hgnc:6080

[PMID:23273569] [SUPPORT] Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. --- Explanation: Landmark study identifying INPPL1 mutations as the cause of opsismodysplasia.

[PMID:23273567] [SUPPORT] INPPL1 mutations explain ~60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases. --- Explanation: Estimates the proportion of clinically diagnosed cases attributable to INPPL1 mutations.

[PMID:34094554] [SUPPORT] Schneckenbecken dysplasia and Opsismodysplasia are allelic disorders caused by pathogenic variants in INPPL1 gene with lethal outcomes in Schneckenbecken dysplasia and nonlethal prognosis in Opsismodysplasia. --- Explanation: Establishes the allelic relationship with Schneckenbecken dysplasia.

[PMID:34094554] [SUPPORT] Prediction of lethality is difficult to determine in prenatal‐onset skeletal dysplasia especially with borderline lethality indices measured in prenatal ultrasound. --- Explanation: Highlights the challenge of predicting lethal versus nonlethal outcomes in prenatal INPPL1-related skeletal dysplasia.


MONDO:0009785

[PMID:23273567] [SUPPORT] mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. --- Explanation: Establishes that biallelic INPPL1 mutations cause autosomal recessive opsismodysplasia.

[PMID:10076884] [SUPPORT] This observation supports the hypothesis of autosomal recessive transmission of opsismodysplasia. --- Explanation: Familial recurrence pattern confirmed autosomal recessive inheritance prior to gene identification.


MONDO:0010703

[PMID:31441224] [SUPPORT] Maternal OTCD can lead to life-threatening hyperammonemia if untreated. --- Explanation: Confirms hyperammonemia as a major clinical risk in OTCD.

[PMID:37146589] [SUPPORT] Individuals with neonatal onset appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma, and death --- Explanation: Confirms hyperammonemia as the pivotal early clinical event in neonatal OTCD.


MONDO:0010703

[PMID:36128655] [SUPPORT] Its clinical manifestations are mainly central nervous system dysfunction caused by high blood ammonia. --- Explanation: Supports encephalopathic CNS dysfunction in OTCD.

[PMID:33409766] [SUPPORT] Hyperammonemia caused by a disorder of the urea cycle is a rare cause of metabolic encephalopathy that may be underdiagnosed by the adult intensivists because of its rarity. --- Explanation: Directly identifies UCD-related hyperammonemia as a cause of metabolic encephalopathy.


MONDO:0010703

[PMID:36128655] [SUPPORT] His first symptoms were nonprojectile vomiting, followed by irritability and disturbance of consciousness, after which the disease progressed rapidly and finally resulted in a coma. --- Explanation: Directly supports vomiting as an early symptom in hyperammonemic decompensation.


MONDO:0010703

[PMID:36128655] [SUPPORT] His first symptoms were nonprojectile vomiting, followed by irritability and disturbance of consciousness, after which the disease progressed rapidly and finally resulted in a coma. --- Explanation: Supports severe neurologic decline during OTCD decompensation episodes.


MONDO:0010703

[PMID:39256843] [SUPPORT] Five boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. --- Explanation: Directly reports seizures as a clinical manifestation in early-onset OTCD.


MONDO:0010703

[PMID:37146589] [SUPPORT] rapidly develop hyperammonemia, which can progress to cerebral edema, coma, and death --- Explanation: Directly supports coma as a progression of hyperammonemia in OTCD.

[PMID:36128655] [SUPPORT] the disease progressed rapidly and finally resulted in a coma --- Explanation: Case report documenting progression to coma in late-onset OTCD.


MONDO:0010703

[PMID:37146589] [SUPPORT] rapidly develop hyperammonemia, which can progress to cerebral edema, coma, and death --- Explanation: Directly names cerebral edema as a complication of hyperammonemia in OTCD.

[PMID:33409766] [SUPPORT] emergent hemodialysis is mandatory before referral to a reference center if ammonia levels are above 200 µmol/l as the risk of cerebral edema is then above 55% --- Explanation: Quantifies the high risk of cerebral edema at severe ammonia levels.


MONDO:0010703

[PMID:36128655] [SUPPORT] However, the child is currently mentally retarded, and the language center has not yet fully recovered. --- Explanation: Supports persistent neurodevelopmental impairment after severe OTCD CNS injury.


MONDO:0010703

[PMID:39256843] [SUPPORT] Five boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. --- Explanation: Directly reports liver failure as a clinical feature in early-onset OTCD.


MONDO:0010703

[PMID:39220945] [SUPPORT] all ten early-onset cases had glutamine concentrations above the upper limit --- Explanation: Directly documents hyperglutaminemia in all early-onset OTCD cases.


MONDO:0010703


MONDO:0010703

[PMID:39220945] [SUPPORT] only five of them had citrulline concentrations below the lower limit of the reference interval --- Explanation: Documents low citrulline in early-onset OTCD, though not universally present.


MONDO:0010703

[PMID:31441224] [INDIRECT EVIDENCE] [SUPPORT] Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked urea cycle disorder. --- Explanation: Supports OTCD as a urea-cycle enzyme deficiency disorder.

[PMID:31110235] [INDIRECT EVIDENCE] [SUPPORT] carbamoylphosphate synthetase 1 and ornithine transcarbamylase are present in the mitochondrial matrix --- Explanation: Confirms mitochondrial matrix localization of OTC enzyme.


MONDO:0010703

[PMID:39328593] [INDIRECT EVIDENCE] [SUPPORT] OTCD typically leads to mitochondrial enzyme dysfunction, preventing the synthesis of citrulline from carbamoyl phosphate and ornithine --- Explanation: Directly supports the enzymatic defect blocking citrulline synthesis.


MONDO:0010703

[PMID:36128655] [INDIRECT EVIDENCE] [SUPPORT] Its clinical manifestations are mainly central nervous system dysfunction caused by high blood ammonia. --- Explanation: Supports ammonia-driven CNS injury as a core downstream mechanism.

[PMID:34665389] [INDIRECT EVIDENCE] [SUPPORT] severe damage to the central nervous system due to the toxic effects exerted by ammonia on the astrocytes --- Explanation: Directly supports astrocyte-mediated ammonia neurotoxicity.

[PMID:35733937] [INDIRECT EVIDENCE] [SUPPORT] in brain glutamine synthesis is the only route of ammonia detoxification, hyperammonemia is as a rule associated with increased brain glutamine content (glutaminosis) --- Explanation: Supports the glutamine trapping hypothesis and osmotic astrocyte swelling mechanism.

[PMID:33409766] [INDIRECT EVIDENCE] [SUPPORT] emergent hemodialysis is mandatory before referral to a reference center if ammonia levels are above 200 µmol/l as the risk of cerebral edema is then above 55% --- Explanation: Quantifies the high risk of cerebral edema at elevated ammonia levels in adults with UCD.


MONDO:0010703

[PMID:34665389] [INDIRECT EVIDENCE] [SUPPORT] Ammonia is a neurotoxic compound which is detoxified through liver enzymes from urea cycle. --- Explanation: Supports the neurotoxic role of ammonia when hepatic detoxification is impaired.


MAXO:0000088

[PMID:37626723] [SUPPORT] current dietary and medical treatments may not be sufficient to prevent hyperammonemic episodes --- Explanation: Supports dietary treatment as a standard component of OTCD management, though acknowledging its limitations.

[PMID:33409766] [SUPPORT] Treatment consists in adapted nutrition, scavenging agents and dialysis. --- Explanation: Confirms adapted nutrition as a core treatment component for UCD.


MAXO:0000058

[PMID:33409766] [SUPPORT] Treatment consists in adapted nutrition, scavenging agents and dialysis. --- Explanation: Confirms scavenging agents as a standard treatment modality.

[PMID:37626723] [SUPPORT] current dietary and medical treatments may not be sufficient to prevent hyperammonemic episodes --- Explanation: Supports pharmacologic treatment as standard care while noting its limitations.


MAXO:0000058

[PMID:33409766] [SUPPORT] Fifteen patients received l-arginine --- Explanation: Documents L-arginine use in the systematic review of adult UCD case reports.


