ROSAH Syndrome

Mendelian MONDO:0013999 Pathograph 46 Show in embeddings browser Autoinflammatory Disease

ROSAH syndrome (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and headache), also called ALPK1-related autoinflammatory disease, is an autosomal dominant autoinflammatory disorder caused by heterozygous gain-of-function missense variants in ALPK1, most often p.Thr237Met. The mutant kinase loses its specificity for the bacterial sugar ADP-heptose and is activated by endogenous nucleotide sugars, driving constitutive ALPK1-TIFA signalling to NF-kappaB with an accompanying interferon/STAT1 signature. Patients show variable intraocular inflammation, optic disc elevation and cone-rod-type retinal degeneration, together with episodic fever, deforming arthritis, splenomegaly with cytopenias, hypohidrosis or anhidrosis from birth, hyposalivation, dental caries and short dental roots, headaches with premature basal ganglia mineralisation, and elevated CRP and TNF. Penetrance appears complete, but expressivity varies widely, even within families.

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Pathophysiology

13
ALPK1 Gain-of-Function Missense Variants
Heterozygous missense variants in the N-terminal ADP-heptose-binding domain of ALPK1 (recurrent p.Thr237Met; also p.Tyr254Cys and p.Ser277Phe) are the initiating lesion. Transfected mutant proteins show constitutive NF-kappaB activity that wild-type ALPK1 does not.
ciliopathy model
ALPK1 hgnc:20917 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALPK1 (hgnc:20917). hgnc:20917 is a gene from the HUGO Gene Nomenclature Committee.
protein serine/threonine kinase activity GO:0004674 ⇑ GAIN OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves protein serine/threonine kinase activity (GO:0004674), qualified as gain of function. GO:0004674 is a molecular function from the Gene Ontology.
Downstream
Loss of ALPK1 Ligand Specificity
Eccrine Sweat Gland Dysfunction
Defective Primary Ciliogenesis ciliopathy model
Show evidence (2 references)
PMID:30967659 SUPPORT Human clinical
"Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder."
Discovery study in five families establishing ALPK1 p.Thr237Met as the cause.
PMID:35868845 SUPPORT In vitro / ex vivo
"Transiently transfected mutant proteins had increased constitutive NF-κB activity relative to the wild-type protein."
Reporter assays show that ROSAH ALPK1 variants are gain-of-function alleles.
Loss of ALPK1 Ligand Specificity
Wild-type ALPK1 is a cytosolic pattern-recognition receptor that is activated when bacterial ADP-heptose binds its N-terminal domain. The ROSAH mutants can also be activated by host nucleotide sugars (UDP-mannose, ADP-ribose, cyclic ADP-ribose), so the kinase signals without infection. The authors propose this loss of specificity as the basis of the disease.
ALPK1 hgnc:20917 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALPK1 (hgnc:20917). hgnc:20917 is a gene from the HUGO Gene Nomenclature Committee.
pattern recognition receptor activity GO:0038187 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal pattern recognition receptor activity (GO:0038187). GO:0038187 is a molecular function from the Gene Ontology.
Downstream
Constitutive TIFA Phosphorylation and TIFAsome Assembly
Show evidence (2 references)
PMID:30111836 SUPPORT In vitro / ex vivo
"ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA."
Defines the normal ligand and the domain the ROSAH variants alter.
PMID:38060563 SUPPORT In vitro / ex vivo
"We propose that the loss of the specificity of ALPK1 for bacterial ADP-heptose underlies ROSAH syndrome"
Biochemical study proposing loss of ligand specificity as the disease mechanism.
Constitutive TIFA Phosphorylation and TIFAsome Assembly
Activated ALPK1 phosphorylates TIFA on threonine 9, which drives TIFA oligomerisation into TIFAsomes that recruit TRAF6. ROSAH mutants assemble TIFAsomes and activate a TIFA-dependent NF-kappaB/AP-1 reporter without ADP-heptose.
TIFA hgnc:19075 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TIFA (hgnc:19075). hgnc:19075 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Constitutive Canonical NF-kappaB Activation
Show evidence (1 reference)
PMID:38060563 SUPPORT In vitro / ex vivo
"unlike wild-type (WT) ALPK1, the disease-causing ALPK1 mutants trigger the TIFA-dependent activation of an NF-κB/activator protein 1 reporter gene in the absence of ADP-heptose"
Ligand-independent, TIFA-dependent signalling by the ROSAH mutants.
Constitutive Canonical NF-kappaB Activation
Patient fibroblasts and transfected cells show increased phosphorylation of IKKalpha/beta and IkappaBalpha, IkappaBalpha degradation and p38/JNK MAPK activation. Whole-blood transcriptomes of untreated patients show activated innate immune pathways. Among immune cells, ALPK1 is most highly transcribed in neutrophils.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
canonical NF-kappaB signal transduction GO:0007249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology.
Downstream
Interferon Signature and STAT1 Activation
Proinflammatory Cytokine Overproduction
Show evidence (2 references)
PMID:35868845 SUPPORT In vitro / ex vivo
"showed increased phosphorylation of IκBα, IKKα/β, and MAP kinases p38 and JNK, which are hallmarks of the activated canonical NF-κB pathway"
Patient-derived fibroblasts show activated canonical NF-kappaB signalling.
PMID:35868845 SUPPORT Other
"Among immune cells, ALPK1 transcription is highest in neutrophils"
Reference expression-atlas data cited by the authors; supports the neutrophil cell-type annotation, not NF-kappaB activation itself.
Interferon Signature and STAT1 Activation
Constitutive STAT1 phosphorylation in transfected cells, patient fibroblasts and untreated patient monocytes, raised CXCL10 and an interferon-regulated gene signature; which interferon type drives the patient signature is not established. IFN-gamma licenses the ALPK1/TIFA pathway in monocytes by upregulating TIFA, and this licensing is blocked by JAK inhibitors.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
type II interferon-mediated signaling pathway GO:0060333 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves type II interferon-mediated signaling pathway (GO:0060333). GO:0060333 is a biological process from the Gene Ontology.
Downstream
Constitutive TIFA Phosphorylation and TIFAsome Assembly Amplification loop: IFN-gamma upregulates TIFA in monocytes, licensing ALPK1/TIFA signalling and promoting expression of the mutant phenotype.
Basal Ganglia Calcification Kozycki et al. noted that the premature basal ganglia mineralisation resembles that of type I interferonopathies such as Aicardi-Goutieres syndrome. This is an analogy, not a demonstrated causal step.
Show evidence (2 references)
PMID:39868044 SUPPORT In vitro / ex vivo
"IFN-γ treatment promoted the phenotypic expression of pathogenic ALPK1 mutations."
IFN-gamma amplifies mutant ALPK1 signalling in monocytes.
PMID:39868044 SUPPORT In vitro / ex vivo
"The licensing effect of IFN-γ in monocytes was blocked by JAK inhibitors."
Places JAK signalling on the path, with possible therapeutic relevance.
Proinflammatory Cytokine Overproduction
Untreated patients show persistently raised plasma TNF, with frequent elevation of IL-6, CCL2, soluble IL-2 receptor alpha, IL-10, CXCL10 and CXCL1, plus episodic CRP elevation.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
Animal models
Alpk1 T237M knock-in Mus musculus Mus musculus partially recapitulates
Downstream
Recurrent Low-Grade Fever
Episodic Malaise
Gastrointestinal Inflammation
Elevated C-Reactive Protein
Deforming Inflammatory Arthritis
AA Amyloidosis
Intraocular Inflammation
Retinal and Optic Nerve Neuroinflammation
Splenic Red Pulp Expansion
Salivary Gland Inflammation and Atrophy
Show evidence (2 references)
PMID:35868845 SUPPORT Human clinical
"Plasma TNF levels were persistently elevated in untreated patients and IL-6, CCL2 (MCP-1), soluble IL-2 receptor alpha and IL-10 were also frequently elevated"
Serum and plasma cytokine profiling of untreated patients.
PMID:31939038 SUPPORT Human clinical
"Elevated TNF-α was their prominent laboratory features."
Independent report of raised TNF-alpha in two p.Thr237Met patients.
Retinal and Optic Nerve Neuroinflammation
In mice heterozygous for human wild-type and T237M ALPK1, the retina, optic nerve and cortex show microglial infiltration, astrocyte activation and cytokine upregulation, all reversed by the ALPK1 inhibitor DF-003. In patients, contrast MRI shows meningeal enhancement and posterior globe thickening or enhancement, and CSF shows raised neopterin and activated cells, consistent with CNS inflammation.
microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
retina UBERON:0000966 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in retina (UBERON:0000966). UBERON:0000966 is an anatomical location from the Uberon multi-species anatomy ontology. optic nerve UBERON:0000941 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in optic nerve, annotated with cranial nerve II (UBERON:0000941). UBERON:0000941 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Heterozygous human ALPK1 wild-type / ALPK1 T237M Mus musculus Mus musculus partially recapitulates
Downstream
Optic Disc Elevation
Recurrent Headache
Show evidence (2 references)
PMID:40925900 SUPPORT Model organism
"Using mice heterozygous for wild-type human ALPK1 and ALPK1T237M established to model ROSAH syndrome that exhibit retinal microglial infiltration, astrocyte activation, and inflammatory cytokine upregulation in the retina, optic nerve, and cortex"
Humanised T237M mouse model showing retinal and optic nerve neuroinflammation.
PMID:35868845 SUPPORT Human clinical
"four showed foci of meningeal enhancement (online supplemental figure 3b), suggesting the possibility of ongoing central nervous system (CNS) inflammation"
Patient imaging consistent with CNS inflammation.
Intraocular Inflammation
Uveitis with keratic precipitates, anterior chamber cells, band keratopathy, retinal vasculitis and cystoid macular edema. Together with optic nerve involvement and retinal degeneration, it is one of the three factors that reduce vision in ROSAH. It is the ocular feature that has responded to IL-6 blockade.
inflammation model
eye UBERON:0000970 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in eye (UBERON:0000970). UBERON:0000970 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Uveitis
Retinal Vasculitis
Cystoid Macular Edema
Cone-Rod Retinal Degeneration Whether the retinal degeneration follows from chronic inflammation, from a cell-intrinsic photoreceptor defect, or both, is unresolved. Degeneration can progress after inflammation is controlled. inflammation model
Show evidence (1 reference)
PMID:36332842 SUPPORT Human clinical
"this study identified 3 main factors as contributing to changes in visual function of patients with ROSAH syndrome: optic nerve involvement; intraocular inflammation, including cystoid macular edema; and retinal degeneration"
Largest single-centre ophthalmic cohort; names the three drivers of visual loss.
Defective Primary Ciliogenesis
The discovery study found ALPK1 at the basal body of the photoreceptor connecting cilium, at centrioles and at the base of primary cilia, and defective ciliogenesis in patient fibroblasts. It proposed ROSAH as a ciliopathy, like other syndromic retinal dystrophies. Later work reframed the disease as autoinflammatory, and this branch has not been followed up.
ciliopathy model
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
cilium assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology.
Downstream
Cone-Rod Retinal Degeneration ciliopathy model
Show evidence (1 reference)
PMID:30967659 SUPPORT Model organism
"Adult mouse retinal section stained with anti-Alpk1 (green, MyBioSource, cat #MBS001969), and DAPI (blue) shows expression of Alpk1 in the RPE and connecting cilium region of the photoreceptor cells."
Immunofluorescence in adult mouse retina places Alpk1 at the photoreceptor connecting cilium, supporting a possible ciliary role. The human data in this paper are expression levels, not localisation.
Cone-Rod Retinal Degeneration
Progressive degeneration resembling a cone-rod dystrophy, with atrophy beginning at the posterior pole and spreading peripherally, causing loss of central and colour vision. Onset and course vary widely, even within one family. Its cause is unresolved. Two models are recorded: a consequence of chronic intraocular inflammation (inflammation_model) and a ciliary defect (ciliopathy_model). Degeneration can progress after inflammation is controlled, so it is probably not purely inflammatory.
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
retina UBERON:0000966 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in retina (UBERON:0000966). UBERON:0000966 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cone-Rod Dystrophy
Progressive Visual Loss
Show evidence (2 references)
PMID:36332842 SUPPORT Human clinical
"Seven patients showed retinal degeneration consistent with a cone-rod dystrophy, with atrophy tending to involve the posterior pole and extending peripherally."
Ophthalmic phenotyping of the retinal degeneration.
PMID:42773882 SUPPORT Human clinical
"The different clinical courses observed in these two related patients raise the possibility that inflammatory and degenerative mechanisms may progress, at least in part, independently."
Supports the description's point that degeneration is not purely a consequence of inflammation.
Splenic Red Pulp Expansion
Massive splenomegaly with congestion and expansion of the red pulp and mild histiocytic hyperplasia, without storage material or portal hypertension. Episodes of CRP elevation coincide with transient cytopenias, and the cytopenias improve after splenectomy, which points to splenic sequestration.
red pulp of spleen UBERON:0001250 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in red pulp of spleen (UBERON:0001250). UBERON:0001250 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Splenomegaly
Transient Cytopenias
Transient Neutropenia
Show evidence (2 references)
PMID:22307799 SUPPORT Human clinical
"All three patients have had splenectomies; histopathology revealed congestion of the red pulp, but otherwise no abnormalities."
Original family report describing splenic red pulp congestion.
PMID:35868845 SUPPORT Human clinical
"Splenic tissue was notable for red pulp expansion"
Confirms red pulp expansion in splenectomy specimens from the larger cohort.
Salivary Gland Inflammation and Atrophy
Labial salivary glands show focal lymphocytic infiltrates, glandular atrophy with fat replacement and mild fibrosis. Salivary flow is reduced, and the dental caries follow a Sjogren-like pattern, but without anti-SSA/SSB antibodies. The eccrine and mammary gland defects (anhidrosis from birth, failure to lactate) also involve exocrine glands, but no study has shown that they share a mechanism.
saliva-secreting gland UBERON:0001044 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in saliva-secreting gland (UBERON:0001044). UBERON:0001044 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hyposalivation
Dental Caries
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Histopathologic analysis of ROSAH labial salivary glands revealed focal inflammation (foci of lymphocytic infiltrate), glandular atrophy with adipocytic replacement and focal mild fibrosis"
Salivary gland histopathology in ROSAH patients.
Eccrine Sweat Gland Dysfunction
Sweating is absent or reduced from birth. Alpk1 is present in mouse sweat gland myoepithelial cells, but how the variant impairs sweating, and whether it involves inflammation, is unknown.
eccrine sweat gland UBERON:0000423 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in eccrine sweat gland (UBERON:0000423). UBERON:0000423 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Anhidrosis or Hypohidrosis
Show evidence (1 reference)
PMID:30967659 SUPPORT Model organism
"In mouse skin, Alpk1 was present in the sweat glands, especially in the myoepithelial cells where there was colocalization with the myoepithelial cell marker α-SMA"
Places Alpk1 in sweat gland myoepithelium; the mechanism of anhidrosis is not established.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ROSAH Syndrome 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

