into mitosis following S-phase arrest."
    explanation: >-
      Documents defective replication fork recovery in SMARCAL1-deficient
      cells.
  - reference: PMID:22888040
    reference_title: "SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We did not find evidence of defective NER or NHEJ; however, Smarcal1-deficient mice were hypersensitive to several genotoxic agents."
    explanation: >-
      Confirms in vivo hypersensitivity of Smarcal1-deficient mice to
      genotoxic agents.
  - reference: PMID:25319549
    reference_title: "Insights into the renal pathogenesis in Schimke immuno-osseous dysplasia: A renal histological characterization and expression analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In renal biopsies from SIOD patients, TUNEL analysis detected marked increases in DNA fragmentation."
    explanation: >-
      Demonstrates DNA damage accumulation in affected patient tissue.
  downstream:
  - target: Impaired Chondrogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Replication stress compromises proliferating growth-plate chondrocytes;
      genotoxic agents reproduce growth-plate chondrocyte loss in
      Smarcal1-deficient mice.
    evidence:
    - reference: PMID:22888040
      reference_title: "SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Also, CPT-11, etoposide, and HU caused decreased growth and loss of growth plate chondrocytes."
      explanation: >-
        Genotoxic stress in Smarcal1-deficient mice produces growth-plate
        chondrocyte loss and decreased growth, linking replication stress to
        the skeletal arm.
  - target: Podocyte Injury and Glomerulosclerosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Genomic instability in the developing and mature kidney, evidenced by
      markedly increased DNA fragmentation in patient renal biopsies, is
      proposed to drive the podocytopathy.
    evidence:
    - reference: PMID:25319549
      reference_title: "Insights into the renal pathogenesis in Schimke immuno-osseous dysplasia: A renal histological characterization and expression analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Further, we suggest that disruptions in genomic integrity during fetal kidney development contribute to the pathogenesis of FSGS in SIOD patients."
      explanation: >-
        Proposes genomic-integrity disruption as the driver of FSGS in SIOD
        kidneys.
  - target: Thymic T-cell Development Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Replication and DNA-damage stress in thymocytes and T cells, together
      with epigenetic silencing of IL7R, restricts T-cell production; patient T
      cells show markedly increased apoptosis after DNA damage.
    evidence:
    - reference: PMID:39153074
      reference_title: "Profound T Lymphocyte and DNA Repair Defect Characterizes Schimke Immuno-Osseous Dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "UV light irradiation caused a severe increase in the apoptosis of T cells"
      explanation: >-
        Patient T cells are hypersensitive to DNA damage, linking the
        genome-maintenance defect to the T-cell compartment.
  - target: Non-Hodgkin lymphoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Genome instability predisposes to malignancy; NHL is the most commonly
      reported cancer in SIOD cohorts.
    evidence:
    - reference: PMID:22888040
      reference_title: "SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Among 71 SIOD patients, three had non-Hodgkin lymphoma (NHL) and one had osteosarcoma."
      explanation: >-
        Documents the increased prevalence of NHL in a large SIOD cohort,
        interpreted by the authors as a consequence of the DNA stress response
        defect.
- name: Impaired Chondrogenesis
  biological_scale: TISSUE
  description: >-
    Defective chondrogenesis with loss of proliferating growth-plate
    chondrocytes underlies the spondyloepiphyseal dysplasia. Autopsy studies
    identify defective chondrogenesis and suggest a regulatory role for
    SMARCAL1 in chondrocyte proliferation; the resulting dysplasia
    predominantly involves the vertebrae, pelvis, and capital femoral
    epiphyses, producing short-trunk disproportionate growth failure.
  cell_types:
  - preferred_term: growth plate chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: chondrocyte proliferation
    term:
      id: GO:0035988
      label: chondrocyte proliferation
    modifier: DECREASED
  - preferred_term: cartilage development
    term:
      id: GO:0051216
      label: cartilage development
    modifier: DECREASED
  evidence:
  - reference: PMID:16840568
    reference_title: "Schimke immuno-osseous dysplasia: a clinicopathological correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As predicted by the clinical course, T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis, cerebral ischaemic lesions and premature atherosclerosis were identified."
    explanation: Autopsy confirmation of defective chondrogenesis in SIOD.
  - reference: PMID:16840568
    reference_title: "Schimke immuno-osseous dysplasia: a clinicopathological correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A regulatory role for the SMARCAL1 protein in the proliferation of chondrocytes, lymphocytes and spermatozoa, as well as in the development or maintenance of cardiomyocytes and in vascular homoeostasis, is suggested."
    explanation: >-
      Implicates SMARCAL1 in chondrocyte proliferation, the cellular basis of
      the impaired chondrogenesis.
  downstream:
  - target: Spondyloepiphyseal dysplasia
    causal_link_type: DIRECT
    description: >-
      Defective chondrogenesis of vertebral and proximal epiphyseal growth
      centers produces the characteristic spondyloepiphyseal dysplasia.
    evidence:
    - reference: PMID:20013129
      reference_title: "Schimke immunoosseous dysplasia: defining skeletal features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal."
      explanation: >-
        Radiographic definition of the SED produced by the skeletal arm of the
        disease.