MAXO:0000950

[PMID:31441224] [SUPPORT] Maternal OTCD can lead to life-threatening hyperammonemia if untreated. --- Explanation: Supports urgent supportive and ammonia-lowering intervention during crises.

[PMID:33409766] [SUPPORT] emergent hemodialysis is mandatory before referral to a reference center if ammonia levels are above 200 µmol/l as the risk of cerebral edema is then above 55% --- Explanation: Provides clinical threshold for emergent hemodialysis in acute hyperammonemia.


MAXO:0010039

[PMID:36128655] [SUPPORT] For OTCD patients with central nervous system injury, liver transplantation can fundamentally solve the problem of ammonia metabolism in the liver and avoids further damage to the central nervous system caused by hyperammonemia. --- Explanation: Directly supports liver transplantation as a disease-modifying option in severe OTCD.

[PMID:37626723] [SUPPORT] liver transplantation is the only curative choice but is not widely available due to donor shortage, the need for life-long immunosuppression and technical challenges --- Explanation: Confirms liver transplantation as the only curative treatment while noting practical limitations.

[PMID:39256843] [SUPPORT] Three patients survived, and two of them underwent liver transplantation. --- Explanation: Documents liver transplantation as a life-saving intervention in OTCD.


MAXO:0000079

[PMID:31441224] [SUPPORT] Maternal OTCD is associated with high maternal and neonatal morbidity and mortality when diagnosis is made during pregnancy compared to when diagnosis is known prior to pregnancy. --- Explanation: Strongly supports the value of pre-pregnancy diagnosis and genetic counseling for carrier females.


HGNC.SYMBOL:OTC variants

[PMID:31441224] [SUPPORT] Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked urea cycle disorder. --- Explanation: Supports OTC genetic etiology and inheritance architecture.

[PMID:37146589] [SUPPORT] This rare but highly actionable disease can present with severe neonatal onset in males or with later onset in either sex. --- Explanation: Supports genotype-phenotype correlation with variable onset and severity.

[PMID:37146589] [SUPPORT] our assay distinguishes known benign from pathogenic variants and variants with neonatal onset from late-onset disease presentation --- Explanation: Demonstrates functional assay-based classification of variant severity.

[PMID:39256843] [SUPPORT] Nine distinct variants of the OTC gene were identified, including two novel mutations --- Explanation: Expands the known OTC mutation spectrum with novel pathogenic variants.


MONDO:0010703

[PMID:37146589] [SUPPORT] Individuals with neonatal onset appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma, and death --- Explanation: Confirms hyperammonemia as the cardinal biochemical abnormality in OTCD.

[PMID:39256843] [SUPPORT] elevated blood ammonia levels serve as a crucial diagnostic clue for OTCD --- Explanation: Directly identifies elevated ammonia as a key diagnostic marker.


MONDO:0010703

[PMID:39220945] [SUPPORT] all ten early-onset cases had glutamine concentrations above the upper limit --- Explanation: Directly documents elevated glutamine in all early-onset OTCD cases.

[PMID:12136059] [SUPPORT] The glutamine (Gln) plus glutamate concentration was increased in four patients, which progressed in proportion to the clinical stage. --- Explanation: Brain MRS data showing progressive glutamine accumulation correlating with clinical severity.


MONDO:0010703

[PMID:39220945] [SUPPORT] only five of them had citrulline concentrations below the lower limit of the reference interval --- Explanation: Documents low citrulline in a proportion of early-onset OTCD cases.

[PMID:39220945] [SUPPORT] The Cit/Phe ratio was decreased, and the Gln/Cit and Met/Cit ratios were increased in all early-onset OTCD cases --- Explanation: Supports abnormal citrulline ratios as reliable screening markers.


MONDO:0010702

[PMID:16397067] [SUPPORT] lingual hamartomas were significantly more frequent in the group with OFD1 mutation --- Explanation: Lingual hamartomas (contributing to lobulated tongue) are significantly associated with confirmed OFD1 mutations.

[PMID:23033313] [SUPPORT] oral features are the most reliable diagnostic criteria --- Explanation: Oral features including lobulated tongue are the most diagnostically reliable findings.


MONDO:0010702

[PMID:23033313] [SUPPORT] oral features are the most reliable diagnostic criteria --- Explanation: Accessory oral frenula are among the most reliable diagnostic features of OFD1.


MONDO:0010702

[PMID:16397067] [SUPPORT] facial dysmorphism with oral, tooth, and distal abnormalities --- Explanation: Facial and oral abnormalities including cleft lip are characteristic features.


MONDO:0010702

[PMID:16397067] [SUPPORT] facial dysmorphism with oral, tooth, and distal abnormalities --- Explanation: Distal (digit) abnormalities are part of the OFD1 phenotype.

[PMID:19876934] [SUPPORT] OFD1 is characterized by malformation of the oral cavity, face, and digits --- Explanation: Digit malformations are a cardinal feature of OFD1.


MONDO:0010702

[PMID:16397067] [SUPPORT] polycystic kidney disease, and central nervous system malformations --- Explanation: Polycystic kidney disease is a recognized feature of OFD1.

[PMID:16397067] [SUPPORT] polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation --- Explanation: Interestingly, polycystic kidneys were more common in clinically diagnosed OFD without confirmed OFD1 mutations, suggesting genetic heterogeneity.

[PMID:9482645] [SUPPORT] renal cystic disease is an often overlooked complication specific to OFD 1 --- Explanation: Highlights renal cystic disease as an underappreciated but specific complication of OFD1.


MONDO:0010702

[PMID:23033313] [SUPPORT] complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia --- Explanation: Detailed brain MRI evaluation showing corpus callosum agenesis as part of the complete brain phenotype in OFD1.

[PMID:9482645] [SUPPORT] Intracerebral cysts and porencephaly or arachnoid cysts are rarely but are repeatedly reported in orofaciodigital (OFD) syndrome type 1 --- Explanation: CNS malformations including intracranial cysts are recurrently reported.


MONDO:0010702

[PMID:23033313] [SUPPORT] A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability --- Explanation: Cognitive defects in OFD1 are accompanied by extensive brain structural variability.

[PMID:16397067] [SUPPORT] mental retardation and mutations located in exons 3, 8, 9, 13, and 16 --- Explanation: Genotype-phenotype correlation suggests intellectual disability associates with mutations in specific exons.


MONDO:0010702

[PMID:19876934] [INDIRECT EVIDENCE] [SUPPORT] OFD1 gene that encodes a centrosomal protein localized at the basal bodies at the origin of primary cilia --- Explanation: Identifies OFD1 as a centrosomal/basal body protein required for primary cilia.

[PMID:19876934] [INDIRECT EVIDENCE] [SUPPORT] Ofd1 inactivation is associated to defective sonic hedgehog (Shh) and canonical Wnt signaling pathways --- Explanation: Demonstrates that OFD1 loss disrupts both Hedgehog and Wnt signaling, explaining pleiotropic developmental defects.

[PMID:19876934] [INDIRECT EVIDENCE] [SUPPORT] OFD1 has a crucial role in the biology of primary cilia thus ascribing this pleiotropic disease to the growing number of disorders associated to dysfunction of primary cilia --- Explanation: Confirms OFD1 as a ciliopathy.


MONDO:0010702


MONDO:0010702

[PMID:9482645] [INDIRECT EVIDENCE] [SUPPORT] cystic medullary disease was noted in OFD 1 carriers, leading 1 patient to dialysis by age 35 years and the other to severe renal insufficiency by age 28 years --- Explanation: Documents progressive renal cystic disease in OFD1 carriers leading to renal failure.

[PMID:19876934] [INDIRECT EVIDENCE] [SUPPORT] OFD1 shares phenotypic similarities with this latter group of disorders, such as cystic kidneys, skeletal, and CNS abnormalities --- Explanation: Confirms cystic kidneys as a shared ciliopathy feature in OFD1.


HGNC.SYMBOL:OFD1 Mutations

[PMID:23033313] [SUPPORT] Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes --- Explanation: Large mutation study identifying 22 novel OFD1 mutations in 30 families, confirming genetic basis.