34
Blood 4
Vitreous Hemorrhage HP:0007902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vitreous hemorrhage (HP:0007902). HP:0007902 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40069099 SUPPORT Human clinical
"To report a case of a 17-year-old female presenting with recurrent vitreous hemorrhage on a background of dental anomalies and anhidrosis."
Single-case report.
Transient Cytopenias Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30967659 SUPPORT Human clinical
"All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some."
Pancytopenia in some patients from the five discovery families.
PMID:35868845 SUPPORT Human clinical
"Seven patients experienced transient neutropenia."
Transient neutropenia in seven of 27 patients.
Transient Neutropenia OCCASIONAL Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Seven patients experienced transient neutropenia."
Seven of 27 patients (26%).
Lymphopenia FREQUENT Decreased total lymphocyte count HP:0001888 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total lymphocyte count (HP:0001888). HP:0001888 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Lymphopenia was present in 41% of the patients (5 of 12) without clear predilection for a specific lineage."
Five of 12 patients with lymphocyte phenotyping.
Breast 1
Failure to Lactate Agalactia HP:0031109 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agalactia (HP:0031109). HP:0031109 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"In this cohort, four parous women were unable to lactate after a total of eight live births."
Lactation failure after every live birth among the parous women.
Cardiovascular 3
Retinal Vasculitis HP:0025188 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal vasculitis (HP:0025188). HP:0025188 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36332842 SUPPORT Human clinical
"cystoid macular edema, and retinal vasculitis on fluorescein angiography"
Retinal vasculitis seen on fluorescein angiography.
Dry Eye Keratoconjunctivitis sicca HP:0001097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keratoconjunctivitis sicca (HP:0001097). HP:0001097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41880066 SUPPORT Human clinical
"Novel findings included keratoconus in one patient and dry eye in all patients."
Dry eye in all four patients.
Splenomegaly FREQUENT HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Most patients evaluated by abdominal ultrasound (72% (13/18)) had splenomegaly, and seven patients underwent splenectomy for abdominal discomfort or cytopenias."
Frequency of splenomegaly (72%) in the 27-patient cohort.
Digestive 1
Hepatomegaly OCCASIONAL HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Five patients had hepatomegaly. Transabdominal ultrasound with Doppler imaging, transient liver elastography and abdominal MRI were not consistent with a diagnosis of portal hypertension."
Five of 27 patients, without evidence of portal hypertension.
Eye 8
Cone-Rod Dystrophy FREQUENT Cone/cone-rod dystrophy HP:0000548 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cone/cone-rod dystrophy (HP:0000548). HP:0000548 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36332842 SUPPORT Human clinical
"Seven patients showed retinal degeneration consistent with a cone-rod dystrophy"
Seven of eleven patients had cone-rod-type degeneration.
PMID:38935811 SUPPORT Other
"ALPK1-related autoinflammatory disease (ALPK1-AD) is characterized by clinical findings that can include intraocular inflammation, retinal degeneration, recurrent fever, deforming arthritis, and headaches."
GeneReviews lists retinal degeneration among the defining features.
Progressive Visual Loss HP:0000529 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive visual loss (HP:0000529). HP:0000529 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22307799 SUPPORT Human clinical
"All three patients developed progressive vision loss such that the two oldest patients are now blind, possibly due to a cone-rod dystrophy."
Progressive visual loss in the original family.
PMID:38935811 SUPPORT Other
"While most adults have ophthalmologic manifestations, vision loss is not universal."
GeneReviews qualifies the penetrance of visual loss.
Optic Disc Elevation VERY_FREQUENT Abnormal optic disc morphology HP:0012795 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal optic disc morphology (HP:0012795). HP:0012795 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36332842 SUPPORT Human clinical
"Ten patients were observed to show optic disc elevation and demonstrated peripapillary thickening on OCT."
Ten of eleven patients had optic disc elevation.
PMID:30967659 SUPPORT Human clinical
"This is not associated with elevated intracranial pressure."
Grounds the decision not to bind Papilledema, which HPO defines by raised CSF pressure.
Uveitis FREQUENT HP:0000554 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Uveitis (HP:0000554). HP:0000554 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36332842 SUPPORT Human clinical
"Variable signs or sequelae of intraocular inflammation were observed in 9 patients, including keratic precipitates, band keratopathy, trace to 2+ anterior chamber cells, cystoid macular edema, and retinal vasculitis on fluorescein angiography."
Nine of eleven patients had signs of intraocular inflammation.
Cystoid Macular Edema HP:0011505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cystoid macular edema (HP:0011505). HP:0011505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36332842 SUPPORT Human clinical
"intraocular inflammation, including cystoid macular edema"
Cystoid macular edema contributes to visual loss.
Vitreous Inflammatory Opacities Vitritis HP:0011531 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vitritis (HP:0011531). HP:0011531 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41046116 SUPPORT Human clinical
"All patients exhibited optic disc edema and significant, persistent vitreous inflammatory opacities as observed in B-scan imaging."
Vitreous inflammation in all five patients.
Angle-Closure Glaucoma HP:0012109 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Angle closure glaucoma (HP:0012109). HP:0012109 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41880066 SUPPORT Human clinical
"Acute angle-closure glaucoma was also observed in four eyes (two patients) with short axial lengths."
Two of four Italian patients.
Keratoconus HP:0000563 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keratoconus (HP:0000563). HP:0000563 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41880066 SUPPORT Human clinical
"Novel findings included keratoconus in one patient and dry eye in all patients."
Single-patient report of keratoconus.
Genitourinary 1
Chronic Kidney Disease HP:0012622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic kidney disease (HP:0012622). HP:0012622 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42112140 SUPPORT Human clinical
"He presented with mild chronic kidney disease and subnephrotic proteinuria."
Case of chronic kidney disease in ROSAH.
PMID:30967659 SUPPORT Human clinical
"All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some."
Mild renal impairment in some patients from the discovery families.
Head and Neck 5
Dental Caries VERY_FREQUENT Carious teeth HP:0000670 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carious teeth (HP:0000670). HP:0000670 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Most patients (85% (23/27)) had multiple dental caries"
Twenty-three of 27 patients.
Short Dental Roots HP:0006336 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short dental root (HP:0006336). HP:0006336 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Radiographic examination revealed presence of short and stunted roots in five of the seven patients"
Five of seven patients examined radiographically.
Taurodontism Taurodontia HP:0000679 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Taurodontia (HP:0000679). HP:0000679 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Enlargement of the pulp cavity leading to short dental roots in a pattern known as taurodontism was noted in four of seven individuals"
Four of seven patients examined.
Enamel Defects Enamel hypoplasia HP:0006297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enamel hypoplasia (HP:0006297). HP:0006297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"all seven patients who underwent dental examination at the NIH had some degree of enamel defects with the severity increasing with age"
All seven patients examined had enamel defects.
Hyposalivation Xerostomia HP:0000217 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Xerostomia (HP:0000217). HP:0000217 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35868845 SUPPORT Human clinical
"Patients had evidence of hyposalivation with decreased mean unstimulated and stimulated salivary flow"
Measured reduction in salivary flow in four patients.
PMID:38935811 SUPPORT Other
"Anhidrosis/hypohidrosis, dental caries, short dental roots, and hyposalivation are common."
GeneReviews baseline 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:30967659 SUPPORT Human clinical
"All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some."
Recurrent infections in some patients from the discovery families.
PMID:35868845 REFUTE Human clinical
"There was no evidence of increased susceptibility to documented bacterial infections."
The larger cohort found no increased bacterial infection susceptibility.
Integument 1
Anhidrosis or Hypohidrosis VERY_FREQUENT HP:0000966 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypohidrosis (HP:0000966), qualified as congenital onset. HP:0000966 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:35868845 SUPPORT Human clinical
"Hypohidrosis or anhidrosis was a nearly universal, present from birth."
Nearly universal congenital hypohidrosis or anhidrosis.
PMID:38935811 SUPPORT Other
"Anhidrosis/hypohidrosis, dental caries, short dental roots, and hyposalivation are common."
GeneReviews baseline feature.
Metabolism 3
Recurrent Low-Grade Fever Recurrent fever HP:0001954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fever (HP:0001954). HP:0001954 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Most patients experienced episodic malaise and many patients experienced non-infectious low-grade fevers."
Recurrent low-grade fever in the cohort.
Elevated C-Reactive Protein Elevated circulating C-reactive protein concentration HP:0011227 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating C-reactive protein concentration (HP:0011227). HP:0011227 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"C reactive protein (CRP) levels were highly variable in untreated patients and significant elevations occurred without change in systemic symptoms and resolved without intervention"
Episodic CRP elevation in untreated patients.
AA Amyloidosis HP:4000041 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is AA amyloidosis (HP:4000041). HP:4000041 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35868845 SUPPORT Human clinical
"Patient F4.1 was found to have microalbuminuria and AA amyloid present on a fat pad biopsy."
A single cohort patient with AA amyloidosis and microalbuminuria.
PMID:41880066 SUPPORT Human clinical
"we report the first case of reactive amyloidosis in ROSAH syndrome, leading to severe renal failure and dialysis dependence"
Reactive amyloidosis progressing to dialysis-dependent renal failure.
Musculoskeletal 2
Basal Ganglia Calcification HP:0002135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Basal ganglia calcification (HP:0002135). HP:0002135 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"seven of the patients had premature mineralisation/calcification of the globus pallidi, red nuclei and substantia nigra, worsening with age, eventually involving the rest of the basal ganglia"
Seven of eight adults whose brain MRIs were reviewed (a selected imaging subset).
Deforming Inflammatory Arthritis HP:0001369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthritis (HP:0001369). HP:0001369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Nine adults had deforming joint disease that was grossly appreciable on clinical examination or as erosive changes visible on X-ray"
Deforming or erosive arthritis in nine adults.
Nervous System 1
Recurrent Headache FREQUENT HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"recurrent headaches were experienced by many patients (50%, (13/26)) and abnormalities on brain MRIs were common"
Half of the cohort had recurrent headaches.
Constitutional 3
Arthralgia FREQUENT HP:0002829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthralgia (HP:0002829). HP:0002829 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Arthralgia was common (77% (20/26)), with patients reporting involvement of the hands, wrists, elbows, spine, knees, ankles and feet."
Twenty of 26 patients.
Gastrointestinal Inflammation FREQUENT Abdominal pain HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Gastrointestinal symptoms were reported in 14 patients and ranged from episodic abdominal pain, gastro-oesophageal reflux disease (GERD) and dysphagia to constipation and ileus."
Fourteen of 27 patients (52%).
Episodic Malaise HP:0033834 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malaise (HP:0033834). HP:0033834 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"Most patients experienced episodic malaise"
Episodic malaise in most of the cohort.
🧬

Genetic Associations

1
ALPK1 (Heterozygous gain-of-function missense variants)
Gene: ALPK1 hgnc:20917 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALPK1 (hgnc:20917). hgnc:20917 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (1 reference)
PMID:30967659 SUPPORT Human clinical
"Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder."
Discovery of the causal gene.
Variants (4)
p.Thr237Met (c.710C>T)
Recurrent pathogenic variant in the N-terminal ADP-heptose-binding domain, carried by most known families.
Show evidence (1 reference)
PMID:30967659 SUPPORT Human clinical
"segregated with disease in all five families"
The variant segregated with disease in all five discovery families.
p.Tyr254Cys (c.761A>G)
Variant in the ligand-binding domain, found in a single sporadic patient. It gives higher NF-kappaB activity than T237M in reporter assays.
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys."
Identification of the second ROSAH variant.
p.Ser277Phe
Variant found in one family of six affected members, all with ocular inflammation and optic nerve elevation. It is activated by UDP-mannose and ADP-ribose more strongly than T237M, and also by GDP-mannose.
Show evidence (1 reference)
PMID:39626775 SUPPORT Human clinical
"Here, we identify a family in which ROSAH syndrome is caused by a novel variant in which Ser277 is changed to Phe."
Family segregation of the variant, with functional characterisation in the same paper.
p.Thr237Ala
A different substitution at the recurrent residue, with a milder, predominantly ocular phenotype in one family.
Show evidence (1 reference)
PMID:41046116 SUPPORT Human clinical
"Notably, individuals with the T237A variant displayed solely ocular manifestations, with no/mild systemic symptoms."
Genotype-phenotype observation in two related patients.
💊