  - target: Disproportionate short stature
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The spondyloepiphyseal dysplasia, with primary involvement of vertebrae
      and proximal epiphyses, results in short-trunk disproportionate growth
      failure.
    evidence:
    - reference: PMID:20013129
      reference_title: "Schimke immunoosseous dysplasia: defining skeletal features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the spondyloepiphyseal dysplasias (SEDs) are characterized by primary involvement of the vertebrae and proximal epiphyseal centers resulting in a short-trunk disproportionate dwarfism"
      explanation: >-
        Explains how the SED yields disproportionate short-trunk short
        stature.
- name: Podocyte Injury and Glomerulosclerosis
  biological_scale: TISSUE
  description: >-
    The nephropathy of SIOD is a podocytopathy. SMARCAL1 is expressed in
    podocytes and glomerular endothelial cells; patient biopsies show the tip
    and collapsing variants of focal segmental glomerulosclerosis with
    ultrastructural podocyte and Bowman's-capsule abnormalities, and the
    podocytopathy usually progresses through FSGS to end-stage kidney disease.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  evidence:
  - reference: PMID:25319549
    reference_title: "Insights into the renal pathogenesis in Schimke immuno-osseous dysplasia: A renal histological characterization and expression analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis of SIOD patient renal biopsies demonstrates the tip and collapsing variants of focal segmental glomerulosclerosis (FSGS)."
    explanation: Histological characterization of the SIOD renal lesion.
  - reference: PMID:25319549
    reference_title: "Insights into the renal pathogenesis in Schimke immuno-osseous dysplasia: A renal histological characterization and expression analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, electron microscopy revealed numerous glomerular abnormalities most notably in the podocyte and Bowman's capsule."
    explanation: Ultrastructural localization of the injury to the podocyte.
  - reference: PMID:35704481
    reference_title: "Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The nephrotic syndrome in SIOD is a podocytopathy that usually progresses to focal segmental glomerulosclerosis and end-stage kidney disease."
    explanation: >-
      Frames the SIOD nephropathy as a podocytopathy progressing through FSGS
      to end-stage kidney disease.
  downstream:
  - target: Focal segmental glomerulosclerosis
    causal_link_type: DIRECT
    description: >-
      Podocyte injury and loss produce segmental scarring of glomeruli — the
      tip and collapsing FSGS variants seen on biopsy.
    evidence:
    - reference: PMID:25319549
      reference_title: "Insights into the renal pathogenesis in Schimke immuno-osseous dysplasia: A renal histological characterization and expression analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our analysis of SIOD patient renal biopsies demonstrates the tip and collapsing variants of focal segmental glomerulosclerosis (FSGS)."
      explanation: Biopsy demonstration of FSGS as the renal lesion of SIOD.
  - target: Steroid-resistant nephrotic syndrome
    causal_link_type: DIRECT
    description: >-
      The podocytopathy manifests clinically as proteinuria and nephrotic
      syndrome that does not respond to corticosteroids.
    evidence:
    - reference: PMID:18785907
      reference_title: "Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke-immuno-osseous dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The main clinical findings are spondyloepiphyseal dysplasia with disproportionate growth restriction, defective cellular immunity, and steroid-resistant nephrotic syndrome secondary to biopsy proven FSGS leading to ESRF."
      explanation: >-
        Attributes the steroid-resistant nephrotic syndrome to biopsy-proven
        FSGS.
  - target: End-stage renal disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The steroid-resistant nephropathy progresses through FSGS to end-stage
      renal disease, usually within five years of the diagnosis of growth
      failure.
    evidence:
    - reference: PMID:20301550
      reference_title: "Schimke Immunoosseous Dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease."
      explanation: >-
        Documents the near-universal progression to end-stage renal disease.
- name: Thymic T-cell Development Failure
  biological_scale: CELLULAR
  description: >-
    T-cell production fails at the level of the thymus. SIOD patient T cells
    have undetectable IL-7 receptor alpha chain (IL7Rα) protein and mRNA with
    hypermethylation of the IL7R promoter and are unresponsive to IL-7,
    restricting T-cell development; residual peripheral T cells are skewed to
    mature/memory phenotypes with exhaustion features. B-cell numbers and
    immunoglobulins are comparatively preserved early, though
    hypogammaglobulinemia — aggravated by nephrotic protein loss — is a
    hallmark of the combined immunodeficiency.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  biological_processes:
  - preferred_term: T cell differentiation in thymus
    term:
      id: GO:0033077
      label: T cell differentiation in thymus
    modifier: DECREASED
  - preferred_term: T cell homeostasis
    term:
      id: GO:0043029
      label: T cell homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:26499378
    reference_title: "Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor."
    explanation: >-
      Documents the loss of functional IL-7 receptor on SIOD T cells.