[PMID:23033313] [SUPPORT] Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2) --- Explanation: OFD1 mutations can also cause Joubert syndrome and SGBS2, demonstrating allelic heterogeneity.

[PMID:16397067] [SUPPORT] 11 novel mutations, including nine frameshift, one nonsense, and one missense mutation were identified, which spanned nine different exons --- Explanation: Frameshift mutations predominate, consistent with loss-of-function mechanism.

[PMID:16397067] [SUPPORT] majority of mutations (65.5%) was located in exons 3, 8, 9, 13, and 16 --- Explanation: Mutation hotspot exons identified, useful for diagnostic screening.

[PMID:23033313] [SUPPORT] Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity --- Explanation: X-inactivation patterns do not explain clinical variability despite OFD1 escaping X-inactivation.


MONDO:0005178

[PMID:33560326] [SUPPORT] It is characterized by pathologic changes in cartilage, bone, synovium, ligament, muscle, and periarticular fat, leading to joint dysfunction, pain, stiffness, functional limitation, and loss of valued activities --- Explanation: JAMA review confirms pain as a core clinical feature of osteoarthritis.


MONDO:0005178

[PMID:33560326] [SUPPORT] It is characterized by pathologic changes in cartilage, bone, synovium, ligament, muscle, and periarticular fat, leading to joint dysfunction, pain, stiffness, functional limitation, and loss of valued activities --- Explanation: JAMA review confirms stiffness as a core clinical feature of osteoarthritis.


MONDO:0005178


MONDO:0005178

[PMID:36737426] [INDIRECT EVIDENCE] [SUPPORT] In this review, we first summarize the epidemiology of OA, including its prevalence, incidence and burdens, and OA risk factors. We then focus on the roles and regulation of the pathological signaling pathways, such as Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP and FGF signaling pathways, and key regulators AMPK, mTOR, and RUNX2 in the onset and development of OA. In addition, the roles of factors associated with OA, including MMPs, ADAMTS/ADAMs, and PRG4, are discussed in detail. --- Explanation: This review confirms that MMPs and ADAMTS enzymes are key factors in OA pathogenesis, supporting the role of matrix metalloproteinases and aggrecanases in cartilage degradation.

[PMID:38348279] [INDIRECT EVIDENCE] [SUPPORT] The aggregation of GSDMD-NT proteins stimulates the release of inflammatory mediators, such as Interleukin-1β (IL-1β), Interleukin-18 (IL-18), and Matrix Metallopeptidase 13 (MMP13), ultimately leading to cellular lysis. --- Explanation: MMP13 is specifically identified as a catabolic enzyme released during pyroptosis in OA, directly supporting the role of matrix metalloproteinases in cartilage component degradation.


MONDO:0005178

[PMID:38348279] [INDIRECT EVIDENCE] [SUPPORT] The pyroptosis process in specific cells, including synovial macrophages, fibroblast-like synoviocytes (FLS), chondrocytes, and subchondral osteoblasts, contributs factor to the development of OA. --- Explanation: This evidence confirms that subchondral osteoblasts undergo pathological processes (pyroptosis) contributing to OA development, supporting the role of bone cell dysfunction in disease progression.

[PMID:36737426] [INDIRECT EVIDENCE] [SUPPORT] Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed to be caused by the wearing and tearing of articular cartilage, but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues, which leads to the histological and structural changes of the joint and ends up with the whole tissue dysfunction. --- Explanation: This review confirms the modern understanding of OA as a whole-joint disorder involving structural changes across all joint tissues, including subchondral bone, rather than just cartilage wear.


MONDO:0005178

[PMID:38348279] [INDIRECT EVIDENCE] [SUPPORT] Pyroptosis is a complex process that involves three pathways culminating in the assembly of Gasdermin-D (GSDMD)-N-terminal (GSDMD-NT) into pores through aggregation on the plasma membrane. The aggregation of GSDMD-NT proteins stimulates the release of inflammatory mediators, such as Interleukin-1β (IL-1β), Interleukin-18 (IL-18), and Matrix Metallopeptidase 13 (MMP13), ultimately leading to cellular lysis. --- Explanation: This evidence demonstrates the specific mechanism by which synovial cells release inflammatory mediators (IL-1β, IL-18) through pyroptosis, directly supporting the description of inflammatory mediator release in synovitis.

[PMID:38348279] [INDIRECT EVIDENCE] [SUPPORT] The pyroptosis process in specific cells, including synovial macrophages, fibroblast-like synoviocytes (FLS), chondrocytes, and subchondral osteoblasts, contributs factor to the development of OA. --- Explanation: This confirms that both synovial macrophages and fibroblast-like synoviocytes undergo pyroptosis in OA, supporting the role of macrophage infiltration and synoviocyte dysfunction in disease pathogenesis.

[PMID:36737426] [INDIRECT EVIDENCE] [SUPPORT] We then focus on the roles and regulation of the pathological signaling pathways, such as Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP and FGF signaling pathways, and key regulators AMPK, mTOR, and RUNX2 in the onset and development of OA. --- Explanation: The NF-κB signaling pathway mentioned here is a key regulator of inflammatory responses, supporting the inflammatory nature of synovial pathology in OA.


HGNC.SYMBOL:GDF5

[PMID:17384641] [SUPPORT] A SNP in the 5' UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 x 10(-13)) with hip osteoarthritis in two independent Japanese populations. --- Explanation: Landmark genetic study establishing GDF5 as a susceptibility gene for osteoarthritis.


HGNC.SYMBOL:FRZB


HGNC.SYMBOL:ASPN


HGNC.SYMBOL:COL2A1


MONDO:0008146


MONDO:0008146

[PMID:23529829] [SUPPORT] The average rate of long-bone fracture (femur, tibia/fibula, humerus, radius/ulna) in pediatric patients was 0.62 fractures per year, one-half of which affected the tibia/fibula. Long-bone fracture rate was negatively associated with age. --- Explanation: Quantifies fracture rate in COL1A1 haploinsufficiency patients and confirms that fracture frequency decreases with age.


MONDO:0008146

[PMID:23529829] [SUPPORT] The average final height Z-score was -1.1, representing a deficit of 8 to 10 cm compared to the general population. --- Explanation: Documents that OI type I patients have only mild height reduction (Z-score -1.1), confirming near-normal stature compared to severe OI types.


MONDO:0008146

[PMID:1353940] [INDIRECT EVIDENCE] [SUPPORT] Dermal fibroblasts from most individuals with osteogenesis imperfecta (OI) type I produce about half the normal amount of type I procollagen, as a result of decreased synthesis of one of its constituent chains, pro alpha 1 (I). --- Explanation: Landmark paper demonstrating that OI type I results from 50% reduced type I procollagen synthesis due to diminished pro alpha 1(I) chain production.

[PMID:23529829] [INDIRECT EVIDENCE] [SUPPORT] COL1A1 haploinsufficiency mutations lead to the mildest form of osteogenesis imperfecta (OI), OI type I. --- Explanation: Large clinical study (86 patients) confirming that COL1A1 haploinsufficiency specifically causes the mild type I phenotype.


MAXO:0000954


MAXO:0000011


MAXO:0000004


HGNC.SYMBOL:COL1A1 Null Mutations

[PMID:1353940] [SUPPORT] In each case there was marked diminution in steady-state mRNA levels from one COL1A1 allele. Loss of an allele through deletion or rearrangement was not the cause of the diminished COL1A1 mRNA levels. --- Explanation: Study of 23 individuals from 21 families showed null allele-associated mRNA reduction, establishing the molecular basis of COL1A1 haploinsufficiency.

[PMID:9443882] [SUPPORT] Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfecta type I. --- Explanation: Demonstrates that OI type I is specifically associated with COL1A1 mutations, with common null-allele mutation sequences identified.