Medical Actions

10
IL-6 Receptor Blockade
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tocilizumab NCIT:C84217 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses tocilizumab (NCIT:C84217). NCIT:C84217 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Tocilizumab is the only anticytokine therapy reported to improve intraocular inflammation (two of two patients in the NIH cohort, and a later case with rapid reduction of macular edema and optic disc swelling). Vision already lost to retinal damage does not recover.
Mechanism Target:
INHIBITS Proinflammatory Cytokine Overproduction
INHIBITS Intraocular Inflammation
Show evidence (1 reference)
PMID:41269507 SUPPORT Human clinical
"Tocilizumab showed significant anatomical benefit in this ROSAH syndrome patient, suggesting a role for IL-6 in disease pathophysiology."
Anatomical response of macular edema and disc swelling to IL-6 receptor blockade.
Show evidence (3 references)
PMID:35868845 SUPPORT Human clinical
"anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients)"
Open-label empirical use in the NIH cohort.
PMID:41269507 SUPPORT Human clinical
"Recently, tocilizumab, an IL-6 receptor antagonist, was added, resulting in significant reduction in macular edema and optic disc swelling just within one month."
Single p.Tyr254Cys case with an anatomical ocular response.
PMID:41880066 SUPPORT Human clinical
"Conventional immunosuppressants were largely ineffective, whereas interleukin-6 inhibition provided systemic benefit but limited ocular improvement."
Systemic benefit with only limited ocular response in a separate series.
TNF Inhibition
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: adalimumab NCIT:C65216 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses adalimumab (NCIT:C65216). NCIT:C65216 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-TNF therapy (adalimumab) suppresses systemic inflammation and improves quality of life, but it has not controlled the ocular disease.
Mechanism Target:
INHIBITS Proinflammatory Cytokine Overproduction
Show evidence (2 references)
PMID:35868845 SUPPORT Human clinical
"While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life"
Systemic benefit of anti-TNF therapy in the cohort.
PMID:31939038 REFUTE Human clinical
"Anti-TNF treatment of adalimumab was applied to patient 1, after which her optic disc edema in the left eye continued and the visual acuity deteriorated further."
Adalimumab did not halt the ocular disease in this patient.
IL-1 Blockade
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anakinra NCIT:C38717 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anakinra (NCIT:C38717). NCIT:C38717 is a therapeutic agent from the NCI Thesaurus. canakinumab NCIT:C80971 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses canakinumab (NCIT:C80971). NCIT:C80971 is a therapeutic agent from the NCI Thesaurus.
Anakinra or canakinumab suppresses systemic inflammatory features but has not been shown to improve intraocular inflammation.
Mechanism Target:
INHIBITS Proinflammatory Cytokine Overproduction
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life"
Systemic benefit of IL-1 blockade in the cohort.
Splenectomy
Category: Therapeutic Action: SplenectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Splenectomy (NCIT:C15328). NCIT:C15328 is a clinical intervention from the NCI Thesaurus. NCIT:C15328
Performed for abdominal discomfort, cytopenias or risk of rupture. The cytopenias improve afterwards, but CRP elevations persist.
Mechanism Target:
INHIBITS Splenic Red Pulp Expansion
Show evidence (1 reference)
PMID:35868845 SUPPORT Human clinical
"While cytopenias appeared to improve after splenectomy"
Removing the enlarged spleen relieves the cytopenias; CRP elevations persisted afterwards.
Show evidence (2 references)
PMID:35868845 SUPPORT Human clinical
"seven patients underwent splenectomy for abdominal discomfort or cytopenias"
Indications for splenectomy in the cohort.
PMID:41880066 SUPPORT Human clinical
"Splenectomy resolved recurrent fever in two patients."
Splenectomy also relieved recurrent fever in two patients.
Local Ocular Therapy for Macular Edema
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dexamethasone CHEBI:41879 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dexamethasone (CHEBI:41879). CHEBI:41879 is a therapeutic agent from Chemical Entities of Biological Interest. bevacizumab NCIT:C2039 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses bevacizumab (NCIT:C2039). NCIT:C2039 is a therapeutic agent from the NCI Thesaurus.
Intravitreal dexamethasone and intravitreal anti-VEGF injection reduce macular edema. The anti-VEGF benefit lasted about six weeks in one case; the report does not name the agent, so bevacizumab stands for the class. Neither prevents the retinal degeneration.
Mechanism Target:
INHIBITS Intraocular Inflammation
Show evidence (1 reference)
PMID:40201710 SUPPORT Human clinical
"While ROSAH-associated ocular inflammation and macular edema may respond to local steroids and immune suppression, retinal degeneration may progress despite these therapies."
Local steroid acts on the inflammatory, not the degenerative, arm.
Show evidence (2 references)
PMID:40201710 SUPPORT Human clinical
"While the proband's macular edema improved with intravitreal dexamethasone and systemic tocilizumab, immune suppression did not prevent retinal degeneration."
Macular edema responded to intravitreal dexamethasone.
PMID:40069099 SUPPORT Human clinical
"The macular edema was responsive to anti-vascular endothelium growth factor (anti-VEGF) injection, however only for a period of 6-weeks before reoccurrence."
Short-lived response to anti-VEGF.
Conventional Immunosuppression
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Methotrexate, sulfasalazine, rituximab and similar agents have been used without controlling the ocular disease.
Show evidence (2 references)
PMID:41880066 REFUTE Human clinical
"Conventional immunosuppressants were largely ineffective"
Conventional immunosuppression failed in this series.
PMID:39847428 REFUTE Human clinical
"severe optic nerve infiltration and retinal pigment atrophy with intraocular inflammation, which were not improved by immunosuppressive treatment"
Ocular disease did not improve with immunosuppression.
Supportive and Dental Care
Category: Therapeutic 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
Low-vision services, dental care for enamel defects, and orthodontic planning that allows for short dental roots.
Show evidence (1 reference)
PMID:38935811 SUPPORT Other
"Supportive treatment involves the following: intraocular inflammation management; low vision services; systemic inflammation management (such as a rheumatologist); dental care of enamel defects; and orthodontic procedures for individuals with short dental roots."
GeneReviews management recommendations.
Multispecialty Surveillance
Category: Monitoring Action: eye examinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is eye examination (NCIT:C38060). NCIT:C38060 is a clinical intervention from the NCI Thesaurus. Ontology label: Eye Examination NCIT:C38060
Regular ophthalmologic, rheumatologic and dental follow-up, including the consequences of anhidrosis.
Show evidence (1 reference)
PMID:38935811 SUPPORT Other
"Surveillance: Regular monitoring by specialists treating the ophthalmologic findings, systemic inflammatory disease, and systemic and dental manifestations of anhidrosis/hypohidrosis."
GeneReviews surveillance recommendations.
Genetic Counseling
Category: Counseling / Informational Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal dominant transmission with a 50% risk to offspring and sibs of a heterozygous parent; prenatal and preimplantation testing are available.
Show evidence (1 reference)
PMID:38935811 SUPPORT Other
"Once the ALPK1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
GeneReviews genetic counseling section.
Selective ALPK1 Inhibition (Preclinical)
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
DF-003, an oral, selective ALPK1 inhibitor, inhibits ALPK1 T237M and reverses retinal, optic nerve and cortical inflammation in a humanised T237M mouse model. It has not been tested in patients.
Mechanism Target:
INHIBITS Constitutive TIFA Phosphorylation and TIFAsome Assembly
Show evidence (1 reference)
PMID:40925900 SUPPORT In vitro / ex vivo
"DF-003 suppresses inflammatory cytokine signaling mediated both by wild-type ALPK1 and the disease-causing ALPK1"
Cell-based inhibition of signalling by the T237M mutant kinase.
Show evidence (1 reference)
PMID:40925900 SUPPORT Model organism
"we show that orally administered DF-003 is sufficient to inhibit these inflammatory phenotypes"
Preclinical efficacy in the ROSAH mouse model.
🔬

Diagnosis

1
ALPK1 molecular genetic testing
The diagnosis is established by finding a heterozygous pathogenic ALPK1 variant in a proband with suggestive findings, typically optic disc elevation, uveitis and retinal degeneration with systemic features. It is usually made by exome sequencing or a retinal dystrophy panel.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:38935811 SUPPORT Other
"The diagnosis of ALPK1-AD is established in a proband with suggestive findings and a heterozygous pathogenic variant in ALPK1 identified by molecular genetic testing."
GeneReviews diagnostic criterion.
PMID:40201710 SUPPORT Human clinical
"A diagnosis of ROSAH syndrome, suggested by the concomitant presentation of optic disc edema, uveitis, and retinal degeneration, can be made by targeted genetic sequencing of the ALKP1 gene."
The clinical triad that prompts testing.
🌍

Epidemiology

1
Ultra-rare
Only a few dozen patients have been described, and no population prevalence is established.
Show evidence (1 reference)
PMID:38935811 SUPPORT Other
"To date, 41 individuals from 19 families with a pathogenic variant in ALPK1 have been described."
GeneReviews case count.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from ROSAH Syndrome:

Cogan Syndrome MONDO:0015453
Overlapping Features In a paediatric Cogan syndrome cohort, one child carried an ALPK1 variant of uncertain significance (p.His735Pro). Children with Cogan-like ocular inflammation and systemic features may therefore warrant ALPK1 testing.
Distinguishing Features
  • Heterozygous ALPK1 variant supports ROSAH syndrome
  • Optic disc elevation, retinal degeneration, anhidrosis or short dental roots point to ROSAH
Show evidence (1 reference)
PMID:42640550 SUPPORT Human clinical
"a novel ALPK1 p.H735P (n = 1), associated with Retinal dystrophy Optic nerve oedema Splenomegaly Anhidrosis Headache (ROSAH) syndrome"
Exome sequencing of a paediatric Cogan cohort found an ALPK1 variant of uncertain significance.
Systemic Lupus Erythematosus MONDO:0007915
Overlapping Features Immune-complex glomerulonephritis in ROSAH has been misdiagnosed as lupus nephritis.
Distinguishing Features
  • Absence of clinical or serological markers of lupus
  • ALPK1 variant with ocular and other ROSAH features
Show evidence (1 reference)
PMID:42112140 SUPPORT Human clinical
"Renal biopsy revealed immune complex-mediated glomerulonephritis with minimal mesangial proliferation, resembling class II lupus nephritis, despite the absence of clinical or serological markers of systemic lupus erythematosus."
Renal ROSAH can mimic lupus nephritis.
🐁

Animal Models

2
Alpk1 T237M knock-in Mus musculus
Knock-in of the recurrent ROSAH variant into mouse Alpk1. The mice show only subclinical inflammation.
Species
Mus musculus
Genotype
Alpk1 T237M knock-in
Publication
PMID:35868845
Pathograph links
Proinflammatory Cytokine Overproduction partially recapitulates fidelity: low observes: organism
Show evidence (1 reference)
PMID:35868845 SUPPORT Model organism
"Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation."
Mild, subclinical inflammatory phenotype.
Heterozygous human ALPK1 wild-type / ALPK1 T237M Mus musculus
Humanised mice carrying wild-type and T237M human ALPK1. They show retinal microglial infiltration, astrocyte activation and cytokine upregulation in the retina, optic nerve and cortex, and were used to test DF-003.
Species
Mus musculus
Genotype
Heterozygous human ALPK1 wild-type / ALPK1 T237M
Publication
PMID:40925900
Pathograph links
Retinal and Optic Nerve Neuroinflammation partially recapitulates fidelity: moderate observes: tissue
Show evidence (1 reference)
PMID:40925900 SUPPORT Model organism
"Using mice heterozygous for wild-type human ALPK1 and ALPK1T237M established to model ROSAH syndrome that exhibit retinal microglial infiltration, astrocyte activation, and inflammatory cytokine upregulation in the retina, optic nerve, and cortex"
Ocular and CNS neuroinflammation in the humanised model.
{ }