  - reference: PMID:26499378
    reference_title: "Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients."
    explanation: >-
      Proposes epigenetic IL7R silencing as the mechanism restricting T-cell
      development.
  - reference: PMID:39153074
    reference_title: "Profound T Lymphocyte and DNA Repair Defect Characterizes Schimke Immuno-Osseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Its hallmarks are severe hypogammaglobulinemia requiring immunoglobulin substitution, as well as impaired function of the thymus resulting in overall T cell lymphopenia"
    explanation: >-
      Attributes the T-cell lymphopenia to impaired thymic function and notes
      the accompanying humoral deficiency.
  downstream:
  - target: T-cell lymphopenia
    causal_link_type: DIRECT
    description: >-
      Restricted thymic T-cell development produces the characteristic
      progressive T-cell lymphopenia.
    evidence:
    - reference: PMID:39153074
      reference_title: "Profound T Lymphocyte and DNA Repair Defect Characterizes Schimke Immuno-Osseous Dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Its hallmarks are severe hypogammaglobulinemia requiring immunoglobulin substitution, as well as impaired function of the thymus resulting in overall T cell lymphopenia"
      explanation: >-
        Links impaired thymic function to the overall T-cell lymphopenia.
  - target: Recurrent infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      T-cell deficiency, aggravated by antibody loss from nephrotic syndrome
      and immunosuppressive treatment, causes recurrent and opportunistic
      infections — the leading cause of death.
    evidence:
    - reference: PMID:26499378
      reference_title: "Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear."
      explanation: >-
        States that recurrent infection results from the T-cell deficiency and
        drives morbidity and mortality.
- name: Defective Elastogenesis and Premature Arteriosclerosis
  biological_scale: TISSUE
  description: >-
    Reduced elastin expression in aorta and lung, with altered expression of
    regulators of elastin gene expression, produces an arteriosclerosis
    characterized by intimal and medial hyperplasia, smooth muscle cell
    hyperplasia and fragmented, disorganized elastin fibers, and an
    emphysema-like panlobular enlargement of air spaces. Vascular disease —
    including premature atherosclerosis and cerebral vaso-occlusion — is a
    major cause of morbidity and mortality.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  biological_processes:
  - preferred_term: elastic fiber assembly
    term:
      id: GO:0048251
      label: elastic fiber assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:22998683
    reference_title: "Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces."
    explanation: >-
      Histopathological definition of the vascular and pulmonary lesions.
  - reference: PMID:22998683
    reference_title: "Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression."
    explanation: >-
      Attributes the lesions to reduced elastogenesis in SMARCAL1-deficient
      tissue.
  downstream:
  - target: Premature atherosclerosis
    causal_link_type: DIRECT
    description: >-
      The elastin-deficient arteriopathy manifests as premature
      atherosclerosis/arteriosclerosis, present in about half of evaluable
      patients.
    evidence:
    - reference: PMID:22998683
      reference_title: "Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema."
      explanation: Quantifies arteriosclerosis prevalence in the SIOD cohort.
  - target: Cerebral ischemic events
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Cerebral vaso-occlusive disease on the background of the arteriopathy
      produces transient ischemic attacks and strokes.
    evidence:
    - reference: PMID:16840568
      reference_title: "Schimke immuno-osseous dysplasia: a clinicopathological correlation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As predicted by the clinical course, T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis, cerebral ischaemic lesions and premature atherosclerosis were identified."
      explanation: >-
        Autopsy demonstration of cerebral ischemic lesions together with
        premature atherosclerosis.
phenotypes:
- name: Disproportionate short stature
  description: >-
    Growth failure with short-trunk disproportionate short stature is the
    presenting feature in most patients, produced by the spondyloepiphyseal
    dysplasia; intrauterine growth retardation frequently precedes it.
  phenotype_term:
    preferred_term: Disproportionate short-trunk short stature
    term:
      id: HP:0003521
      label: Disproportionate short-trunk short stature
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T cell deficiency."
    explanation: >-
      GeneReviews names SED-related short stature as a defining
      (characterizing) feature, supporting the very-frequent band.
  - reference: PMID:18785907
    reference_title: "Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke-immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical findings are spondyloepiphyseal dysplasia with disproportionate growth restriction, defective cellular immunity, and steroid-resistant nephrotic syndrome secondary to biopsy proven FSGS leading to ESRF."
    explanation: Documents the disproportionate growth restriction.