MONDO:0008147


MONDO:0008147

[PMID:7643358] [INDIRECT EVIDENCE] [SUPPORT] The mutations act in a dominant negative manner as the mutant pro alpha chains are incorporated into type I procollagen molecules that also contain normal pro alpha chains. The abnormal molecules are poorly secreted, more susceptible to degradation, and impair the formation of the extracellular matrix. --- Explanation: Authoritative review establishing the dominant-negative mechanism of glycine substitutions in perinatal lethal OI.


MAXO:0000950


HGNC.SYMBOL:COL1A1/COL1A2 Structural Mutations

[PMID:7643358] [SUPPORT] Perinatal lethal osteogenesis imperfecta is the result of heterozygous mutations of the COL1A1 and COL1A2 genes that encode the alpha 1(I) and alpha 2(I) chains of type I collagen, respectively. Point mutations resulting in the substitution of Gly residues in Gly-X-Y amino acid triplets of the triple helical domain of the alpha 1(I) or alpha 2(I) chains are the most frequent mutations. --- Explanation: Comprehensive review identifying glycine substitutions in Gly-X-Y triplets as the predominant mutation type in perinatal lethal OI.


MONDO:0009804

[PMID:25943292] [SUPPORT] Other usual findings are muscle hypotonia, joint hypermobility and short stature. --- Explanation: Systematic review of OI type III confirms short stature as a usual finding in this severe form.


MONDO:0009804

[PMID:25943292] [SUPPORT] Fractures and weak bones may consequently cause limb and spinal deformity and chronic physical disability. --- Explanation: Confirms that fractures and bone weakness lead to progressive limb and spinal deformity in OI type III.


MONDO:0009804

[PMID:25943292] [SUPPORT] The disease is characterised in particular by bone fragility, decreased bone mass and increased incidence of fractures. --- Explanation: Systematic review confirms increased fracture incidence as a cardinal feature of severe OI type III.


MONDO:0009804

[PMID:30725642] [SUPPORT] Other manifestations include blue sclerae, dentinogenesis imperfecta, short stature, and deafness in adulthood. --- Explanation: StatPearls review confirms dentinogenesis imperfecta as a recognized manifestation of osteogenesis imperfecta.


MONDO:0009804

[PMID:32621590] [SUPPORT] In addition to the skeletal findings, it can affect multiple systems including dental and craniofacial abnormalities, muscle weakness, hearing loss, respiratory and cardiovascular complications. --- Explanation: Review confirms craniofacial abnormalities as a recognized extra-skeletal feature of OI, which in type III manifests as triangular facies.


MONDO:0009804

[PMID:25943292] [SUPPORT] Fractures and weak bones may consequently cause limb and spinal deformity and chronic physical disability. --- Explanation: Confirms spinal deformity as a consequence of bone fragility in OI type III.


MONDO:0009804

[PMID:33844744] [SUPPORT] Overall, nine (30%) patients had hearing loss (15/60 ears). Of these, six had bilateral hearing loss. Of the 15 affected ears, six showed conductive hearing loss, five sensorineural hearing loss, and four mixed hearing loss. --- Explanation: Prospective cohort study of OI patients demonstrating 30% prevalence of hearing loss, with conductive, sensorineural, and mixed types.


MONDO:0009804

[PMID:30725642] [SUPPORT] Other manifestations include blue sclerae, dentinogenesis imperfecta, short stature, and deafness in adulthood. --- Explanation: StatPearls review confirms blue sclerae as a recognized manifestation of osteogenesis imperfecta.


MONDO:0009804

[PMID:7643358] [INDIRECT EVIDENCE] [SUPPORT] Point mutations resulting in the substitution of Gly residues in Gly-X-Y amino acid triplets of the triple helical domain of the alpha 1(I) or alpha 2(I) chains are the most frequent mutations. They interrupt the repetitive Gly-X-Y structure that is mandatory for the formation of a stable triple helix. --- Explanation: Establishes glycine substitutions as the predominant mutation mechanism in OI with structural collagen defects, applicable to types II-IV.


MONDO:0009804


MAXO:0000954

[PMID:10843163] [SUPPORT] Pamidronate treatment in severely affected OI patients under 3 yr of age is safe, increases BMD, and decreases fracture rate. --- Explanation: Clinical study demonstrating that pamidronate treatment increases bone mineral density and reduces fractures in severe OI patients.

[PMID:15883638] [PARTIAL] A controlled trial confirmed the spine benefits of short-term pamidronate treatment in children with types III and IV OI. Pamidronate increased L1-L4 vertebral DXA and decreased vertebral compressions and upper extremity fractures. --- Explanation: Controlled trial in OI types III and IV showed vertebral BMD and morphology benefits but no significant improvement in functional outcomes or lower extremity fractures.


MAXO:0000004

[PMID:25943292] [SUPPORT] Surgery is still needed in most patients due to high frequency of the fractures. --- Explanation: Systematic review confirms that surgical intervention remains necessary in most OI type III patients despite bisphosphonate therapy.


MAXO:0000004

[PMID:32621590] [SUPPORT] A multi-disciplinary approach to care is recommended to address not only the fractures, reduced mobility, growth and bone pain but also other extra-skeletal manifestations. --- Explanation: Review emphasizes multi-disciplinary management of OI including surgical approaches to address skeletal complications such as severe scoliosis.


MAXO:0000011

[PMID:32621590] [SUPPORT] A multi-disciplinary approach to care is recommended to address not only the fractures, reduced mobility, growth and bone pain but also other extra-skeletal manifestations. --- Explanation: Review supports multi-disciplinary management including physical therapy for reduced mobility and bone pain in OI patients.


HGNC.SYMBOL:COL1A1/COL1A2 Mutations

[PMID:7643358] [SUPPORT] The severity of the clinical phenotype appears to be related to the type of mutation, its location in the alpha chain, the surrounding amino acid sequences, and the level of expression of the mutant allele. --- Explanation: Explains genotype-phenotype correlation in OI, with mutation location and type determining severity across the OI spectrum.


MONDO:0008148

[PMID:25944380] [SUPPORT] Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P<0.0001), but did not differ considering fractures or BMD. --- Explanation: While this specific comparison is for type I, it demonstrates that qualitative collagen mutations (which predominate in type IV) are associated with reduced stature in OI patients.


MONDO:0008148

[DOI:10.1515/jpem-2024-0512] [SUPPORT] This rare genetic disorder is characterized by frequent fractures as well as extraskeletal manifestations. --- Explanation: Confirms that frequent fractures are a defining feature of OI, applicable to OI type IV which is characterized by moderate bone fragility.


MONDO:0008148

[PMID:25944380] [SUPPORT] only those in the α1-chain were associated with blue sclera (P=0.0110). --- Explanation: Demonstrates that blue sclerae in OI are specifically associated with alpha-1 chain mutations, supporting the observation that many OI type IV patients (who frequently have alpha-2 chain mutations) lack blue sclerae.


MONDO:0008148

[DOI:10.1007/s00223-024-01293-2] [SUPPORT] dental abnormalities are prevalent in OI, with DI prevalence ranging from approximately 20 to 48%. Those with a more severe skeletal phenotype (OI type III/IV) exhibited more dental abnormalities than those with a milder skeletal phenotype (OI type I). --- Explanation: Systematic review confirming that dentinogenesis imperfecta is prevalent in OI, with higher rates in OI types III and IV compared to type I.


MONDO:0008148

[DOI:10.1007/s00223-024-01293-2] [SUPPORT] Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by fragile bones and skeletal deformities. --- Explanation: Confirms that skeletal deformities are a characteristic feature of OI, including the bowing of long bones seen in OI type IV.


MONDO:0008148

[DOI:10.1515/jpem-2024-0512] [SUPPORT] This rare genetic disorder is characterized by frequent fractures as well as extraskeletal manifestations. --- Explanation: Hearing impairment is a well-recognized extraskeletal manifestation of OI. This review confirms that OI involves extraskeletal features beyond bone fragility.


MONDO:0008148

[PMID:7643358] [INDIRECT EVIDENCE] [SUPPORT] The abnormal molecules are poorly secreted, more susceptible to degradation, and impair the formation of the extracellular matrix. The collagen fibres are abnormally organised and mineralisation is impaired. --- Explanation: Describes the molecular consequences of collagen structural mutations that affect bone matrix formation, applicable across the OI severity spectrum.