Source YAML

click to show 
name: ROSAH Syndrome
creation_date: "2026-10-19T05:00:00Z"
category: Mendelian
parents:
- Autoinflammatory Disease
description: >-
  ROSAH syndrome (retinal dystrophy, optic nerve edema, splenomegaly,
  anhidrosis and headache), also called ALPK1-related autoinflammatory disease,
  is an autosomal dominant autoinflammatory disorder caused by heterozygous
  gain-of-function missense variants in ALPK1, most often p.Thr237Met. The
  mutant kinase loses its specificity for the bacterial sugar ADP-heptose and
  is activated by endogenous nucleotide sugars, driving constitutive
  ALPK1-TIFA signalling to NF-kappaB with an accompanying interferon/STAT1
  signature. Patients show variable intraocular inflammation, optic disc
  elevation and cone-rod-type retinal degeneration, together with episodic
  fever, deforming arthritis, splenomegaly with cytopenias, hypohidrosis or
  anhidrosis from birth, hyposalivation, dental caries and short dental roots,
  headaches with premature basal ganglia mineralisation, and elevated CRP and
  TNF. Penetrance appears complete, but expressivity varies widely, even within
  families.
disease_term:
  preferred_term: ROSAH syndrome
  term:
    id: MONDO:0013999
    label: retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome
synonyms:
- ROSAH
- ROSAH syndrome
- ALPK1-related autoinflammatory disease
- optic nerve edema-splenomegaly syndrome
- retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache
pathophysiology:
- name: ALPK1 Gain-of-Function Missense Variants
  description: >-
    Heterozygous missense variants in the N-terminal ADP-heptose-binding domain
    of ALPK1 (recurrent p.Thr237Met; also p.Tyr254Cys and p.Ser277Phe) are the
    initiating lesion. Transfected mutant proteins show constitutive
    NF-kappaB activity that wild-type ALPK1 does not.
  biological_scale: MOLECULAR
  gene:
    preferred_term: ALPK1
    term:
      id: hgnc:20917
      label: ALPK1
  molecular_functions:
  - preferred_term: protein serine/threonine kinase activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
  evidence:
  - reference: PMID:30967659
    reference_title: "ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder."
    explanation: Discovery study in five families establishing ALPK1 p.Thr237Met as the cause.
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transiently transfected mutant proteins had increased constitutive NF-κB activity relative to the wild-type protein."
    explanation: Reporter assays show that ROSAH ALPK1 variants are gain-of-function alleles.
  downstream:
  - target: Loss of ALPK1 Ligand Specificity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38060563
      reference_title: "ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "they can also be activated by nucleotide sugars present in human cells (UDP-mannose, ADP-ribose, and cyclic ADP-ribose) which can be prevented by disruption of the ADP-heptose binding site"
      explanation: The T237M mutant, unlike wild-type ALPK1, responds to endogenous nucleotide sugars through its ADP-heptose binding site.
  - target: Eccrine Sweat Gland Dysfunction
    causal_link_type: UNKNOWN
  - target: Defective Primary Ciliogenesis
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - ciliopathy_model
    evidence:
    - reference: PMID:30967659
      reference_title: "ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Affected family member fibroblasts demonstrated defective ciliogenesis."
      explanation: Patient fibroblasts carrying p.Thr237Met showed defective ciliogenesis.
- name: Loss of ALPK1 Ligand Specificity
  description: >-
    Wild-type ALPK1 is a cytosolic pattern-recognition receptor that is
    activated when bacterial ADP-heptose binds its N-terminal domain. The ROSAH
    mutants can also be activated by host nucleotide sugars (UDP-mannose,
    ADP-ribose, cyclic ADP-ribose), so the kinase signals without infection.
    The authors propose this loss of specificity as the basis of the disease.
  biological_scale: MOLECULAR
  gene:
    preferred_term: ALPK1
    term:
      id: hgnc:20917
      label: ALPK1
  molecular_functions:
  - preferred_term: pattern recognition receptor activity
    modifier: ABNORMAL
    term:
      id: GO:0038187
      label: pattern recognition receptor activity
  evidence:
  - reference: PMID:30111836
    reference_title: "Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA."
    explanation: Defines the normal ligand and the domain the ROSAH variants alter.
  - reference: PMID:38060563
    reference_title: "ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We propose that the loss of the specificity of ALPK1 for bacterial ADP-heptose underlies ROSAH syndrome"
    explanation: Biochemical study proposing loss of ligand specificity as the disease mechanism.
  downstream:
  - target: Constitutive TIFA Phosphorylation and TIFAsome Assembly
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37072480
      reference_title: "In vitro kinase assay reveals ADP-heptose-dependent ALPK1 autophosphorylation and altered kinase activity of disease-associated ALPK1 mutants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "T237M and V1092A mutations associated with ROSAH syndrome and spiradenoma/spiradenocarcinoma respectively, exhibit enhanced ADPH-induced kinase activity and constitutive assembly of TIFAsomes."
      explanation: The T237M mutant assembles TIFA oligomers constitutively.
- name: Constitutive TIFA Phosphorylation and TIFAsome Assembly
  description: >-
    Activated ALPK1 phosphorylates TIFA on threonine 9, which drives TIFA
    oligomerisation into TIFAsomes that recruit TRAF6. ROSAH mutants assemble
    TIFAsomes and activate a TIFA-dependent NF-kappaB/AP-1 reporter without
    ADP-heptose.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TIFA
    term:
      id: hgnc:19075
      label: TIFA
  evidence:
  - reference: PMID:38060563
    reference_title: "ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "unlike wild-type (WT) ALPK1, the disease-causing ALPK1 mutants trigger the TIFA-dependent activation of an NF-κB/activator protein 1 reporter gene in the absence of ADP-heptose"
    explanation: Ligand-independent, TIFA-dependent signalling by the ROSAH mutants.
  downstream:
  - target: Constitutive Canonical NF-kappaB Activation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37072480
      reference_title: "In vitro kinase assay reveals ADP-heptose-dependent ALPK1 autophosphorylation and altered kinase activity of disease-associated ALPK1 mutants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This leads to the assembly of large TIFA oligomers called TIFAsomes, activation of NF-κB and pro-inflammatory gene expression."
      explanation: TIFAsome assembly is the step that couples ALPK1 to NF-kappaB.
- name: Constitutive Canonical NF-kappaB Activation
  description: >-
    Patient fibroblasts and transfected cells show increased phosphorylation
    of IKKalpha/beta and IkappaBalpha, IkappaBalpha degradation and p38/JNK
    MAPK activation. Whole-blood transcriptomes of untreated patients show
    activated innate immune pathways. Among immune cells, ALPK1 is most highly
    transcribed in neutrophils.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "showed increased phosphorylation of IκBα, IKKα/β, and MAP kinases p38 and JNK, which are hallmarks of the activated canonical NF-κB pathway"
    explanation: Patient-derived fibroblasts show activated canonical NF-kappaB signalling.
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Among immune cells, ALPK1 transcription is highest in neutrophils"
    explanation: >-
      Reference expression-atlas data cited by the authors; supports the
      neutrophil cell-type annotation, not NF-kappaB activation itself.
  downstream:
  - target: Interferon Signature and STAT1 Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35868845
      reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ROSAH-associated mutations result in constitutive STAT1 activation"
      explanation: Mutant ALPK1 constructs induce STAT1 activation; the link from NF-kappaB to STAT1 is not defined.
  - target: Proinflammatory Cytokine Overproduction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32591860
      reference_title: "ADP-heptose: a bacterial PAMP detected by the host sensor ALPK1."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "its downstream signaling pathway that involves the proteins TIFA and TRAF6 and induces the activation of NF-κB and the secretion of inflammatory cytokines"
      explanation: Review placing inflammatory cytokine secretion downstream of ALPK1-TIFA-TRAF6 NF-kappaB activation.
- name: Interferon Signature and STAT1 Activation
  description: >-
    Constitutive STAT1 phosphorylation in transfected cells, patient
    fibroblasts and untreated patient monocytes, raised CXCL10 and an
    interferon-regulated gene signature; which interferon type drives the
    patient signature is not established. IFN-gamma licenses the ALPK1/TIFA
    pathway in monocytes by upregulating TIFA, and this licensing is blocked by
    JAK inhibitors.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: type II interferon-mediated signaling pathway
    term:
      id: GO:0060333
      label: type II interferon-mediated signaling pathway
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  evidence:
  - reference: PMID:39868044
    reference_title: "IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "IFN-γ treatment promoted the phenotypic expression of pathogenic ALPK1 mutations."
    explanation: IFN-gamma amplifies mutant ALPK1 signalling in monocytes.
  - reference: PMID:39868044
    reference_title: "IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The licensing effect of IFN-γ in monocytes was blocked by JAK inhibitors."
    explanation: Places JAK signalling on the path, with possible therapeutic relevance.
  downstream:
  - target: Constitutive TIFA Phosphorylation and TIFAsome Assembly
    causal_link_type: DIRECT
    description: >-
      Amplification loop: IFN-gamma upregulates TIFA in monocytes, licensing
      ALPK1/TIFA signalling and promoting expression of the mutant phenotype.
    evidence:
    - reference: PMID:39868044
      reference_title: "IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "IFN-γ induced TIFA upregulation in monocytes, and TIFA induction was sufficient to recapitulate the licensing effect of IFN-γ."
      explanation: IFN-gamma acts upstream on TIFA, closing a feed-forward loop.
  - target: Basal Ganglia Calcification
    causal_link_type: UNKNOWN
    description: >-
      Kozycki et al. noted that the premature basal ganglia mineralisation
      resembles that of type I interferonopathies such as Aicardi-Goutieres
      syndrome. This is an analogy, not a demonstrated causal step.
    evidence:
    - reference: PMID:35868845
      reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Based on the presence of premature CNS basal ganglia mineralisation reminiscent of that seen in classic type-I interferonopathies including AGS"
      explanation: The authors' rationale for the interferon link; an analogy, not a demonstrated mechanism.
- name: Proinflammatory Cytokine Overproduction
  description: >-
    Untreated patients show persistently raised plasma TNF, with frequent
    elevation of IL-6, CCL2, soluble IL-2 receptor alpha, IL-10, CXCL10 and
    CXCL1, plus episodic CRP elevation.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma TNF levels were persistently elevated in untreated patients and IL-6, CCL2 (MCP-1), soluble IL-2 receptor alpha and IL-10 were also frequently elevated"
    explanation: Serum and plasma cytokine profiling of untreated patients.
  - reference: PMID:31939038
    reference_title: "Juvenile Onset Splenomegaly and Oculopathy Due to Germline Mutation in ALPK1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated TNF-α was their prominent laboratory features."
    explanation: Independent report of raised TNF-alpha in two p.Thr237Met patients.
  downstream:
  - target: Recurrent Low-Grade Fever
    causal_link_type: DIRECT
  - target: Episodic Malaise
    causal_link_type: DIRECT
  - target: Gastrointestinal Inflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elevated C-Reactive Protein
    causal_link_type: DIRECT
  - target: Deforming Inflammatory Arthritis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: AA Amyloidosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic hepatic serum amyloid A production
  - target: Intraocular Inflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Retinal and Optic Nerve Neuroinflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Splenic Red Pulp Expansion
    causal_link_type: UNKNOWN
  - target: Salivary Gland Inflammation and Atrophy
    causal_link_type: UNKNOWN
- name: Retinal and Optic Nerve Neuroinflammation
  description: >-
    In mice heterozygous for human wild-type and T237M ALPK1, the retina, optic
    nerve and cortex show microglial infiltration, astrocyte activation and
    cytokine upregulation, all reversed by the ALPK1 inhibitor DF-003. In
    patients, contrast MRI shows meningeal enhancement and posterior globe
    thickening or enhancement, and CSF shows raised neopterin and activated
    cells, consistent with CNS inflammation.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  - preferred_term: optic nerve
    term:
      id: UBERON:0000941
      label: cranial nerve II
  evidence:
  - reference: PMID:40925900
    reference_title: "Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Using mice heterozygous for wild-type human ALPK1 and ALPK1T237M established to model ROSAH syndrome that exhibit retinal microglial infiltration, astrocyte activation, and inflammatory cytokine upregulation in the retina, optic nerve, and cortex"
    explanation: Humanised T237M mouse model showing retinal and optic nerve neuroinflammation.
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "four showed foci of meningeal enhancement (online supplemental figure 3b), suggesting the possibility of ongoing central nervous system (CNS) inflammation"
    explanation: Patient imaging consistent with CNS inflammation.
  downstream:
  - target: Optic Disc Elevation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41269507
      reference_title: "Tocilizumab as a treatment tool for ROSAH syndrome: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "resulting in significant reduction in macular edema and optic disc swelling just within one month"
      explanation: Disc swelling regressed with IL-6 blockade, implying an inflammatory component.
  - target: Recurrent Headache
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Intraocular Inflammation
  description: >-
    Uveitis with keratic precipitates, anterior chamber cells, band
    keratopathy, retinal vasculitis and cystoid macular edema. Together with
    optic nerve involvement and retinal degeneration, it is one of the three
    factors that reduce vision in ROSAH. It is the ocular feature that has
    responded to IL-6 blockade.
  biological_scale: TISSUE
  locations:
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  evidence:
  - reference: PMID:36332842
    reference_title: "Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this study identified 3 main factors as contributing to changes in visual function of patients with ROSAH syndrome: optic nerve involvement; intraocular inflammation, including cystoid macular edema; and retinal degeneration"
    explanation: Largest single-centre ophthalmic cohort; names the three drivers of visual loss.
  downstream:
  - target: Uveitis
    causal_link_type: DIRECT
  - target: Retinal Vasculitis
    causal_link_type: DIRECT
  - target: Cystoid Macular Edema
    causal_link_type: DIRECT
  - target: Cone-Rod Retinal Degeneration
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - inflammation_model
    description: >-
      Whether the retinal degeneration follows from chronic inflammation, from a
      cell-intrinsic photoreceptor defect, or both, is unresolved. Degeneration
      can progress after inflammation is controlled.
    evidence:
    - reference: PMID:40201710
      reference_title: "Case Report: ROSAH syndrome presents diagnostic and therapeutic challenges."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: "While the proband's macular edema improved with intravitreal dexamethasone and systemic tocilizumab, immune suppression did not prevent retinal degeneration."
      explanation: Degeneration continued after the inflammation was suppressed.
- name: Defective Primary Ciliogenesis
  description: >-
    The discovery study found ALPK1 at the basal body of the photoreceptor
    connecting cilium, at centrioles and at the base of primary cilia, and
    defective ciliogenesis in patient fibroblasts. It proposed ROSAH as a
    ciliopathy, like other syndromic retinal dystrophies. Later work reframed
    the disease as autoinflammatory, and this branch has not been followed up.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  evidence:
  - reference: PMID:30967659
    reference_title: "ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Adult mouse retinal section stained with anti-Alpk1 (green, MyBioSource, cat #MBS001969), and DAPI (blue) shows expression of Alpk1 in the RPE and connecting cilium region of the photoreceptor cells."
    explanation: >-
      Immunofluorescence in adult mouse retina places Alpk1 at the photoreceptor
      connecting cilium, supporting a possible ciliary role. The human data in
      this paper are expression levels, not localisation.
  downstream:
  - target: Cone-Rod Retinal Degeneration
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - ciliopathy_model
- name: Cone-Rod Retinal Degeneration
  description: >-
    Progressive degeneration resembling a cone-rod dystrophy, with atrophy
    beginning at the posterior pole and spreading peripherally, causing loss of
    central and colour vision. Onset and course vary widely, even within one
    family. Its cause is unresolved. Two models are recorded: a consequence of
    chronic intraocular inflammation (inflammation_model) and a ciliary defect
    (ciliopathy_model). Degeneration can progress after inflammation is
    controlled, so it is probably not purely inflammatory.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  evidence:
  - reference: PMID:36332842
    reference_title: "Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients showed retinal degeneration consistent with a cone-rod dystrophy, with atrophy tending to involve the posterior pole and extending peripherally."
    explanation: Ophthalmic phenotyping of the retinal degeneration.
  - reference: PMID:42773882
    reference_title: "Familial ROSAH Syndrome Associated with the ALPK1 p.Thr237Ala Variant: Divergent Ocular Phenotypes and Partial Response to IL-6 Blockade."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The different clinical courses observed in these two related patients raise the possibility that inflammatory and degenerative mechanisms may progress, at least in part, independently."
    explanation: Supports the description's point that degeneration is not purely a consequence of inflammation.
  downstream:
  - target: Cone-Rod Dystrophy
    causal_link_type: DIRECT
  - target: Progressive Visual Loss
    causal_link_type: DIRECT
- name: Splenic Red Pulp Expansion
  description: >-
    Massive splenomegaly with congestion and expansion of the red pulp and mild
    histiocytic hyperplasia, without storage material or portal hypertension.
    Episodes of CRP elevation coincide with transient cytopenias, and the
    cytopenias improve after splenectomy, which points to splenic
    sequestration.
  biological_scale: TISSUE
  locations:
  - preferred_term: red pulp of spleen
    term:
      id: UBERON:0001250
      label: red pulp of spleen
  evidence:
  - reference: PMID:22307799
    reference_title: "An inherited disorder with splenomegaly, cytopenias, and vision loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three patients have had splenectomies; histopathology revealed congestion of the red pulp, but otherwise no abnormalities."
    explanation: Original family report describing splenic red pulp congestion.
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Splenic tissue was notable for red pulp expansion"
    explanation: Confirms red pulp expansion in splenectomy specimens from the larger cohort.
  downstream:
  - target: Splenomegaly
    causal_link_type: DIRECT
  - target: Transient Cytopenias
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Transient Neutropenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Salivary Gland Inflammation and Atrophy
  description: >-
    Labial salivary glands show focal lymphocytic infiltrates, glandular atrophy
    with fat replacement and mild fibrosis. Salivary flow is reduced, and the
    dental caries follow a Sjogren-like pattern, but without anti-SSA/SSB
    antibodies. The eccrine and mammary gland defects (anhidrosis from birth,
    failure to lactate) also involve exocrine glands, but no study has shown
    that they share a mechanism.
  biological_scale: TISSUE
  locations:
  - preferred_term: saliva-secreting gland
    term:
      id: UBERON:0001044
      label: saliva-secreting gland
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathologic analysis of ROSAH labial salivary glands revealed focal inflammation (foci of lymphocytic infiltrate), glandular atrophy with adipocytic replacement and focal mild fibrosis"
    explanation: Salivary gland histopathology in ROSAH patients.
  downstream:
  - target: Hyposalivation
    causal_link_type: DIRECT
  - target: Dental Caries
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced salivary protection of enamel
- name: Eccrine Sweat Gland Dysfunction
  description: >-
    Sweating is absent or reduced from birth. Alpk1 is present in mouse sweat
    gland myoepithelial cells, but how the variant impairs sweating, and
    whether it involves inflammation, is unknown.
  biological_scale: TISSUE
  locations:
  - preferred_term: eccrine sweat gland
    term:
      id: UBERON:0000423
      label: eccrine sweat gland
  evidence:
  - reference: PMID:30967659
    reference_title: "ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mouse skin, Alpk1 was present in the sweat glands, especially in the myoepithelial cells where there was colocalization with the myoepithelial cell marker α-SMA"
    explanation: Places Alpk1 in sweat gland myoepithelium; the mechanism of anhidrosis is not established.
  downstream:
  - target: Anhidrosis or Hypohidrosis
    causal_link_type: DIRECT
phenotypes:
- name: Cone-Rod Dystrophy
  category: Ophthalmologic
  description: >-
    Retinal degeneration of cone-rod type, often leading to legal blindness by
    early adulthood, though some adult carriers have no visual deficit.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cone/cone-rod dystrophy
    term:
      id: HP:0000548
      label: Cone/cone-rod dystrophy
  evidence:
  - reference: PMID:36332842
    reference_title: "Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients showed retinal degeneration consistent with a cone-rod dystrophy"
    explanation: Seven of eleven patients had cone-rod-type degeneration.
  - reference: PMID:38935811
    reference_title: "ALPK1-Related Autoinflammatory Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALPK1-related autoinflammatory disease (ALPK1-AD) is characterized by clinical findings that can include intraocular inflammation, retinal degeneration, recurrent fever, deforming arthritis, and headaches."
    explanation: GeneReviews lists retinal degeneration among the defining features.
- name: Progressive Visual Loss
  category: Ophthalmologic
  description: >-
    Progressive loss of central and colour vision, first noticed at a mean age
    of about 15 years. Vision loss is not universal.
  phenotype_term:
    preferred_term: Progressive visual loss
    term:
      id: HP:0000529
      label: Progressive visual loss
  evidence:
  - reference: PMID:22307799
    reference_title: "An inherited disorder with splenomegaly, cytopenias, and vision loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three patients developed progressive vision loss such that the two oldest patients are now blind, possibly due to a cone-rod dystrophy."
    explanation: Progressive visual loss in the original family.
  - reference: PMID:38935811
    reference_title: "ALPK1-Related Autoinflammatory Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While most adults have ophthalmologic manifestations, vision loss is not universal."
    explanation: GeneReviews qualifies the penetrance of visual loss.
- name: Optic Disc Elevation
  category: Ophthalmologic
  description: >-
    Bilateral optic disc elevation with peripapillary thickening on OCT, nearly
    universal, sometimes dramatic and sometimes subtle. It is not caused by
    raised intracranial pressure, so the HPO term Papilledema (HP:0001085),
    which is defined by raised CSF pressure, is deliberately not used.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal optic disc morphology
    term:
      id: HP:0012795
      label: Abnormal optic disc morphology
  evidence:
  - reference: PMID:36332842
    reference_title: "Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten patients were observed to show optic disc elevation and demonstrated peripapillary thickening on OCT."
    explanation: Ten of eleven patients had optic disc elevation.
  - reference: PMID:30967659
    reference_title: "ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is not associated with elevated intracranial pressure."
    explanation: Grounds the decision not to bind Papilledema, which HPO defines by raised CSF pressure.
- name: Uveitis
  category: Ophthalmologic
  description: >-
    Low-grade anterior and posterior intraocular inflammation with keratic
    precipitates, anterior chamber cells and band keratopathy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Uveitis
    term:
      id: HP:0000554
      label: Uveitis
  evidence:
  - reference: PMID:36332842
    reference_title: "Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variable signs or sequelae of intraocular inflammation were observed in 9 patients, including keratic precipitates, band keratopathy, trace to 2+ anterior chamber cells, cystoid macular edema, and retinal vasculitis on fluorescein angiography."
    explanation: Nine of eleven patients had signs of intraocular inflammation.
- name: Retinal Vasculitis
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Retinal vasculitis
    term:
      id: HP:0025188
      label: Retinal vasculitis
  evidence:
  - reference: PMID:36332842
    reference_title: "Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cystoid macular edema, and retinal vasculitis on fluorescein angiography"
    explanation: Retinal vasculitis seen on fluorescein angiography.
- name: Cystoid Macular Edema
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Cystoid macular edema
    term:
      id: HP:0011505
      label: Cystoid macular edema
  evidence:
  - reference: PMID:36332842
    reference_title: "Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intraocular inflammation, including cystoid macular edema"
    explanation: Cystoid macular edema contributes to visual loss.
- name: Vitreous Inflammatory Opacities
  category: Ophthalmologic
  description: Persistent vitreous inflammatory opacities on B-scan imaging.
  phenotype_term:
    preferred_term: Vitritis
    term:
      id: HP:0011531
      label: Vitritis
  evidence:
  - reference: PMID:41046116
    reference_title: "Ocular Manifestations of ROSAH Syndrome Caused by Different Mutations of the ALPK1 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients exhibited optic disc edema and significant, persistent vitreous inflammatory opacities as observed in B-scan imaging."
    explanation: Vitreous inflammation in all five patients.
- name: Angle-Closure Glaucoma
  category: Ophthalmologic
  description: Acute angle-closure glaucoma in eyes with short axial length.
  phenotype_term:
    preferred_term: Angle closure glaucoma
    term:
      id: HP:0012109
      label: Angle closure glaucoma
  evidence:
  - reference: PMID:41880066
    reference_title: "Irreversible Ocular and Systemic Damage in ROSAH Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute angle-closure glaucoma was also observed in four eyes (two patients) with short axial lengths."
    explanation: Two of four Italian patients.
- name: Keratoconus
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Keratoconus
    term:
      id: HP:0000563
      label: Keratoconus
  evidence:
  - reference: PMID:41880066
    reference_title: "Irreversible Ocular and Systemic Damage in ROSAH Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel findings included keratoconus in one patient and dry eye in all patients."
    explanation: Single-patient report of keratoconus.
- name: Dry Eye
  category: Ophthalmologic
  description: >-
    Dry eye in all four patients of one series. Subjective dryness was not
    prominent in the NIH cohort.
  phenotype_term:
    preferred_term: Keratoconjunctivitis sicca
    term:
      id: HP:0001097
      label: Keratoconjunctivitis sicca
  evidence:
  - reference: PMID:41880066
    reference_title: "Irreversible Ocular and Systemic Damage in ROSAH Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel findings included keratoconus in one patient and dry eye in all patients."
    explanation: Dry eye in all four patients.
- name: Vitreous Hemorrhage
  category: Ophthalmologic
  description: >-
    Recurrent vitreous hemorrhage from preretinal neovascularisation around the
    disc and along the arcades, without retinal capillary closure.
  phenotype_term:
    preferred_term: Vitreous hemorrhage
    term:
      id: HP:0007902
      label: Vitreous hemorrhage
  evidence:
  - reference: PMID:40069099
    reference_title: "ROSAH syndrome presenting with recurrent vitreous hemorrhage: a multimodal imaging study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To report a case of a 17-year-old female presenting with recurrent vitreous hemorrhage on a background of dental anomalies and anhidrosis."
    explanation: Single-case report.
- name: Splenomegaly
  category: Hematologic
  description: >-
    Splenomegaly, often massive and causing abdominal discomfort. Several
    patients have had a splenectomy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients evaluated by abdominal ultrasound (72% (13/18)) had splenomegaly, and seven patients underwent splenectomy for abdominal discomfort or cytopenias."