- name: Spondyloepiphyseal dysplasia
  description: >-
    The skeletal dysplasia is essentially limited to the spine, pelvis, and
    capital femoral epiphyses: ovoid and mildly flattened vertebral bodies,
    small ilia with shallow dysplastic acetabular fossae, and small deformed
    capital femoral epiphyses; hands and other long bones are largely normal.
    Osteopenia/osteoporosis and degenerative hip disease develop in older
    patients.
  phenotype_term:
    preferred_term: Spondyloepiphyseal dysplasia
    term:
      id: HP:0002655
      label: Spondyloepiphyseal dysplasia
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses."
    explanation: GeneReviews radiographic definition of the SED.
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T cell deficiency."
    explanation: >-
      SED is a defining feature of the disease, supporting the very-frequent
      band.
  - reference: PMID:20013129
    reference_title: "Schimke immunoosseous dysplasia: defining skeletal features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal."
    explanation: Defines the anatomical distribution of the SED.
- name: Intrauterine growth retardation
  description: >-
    Prenatal-onset growth deficiency is common, particularly at the severe end
    of the spectrum, where disease onset can be in utero.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  frequency: FREQUENT
  evidence:
  - reference: PMID:40004207
    reference_title: "Genetic and Clinical Features of Schimke Immuno-Osseous Dysplasia: Single-Centre Retrospective Study of 21 Unrelated Paediatric Patients over a Period of 20 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many SIOD patients have intrauterine growth retardation, and they are usually intellectually intact"
    explanation: >-
      "Many" patients supports the frequent band for intrauterine growth
      retardation.
- name: Steroid-resistant nephrotic syndrome
  description: >-
    Nearly all patients develop progressive steroid-resistant nephropathy —
    clinically a nephrotic syndrome unresponsive to corticosteroids — usually
    within five years of the diagnosis of growth failure.
  phenotype_term:
    preferred_term: Steroid-resistant nephrotic syndrome
    term:
      id: HP:0012588
      label: Steroid-resistant nephrotic syndrome
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease."
    explanation: >-
      "Nearly all" supports the very-frequent band for steroid-resistant
      nephropathy.
  - reference: PMID:18785907
    reference_title: "Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke-immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical findings are spondyloepiphyseal dysplasia with disproportionate growth restriction, defective cellular immunity, and steroid-resistant nephrotic syndrome secondary to biopsy proven FSGS leading to ESRF."
    explanation: Names steroid-resistant nephrotic syndrome as a main finding.
- name: Focal segmental glomerulosclerosis
  description: >-
    Renal biopsy shows FSGS — characteristically the tip and collapsing
    variants — as the histological substrate of the nephrotic syndrome.
  phenotype_term:
    preferred_term: Focal segmental glomerulosclerosis
    term:
      id: HP:0000097
      label: Focal segmental glomerulosclerosis
  evidence:
  - reference: PMID:25319549
    reference_title: "Insights into the renal pathogenesis in Schimke immuno-osseous dysplasia: A renal histological characterization and expression analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis of SIOD patient renal biopsies demonstrates the tip and collapsing variants of focal segmental glomerulosclerosis (FSGS)."
    explanation: Biopsy demonstration of FSGS variants in SIOD.
  - reference: PMID:16840568
    reference_title: "Schimke immuno-osseous dysplasia: a clinicopathological correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As predicted by the clinical course, T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis, cerebral ischaemic lesions and premature atherosclerosis were identified."
    explanation: Autopsy confirmation of FSGS.
- name: Proteinuria
  description: >-
    Proteinuria with progressive renal failure is one of the characteristic
    features; in a 21-patient series proteinuria of varying severity was seen
    in 16 (76%).
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  frequency: FREQUENT
  evidence:
  - reference: PMID:10653321
    reference_title: "Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia."
    explanation: Proteinuria is one of the four characteristic features.
  - reference: PMID:40004207
    reference_title: "Genetic and Clinical Features of Schimke Immuno-Osseous Dysplasia: Single-Centre Retrospective Study of 21 Unrelated Paediatric Patients over a Period of 20 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proteinuria of varying severity was observed in 16 cases."
    explanation: >-
      16 of 21 patients (76%) had proteinuria, supporting the frequent band.
- name: End-stage renal disease
  description: >-
    The nephropathy terminates in end-stage renal disease in nearly all
    affected individuals, necessitating renal replacement therapy or
    transplantation.
  phenotype_term:
    preferred_term: End-stage renal disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease."
    explanation: >-
      "Nearly all" individuals progress to end-stage renal disease, supporting
      the very-frequent band.