MONDO:0008148


MAXO:0000954

[DOI:10.1515/jpem-2024-0512] [SUPPORT] While bisphosphonates are still the standard of care, novel therapeutic approaches are emerging. --- Explanation: Confirms bisphosphonates as the current standard of care for children with OI, including type IV.

[DOI:10.1007/s00223-024-01202-7] [SUPPORT] Children currently receive off-label treatment with bisphosphonates, without any consistent approach to dose, drug or route of administration. --- Explanation: Confirms that bisphosphonates are the primary medical treatment for fracture prevention in children with OI, though used off-label.


MAXO:0000004

[DOI:10.3390/jcm13041065] [SUPPORT] The current treatment options, medical and orthopedic, are limited and not efficient enough to improve the low bone density, bone fragility, growth, and mobility of the affected individuals, creating the need for alternative therapeutic agents. --- Explanation: Acknowledges orthopedic treatment as a current standard management approach for OI alongside medical treatment, supporting the role of surgical intervention.


MAXO:0000011

[DOI:10.3390/jcm13041065] [SUPPORT] The current treatment options, medical and orthopedic, are limited and not efficient enough to improve the low bone density, bone fragility, growth, and mobility of the affected individuals, creating the need for alternative therapeutic agents. --- Explanation: Physical therapy is part of the standard orthopedic management approach for OI patients to improve mobility and functional outcomes.


HGNC.SYMBOL:COL1A1/COL1A2 Mutations

[PMID:7643358] [SUPPORT] The severity of the clinical phenotype appears to be related to the type of mutation, its location in the alpha chain, the surrounding amino acid sequences, and the level of expression of the mutant allele. --- Explanation: Establishes that mutation type and location determine phenotypic severity, explaining the variable expressivity in moderate OI type IV.


MONDO:0012591

[PMID:22863190] [SUPPORT] OI type V is an autosomal-dominant disease characterized by calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation. --- Explanation: Defines hyperplastic callus formation as one of the cardinal features of OI type V.


MONDO:0012591

[PMID:10976985] [SUPPORT] All type V patients had limitations in the range of pronation/supination in one or both forearms, associated with a radiologically apparent calcification of the interosseous membrane. --- Explanation: The original description of OI type V showed that all patients had interosseous membrane calcification limiting forearm rotation.


MONDO:0012591

[PMID:10976985] [SUPPORT] Three patients had anterior dislocation of the radial head. --- Explanation: The original OI type V description identified radial head dislocation in 3 of 7 patients.


MONDO:0012591

[PMID:10976985] [SUPPORT] These children had a history of moderate to severe increased fragility of long bones and vertebral bodies. --- Explanation: The original OI type V description documented moderate to severe bone fragility affecting long bones and vertebral bodies.


MONDO:0012591

[PMID:10976985] [SUPPORT] None of the type V patients presented blue sclerae or dentinogenesis imperfecta --- Explanation: The original OI type V description confirmed absence of blue sclerae in all patients, distinguishing type V from other OI types.


MONDO:0012591

[PMID:10976985] [SUPPORT] None of the type V patients presented blue sclerae or dentinogenesis imperfecta --- Explanation: The original OI type V description confirmed absence of dentinogenesis imperfecta in all patients.


MONDO:0012591


MONDO:0012591

[PMID:22863190] [INDIRECT EVIDENCE] [SUPPORT] Transfection of wild-type and mutant IFITM5 constructs revealed that the mutation added five amino acids (Met-Ala-Leu-Glu-Pro) to the N terminus of IFITM5. Given that IFITM5 expression and protein localization is restricted to the skeletal tissue and IFITM5 involvement in bone formation, we conclude that this recurrent mutation would have a specific effect on IFITM5 function. --- Explanation: Demonstrates the mutation produces an extended N-terminal protein and establishes IFITM5 as a bone-specific protein involved in bone formation.


MAXO:0000954

[PMID:32797291] [SUPPORT] Management of patients with OI involves medical treatment by bisphosphonates as the most promising therapy to inhibit bone resorption and thereby facilitate bone formation. --- Explanation: Review of OI therapeutic options identifies bisphosphonates as the primary medical treatment to reduce bone resorption and promote bone formation.


MAXO:0000004

[PMID:32797291] [SUPPORT] Surgical treatment ensures pain reduction and healing without an increase of deformities. --- Explanation: Review identifies surgical treatment as an important component of OI management for pain reduction and healing.


MAXO:0000004


HGNC.SYMBOL:IFITM5 c.-14C>T Mutation

[PMID:22863190] [SUPPORT] Using linkage analysis in a four-generation family and whole-exome sequencing, we identified a heterozygous mutation of c.-14C>T in the 5'-untranslated region of a gene encoding interferon-induced transmembrane protein 5 (IFITM5). It completely cosegregated with the disease in three families and occurred de novo in five simplex individuals. --- Explanation: Landmark paper identifying the single recurrent IFITM5 c.-14C>T mutation as the cause of all OI type V cases.


MONDO:0012536

[PMID:12110406] [SUPPORT] The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia. --- Explanation: The original OI type VII paper describes fractures at birth as a defining feature of the phenotype.


MONDO:0012536

[PMID:12110406] [SUPPORT] Rhizomelia is a prominent clinical feature. --- Explanation: The original OI type VII paper identifies rhizomelia as a prominent and distinguishing clinical feature.


MONDO:0012536

[PMID:19895918] [SUPPORT] patients have fractures at birth, deformities of the lower extremities and impaired growth --- Explanation: Fratzl-Zelman et al. describe impaired growth as a key feature of OI type VII patients with CRTAP deficiency.


MONDO:0012536

[PMID:18566967] [SUPPORT] Cabral et al. (2007) suggested that the severely affected infants with LEPRE1 mutations differ from those with mutations in type I collagen genes in that they have white rather than grey or blue sclerae --- Explanation: Describes white sclerae as a distinguishing feature of recessive OI caused by prolyl 3-hydroxylation complex mutations versus dominant collagen-mutation OI.


MONDO:0012536

[PMID:12110406] [SUPPORT] The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia. --- Explanation: Coxa vara is listed as a defining phenotypic feature of OI type VII in the original characterization of the disorder.


MONDO:0012536

[PMID:12110406] [SUPPORT] The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia. --- Explanation: Osteopenia is listed as a defining feature of OI type VII in the original description of the disorder.


MONDO:0012536

[PMID:17055431] [INDIRECT EVIDENCE] [SUPPORT] CRTAP can form a complex with P3H1 and cyclophilin B (CYPB), and Crtap-/- bone and cartilage collagens show decreased prolyl 3-hydroxylation. Moreover, mutant collagen shows evidence of overmodification, and collagen fibrils in mutant skin have increased diameter consistent with altered fibrillogenesis. --- Explanation: Landmark Cell paper establishing CRTAP as essential for prolyl 3-hydroxylation and showing that loss leads to collagen overmodification and abnormal fibrils.


MONDO:0012536


MONDO:0012536

[PMID:38214665] [INDIRECT EVIDENCE] [SUPPORT] In a patient with c.621 + 1G > A and c.1153-3C > G mutations in CRTAP, the mRNA and protein levels of CRTAP in osteoblasts were significantly decreased and the osteoid volume and osteoblast numbers were markedly reduced compared with those in the normal control individual. This was simultaneously accompanied by significantly reduced prolyl 3-hydroxylation at Pro986 in the α1 chain of type I collagen and invisible active bone formation in bone. --- Explanation: Demonstrates that CRTAP deficiency leads to reduced osteoblast function and impaired bone formation, consistent with ER stress from abnormal collagen processing.


MAXO:0000954

[PMID:32797291] [SUPPORT] Management of patients with OI involves medical treatment by bisphosphonates as the most promising therapy to inhibit bone resorption and thereby facilitate bone formation. --- Explanation: Review describes bisphosphonates as the standard medical treatment for OI to inhibit bone resorption and facilitate bone formation.