    explanation: Frequency of splenomegaly (72%) in the 27-patient cohort.
- name: Hepatomegaly
  category: Gastrointestinal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients had hepatomegaly. Transabdominal ultrasound with Doppler imaging, transient liver elastography and abdominal MRI were not consistent with a diagnosis of portal hypertension."
    explanation: Five of 27 patients, without evidence of portal hypertension.
- name: Transient Cytopenias
  category: Hematologic
  description: >-
    Transient cytopenias accompanying CRP flares, including neutropenia and
    pancytopenia, with normocellular marrow. They improve after splenectomy.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:30967659
    reference_title: "ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some."
    explanation: Pancytopenia in some patients from the five discovery families.
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients experienced transient neutropenia."
    explanation: Transient neutropenia in seven of 27 patients.
- name: Transient Neutropenia
  category: Hematologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients experienced transient neutropenia."
    explanation: Seven of 27 patients (26%).
- name: Lymphopenia
  category: Hematologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Decreased total lymphocyte count
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphopenia was present in 41% of the patients (5 of 12) without clear predilection for a specific lineage."
    explanation: Five of 12 patients with lymphocyte phenotyping.
- name: Anhidrosis or Hypohidrosis
  category: Dermatologic
  description: >-
    Absent or reduced sweating, present from birth and nearly universal.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypohidrosis
    term:
      id: HP:0000966
      label: Hypohidrosis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypohidrosis or anhidrosis was a nearly universal, present from birth."
    explanation: Nearly universal congenital hypohidrosis or anhidrosis.
  - reference: PMID:38935811
    reference_title: "ALPK1-Related Autoinflammatory Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Anhidrosis/hypohidrosis, dental caries, short dental roots, and hyposalivation are common."
    explanation: GeneReviews baseline feature.
- name: Recurrent Headache
  category: Neurological
  description: >-
    Recurrent headaches, migraine-like in the original families. Brain MRI may
    show meningeal enhancement and white-matter hyperintensities.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent headaches were experienced by many patients (50%, (13/26)) and abnormalities on brain MRIs were common"
    explanation: Half of the cohort had recurrent headaches.
- name: Basal Ganglia Calcification
  category: Neurological
  description: >-
    Premature mineralisation of the globus pallidus, red nuclei and substantia
    nigra on susceptibility-weighted MRI. It worsens with age and later involves
    the caudate and putamen, usually without extrapyramidal signs.
  phenotype_term:
    preferred_term: Basal ganglia calcification
    term:
      id: HP:0002135
      label: Basal ganglia calcification
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seven of the patients had premature mineralisation/calcification of the globus pallidi, red nuclei and substantia nigra, worsening with age, eventually involving the rest of the basal ganglia"
    explanation: Seven of eight adults whose brain MRIs were reviewed (a selected imaging subset).
- name: Recurrent Low-Grade Fever
  category: Constitutional
  description: >-
    Episodic, non-infectious low-grade fevers lasting under 24 hours, with
    malaise.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients experienced episodic malaise and many patients experienced non-infectious low-grade fevers."
    explanation: Recurrent low-grade fever in the cohort.
- name: Elevated C-Reactive Protein
  category: Laboratory
  description: >-
    Episodic, highly variable CRP elevations that can occur without a change in
    symptoms and resolve spontaneously.
  phenotype_term:
    preferred_term: Elevated circulating C-reactive protein concentration
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C reactive protein (CRP) levels were highly variable in untreated patients and significant elevations occurred without change in systemic symptoms and resolved without intervention"
    explanation: Episodic CRP elevation in untreated patients.
- name: Deforming Inflammatory Arthritis
  category: Musculoskeletal
  description: >-
    Inflammatory arthritis with erosive and deforming changes of the wrists,
    metacarpophalangeal and interphalangeal joints. It sometimes begins in early
    childhood and can be mistaken for systemic juvenile idiopathic arthritis.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine adults had deforming joint disease that was grossly appreciable on clinical examination or as erosive changes visible on X-ray"
    explanation: Deforming or erosive arthritis in nine adults.
- name: Arthralgia
  category: Musculoskeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arthralgia was common (77% (20/26)), with patients reporting involvement of the hands, wrists, elbows, spine, knees, ankles and feet."
    explanation: Twenty of 26 patients.
- name: Gastrointestinal Inflammation
  category: Gastrointestinal
  description: >-
    Episodic abdominal pain, reflux, dysphagia, constipation and ileus. On
    endoscopy: oesophageal furrows, gastric erythema and duodenal erosions.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal symptoms were reported in 14 patients and ranged from episodic abdominal pain, gastro-oesophageal reflux disease (GERD) and dysphagia to constipation and ileus."
    explanation: Fourteen of 27 patients (52%).
- name: Episodic Malaise
  category: Constitutional
  phenotype_term:
    preferred_term: Malaise
    term:
      id: HP:0033834
      label: Malaise
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients experienced episodic malaise"
    explanation: Episodic malaise in most of the cohort.
- name: Recurrent Infections
  category: Immunologic
  description: >-
    Reported in some of the discovery families, but the NIH cohort found no
    increased susceptibility to documented bacterial infections.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:30967659
    reference_title: "ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some."
    explanation: Recurrent infections in some patients from the discovery families.
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no evidence of increased susceptibility to documented bacterial infections."
    explanation: The larger cohort found no increased bacterial infection susceptibility.
- name: Dental Caries
  category: Dental
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Carious teeth
    term:
      id: HP:0000670
      label: Carious teeth
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients (85% (23/27)) had multiple dental caries"
    explanation: Twenty-three of 27 patients.
- name: Short Dental Roots
  category: Dental
  description: >-
    Short, stunted roots, sometimes under half the crown length, with
    taurodontism in some patients.
  phenotype_term:
    preferred_term: Short dental root
    term:
      id: HP:0006336
      label: Short dental root
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic examination revealed presence of short and stunted roots in five of the seven patients"
    explanation: Five of seven patients examined radiographically.
- name: Taurodontism
  category: Dental
  phenotype_term:
    preferred_term: Taurodontia
    term:
      id: HP:0000679
      label: Taurodontia
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enlargement of the pulp cavity leading to short dental roots in a pattern known as taurodontism was noted in four of seven individuals"
    explanation: Four of seven patients examined.
- name: Enamel Defects
  category: Dental
  description: Enamel pitting and grooves, progressing with age to loss of enamel.
  phenotype_term:
    preferred_term: Enamel hypoplasia
    term:
      id: HP:0006297
      label: Enamel hypoplasia
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all seven patients who underwent dental examination at the NIH had some degree of enamel defects with the severity increasing with age"
    explanation: All seven patients examined had enamel defects.
- name: Hyposalivation
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Xerostomia
    term:
      id: HP:0000217
      label: Xerostomia
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had evidence of hyposalivation with decreased mean unstimulated and stimulated salivary flow"
    explanation: Measured reduction in salivary flow in four patients.
  - reference: PMID:38935811
    reference_title: "ALPK1-Related Autoinflammatory Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Anhidrosis/hypohidrosis, dental caries, short dental roots, and hyposalivation are common."
    explanation: GeneReviews baseline feature.
- name: Failure to Lactate
  category: Reproductive
  phenotype_term:
    preferred_term: Agalactia
    term:
      id: HP:0031109
      label: Agalactia
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this cohort, four parous women were unable to lactate after a total of eight live births."
    explanation: Lactation failure after every live birth among the parous women.
- name: AA Amyloidosis
  category: Renal
  phenotype_term:
    preferred_term: AA amyloidosis
    term:
      id: HP:4000041
      label: AA amyloidosis
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient F4.1 was found to have microalbuminuria and AA amyloid present on a fat pad biopsy."
    explanation: A single cohort patient with AA amyloidosis and microalbuminuria.
  - reference: PMID:41880066
    reference_title: "Irreversible Ocular and Systemic Damage in ROSAH Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report the first case of reactive amyloidosis in ROSAH syndrome, leading to severe renal failure and dialysis dependence"
    explanation: Reactive amyloidosis progressing to dialysis-dependent renal failure.
- name: Chronic Kidney Disease
  category: Renal
  description: >-
    Mild renal impairment, including immune-complex glomerulonephritis that was
    misdiagnosed as lupus nephritis.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:42112140
    reference_title: "Renal Disease in ROSAH Syndrome Masquerading as Lupus Nephritis: A Case Report and Cohort Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He presented with mild chronic kidney disease and subnephrotic proteinuria."
    explanation: Case of chronic kidney disease in ROSAH.
  - reference: PMID:30967659
    reference_title: "ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some."
    explanation: Mild renal impairment in some patients from the discovery families.
epidemiology:
- name: Ultra-rare
  description: >-
    Only a few dozen patients have been described, and no population
    prevalence is established.
  evidence:
  - reference: PMID:38935811
    reference_title: "ALPK1-Related Autoinflammatory Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To date, 41 individuals from 19 families with a pathogenic variant in ALPK1 have been described."
    explanation: GeneReviews case count.
diagnosis:
- name: ALPK1 molecular genetic testing
  description: >-
    The diagnosis is established by finding a heterozygous pathogenic ALPK1
    variant in a proband with suggestive findings, typically optic disc
    elevation, uveitis and retinal degeneration with systemic features. It is
    usually made by exome sequencing or a retinal dystrophy panel.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:38935811
    reference_title: "ALPK1-Related Autoinflammatory Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of ALPK1-AD is established in a proband with suggestive findings and a heterozygous pathogenic variant in ALPK1 identified by molecular genetic testing."
    explanation: GeneReviews diagnostic criterion.
  - reference: PMID:40201710
    reference_title: "Case Report: ROSAH syndrome presents diagnostic and therapeutic challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A diagnosis of ROSAH syndrome, suggested by the concomitant presentation of optic disc edema, uveitis, and retinal degeneration, can be made by targeted genetic sequencing of the ALKP1 gene."
    explanation: The clinical triad that prompts testing.
differential_diagnoses:
- name: Cogan Syndrome
  disease_term:
    preferred_term: Cogan syndrome
    term:
      id: MONDO:0015453
      label: Cogan syndrome
  description: >-
    In a paediatric Cogan syndrome cohort, one child carried an ALPK1 variant
    of uncertain significance (p.His735Pro). Children with Cogan-like ocular
    inflammation and systemic features may therefore warrant ALPK1 testing.
  distinguishing_features:
  - Heterozygous ALPK1 variant supports ROSAH syndrome
  - Optic disc elevation, retinal degeneration, anhidrosis or short dental roots point to ROSAH
  evidence:
  - reference: PMID:42640550
    reference_title: "Whole exome sequencing of paediatric patients with Cogan's syndrome to identify monogenic mimics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a novel ALPK1 p.H735P (n = 1), associated with Retinal dystrophy Optic nerve oedema Splenomegaly Anhidrosis Headache (ROSAH) syndrome"
    explanation: Exome sequencing of a paediatric Cogan cohort found an ALPK1 variant of uncertain significance.
- name: Systemic Lupus Erythematosus
  disease_term:
    preferred_term: systemic lupus erythematosus
    term:
      id: MONDO:0007915
      label: systemic lupus erythematosus
  description: >-
    Immune-complex glomerulonephritis in ROSAH has been misdiagnosed as lupus
    nephritis.
  distinguishing_features:
  - Absence of clinical or serological markers of lupus
  - ALPK1 variant with ocular and other ROSAH features
  evidence:
  - reference: PMID:42112140
    reference_title: "Renal Disease in ROSAH Syndrome Masquerading as Lupus Nephritis: A Case Report and Cohort Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal biopsy revealed immune complex-mediated glomerulonephritis with minimal mesangial proliferation, resembling class II lupus nephritis, despite the absence of clinical or serological markers of systemic lupus erythematosus."
    explanation: Renal ROSAH can mimic lupus nephritis.
genetic:
- name: ALPK1
  association: Heterozygous gain-of-function missense variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: ALPK1
    term:
      id: hgnc:20917
      label: ALPK1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: COMPLETE
    expressivity: VARIABLE
    evidence:
    - reference: PMID:38935811
      reference_title: "ALPK1-Related Autoinflammatory Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "ALPK1-AD is inherited in an autosomal dominant manner."
      explanation: GeneReviews states the mode of inheritance.
    - reference: PMID:38935811
      reference_title: "ALPK1-Related Autoinflammatory Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "If a parent of the proband has the ALPK1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%."
      explanation: GeneReviews recurrence risk.
    - reference: PMID:35868845
      reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "penetrance was complete in all identified family members"
      explanation: Complete penetrance across the 27-patient cohort.
    - reference: PMID:35868845
      reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "there was significant phenotypic variation, even within families and some adults lacked functional visual deficits"
      explanation: Variable expressivity, including within families.
    - reference: PMID:39847428
      reference_title: "Two Cases of ROSAH-Like Syndrome Restricted to the Ophthalmologic Presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ALPK1 variant responsible for ROSAH syndrome may cause severe retinal dystrophy and an uveitis-like presentation resistant to conventional immunosuppressive drugs, without the systemic symptoms common to the ROSAH syndrome."
      explanation: T237M carriers with an ocular-only phenotype.
  variants:
  - name: p.Thr237Met (c.710C>T)
    description: >-
      Recurrent pathogenic variant in the N-terminal ADP-heptose-binding domain,
      carried by most known families.
    evidence:
    - reference: PMID:30967659
      reference_title: "ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "segregated with disease in all five families"
      explanation: The variant segregated with disease in all five discovery families.
  - name: p.Tyr254Cys (c.761A>G)
    description: >-
      Variant in the ligand-binding domain, found in a single sporadic patient.
      It gives higher NF-kappaB activity than T237M in reporter assays.
    evidence:
    - reference: PMID:35868845
      reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys."
      explanation: Identification of the second ROSAH variant.
  - name: p.Ser277Phe
    description: >-
      Variant found in one family of six affected members, all with ocular
      inflammation and optic nerve elevation. It is activated by UDP-mannose and
      ADP-ribose more strongly than T237M, and also by GDP-mannose.
    evidence:
    - reference: PMID:39626775
      reference_title: "Discovery and functional analysis of a novel ALPK1 variant in ROSAH syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we identify a family in which ROSAH syndrome is caused by a novel variant in which Ser277 is changed to Phe."
      explanation: Family segregation of the variant, with functional characterisation in the same paper.
  - name: p.Thr237Ala
    description: >-
      A different substitution at the recurrent residue, with a milder,
      predominantly ocular phenotype in one family.
    evidence:
    - reference: PMID:41046116
      reference_title: "Ocular Manifestations of ROSAH Syndrome Caused by Different Mutations of the ALPK1 Gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Notably, individuals with the T237A variant displayed solely ocular manifestations, with no/mild systemic symptoms."
      explanation: Genotype-phenotype observation in two related patients.
  evidence:
  - reference: PMID:30967659
    reference_title: "ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder."
    explanation: Discovery of the causal gene.
treatments:
- name: IL-6 Receptor Blockade
  description: >-
    Tocilizumab is the only anticytokine therapy reported to improve
    intraocular inflammation (two of two patients in the NIH cohort, and a
    later case with rapid reduction of macular edema and optic disc swelling).
    Vision already lost to retinal damage does not recover.
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tocilizumab
      term:
        id: NCIT:C84217
        label: Tocilizumab
  target_mechanisms:
  - target: Proinflammatory Cytokine Overproduction
    treatment_effect: INHIBITS
  - target: Intraocular Inflammation
    treatment_effect: INHIBITS
    evidence:
    - reference: PMID:41269507
      reference_title: "Tocilizumab as a treatment tool for ROSAH syndrome: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Tocilizumab showed significant anatomical benefit in this ROSAH syndrome patient, suggesting a role for IL-6 in disease pathophysiology."
      explanation: Anatomical response of macular edema and disc swelling to IL-6 receptor blockade.
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients)"
    explanation: Open-label empirical use in the NIH cohort.
  - reference: PMID:41269507
    reference_title: "Tocilizumab as a treatment tool for ROSAH syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, tocilizumab, an IL-6 receptor antagonist, was added, resulting in significant reduction in macular edema and optic disc swelling just within one month."
    explanation: Single p.Tyr254Cys case with an anatomical ocular response.
  - reference: PMID:41880066
    reference_title: "Irreversible Ocular and Systemic Damage in ROSAH Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conventional immunosuppressants were largely ineffective, whereas interleukin-6 inhibition provided systemic benefit but limited ocular improvement."
    explanation: Systemic benefit with only limited ocular response in a separate series.
- name: TNF Inhibition
  description: >-
    Anti-TNF therapy (adalimumab) suppresses systemic inflammation and improves
    quality of life, but it has not controlled the ocular disease.
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
  target_mechanisms:
  - target: Proinflammatory Cytokine Overproduction
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life"
    explanation: Systemic benefit of anti-TNF therapy in the cohort.
  - reference: PMID:31939038
    reference_title: "Juvenile Onset Splenomegaly and Oculopathy Due to Germline Mutation in ALPK1."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Anti-TNF treatment of adalimumab was applied to patient 1, after which her optic disc edema in the left eye continued and the visual acuity deteriorated further."
    explanation: Adalimumab did not halt the ocular disease in this patient.
- name: IL-1 Blockade
  description: >-
    Anakinra or canakinumab suppresses systemic inflammatory features but has
    not been shown to improve intraocular inflammation.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
    - preferred_term: canakinumab
      term:
        id: NCIT:C80971
        label: Canakinumab
  target_mechanisms:
  - target: Proinflammatory Cytokine Overproduction
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life"
    explanation: Systemic benefit of IL-1 blockade in the cohort.
- name: Splenectomy
  description: >-
    Performed for abdominal discomfort, cytopenias or risk of rupture. The
    cytopenias improve afterwards, but CRP elevations persist.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  target_mechanisms:
  - target: Splenic Red Pulp Expansion
    treatment_effect: INHIBITS
    evidence:
    - reference: PMID:35868845
      reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "While cytopenias appeared to improve after splenectomy"
      explanation: Removing the enlarged spleen relieves the cytopenias; CRP elevations persisted afterwards.
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seven patients underwent splenectomy for abdominal discomfort or cytopenias"
    explanation: Indications for splenectomy in the cohort.
  - reference: PMID:41880066
    reference_title: "Irreversible Ocular and Systemic Damage in ROSAH Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Splenectomy resolved recurrent fever in two patients."
    explanation: Splenectomy also relieved recurrent fever in two patients.
- name: Local Ocular Therapy for Macular Edema
  description: >-
    Intravitreal dexamethasone and intravitreal anti-VEGF injection reduce
    macular edema. The anti-VEGF benefit lasted about six weeks in one case;
    the report does not name the agent, so bevacizumab stands for the class.
    Neither prevents the retinal degeneration.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
    - preferred_term: bevacizumab
      term:
        id: NCIT:C2039
        label: Bevacizumab
  target_mechanisms:
  - target: Intraocular Inflammation
    treatment_effect: INHIBITS
    evidence:
    - reference: PMID:40201710
      reference_title: "Case Report: ROSAH syndrome presents diagnostic and therapeutic challenges."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "While ROSAH-associated ocular inflammation and macular edema may respond to local steroids and immune suppression, retinal degeneration may progress despite these therapies."
      explanation: Local steroid acts on the inflammatory, not the degenerative, arm.
  evidence:
  - reference: PMID:40201710
    reference_title: "Case Report: ROSAH syndrome presents diagnostic and therapeutic challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While the proband's macular edema improved with intravitreal dexamethasone and systemic tocilizumab, immune suppression did not prevent retinal degeneration."
    explanation: Macular edema responded to intravitreal dexamethasone.
  - reference: PMID:40069099
    reference_title: "ROSAH syndrome presenting with recurrent vitreous hemorrhage: a multimodal imaging study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The macular edema was responsive to anti-vascular endothelium growth factor (anti-VEGF) injection, however only for a period of 6-weeks before reoccurrence."
    explanation: Short-lived response to anti-VEGF.
- name: Conventional Immunosuppression
  description: >-
    Methotrexate, sulfasalazine, rituximab and similar agents have been used
    without controlling the ocular disease.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:41880066
    reference_title: "Irreversible Ocular and Systemic Damage in ROSAH Syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Conventional immunosuppressants were largely ineffective"
    explanation: Conventional immunosuppression failed in this series.
  - reference: PMID:39847428
    reference_title: "Two Cases of ROSAH-Like Syndrome Restricted to the Ophthalmologic Presentation."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "severe optic nerve infiltration and retinal pigment atrophy with intraocular inflammation, which were not improved by immunosuppressive treatment"
    explanation: Ocular disease did not improve with immunosuppression.
- name: Supportive and Dental Care
  description: >-
    Low-vision services, dental care for enamel defects, and orthodontic
    planning that allows for short dental roots.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:38935811
    reference_title: "ALPK1-Related Autoinflammatory Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Supportive treatment involves the following: intraocular inflammation management; low vision services; systemic inflammation management (such as a rheumatologist); dental care of enamel defects; and orthodontic procedures for individuals with short dental roots."
    explanation: GeneReviews management recommendations.
- name: Multispecialty Surveillance
  description: >-
    Regular ophthalmologic, rheumatologic and dental follow-up, including the
    consequences of anhidrosis.
  action_category: MONITORING
  treatment_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:38935811
    reference_title: "ALPK1-Related Autoinflammatory Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Surveillance: Regular monitoring by specialists treating the ophthalmologic findings, systemic inflammatory disease, and systemic and dental manifestations of anhidrosis/hypohidrosis."
    explanation: GeneReviews surveillance recommendations.
- name: Genetic Counseling
  description: >-
    Autosomal dominant transmission with a 50% risk to offspring and sibs of a
    heterozygous parent; prenatal and preimplantation testing are available.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38935811
    reference_title: "ALPK1-Related Autoinflammatory Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Once the ALPK1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
    explanation: GeneReviews genetic counseling section.
- name: Selective ALPK1 Inhibition (Preclinical)
  description: >-
    DF-003, an oral, selective ALPK1 inhibitor, inhibits ALPK1 T237M and
    reverses retinal, optic nerve and cortical inflammation in a humanised
    T237M mouse model. It has not been tested in patients.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Constitutive TIFA Phosphorylation and TIFAsome Assembly
    treatment_effect: INHIBITS
    evidence:
    - reference: PMID:40925900
      reference_title: "Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "DF-003 suppresses inflammatory cytokine signaling mediated both by wild-type ALPK1 and the disease-causing ALPK1"
      explanation: Cell-based inhibition of signalling by the T237M mutant kinase.
  evidence:
  - reference: PMID:40925900
    reference_title: "Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we show that orally administered DF-003 is sufficient to inhibit these inflammatory phenotypes"
    explanation: Preclinical efficacy in the ROSAH mouse model.
animal_models:
- species: Mus musculus
  genotype: Alpk1 T237M knock-in
  description: >-
    Knock-in of the recurrent ROSAH variant into mouse Alpk1. The mice show
    only subclinical inflammation.
  publication: PMID:35868845
  modeled_mechanisms:
  - target: Proinflammatory Cytokine Overproduction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
  evidence:
  - reference: PMID:35868845
    reference_title: "Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation."
    explanation: Mild, subclinical inflammatory phenotype.
- species: Mus musculus
  genotype: Heterozygous human ALPK1 wild-type / ALPK1 T237M
  description: >-
    Humanised mice carrying wild-type and T237M human ALPK1. They show retinal
    microglial infiltration, astrocyte activation and cytokine upregulation in
    the retina, optic nerve and cortex, and were used to test DF-003.
  publication: PMID:40925900
  modeled_mechanisms:
  - target: Retinal and Optic Nerve Neuroinflammation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
  evidence:
  - reference: PMID:40925900
    reference_title: "Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Using mice heterozygous for wild-type human ALPK1 and ALPK1T237M established to model ROSAH syndrome that exhibit retinal microglial infiltration, astrocyte activation, and inflammatory cytokine upregulation in the retina, optic nerve, and cortex"
    explanation: Ocular and CNS neuroinflammation in the humanised model.
references:
- reference: PMID:38935811
  title: "ALPK1-Related Autoinflammatory Disease."
  tags:
  - GeneReviews
notes: >-
  GeneReviews covers this disease as "ALPK1-Related Autoinflammatory Disease"
  (PMID:38935811). Only its abstract was cached, so the abstract served as the
  baseline: its clinical characteristics, diagnosis, management, surveillance
  and genetic counseling statements are each cited above. Optic disc swelling
  in ROSAH is not caused by raised intracranial pressure, and HPO has no
  optic-disc-edema term outside Papilledema (HP:0001085), which is defined by
  raised CSF pressure; Abnormal optic disc morphology (HP:0012795) is used
  instead.
📚