- name: T-cell lymphopenia
  description: >-
    Progressive T-cell lymphopenia from impaired thymic output is the core
    immunological defect; residual T cells lack IL7Rα, are skewed toward
    memory phenotypes, and show features of exhaustion.
  phenotype_term:
    preferred_term: T-cell lymphopenia
    term:
      id: HP:0005403
      label: Decreased total T cell count
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of tested individuals have T cell deficiency and an associated risk for opportunistic infection, a common cause of death."
    explanation: >-
      "The majority of tested individuals" supports the frequent band for
      T-cell deficiency.
  - reference: PMID:39153074
    reference_title: "Profound T Lymphocyte and DNA Repair Defect Characterizes Schimke Immuno-Osseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Its hallmarks are severe hypogammaglobulinemia requiring immunoglobulin substitution, as well as impaired function of the thymus resulting in overall T cell lymphopenia"
    explanation: Documents the overall T-cell lymphopenia.
- name: Recurrent infections
  description: >-
    Recurrent bacterial, viral, and fungal infections — including
    opportunistic infections — result from the combined T-cell and humoral
    deficiency and are a leading cause of death.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:10653321
    reference_title: "Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia."
    explanation: Recurrent infections are one of the characteristic features.
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of tested individuals have T cell deficiency and an associated risk for opportunistic infection, a common cause of death."
    explanation: >-
      Documents the associated opportunistic-infection risk and its
      contribution to mortality.
- name: Cerebral ischemic events
  description: >-
    Transient ischemic attacks and strokes on the background of the cerebral
    arteriopathy occur at high incidence; stroke accounts for about 17% of
    deaths.
  phenotype_term:
    preferred_term: Cerebral ischemic events (TIA/stroke)
    term:
      id: HP:0002637
      label: Cerebral ischemia
  frequency: FREQUENT
  evidence:
  - reference: PMID:10653321
    reference_title: "Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies."
    explanation: >-
      Reports a high incidence of cerebral ischemia, supporting the frequent
      band.
  - reference: PMID:23950031
    reference_title: "Bone marrow transplantation in Schimke immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with SIOD usually die within the first two decades of life from infections (23%), stroke (17%), renal failure (15%), pulmonary hypertension and congestive heart failure (15%), complications of organ transplantation (9%), complications of lymphoproliferative disease (9%), gastrointestinal bleeding (6%), bone marrow failure (3%), and unspecified acute restrictive lung disease (3%)"
    explanation: Stroke accounts for 17% of deaths in SIOD.
- name: Premature atherosclerosis
  description: >-
    Premature, elastin-deficient arteriosclerosis/atherosclerosis was present
    in about half of evaluable patients in the largest vascular series and is
    confirmed at autopsy.
  phenotype_term:
    preferred_term: Premature atherosclerosis
    term:
      id: HP:0002621
      label: Atherosclerosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:22998683
    reference_title: "Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema."
    explanation: >-
      32 of 63 patients (51%) had arteriosclerosis, supporting the frequent
      band.
  - reference: PMID:16840568
    reference_title: "Schimke immuno-osseous dysplasia: a clinicopathological correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As predicted by the clinical course, T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis, cerebral ischaemic lesions and premature atherosclerosis were identified."
    explanation: Autopsy confirmation of premature atherosclerosis.
- name: Hyperpigmented macules
  description: >-
    Hyperpigmented macules, typically on the trunk, are part of the
    characteristic ectodermal presentation noted since the original
    description.
  phenotype_term:
    preferred_term: Hyperpigmented macules
    term:
      id: HP:0001034
      label: Hypermelanotic macule
  evidence:
  - reference: PMID:10653321
    reference_title: "Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia."
    explanation: Hyperpigmented macules are a characteristic feature.
  - reference: PMID:2066860
    reference_title: "Schimke immuno-osseous dysplasia: a newly recognized multisystem disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe a disorder characterized by skeletal dysplasia, rapidly progressive nephropathy, episodes of lymphopenia, and pigmentary skin changes"
    explanation: >-
      Pigmentary skin changes were part of the original disease description.
- name: Characteristic facies
  description: >-
    An unusual facies — with features such as a broad, depressed nasal bridge
    and bulbous nasal tip — accompanies the short stature; facial anomalies
    are described as mild.
  phenotype_term:
    preferred_term: Unusual facies
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:10653321
    reference_title: "Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia."
    explanation: An unusual facies is a characteristic feature.
- name: Sparse hair
  description: >-
    Sparse or fine hair is among the less prominent ectodermal features.
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:22888040
    reference_title: "SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional less prominent features include hyperpigmented macules, sparse hair, migraine-like headaches, atherosclerosis with cerebral ischemia, deficiency of other blood cell lineages, hypothyroidism, opportunistic infections, dental anomalies, corneal opacities, autoimmune enteropathy, and pulmonary hypertension"
    explanation: Lists sparse hair among the recognized features of SIOD.