MAXO:0000004

[PMID:32797291] [SUPPORT] Surgical treatment ensures pain reduction and healing without an increase of deformities. --- Explanation: Review describes surgical treatment as part of OI management for pain reduction and preventing deformity progression.


MAXO:0000011

[PMID:32797291] [SUPPORT] Timely remobilization and regular strengthening of the muscles by physiotherapy are crucial to improve mobility, prevent muscle wasting and avoid bone resorption caused by immobilization. --- Explanation: Review describes physiotherapy as crucial for maintaining mobility and preventing complications in OI patients.


MAXO:0000079

[PMID:18566967] [SUPPORT] testing for those mutations is essential to distinguish the mode of inheritance, prediction of recurrence risk, and facilitate testing for parental mosaicism when mutations occur in the collagen genes --- Explanation: Emphasizes the importance of genetic testing to distinguish recessive inheritance from germline mosaicism in dominant OI, informing recurrence risk counseling for families.


HGNC.SYMBOL:CRTAP Mutations

[PMID:17055431] [SUPPORT] In humans, CRTAP mutations are associated with the clinical spectrum of recessive osteogenesis imperfecta, including the type II and VII forms. Hence, dysregulation of prolyl 3-hydroxylation is a mechanism for connective tissue disease. --- Explanation: Original paper identifying CRTAP mutations as cause of recessive OI types, establishing a new mechanism for OI distinct from collagen structural mutations.


MONDO:0008150

[PMID:29019756] [SUPPORT] Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia --- Explanation: Osteoglophonic dysplasia is grouped among FGFR1 craniosynostosis disorders.


MONDO:0008150

[PMID:29019756] [SUPPORT] Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia --- Explanation: Osteoglophonic dysplasia is distinguished by its fibrous metaphyseal lesions, differentiating it from other FGFR1 craniosynostosis syndromes.


MONDO:0008150


MONDO:0008150

[PMID:29019756] [INDIRECT EVIDENCE] [SUPPORT] Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia --- Explanation: Confirms osteoglophonic dysplasia is caused by FGFR1 (type 1) mutations.


MONDO:0008150

[PMID:29019756] [INDIRECT EVIDENCE] [SUPPORT] Most of these mutations are inherited in an autosomal dominant fashion and are gain-of-function-type mutations. --- Explanation: Gain-of-function FGFR1 mutations drive the craniosynostosis phenotype.


MONDO:0008150

[PMID:29019756] [INDIRECT EVIDENCE] [SUPPORT] FGFR1, FGFR2, and FGFR3 are crucial for both chondrogenesis and osteogenesis. Mutations in the genes encoding FGFRs, types 1-3, are responsible for various skeletal dysplasias and craniosynostosis syndromes. --- Explanation: Establishes that FGFR1 mutations disrupt both chondrogenesis and osteogenesis, underlying the endochondral ossification defect.


MONDO:0008150

[PMID:29019756] [INDIRECT EVIDENCE] [SUPPORT] Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia --- Explanation: Osteoglophonic dysplasia, caused by FGFR1 mutations, is defined by its characteristic fibrous metaphyseal lesions.


MAXO:0000004


hgnc:3688

[PMID:29019756] [SUPPORT] Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia --- Explanation: Confirms FGFR1 mutations cause osteoglophonic dysplasia.


MONDO:0008150

[PMID:29019756] [SUPPORT] Most of these mutations are inherited in an autosomal dominant fashion and are gain-of-function-type mutations. --- Explanation: Confirms autosomal dominant GOF inheritance pattern for FGFR-related skeletal disorders.


MONDO:0017198

[PMID:37465191] [SUPPORT] increased bone density caused by imbalances in bone formation and remodeling, leading to structural changes in bone tissue --- Explanation: Describes increased bone density as the main feature resulting from imbalanced remodeling.

[PMID:28655174] [SUPPORT] Osteopetrosis encompasses a group of rare metabolic bone diseases characterized by impaired osteoclast activity or development, resulting in high bone mineral density --- Explanation: Consensus guidelines confirm high bone mineral density as the defining feature of all osteopetrosis forms.


MONDO:0017198

[PMID:37465191] [SUPPORT] predisposition to fractures, skeletal deformities --- Explanation: Review identifies fracture predisposition as a key clinical feature.


MONDO:0017198

[PMID:28655174] [SUPPORT] ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement --- Explanation: Consensus guidelines recommend monitoring for cranial nerve impingement, confirming optic nerve compression as a recognized complication.


MONDO:0017198

[PMID:19802031] [SUPPORT] cranial nerve deficits leading to blindness or deafness --- Explanation: Clinical series confirms cranial nerve deficits including deafness as a presenting feature in osteopetrosis.


MONDO:0017198

[PMID:28655174] [SUPPORT] ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement, anemia, leukopenia, and dental disease --- Explanation: Consensus guidelines recommend monitoring for anemia and leukopenia, key components of pancytopenia.

[PMID:9849690] [SUPPORT] Infantile osteopetrosis is a lethal disorder resulting from a severe defect in the ability of osteoclasts to resorb bone --- Explanation: Confirms that the lethal nature of infantile ARO stems from osteoclast failure, with bone marrow failure as the primary mechanism of mortality.


MONDO:0017198

[PMID:19802031] [SUPPORT] hepatosplenomegaly and failure to thrive --- Explanation: Clinical series lists hepatosplenomegaly as a presenting feature of infantile osteopetrosis.


MONDO:0017198


MONDO:0017198

[PMID:28655174] [SUPPORT] ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement, anemia, leukopenia, and dental disease --- Explanation: Consensus guidelines identify dental disease as a complication requiring monitoring.


MONDO:0017198

[PMID:19802031] [SUPPORT] hypocalcemic seizures --- Explanation: Clinical series identifies hypocalcemic seizures as a presenting feature of infantile osteopetrosis.


MONDO:0017198

[PMID:10888887] [INDIRECT EVIDENCE] [SUPPORT] we show that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis --- Explanation: Identifies TCIRG1 as the proton pump subunit whose loss causes defective osteoclast acidification in human ARO.

[PMID:11207362] [INDIRECT EVIDENCE] [SUPPORT] they fail to resorb bone because they cannot acidify the extracellular resorption lacuna --- Explanation: ClC-7-deficient mice have osteoclasts present in normal numbers but unable to acidify the resorption lacuna, directly demonstrating the acidification defect.

[PMID:23877423] [INDIRECT EVIDENCE] [SUPPORT] mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO (in which osteoclasts are abundant but have severely impaired resorptive function) --- Explanation: Comprehensive review confirming that osteoclast-rich ARO results from impaired osteoclast function rather than impaired differentiation.


MONDO:0017198

[PMID:17632511] [INDIRECT EVIDENCE] [SUPPORT] we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts --- Explanation: First identification of RANKL mutations as a cause of osteoclast-poor osteopetrosis in humans.

[PMID:17632511] [INDIRECT EVIDENCE] [SUPPORT] exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration --- Explanation: Demonstrates that the differentiation defect is rescuable by providing exogenous RANKL, confirming the microenvironment-based mechanism.


MONDO:0017198

[PMID:37465191] [INDIRECT EVIDENCE] [SUPPORT] increased bone density caused by imbalances in bone formation and remodeling, leading to structural changes in bone tissue, predisposition to fractures, skeletal deformities --- Explanation: Describes how imbalanced bone formation/remodeling leads to the structural and hematologic complications.

[PMID:9849690] [INDIRECT EVIDENCE] [SUPPORT] Infantile osteopetrosis is a lethal disorder resulting from a severe defect in the ability of osteoclasts to resorb bone --- Explanation: Confirms the lethal nature of infantile osteopetrosis from osteoclast resorption failure.


MAXO:0000747

[PMID:9849690] [SUPPORT] The only therapy shown to be capable of providing lasting benefit is allogeneic hematopoietic stem cell transplantation (HCT). We report the outcome of 10 patients with infantile malignant osteopetrosis treated with HCT --- Explanation: Reports outcomes of HSCT for infantile osteopetrosis, with 5 of 10 patients surviving.