References & Deep Research

References

1
PMID:38935811
ALPK1-Related Autoinflammatory Disease.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: ROSAH_Syndrome · 2026-10-19T05:00:44Z · View source

New entry for ROSAH syndrome (MONDO:0013999; ALPK1 gain-of-function autoinflammatory disease), claim issue #14873. Deep research was requested from falcon; Edison returned 403 (authentication), so the run fell back and research/ROSAH_Syndrome-deep-research-openscientist.md (openscientist) is the report used. Its 24 references all resolved; the one flagged off topic (PMID:31075211, H. pylori ADP-heptose) was not cited; preflight-dr warnings were TIFA (the pathway substrate, same disease) and OMIM 607347 (the ALPK1 gene MIM), both benign. GeneReviews chapter PMID:38935811 (abstract only) is tagged and used as baseline for phenotypes, diagnosis, management, surveillance and counseling. Primary sources: Kozycki 2022 (PMID:35868845), Williams 2019 (PMID:30967659), Tantravahi 2012 (PMID:22307799), Huryn 2023 ophthalmic cohort (PMID:36332842), Snelling 2023 and 2024 (PMID:38060563, 39626775), plus case series. Optic disc elevation bound to HP:0012795 rather than Papilledema (defined by raised CSF pressure). PMID:38251500 was cached with no quotable text and is not cited. A fresh-context red-team review (dismech-pr-review) was run before the PR and its important findings fixed (diagnosis section, GI/malaise phenotypes, ciliary evidence_source, IFN-gamma loop direction, animal models, Cogan wording). Validated with just validate (111/111 snippets verified, terms and schema clean), check-entity-refs, check-genereviews and validate-disorders.

OpenScientist ▸
ROSAH Syndrome — Comprehensive Disease Characteristics Report
openscientist-autonomous 24 citations 2026-10-19T00:47:13.448023

ROSAH Syndrome — Comprehensive Disease Characteristics Report

Disease: ROSAH Syndrome (Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis, and Headache) MONDO: MONDO:0013999 · OMIM: #614979 · Orphanet: ORPHA:313800 · Causal gene: ALPK1 (HGNC:20917)

Summary

ROSAH syndrome is an ultra-rare, autosomal dominant systemic autoinflammatory disease caused by heterozygous gain-of-function missense variants in ALPK1 (alpha-kinase 1). First delineated in 2019 in five unrelated families, the syndrome is named for its cardinal features — Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis, and Headache — but is now understood to be a far broader multisystem inflammatory disorder. The defining molecular lesion is a recurrent variant, c.710C>T (p.Thr237Met), with a second recurrent allele p.Tyr254Cys and additional rarer variants (p.Ser277Phe, p.His735Pro, p.Thr237Ala). Mechanistically, wild-type ALPK1 is a cytosolic innate-immune receptor that senses the bacterial metabolite ADP-heptose and signals through TIFA–TRAF6 to activate NF-κB. The ROSAH variants are neomorphic: they alter the kinase's ligand specificity so it becomes aberrantly activated by endogenous host nucleotide sugars (e.g., UDP-mannose, ADP-ribose), producing constitutive NF-κB plus type I/II interferon signaling in the absence of any infection.