- name: Hypothyroidism
  description: >-
    Thyroid dysfunction, usually hypothyroidism (often subclinical), occurs at
    high incidence and is managed with levothyroxine.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  frequency: FREQUENT
  evidence:
  - reference: PMID:10653321
    reference_title: "Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies."
    explanation: >-
      Reports a high incidence of thyroid dysfunction, supporting the frequent
      band.
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "agents that improve blood flow or decrease coagulability to treat transient ischemic attacks or strokes; blood pressure control; levothyroxine for hypothyroidism"
    explanation: >-
      GeneReviews management includes levothyroxine for the hypothyroidism of
      SIOD.
- name: Bone marrow failure
  description: >-
    Cytopenias beyond lymphopenia — including neutropenia, anemia, and
    thrombocytopenia — occur at high incidence, and frank bone marrow failure
    is a major cause of morbidity and an indication considered for
    hematopoietic stem cell transplantation.
  phenotype_term:
    preferred_term: Bone marrow failure
    term:
      id: HP:0005528
      label: Bone marrow hypocellularity
  evidence:
  - reference: PMID:23950031
    reference_title: "Bone marrow transplantation in Schimke immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two features of SIOD causing much morbidity and mortality are bone marrow failure and T-cell deficiency with the consequent opportunistic infections."
    explanation: Names bone marrow failure as a major cause of morbidity.
  - reference: PMID:10653321
    reference_title: "Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies."
    explanation: Documents the high incidence of blood cytopenias.
- name: Thrombocytopenia
  description: >-
    Episodic, often autoimmune, cytopenias — mainly transient anemia or
    thrombocytopenia — are among the hematological manifestations.
  phenotype_term:
    preferred_term: Transient thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    temporality: TRANSIENT
  evidence:
  - reference: PMID:39153074
    reference_title: "Profound T Lymphocyte and DNA Repair Defect Characterizes Schimke Immuno-Osseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other symptoms may be present, including skin hyperpigmentations, refractory migraines, hypothyroidism or autoimmune diseases, mainly transient anemia or thrombocytopenia."
    explanation: >-
      Documents transient thrombocytopenia (and anemia) among the autoimmune
      manifestations.
- name: Non-Hodgkin lymphoma
  description: >-
    SIOD carries an increased prevalence of malignancy, most commonly
    non-Hodgkin lymphoma (3 of 71 patients, with one osteosarcoma), consistent
    with the underlying genome instability.
  phenotype_term:
    preferred_term: Non-Hodgkin lymphoma
    term:
      id: HP:0012539
      label: Non-Hodgkin lymphoma
  frequency: VERY_RARE
  evidence:
  - reference: PMID:22888040
    reference_title: "SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 71 SIOD patients, three had non-Hodgkin lymphoma (NHL) and one had osteosarcoma."
    explanation: >-
      3 of 71 patients (4%) had NHL, supporting the very-rare (1-4%) band
      while documenting the predisposition.
- name: Migraine-like headaches
  description: >-
    Migraine-like, often refractory, headaches are a recognized neurological
    feature distinct from the ischemic events.
  phenotype_term:
    preferred_term: Migraine-like headaches
    term:
      id: HP:0002076
      label: Migraine
  evidence:
  - reference: PMID:22888040
    reference_title: "SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional less prominent features include hyperpigmented macules, sparse hair, migraine-like headaches, atherosclerosis with cerebral ischemia, deficiency of other blood cell lineages, hypothyroidism, opportunistic infections, dental anomalies, corneal opacities, autoimmune enteropathy, and pulmonary hypertension"
    explanation: Lists migraine-like headaches among recognized features.
  - reference: PMID:39153074
    reference_title: "Profound T Lymphocyte and DNA Repair Defect Characterizes Schimke Immuno-Osseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other symptoms may be present, including skin hyperpigmentations, refractory migraines, hypothyroidism or autoimmune diseases, mainly transient anemia or thrombocytopenia."
    explanation: Documents refractory migraines among the symptoms.
genetic:
- name: SMARCAL1
  gene_term:
    preferred_term: SMARCAL1
    term:
      id: hgnc:11102
      label: SMARCAL1
  relationship_type: CAUSATIVE
  association: >-
    Biallelic germline loss-of-function variants in SMARCAL1 cause SIOD;
    genotype tracks with severity — biallelic nonsense/frameshift/splicing
    genotypes cause severe disease, biallelic missense variants retaining
    partial function cause milder disease.
  notes: >-
    SMARCAL1 (HARP) encodes an SNF2-family ATP-driven annealing helicase.
    A Russian founder variant, c.2542G>T (p.E848*), accounted for 14 of 19
    genotyped patients in the largest single-centre series. Approximately half
    of patients referred with an SIOD-like phenotype have no detectable
    SMARCAL1 mutation, suggesting genetic heterogeneity of the broader
    phenotype.
  evidence:
  - reference: PMID:11799392
    reference_title: "Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD."
    explanation: Establishes SMARCAL1 as the causative gene.