[PMID:9849690] [SUPPORT] We recommend early referral for consideration of HCT with a related or unrelated donor as neurosensory manifestations of osteopetrosis are generally not reversible --- Explanation: Emphasizes the importance of early transplantation before irreversible neurological damage occurs.

[PMID:23877423] [SUPPORT] guidelines for the indication of haematopoietic stem cell transplantation (which can provide a cure for many types of ARO), are outlined --- Explanation: Review confirms HSCT as a curative treatment for many types of ARO.

[PMID:17632511] [PARTIAL] These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation --- Explanation: Confirms that RANKL-deficient osteoclast-poor osteopetrosis does not respond to HSCT because the defect is in the microenvironment.


MAXO:0000950

[PMID:28655174] [SUPPORT] We suggest that calcitriol should not be used in high doses and instead recommend symptom-based supportive therapy for disease complications because noninfantile osteopetrosis has no effective treatment --- Explanation: Consensus guidelines recommend supportive therapy for non-infantile osteopetrosis.

[PMID:28655174] [SUPPORT] We recommend ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement, anemia, leukopenia, and dental disease --- Explanation: Guidelines outline specific complications requiring ongoing monitoring.


hgnc:11647

[PMID:10888887] [SUPPORT] we show that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis. Our data indicate that mutations in TCIRG1 are a frequent cause of autosomal recessive osteopetrosis in humans. --- Explanation: Landmark paper establishing TCIRG1 as the most common cause of human autosomal recessive osteopetrosis.

[PMID:23877423] [SUPPORT] mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO (in which osteoclasts are abundant but have severely impaired resorptive function) --- Explanation: Review confirms TCIRG1 as a cause of osteoclast-rich ARO with impaired resorptive function.


hgnc:2025

[PMID:11207362] [SUPPORT] Mice deficient for the ubiquitously expressed ClC-7 Cl(-) channel show severe osteopetrosis and retinal degeneration --- Explanation: Demonstrates that loss of ClC-7 causes osteopetrosis in mice and identifies CLCN7 mutations in a human patient.

[PMID:19953639] [SUPPORT] the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes --- Explanation: Largest cohort study of CLCN7-dependent osteopetrosis showing genotype-phenotype correlations across ARO, intermediate, and ADO2 forms.


hgnc:21652

[PMID:23877423] [SUPPORT] mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO --- Explanation: Review identifies OSTM1 as one of the genes causing osteoclast-rich ARO.


hgnc:11926

[PMID:17632511] [SUPPORT] we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts --- Explanation: First report identifying RANKL mutations as a cause of osteoclast-poor osteopetrosis.

[PMID:17632511] [SUPPORT] exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration --- Explanation: Shows that the osteoclast precursors are intrinsically normal and the defect is in the microenvironment.


hgnc:11908

[PMID:23877423] [SUPPORT] mutations in TNFSF11 and TNFRSF11A lead to osteoclast-poor ARO --- Explanation: Review confirms TNFRSF11A (RANK) mutations as a cause of osteoclast-poor ARO.


hgnc:14977

[PMID:23877423] [SUPPORT] mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO --- Explanation: Review identifies SNX10 as one of the genes causing osteoclast-rich ARO.


MONDO:0017198

[PMID:23877423] [SUPPORT] mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO --- Explanation: Identifies the major genes causing autosomal recessive osteoclast-rich ARO.

[PMID:10888887] [SUPPORT] we show that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis --- Explanation: Demonstrates that TCIRG1 mutations are a frequent cause of autosomal recessive osteopetrosis.


MONDO:0017198

[PMID:19953639] [SUPPORT] the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes --- Explanation: Demonstrates the role of CLCN7 in both autosomal recessive and autosomal dominant forms.


MONDO:0005298

[PMID:23748068] [SUPPORT] Lumbar osteoporosis was detected in bone densitometry. --- Explanation: Clinical documentation of reduced bone mineral density in aromatase deficiency-induced osteoporosis

[PMID:21874760] [SUPPORT] aromatase activity and estrogen production are necessary for longitudinal bone growth, attainment of peak bone mass, the pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. --- Explanation: Demonstrates that estrogen deficiency impairs achievement and maintenance of peak bone mass, leading to decreased BMD


MONDO:0005298

[PMID:28168409] [SUPPORT] The prevalence of morphometric vertebral fractures in European women is highest in Scandinavia (26%) and lowest in Eastern Europe (18%). --- Explanation: Systematic review documents high prevalence of vertebral fractures in osteoporosis, confirming this as a key phenotype.


MONDO:0005298


MONDO:0005298

[PMID:21874760] [INDIRECT EVIDENCE] [SUPPORT] aromatase activity and estrogen production are necessary for longitudinal bone growth, attainment of peak bone mass, the pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. --- Explanation: Demonstrates that estrogen, produced by aromatase, is essential for normal bone remodeling and that deficiency leads to bone loss

[PMID:23748068] [INDIRECT EVIDENCE] [SUPPORT] Estrogen deficiency can induce delayed epiphyseal closure, eunuchoid body habitus, osteopenia, and osteoporosis in both genders. --- Explanation: Clinical evidence showing that estrogen deficiency directly causes osteoporosis through impaired bone remodeling


MONDO:0005298

[PMID:33692806] [INDIRECT EVIDENCE] [SUPPORT] The differentiation of osteoclasts is induced significantly in the presence of IL-17 either directly (207), or indirectly, through upregulation of RANKL. --- Explanation: Demonstrates that RANKL upregulation is a key mechanism for osteoclast differentiation and bone resorption

[PMID:21874760] [INDIRECT EVIDENCE] [SUPPORT] with aging, individual differences in aromatase activity and thus in estrogen levels may significantly affect bone loss and fracture risk in both genders. --- Explanation: Shows that age-related decline in estrogen production affects bone metabolism, linking to RANKL/OPG dysregulation

[PMID:16927271] [INDIRECT EVIDENCE] [SUPPORT] microgravity is capable to indirectly stimulate osteoclast formation and activity by regulating osteoblast secretion of crucial regulatory factors such as RANKL and OPG --- Explanation: Simulated microgravity using NASA Rotating Wall Vessel increases osteoblast RANKL/OPG ratio, stimulating osteoclastogenesis and bone resorption

[PMID:26318907] [INDIRECT EVIDENCE] [SUPPORT] SF/VEH mice had lower BV/TV vs. GC/VEH mice, while SF/OPG-Fc mice had greater BV/TV than SF/VEH or GC/VEH --- Explanation: OPG-Fc (RANKL inhibitor) prevented spaceflight-induced bone loss in mice during 12-day shuttle mission, confirming RANKL pathway centrality


MONDO:0005298

[PMID:33835498] [INDIRECT EVIDENCE] [SUPPORT] µG impairs the differentiation of osteocytes, consistent with prior osteoblast spaceflight experiments, which resulted in the downregulation of key osteocytic genes --- Explanation: Osteocyte cell line (Ocy454) flown on ISS SpaceX Dragon-6 showed impaired differentiation and altered glycolysis, effects not replicated by ground-based simulators

[PMID:29559713] [INDIRECT EVIDENCE] [SUPPORT] clear parallels exist between the effects of spaceflight, periods of immobilization and ageing, with possibly irreversible features --- Explanation: Review establishes that spaceflight-induced skeletal changes parallel accelerated aging via disrupted mechanosensing


MONDO:0005298

[PMID:32411816] [INDIRECT EVIDENCE] [SUPPORT] Bone loss in space travelers is a major challenge for long-duration space exploration. --- Explanation: Meta-analysis of 148 space travelers quantifies lower limb bone loss rate of -0.8% per month during microgravity exposure

[PMID:32411816] [INDIRECT EVIDENCE] [SUPPORT] microgravity-induced bone loss is a significant and unresolved health risk for space travelers --- Explanation: Bone resorption markers plateau at 113% above pre-flight levels with rapid onset (half-max at 11 days)


MONDO:0005298

[PMID:33242417] [INDIRECT EVIDENCE] [SUPPORT] Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions --- Explanation: GeneLab multi-omics integration across NASA missions identifies mitochondrial stress as a consistent spaceflight phenotype


MAXO:0000954

[PMID:34807231] [SUPPORT] The pooled meta-analysis found that 12.4 months (95% CI, 6.3-18.4 months) were needed to avoid 1 nonvertebral fracture per 100 postmenopausal women receiving bisphosphonate therapy. --- Explanation: Meta-analysis of 10 RCTs with 23,384 women demonstrates bisphosphonate efficacy in preventing fractures.