Clinically, the disease presents in early childhood with near-universal, frequently blinding bilateral ocular disease (optic disc edema, cone-rod retinal dystrophy resembling retinitis pigmentosa, low-grade uveitis/vitritis, and macular edema) accompanied by variable systemic features: splenomegaly (often with cytopenias), anhidrosis/hypohidrosis, migrainous headache, short dental roots, recurrent fever, deforming arthritis, premature basal-ganglia/brainstem mineralization on MRI, and a risk of AA (reactive) amyloidosis with renal failure. Expressivity is strikingly variable even within a single family; some individuals (notably with p.Thr237Ala) have a predominantly or exclusively ocular phenotype.

Therapeutically, cytokine blockade — particularly IL-6 receptor inhibition with tocilizumab — best controls systemic and intraocular inflammation and can reverse macular edema and optic-disc swelling, but retinal/optic neurodegeneration frequently progresses despite immunosuppression, suggesting a degenerative component partly uncoupled from controllable inflammation. The first selective ALPK1 inhibitor, DF-003, has been designed for oral dosing and is advancing toward the clinic. The same gene, mutated somatically at a different residue (p.Val1092Ala), drives the skin tumors spiradenoma and spiradenocarcinoma, placing ROSAH within an ALPK1/NF-κB "gain-of-function" allelic series.

Section 1 — Disease Information

Overview. ROSAH syndrome is a monogenic, autosomal dominant, systemic autoinflammatory disorder with prominent ophthalmologic involvement. Although the acronym (Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis, Headache) captures the cardinal features originally described, the condition is now recognized as a broad autoinflammatory disease with ocular, hematologic, neurologic, dermatologic, dental, rheumatologic, and renal manifestations.

Key identifiers (verified via EBI OLS / MONDO and mygene.info):

Resource Identifier
MONDO MONDO:0013999 ("retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome")
OMIM (phenotype) #614979
Orphanet ORPHA:313800
UMLS C4749914
GARD 0017411
MedGen 1662266
Causal gene ALPK1 HGNC:20917; NCBI Gene 80216; Ensembl ENSG00000073331; gene OMIM 607347; UniProt Q96QP1; cytoband 4q25

Synonyms / alternative names: ROSAH syndrome; Retinal dystrophy–optic nerve edema–splenomegaly–anhidrosis–headache syndrome; ALPK1-associated autoinflammatory disease. A related "ROSAH-like" presentation restricted to ophthalmologic features has been reported (PMID: 39847428).

Information source. Knowledge for this entry is derived from aggregated disease-level resources (OMIM, Orphanet, MONDO) combined with individual-patient clinical reports and cohorts (e.g., the n=27 cohort of Kozycki et al. 2022 and numerous case series). It is not derived from a single EHR dataset.

Section 2 — Etiology

Primary cause — genetic. ROSAH is caused by heterozygous gain-of-function missense variants in ALPK1. The founding variant c.710C>T (p.Thr237Met) segregated with disease across five unrelated families (PMID: 30967659). The disorder is autosomal dominant with variable expressivity.

"We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families." — PMID: 30967659

Genetic risk factors. The disease is essentially monogenic; the causal alleles are the risk factors. Recurrent variants: p.Thr237Met (most common) and p.Tyr254Cys; additional reported alleles include p.Ser277Phe, p.His735Pro, and p.Thr237Ala (the latter associated with a milder, largely ocular phenotype). No susceptibility loci or polygenic contributions have been defined.

Environmental / modifier factors. No environmental exposure is required to cause disease. However, the inflammatory context modulates the pathway: IFN-γ "licenses" (primes/amplifies) the ALPK1/TIFA axis in human monocytes (PMID: 39868044), and concurrent gram-negative infection (supplying ADP-heptose) could in principle further activate even wild-type ALPK1. These represent plausible gene-environment / cytokine-context interactions that may contribute to episodic flares and variable expressivity, though this remains inferred rather than demonstrated in patients.

Protective factors. None established. No protective alleles or lifestyle factors are known for this ultra-rare Mendelian disease.

Section 3 — Phenotypes

ROSAH has a near-universal, early-onset ocular core with variable multisystem involvement. Onset is typically pediatric (early childhood); penetrance for ocular disease appears high/near-complete, but expressivity varies even within families.

Phenotype Type HPO suggestion Frequency / notes
Bilateral optic disc / nerve edema Clinical sign HP:0000543 (optic disc edema) Near-universal; often presenting feature
Cone-rod retinal dystrophy (RP-like) Clinical sign HP:0000541 / HP:0000510 Near-universal; progressive; rod function often more reduced than cone (PMID: 41046116)
Low-grade uveitis / vitritis, vitreous opacities Clinical sign HP:0000554 (uveitis) Common; persistent vitreous inflammatory opacities
Macular edema Clinical sign HP:0040049 Common; may respond to steroid/anti-VEGF/IL-6 blockade
Progressive vision loss / blindness Symptom HP:0000618 / HP:0000572 Major morbidity driver
Glaucoma / acute angle-closure (short axial length) Clinical sign HP:0000501 Reported subset (PMID: 41880066)
Keratoconus, dry eye Clinical sign HP:0000563 / HP:0000517 Newly described ocular-surface features (PMID: 41880066)
Splenomegaly Physical manifestation HP:0001744 Characteristic; often with cytopenias/pancytopenia (HP:0001876)
Anhidrosis / hypohidrosis Clinical sign HP:0000970 Characteristic
Headache / migraine Symptom HP:0002076 Common; sometimes with meningeal enhancement
Short / abnormal dental roots Physical manifestation HP (dental root anomaly) Characteristic dental feature
Recurrent fever Symptom HP:0001945 Inflammatory feature
Deforming arthritis / arthralgia Clinical sign HP:0002758 Inflammatory feature
Premature basal-ganglia/brainstem mineralization Imaging/laboratory HP:0002452 (basal ganglia calcification) On MRI (PMID: 35868845)
AA (reactive) amyloidosis → renal failure Laboratory/clinical HP:0011035 / HP:0000121 Serious complication (PMID: 41880066)
Recurrent infections Clinical sign HP:0002719 Reported subset
Urticaria Clinical sign HP:0000988 Listed among MONDO features

"Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis." — PMID: 35868845

"The clinical manifestations were relatively homogeneous, prominently presenting with juvenile onset oculopathy and splenomegaly." — PMID: 31939038

Quality-of-life impact. Progressive, often irreversible vision loss is the dominant QoL burden. Systemic inflammation (fever, arthritis) and complications such as amyloidosis/renal failure add substantial morbidity. No formal EQ-5D/SF-36 studies exist for this rare disease.

Section 4 — Genetic / Molecular Information

Causal gene. ALPK1 (alpha-kinase 1), HGNC:20917, NCBI Gene 80216, Ensembl ENSG00000073331, UniProt Q96QP1, cytoband 4q25. ALPK1 is a cytosolic serine/threonine alpha-kinase that functions as an innate-immune receptor.

Pathogenic variants.

Variant (protein) cDNA Type Classification Notes
p.Thr237Met c.710C>T Missense Pathogenic Recurrent founding allele; multiple ancestries
p.Tyr254Cys — Missense Pathogenic Second recurrent allele (Kozycki 2022)
p.Ser277Phe — Missense Likely pathogenic Strong neomorphic activation (PMID: 39626775)
p.His735Pro — Missense VUS → likely pathogenic pCS/ROSAH case (PMID: 42640550)
p.Thr237Ala — Missense Pathogenic Milder, largely ocular phenotype (PMID: 41046116)
  • Variant class: all reported ROSAH alleles are missense, clustering in/near the kinase/ligand-binding region.
  • Allele frequency: absent/extremely rare in gnomAD (consistent with highly penetrant disease alleles).
  • Origin: germline for ROSAH (de novo capable, given recurrence across diverse ancestries). The same gene mutated somatically at a different residue (p.Val1092Ala) causes spiradenoma (PMID: 31101826).
  • Functional consequence: gain of function / neomorphic — constitutive NF-κB activation; not loss of function.

"The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys." — PMID: 35868845

Modifier genes / epigenetics / chromosomal abnormalities. No specific modifier genes or epigenetic mechanisms have been established for ROSAH, and there are no associated chromosomal abnormalities (this is a single-nucleotide-variant disease). IFN-γ cytokine priming (PMID: 39868044) acts as a functional modifier of pathway output.

Section 5 — Environmental Information

ROSAH is a Mendelian disorder with no required environmental cause. Relevant non-genetic contributors are inflammatory/cytokine context rather than toxins or lifestyle:

  • Infectious / PAMP context: Wild-type ALPK1 is the sensor for bacterial ADP-heptose (CHEBI), a gram-negative LPS-biosynthesis metabolite (PMID: 30111836, PMID: 31075211). While ROSAH variants are activated without infection, microbial ADP-heptose could further amplify signaling.
  • Cytokine priming: IFN-γ licenses the ALPK1/TIFA pathway (PMID: 39868044), a plausible trigger for flares.
  • Lifestyle factors: none identified.

Section 6 — Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A heterozygous gain-of-function missense variant in ALPK1 (e.g., p.Thr237Met, p.Tyr254Cys, p.Ser277Phe) alters the kinase's ligand-binding pocket, changing its specificity for allosteric nucleotide-sugar activators.
  2. The altered pocket leads to aberrant activation of ALPK1 by endogenous host metabolites (UDP-mannose, ADP-ribose; also GDP-mannose for p.Ser277Phe) — i.e., activation without microbial ADP-heptose (PMID: 39626775, PMID: 39580356).
  3. Constitutively active ALPK1 phosphorylates TIFA, which results in TIFA oligomerization.
  4. Oligomerized TIFA recruits TRAF6, which leads to activation of the NF-κB and AP-1 transcription factors (PMID: 32591860, PMID: 30111836).
  5. (Branch, inferred amplification) IFN-γ licenses/primes the same pathway, amplifying signaling in monocytes (PMID: 39868044).
  6. NF-κB/AP-1 activation results in chronic production of proinflammatory cytokines (TNF, IL-1, IL-6, IL-18) and, in parallel, STAT1 phosphorylation and a type I/II interferon gene-expression signature (PMID: 35868845).
  7. Systemic cytokine excess leads to multisystem autoinflammation → recurrent fever, deforming arthritis, splenomegaly, meningeal enhancement, premature basal-ganglia/brainstem mineralization, and (chronically) AA amyloidosis with renal failure.
  8. (Branch — tissue-specific) ALPK1 is expressed in retina, RPE, and optic nerve, localizing to the photoreceptor connecting-cilium basal body; local inflammation plus a possible ciliogenesis/degenerative component results in optic-nerve edema, uveitis, macular edema, and progressive cone-rod retinal dystrophy — the latter frequently progressing despite inflammation control, implying a partly inflammation-independent neurodegenerative arm (inferred; PMID: 30967659, PMID: 42773882).

Supporting detail

  • Molecular pathways: ALPK1 → TIFA → TRAF6 → NF-κB (GO:0038061, NIK/NF-κB signaling) and AP-1; innate-immune TLR-like signaling (GO:0002224); JAK-STAT/interferon (STAT1).
  • Cellular processes: chronic inflammation, cytokine secretion; GSDMD-mediated pyroptosis implicated in related ALPK1/retinal contexts (PMID: 41006430); defective ciliogenesis in patient fibroblasts (PMID: 30967659).
  • Protein dysfunction: neomorphic gain of function — altered specificity for allosteric nucleotide-sugar activators rather than misfolding/aggregation (PMID: 39580356).
  • Immune involvement: autoinflammation with combined NF-κB and interferon signatures.
  • Subcellular localization (GO CC): ciliary basal body (GO:0036064), centriole (GO:0005814), microtubule-organizing center (GO:0005815), spindle pole during metaphase.

"Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature." — PMID: 35868845

"...the mechanism of ADP-heptose sensing by alpha-protein kinase 1 (ALPK1) and its downstream signaling pathway that involves the proteins TIFA and TRAF6 and induces the activation of NF-κB and the secretion of inflammatory cytokines." — PMID: 32591860

"In contrast to wild-type ALPK1, which is activated specifically by bacterial ADP-heptose, ALPK1[Ser277Phe] is also activated by the human metabolites UDP-mannose and ADP-ribose." — PMID: 39626775

GOF ALPK1 variant
      │ altered ligand specificity
      ▼
host nucleotide sugars (UDP-mannose, ADP-ribose) ──► ALPK1 constitutively active
      ▼ (IFN-γ licenses/amplifies)
TIFA phosphorylation ──► TIFA oligomerization ──► TRAF6 recruitment
      ▼
NF-κB + AP-1  ─────────────► TNF / IL-1 / IL-6 / IL-18
STAT1 / IFN signature                     │
      ▼                                    ▼
  ┌───────────────┐              multisystem autoinflammation
  │ ocular tissue │              (fever, arthritis, splenomegaly,
  │ (retina/RPE/  │               CNS mineralization, AA amyloidosis)
  │  optic nerve) │
  └──────┬────────┘
 ▼
  optic disc edema, uveitis, macular edema,
  progressive cone-rod dystrophy  ◄── partly inflammation-independent (inferred)

Section 7 — Anatomical Structures Affected

  • Primary organs: eye (UBERON:0000970) — retina (UBERON:0001782), retinal pigment epithelium, optic nerve (UBERON:0000941), macula, cornea (UBERON:0000964); spleen (UBERON:0002106).
  • Secondary / systemic: skin/sweat glands (anhidrosis), brain (basal-ganglia/brainstem mineralization; meningeal enhancement), joints (deforming arthritis), teeth (short dental roots), kidney (AA amyloidosis → renal failure), bone marrow/hematologic (cytopenias).
  • Body systems: visual/ophthalmic, hematologic/reticuloendothelial, nervous, integumentary, musculoskeletal, renal.
  • Cell types (CL): retinal cone cell (CL:0000573), retinal rod cell (CL:0000604), retinal pigment epithelial cell (CL:0002586), sweat gland cell (CL:0000650), monocytes/macrophages (effectors of autoinflammation).
  • Subcellular (GO CC): ciliary basal body (GO:0036064), centriole (GO:0005814), MTOC (GO:0005815), cytosol.
  • Lateralization: ocular disease is bilateral; splenomegaly is left-sided/midline per anatomy.

"ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands." — PMID: 30967659

Section 8 — Temporal Development

  • Onset: typically pediatric / early childhood; ocular symptoms are frequently the presenting and sometimes the exclusive early feature. Some cases show subtle signs in infancy (e.g., hand abnormalities by 18 months; PMID: 41269507).
  • Onset pattern: chronic / insidious, with superimposed episodic inflammatory flares (fever).
  • Progression: progressive, particularly the retinal degeneration, which advances like retinitis pigmentosa. Systemic inflammation can be episodic/relapsing.
  • Disease course / duration: chronic, lifelong.
  • Remission: inflammatory manifestations can enter treatment-induced remission with cytokine blockade; retinal/optic degeneration generally does not remit and may progress despite therapy.
  • Critical period: early diagnosis and anti-inflammatory intervention before irreversible retinal/optic damage represents the key window of opportunity (PMID: 41880066, PMID: 40201710).