  - reference: PMID:11799392
    reference_title: "Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele"
    explanation: Documents the genotype-severity correlation.
  - reference: PMID:40004207
    reference_title: "Genetic and Clinical Features of Schimke Immuno-Osseous Dysplasia: Single-Centre Retrospective Study of 21 Unrelated Paediatric Patients over a Period of 20 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most common was c.2542G>T, resulting in premature translation termination (p.E848*), and it was found in 14 patients either in a homozygous (four patients) or compound-heterozygous (10 patients) state"
    explanation: Documents the recurrent founder truncating variant.
  - reference: PMID:20013129
    reference_title: "Schimke immunoosseous dysplasia: defining skeletal features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1."
    explanation: >-
      SMARCAL1 is the only identified cause; a fraction of clinically similar
      patients remain unexplained.
treatments:
- name: Kidney transplantation
  description: >-
    Kidney transplantation is the therapy of choice for the end-stage renal
    failure of SIOD because FSGS does not recur in the graft; GeneReviews
    recommends transplantation with mild immunosuppressive therapy given the
    underlying immunodeficiency.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: kidney transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  target_mechanisms:
  - target: Podocyte Injury and Glomerulosclerosis
    treatment_effect: BYPASSES
    description: >-
      Transplantation replaces the sclerosed kidney rather than correcting the
      SMARCAL1 defect; because the podocytopathy is cell-autonomous, FSGS does
      not recur in the donor graft.
    evidence:
    - reference: PMID:18785907
      reference_title: "Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke-immuno-osseous dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Concerning ESRF, kidney transplantation is the therapy of choice since FSGS does not recur in the graft."
      explanation: >-
        Transplantation bypasses the intrinsic podocytopathy, and the disease
        does not recur in donor tissue.
  evidence:
  - reference: PMID:18785907
    reference_title: "Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke-immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Concerning ESRF, kidney transplantation is the therapy of choice since FSGS does not recur in the graft."
    explanation: Establishes kidney transplantation as the therapy of choice.
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "renal transplantation as indicated using mild immunosuppressive therapy"
    explanation: GeneReviews management recommendation for renal transplantation.
- name: Minimized post-transplant immunosuppression
  description: >-
    Because of the underlying T-cell immunodeficiency, conventional
    combination immunosuppression after renal transplantation has led to
    severe disseminated cutaneous papillomavirus infections and
    EBV-associated lymphoproliferative disease; immunosuppressive monotherapy
    maintenance gives good graft outcomes with fewer severe infections, and
    limited immunosuppression appears possible without increased rejection
    risk.
  treatment_term:
    preferred_term: immunosuppressive therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
  evidence:
  - reference: PMID:18785907
    reference_title: "Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke-immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have found that post-renal transplantation immunosuppressive monotherapy results in a good outcome with a reduced number of severe infections."
    explanation: Supports monotherapy maintenance immunosuppression in SIOD.
  - reference: PMID:18785907
    reference_title: "Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke-immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Under conventional immunosuppressive regimens some SIOD patients have developed severe disseminated cutaneous papilloma virus infections or EBV associated lymphoproliferative disease."
    explanation: >-
      Documents the infectious complications of conventional-intensity
      immunosuppression that motivate minimization.
- name: Hematopoietic stem cell transplantation
  description: >-
    HSCT is a potential definitive therapy for the T-cell immunodeficiency and
    bone marrow failure, but the historical experience is poor: only one of
    the first five transplanted patients survived, with the four deaths
    following myeloablative conditioning — a toxicity plausibly linked to the
    hypersensitivity of SMARCAL1-deficient cells to DNA-damaging agents.
    Reduced-intensity conditioning with alpha-beta T-cell-depleted
    haploidentical grafts underlies the more recent successes.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Thymic T-cell Development Failure
    treatment_effect: RESTORES
    description: >-
      Successful engraftment replaces the SMARCAL1-deficient hematopoietic
      compartment, restoring T-cell immunity; full donor chimerism has been
      achieved with reduced-intensity haploidentical protocols.
    evidence:
    - reference: PMID:35704481
      reference_title: "Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation."
      explanation: >-
        Demonstrates full donor hematopoietic reconstitution in SIOD patients
        after reduced-intensity haploidentical HSCT.
  evidence:
  - reference: PMID:23950031
    reference_title: "Bone marrow transplantation in Schimke immuno-osseous dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We find that only one patient survived the transplantation procedure and that the existing indicators of a good prognosis for bone marrow transplantation were not predictive in this small cohort."
    explanation: >-
      Documents the very high procedure-related mortality of early BMT in
      SIOD, the stated caveat for this treatment.
  - reference: PMID:35704481
    reference_title: "Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, four of five patients with SIOD who underwent HSCT after myeloablative conditioning died from HSCT-related causes, including infections and GVHD"
    explanation: >-
      Attributes the historical HSCT deaths to myeloablative-conditioning-era
      protocols.
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hematopoietic stem cell transplantation as indicated"
    explanation: GeneReviews lists HSCT among management options as indicated.
- name: Sequential haploidentical HSCT and kidney transplantation
  description: >-
    Sequential transplantation of alpha-beta T-cell-depleted, CD19
    B-cell-depleted haploidentical hematopoietic stem cells followed by a
    kidney from the same donor established full donor chimerism and immune
    tolerance in three children with SIOD, who maintained normal renal
    function without any immunosuppression at 22 to 34 months — addressing the
    immunodeficiency and the renal failure with a single donor while
    eliminating post-transplant immunosuppression.
  treatment_term:
    preferred_term: sequential stem cell and kidney transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Thymic T-cell Development Failure
    treatment_effect: RESTORES
    description: >-
      The haploidentical HSCT arm replaces the defective hematopoietic and
      immune compartment.
    evidence:
    - reference: PMID:35704481
      reference_title: "Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation."
      explanation: >-
        Documents immune reconstitution with donor chimerism and tolerance.
  - target: Podocyte Injury and Glomerulosclerosis
    treatment_effect: BYPASSES
    description: >-
      The same-donor kidney replaces the failed organ, and the induced
      tolerance removes the need for maintenance immunosuppression.
    evidence:
    - reference: PMID:35704481
      reference_title: "Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Each patient received sequential transplants of αβ T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor."
      explanation: >-
        Describes the sequential same-donor stem cell and kidney
        transplantation strategy.
  evidence:
  - reference: PMID:35704481
    reference_title: "Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation."
    explanation: >-
      Reports the immunosuppression-free outcome of sequential stem
      cell-kidney transplantation in three SIOD patients.
- name: Supportive and preventive management
  description: >-
    Multidisciplinary supportive care includes acyclovir for recurrent
    herpetic infections, imiquimod and cidofovir for severe disseminated
    cutaneous papillomavirus infections, G-CSF or GM-CSF for neutropenia,
    levothyroxine for hypothyroidism, agents that improve blood flow or reduce
    coagulability for ischemic events, and blood-pressure control.
    Live-attenuated vaccines should be avoided in T-cell-deficient patients;
    hypertension, heat, stress, and sleep deprivation can precipitate
    neurovascular events; and DNA-damaging anti-cancer therapies must be used
    with caution given the genotoxic hypersensitivity.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "acyclovir for recurrent herpetic infections and/or shingles; imiquimod and cidofovir for severe disseminated cutaneous papilloma virus infections"
    explanation: GeneReviews anti-infective supportive measures.
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Avoid hypertension; heat, stress, and lack of sleep; and live attenuated immunizations in those who are T cell deficient. Use DNA-damaging anti-cancer therapies with caution due to evidence of susceptibility to genotoxic agents."
    explanation: >-
      GeneReviews agents/circumstances to avoid, including the genotoxic
      caution that follows from the replication-stress mechanism.
diagnosis:
- name: Clinical, laboratory, and radiographic diagnosis with molecular confirmation
  description: >-
    The diagnosis is established in a proband with the characteristic
    combination of spondyloepiphyseal dysplasia, progressive steroid-resistant
    nephropathy, and T-cell deficiency — clinical, laboratory, and radiographic
    features — and/or biallelic pathogenic SMARCAL1 variants on molecular
    genetic testing. Molecular confirmation matters because a fraction of
    clinically typical cases have no detectable SMARCAL1 variant.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20301550
    reference_title: "Schimke Immunoosseous Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of SIOD is established in a proband with the characteristic clinical, laboratory, and radiographic features and/or biallelic pathogenic variants in SMARCAL1 identified on molecular genetic testing."
    explanation: >-
      GeneReviews states the diagnostic criterion: characteristic features
      and/or biallelic SMARCAL1 variants.
references:
- reference: PMID:20301550
  title: "Schimke Immunoosseous Dysplasia."
  tags:
  - GeneReviews
notes: >-
  The Orphanet code for SIOD is ORPHA:1830 (MONDO:0009458 xref); a structured
  ORPHA cache entry could not be generated at curation time because the live
  Orphadata bulk XML no longer matches the repository's pinned manifest
  checksum. OMIM:242900. Curated from PubMed-verified primary literature and
  GeneReviews; deep-research providers were not used for this entry.
📚

References & Deep Research

References

1
PMID:20301550
Schimke Immunoosseous Dysplasia.
No top-level findings curated for this source.