Section 9 — Inheritance and Population

  • Inheritance: autosomal dominant, heterozygous gain-of-function.
  • Penetrance / expressivity: high/near-complete penetrance for ocular disease; markedly variable expressivity, including intrafamilial (e.g., mother–daughter pair with very different courses, PMID: 42773882; p.Thr237Ala with ocular-only phenotype, PMID: 41046116).
  • De novo / recurrence: recurrent identical missense alleles across diverse ancestries indicate recurrent, de-novo-capable mutations rather than a single founder effect.
  • Epidemiology: ultra-rare. Only ~18 patients were reported by 2020 (PMID: 31939038); the largest single cohort is n=27 (PMID: 35868845). Cumulative literature remains on the order of tens of families worldwide. No formal prevalence or incidence has been established.
  • Population demographics: reported across US/European, Chinese, Polish, Italian, and Brazilian ancestries, consistent with recurrent alleles rather than population-specific founders. No strong sex skew documented.

"Up to date, 18 patients of ROSAH syndrome have been reported." — PMID: 31939038

Section 10 — Diagnostics

  • Genetic testing (confirmatory): molecular confirmation of a pathogenic ALPK1 variant via whole-exome sequencing (most common diagnostic route), targeted/retinal-dystrophy gene panels, or single-gene ALPK1 sequencing. Advocacy exists for including ALPK1 on panels for optic neuropathies, retinal disorders, and unexplained arthropathy (PMID: 41269507).
  • Ophthalmic work-up: fundus photography, OCT / OCT-angiography (macular edema, ellipsoid-zone loss), fundus autofluorescence (hyperautofluorescent ring around disc), full-field ERG (rod > cone dysfunction), visual fields, fluorescein angiography (lack of capillary closure; preretinal neovascularization) — PMID: 41046116, PMID: 40069099.
  • Systemic work-up: abdominal ultrasound (splenomegaly); CBC (cytopenias/pancytopenia); inflammatory markers; brain MRI (meningeal enhancement, basal-ganglia/brainstem mineralization); renal assessment and tissue biopsy if amyloidosis suspected.
  • Clinical criteria: diagnosis rests on the characteristic combination of optic disc edema, uveitis, and retinal degeneration plus systemic features, confirmed by ALPK1 genetic testing (PMID: 40201710).
  • Differential diagnosis: retinitis pigmentosa / inherited retinal dystrophies, uveitis of other causes, Cogan's syndrome (ROSAH can masquerade as pediatric Cogan's; PMID: 42640550), lupus nephritis (renal ROSAH masquerade; PMID: 42112140), other autoinflammatory syndromes (e.g., CAPS/NLRP3).

"A diagnosis of ROSAH syndrome... can be made by targeted genetic sequencing of the ALKP1 gene." — PMID: 40201710

Section 11 — Outcome / Prognosis

  • Survival / mortality: not systematically quantified; the disease is chronic and disabling rather than rapidly fatal, but AA amyloidosis → renal failure/dialysis dependence is a serious, potentially life-limiting complication (PMID: 41880066).
  • Morbidity / function: dominated by progressive, often irreversible vision loss / blindness; additional morbidity from arthritis, recurrent fever, cytopenias, and renal disease.
  • Complications: amyloidosis with renal failure, glaucoma (including acute angle-closure), vitreous hemorrhage, recurrent infections, cytopenias.
  • Recovery potential: inflammation is often controllable; retinal/optic neurodegeneration generally does not recover once established — inflammatory and degenerative processes appear to progress at least partly independently (PMID: 42773882).
  • Prognostic factors: early diagnosis and timely anti-inflammatory therapy before irreversible retinal damage are the key favorable factors; advanced retinal degeneration at diagnosis predicts poor visual outcome despite treatment.

Section 12 — Treatment

Pharmacotherapy — cytokine blockade (mainstay).

Agent Target (NCIT class) Effect Evidence
Tocilizumab IL-6 receptor antagonist Best control of intraocular inflammation; reduces macular edema & optic-disc swelling; improves systemic inflammation PMID: 35868845, PMID: 41269507, PMID: 41880066
Anti-TNF (e.g., adalimumab) TNF inhibitor Suppresses systemic inflammation, improves QoL; limited ocular benefit PMID: 35868845
Anti-IL-1 (e.g., anakinra) IL-1 inhibitor Suppresses systemic inflammation; limited ocular benefit PMID: 35868845
Methotrexate / rituximab Conventional/B-cell immunosuppression Generally ineffective for ocular degeneration PMID: 41269507, PMID: 41880066

"While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients)." — PMID: 35868845

Targeted therapy (upstream, investigational). DF-003, a selective ALPK1 inhibitor with pharmacokinetics suitable for once-daily oral dosing, targets the TIFA/TRAF6/NF-κB axis (PMID: 40925900).

"Here, we report the design of an ALPK1 inhibitor, DF-003, with pharmacokinetic properties suitable for daily oral dosing." — PMID: 40925900

Local ocular / supportive measures. Intravitreal dexamethasone and anti-VEGF (transient macular-edema benefit, ~6 weeks; PMID: 40069099); splenectomy resolves recurrent fever in selected patients (PMID: 41880066); renal replacement therapy for amyloidosis-related failure.

Important caveat. Across multiple reports, immune suppression controls inflammation but does not reliably prevent retinal degeneration or restore lost vision (PMID: 40201710, PMID: 42773882).

Section 13 — Prevention

  • Primary prevention: none — this is a genetic disease; no vaccination or risk-factor modification prevents it.
  • Secondary prevention / early detection: early genetic diagnosis (including ALPK1 on retinal/optic-neuropathy and autoinflammatory panels) to enable prompt anti-inflammatory therapy before irreversible ocular damage (PMID: 40270650, PMID: 41269507).
  • Tertiary prevention: cytokine blockade to prevent systemic complications (amyloidosis, deforming arthritis); monitoring for renal amyloidosis; ophthalmologic surveillance for glaucoma/edema.
  • Counseling: genetic counseling for autosomal dominant inheritance (50% transmission risk); options include prenatal/preimplantation testing given known familial variants.
  • Screening: cascade genetic testing of at-risk relatives once a familial variant is identified.

Section 14 — Other Species / Natural Disease

  • Orthologous gene: mouse Alpk1 (ortholog of human ALPK1, NCBI Gene 80216). The ALPK1–TIFA–TRAF6–NF-κB ADP-heptose-sensing pathway is evolutionarily conserved.
  • Natural disease in other species: no naturally occurring ROSAH-equivalent disease has been described in companion animals or wildlife (OMIA has no established ROSAH entry).
  • Comparative biology: ADP-heptose/ALPK1 innate immunity is conserved; ALPK1-TIFA signaling controls intestinal stem-cell regeneration in mouse models (PMID: 40651470), illustrating conserved physiological roles.
  • Zoonotic potential: not applicable (non-infectious genetic disease).

Section 15 — Model Organisms

  • Knock-in mouse: Kozycki et al. (2022) generated an Alpk1 knock-in mouse carrying the ROSAH mutation as an in-vivo model of the autoinflammatory phenotype (PMID: 35868845).
  • Cellular / in-vitro models: patient-derived fibroblasts (showed defective ciliogenesis; PMID: 30967659); ALPK1-knockout HEK-Blue NF-κB/AP-1 reporter cells for quantifying variant activity and screening VUS (PMID: 39600975); transfected-cell NF-κB/AP-1 assays establishing gain-of-function/altered specificity (PMID: 39626775, PMID: 39580356).
  • Phenotype recapitulation: the knock-in mouse enables study of the inflammatory arm; cellular assays faithfully reproduce constitutive/neomorphic NF-κB activation.
  • Limitations: models of the retinal-degeneration arm and long-term ocular neurodegeneration are less developed; capturing the human ocular phenotype in rodents remains a gap.

Mechanistic Model / Interpretation

ROSAH is best understood as a neomorphic kinase disease converging on NF-κB-driven autoinflammation plus a partly separable ocular neurodegeneration. The unifying molecular theme — shared with somatic ALPK1-driven spiradenoma — is aberrant NF-κB activation from a gain-of-function/altered-specificity ALPK1 allele. Upstream (causal) events are the germline mutation and the resulting constitutive ALPK1→TIFA→TRAF6 signaling; downstream (effector) events are cytokine excess (IL-6, TNF, IL-1, IL-18), the interferon signature, and the end-organ consequences. The ocular phenotype has two plausible contributors: (i) local inflammation in ALPK1-expressing retina/RPE/optic nerve, and (ii) a possible cilium-related degenerative process (defective ciliogenesis; connecting-cilium basal-body localization). The clinical observation that IL-6 blockade reverses inflammation but not degeneration argues that arm (ii) is at least partly inflammation-independent — the single most important mechanistic and therapeutic gap.

     ┌──────────── germline (ROSAH) ────────────┐
     │                                           │
  p.Thr237Met/p.Tyr254Cys/p.Ser277Phe           p.Val1092Ala (somatic)
     │                                           │
     ▼                                           ▼
   neomorphic ALPK1 (host sugar sensing)        spiradenoma / spiradenocarcinoma
     │                                           │
     └──────────► NF-κB / AP-1 ◄─────────────────┘
                      │
    ┌─────────────────┴──────────────────┐
     systemic autoinflammation            ocular disease
     (fever, arthritis, spleen,          (edema, uveitis,
      CNS mineralization, amyloid)        cone-rod dystrophy)
    │ responds to IL-6 block            │ degeneration progresses

Evidence Base

PMID Role in this report
30967659 Founding paper: ALPK1 p.Thr237Met in 5 families; tissue localization; ciliogenesis defect
35868845 n=27 cohort; autoinflammatory mechanism; p.Tyr254Cys; tocilizumab ocular benefit; knock-in mouse
32591860 Defines normal ALPK1-TIFA-TRAF6-NF-κB axis
30111836 ALPK1 as cytosolic receptor for bacterial ADP-heptose
39626775 p.Ser277Phe neomorphic activation by host UDP-mannose/ADP-ribose
39580356 Altered-specificity mechanism unifying ROSAH and spiradenoma
31101826 Somatic ALPK1 hotspot driving spiradenoma/spiradenocarcinoma
39868044 IFN-γ licenses the ALPK1/TIFA pathway (modifier)
40925900 DF-003 selective ALPK1 inhibitor
31939038 Juvenile oculopathy + splenomegaly; ultra-rare epidemiology
41046116 Ocular manifestations; p.Thr237Ala milder/ocular-only
42773882 Intrafamilial variability; inflammation vs degeneration uncoupling
41880066 Reactive amyloidosis; novel ocular features; IL-6 systemic benefit
40201710 Diagnosis by ALPK1 sequencing; degeneration progresses despite therapy
41269507 Tocilizumab anatomical benefit; p.Tyr254Cys
39600975 NF-κB/AP-1 reporter assay for variant functional testing
42640550 ALPK1 p.His735Pro; ROSAH as Cogan's-syndrome mimic
42112140 Renal ROSAH masquerading as lupus nephritis
40069099 Anti-VEGF transient benefit; vitreous hemorrhage phenotype

Limitations and Knowledge Gaps

  1. Ultra-rarity: With only tens of reported families, epidemiologic parameters (prevalence, incidence, sex ratio, penetrance estimates, survival) are uncertain and largely qualitative.
  2. Ocular neurodegeneration mechanism: It remains unresolved whether retinal/optic degeneration is driven primarily by local inflammation, a cilium/ciliogenesis defect, or an independent neurodegenerative process; the apparent uncoupling of inflammation control from degeneration progression is clinically observed but mechanistically unexplained.
  3. Genotype–phenotype correlation: Why p.Thr237Ala yields a mild/ocular-only phenotype while p.Thr237Met and p.Tyr254Cys cause full multisystem disease is not fully understood.
  4. Treatment evidence: Therapeutic data derive from small cohorts and case reports, not controlled trials; no therapy is proven to halt vision loss.
  5. Model limitations: Current models capture inflammation better than the ocular phenotype.

Proposed Follow-up Experiments / Actions

  1. Natural-history registry to quantify penetrance, progression rates, visual outcomes, and amyloidosis risk across ALPK1 genotypes.
  2. Mechanistic dissection of the ocular arm: retinal organoids/iPSC-RPE and refined knock-in mice to test whether vision loss is inflammation-dependent, cilium-dependent, or neurodegenerative — directly informing whether upstream ALPK1 inhibition (DF-003) can protect vision where cytokine blockade fails.
  3. Clinical evaluation of DF-003 and head-to-head comparison with tocilizumab for ocular endpoints.
  4. Structural studies (crystallography/cryo-EM/AlphaFold) of mutant ALPK1 bound to host nucleotide sugars to enable variant-selective inhibitor design sparing normal innate immunity.
  5. Functional classification pipeline using the NF-κB/AP-1 reporter assay (PMID: 39600975) to reclassify ALPK1 VUS and support genetic diagnosis.
  6. Biomarker development (interferon signature, serum amyloid A) for monitoring disease activity and treatment response.

Report compiled from 27 reviewed publications and 9 confirmed findings. Evidence sources span human clinical cohorts/case reports, in-vitro reporter and biochemical assays, and a knock-in mouse model. Primary genetic and mechanistic claims are anchored to PMIDs 30967659, 35868845, 32591860, 39626775, and 39580356.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 24
Resolved 24
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 24
On topic 17
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:31075211 (3 mentions) - ADP heptose, a novel pathogen-associated molecular pattern identified in Helicobacter pylori.
  • shared terms: tifa, gene

Weighed against this report's own most characteristic terms: alpk1, disease, ocular, retinal, rosah, optic, inflammation, systemic, phenotype, renal, cytokine, variant, amyloidosis, inflammatory, tifa, edema, gene, recurrent, splenomegaly, degeneration.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 38
Resolved 35
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 2
Terms whose name was checked 14
Terms named correctly 3
Terms named as a different term 10
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0040049 (1 mention) - the report calls it "Clinical sign"; HP calls it Macular edema
  • HP:0000501 (1 mention) - the report calls it "Clinical sign"; HP calls it Glaucoma
  • HP:0001744 (1 mention) - the report calls it "Physical manifestation"; HP calls it Splenomegaly
  • HP:0000970 (1 mention) - the report calls it "Clinical sign"; HP calls it Anhidrosis
  • HP:0002076 (1 mention) - the report calls it "Symptom"; HP calls it Migraine
  • HP:0001945 (1 mention) - the report calls it "Symptom"; HP calls it Fever
  • HP:0002758 (1 mention) - the report calls it "Clinical sign"; HP calls it Osteoarthritis
  • HP:0002719 (1 mention) - the report calls it "Clinical sign"; HP calls it Recurrent infections
  • HP:0000988 (1 mention) - the report calls it "Clinical sign"; HP calls it Skin rash
  • UBERON:0000970 (1 mention) - the report calls it "eye", "Primary organs: eye"; UBERON calls it eye

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0002452 (1 mention), reported as "basal ganglia calcification" - HP does not contain this term

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0000543 (1 mention) - the report calls it "optic disc edema"; HP calls it Optic disc pallor

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • UBERON:0000970 - called "eye", "Primary organs: eye"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.