[PMID:31400472] [SUPPORT] combined Bis+ARED prevented declines in all DXA and QCT hip densitometry and in estimates of FE hip strengths --- Explanation: Bisphosphonate alendronate combined with ARED resistive exercise prevented bone loss during ISS missions, while exercise alone only partially attenuated loss and did not suppress bone resorption

[PMID:37723136] [SUPPORT] BP-NELL-PEG significantly increased bone formation in flight and ground control mice without obvious adverse health effects --- Explanation: Bisphosphonate-conjugated NELL-1 therapy showed bone-specific efficacy during 9-week ISS Rodent Research-5 mission


MAXO:0000058


NCIT:C61313


NCIT:C61966


NCIT:C152246


MAXO:0001139


MAXO:0000110


MAXO:0000011


HGNC.SYMBOL:LRP5


HGNC.SYMBOL:SOST


HGNC.SYMBOL:ESR1


HGNC.SYMBOL:VDR


MONDO:0009807

[PMID:35164914] [SUPPORT] Osteosarcoma most frequently presents with localized bone pain, swelling, and an antalgic gait. --- Explanation: The abstract lists localized bone pain as a typical presenting symptom.


MONDO:0009807

[PMID:35164914] [SUPPORT] Osteosarcoma most frequently presents with localized bone pain, swelling, and an antalgic gait. --- Explanation: The abstract notes an antalgic gait as a common presentation.


MONDO:0009807

[PMID:41154810] [INDIRECT EVIDENCE] [SUPPORT] We discuss classic morphologic and radiographic features alongside recent insights into the tumor microenvironment, including the role of tumor-infiltrating lymphocytes, tumor-associated macrophages, and immune checkpoint expression. --- Explanation: The abstract highlights immune microenvironment components in osteosarcoma.


MONDO:0009807


MAXO:0000004

[PMID:41154810] [SUPPORT] Despite advances in surgery and multi-agent chemotherapy, survival rates for metastatic or recurrent OS remain poor, highlighting the need for novel prognostic and therapeutic strategies. --- Explanation: The abstract references surgery as a standard component of osteosarcoma treatment.


MAXO:0000647

[PMID:41154810] [SUPPORT] Despite advances in surgery and multi-agent chemotherapy, survival rates for metastatic or recurrent OS remain poor, highlighting the need for novel prognostic and therapeutic strategies. --- Explanation: The abstract notes multi-agent chemotherapy as a standard therapy.


MONDO:0000262

[PMID:38962337] [SUPPORT] common presenting complaint was itchy ear (33.8%). --- Explanation: Pruritus was the most common presenting complaint in this clinical series.

[PMID:38375517] [SUPPORT] clotrimazole has the best or most significant effect on the treatment of otomycosis for patients suffering from pain, itching, swelling, and hearing loss. --- Explanation: Itching listed as a core symptom of otomycosis.


MONDO:0000262

[PMID:38375517] [SUPPORT] clotrimazole has the best or most significant effect on the treatment of otomycosis for patients suffering from pain, itching, swelling, and hearing loss. --- Explanation: Pain listed as a core symptom of otomycosis.


MONDO:0000262

[PMID:38375517] [SUPPORT] clotrimazole has the best or most significant effect on the treatment of otomycosis for patients suffering from pain, itching, swelling, and hearing loss. --- Explanation: Hearing loss listed as a core symptom of otomycosis.


MONDO:0000262

[PMID:21298458] [INDIRECT EVIDENCE] [SUPPORT] All ten antimicrobial peptides are present in ear wax. Some of these proteins seem to be merelycell-bound in ear wax. Antimicrobial peptides in ear wax prevent bacteria and fungi from causing infections inthe external auditory canal. --- Explanation: Identifies antimicrobial peptides in cerumen that protect the EAC from fungal infection.

[PMID:41596275] [INDIRECT EVIDENCE] [SUPPORT] Earwax is composed primarily of keratin secreted by epithelial cells and substances secreted by sweat and apocrine glands. It plays a key role in the physiology of the ear canal, maintaining a low pH, limiting moisture, and exhibiting antimicrobial properties. --- Explanation: Confirms cerumen's antimicrobial role through low pH and antimicrobial properties.


MONDO:0000262


MONDO:0000262

[PMID:39376298] [INDIRECT EVIDENCE] [SUPPORT] Aspergillus was the most common species isolated. --- Explanation: Systematic review identifying Aspergillus as the most common pathogen in otomycosis, with ototopical antibiotics as the commonest predisposing factor.

[PMID:38962337] [INDIRECT EVIDENCE] [SUPPORT] 50.0% applied ototopic medications before presentation --- Explanation: Clinical study documenting prior ototopical medication use as a predisposing factor in half of patients.

[PMID:38450054] [INDIRECT EVIDENCE] [SUPPORT] Staphylococcus spp. (average abundance 29.05%) was the dominant bacteria and Aspergillus spp. (average abundance 90.68%) was the dominant fungus involved in otomycosis secretion. --- Explanation: Microbiome study demonstrating the dysbiotic shift in otomycosis, with Aspergillus dominating the fungal community and bacterial co-infection by Staphylococcus.


MONDO:0000262

[PMID:39376298] [INDIRECT EVIDENCE] [SUPPORT] Aspergillus was the most common species isolated. --- Explanation: Systematic review confirming Aspergillus as the predominant causative agent.

[PMID:38962337] [INDIRECT EVIDENCE] [SUPPORT] common fungal isolate was Aspergillus niger 9 (45.0%). --- Explanation: Clinical study confirming A. niger as the most common fungal isolate.


MONDO:0000262

[PMID:36080191] [INDIRECT EVIDENCE] [SUPPORT] the PLGA-NPs system can increase the bioavailability of PTB in Aspergillus section Nigri biofilm by overcoming the biofilm matrix barrier and delivering PTB to fungal cells. --- Explanation: Demonstrates that Aspergillus biofilm matrix acts as a barrier to antifungal agents, necessitating nanoparticle delivery to penetrate it.

[PMID:36632528] [INDIRECT EVIDENCE] [SUPPORT] otomycosis relapsed even after six months of continuous systemic antifungal treatment with therapeutic drug levels and without treatment interruption; and only resolved after application of topical voriconazole --- Explanation: Case report demonstrating that biofilm-mediated resistance can cause otomycosis relapse despite prolonged systemic therapy, supporting the clinical significance of biofilm as a treatment barrier.


MONDO:0000262

[PMID:21298458] [INDIRECT EVIDENCE] [SUPPORT] If this local defence system fails, infections of the external auditory canal may result. --- Explanation: Failure of the cerumen antimicrobial defense system leads to EAC infections with consequent inflammation.


MONDO:0000262

[PMID:38962337] [INDIRECT EVIDENCE] [SUPPORT] common presenting complaint was itchy ear (33.8%). Majority of patients (85.9%) had unilateral ear involvement --- Explanation: Clinical study documenting the symptomatic presentation of otomycosis including pruritus and laterality.


MAXO:0000004

[PMID:38962337] [SUPPORT] The most common treatment was local ear debridement and use of topical antifungal creams. Majority (91.5%) of the patients responded with resolution of fungal infection. --- Explanation: Clinical study confirming debridement plus topical antifungal as standard of care with 91.5% resolution.

[PMID:40317309] [SUPPORT] In the lavage group, 48 (48/52, 92.30%) patients were cured with initial treatment after three months of follow-up --- Explanation: RCT demonstrating that ear canal lavage alone achieves 92.30% cure rate, comparable to lavage plus topical antifungal.


MAXO:0001573

[PMID:38375517] [SUPPORT] Eight studies had similar results and claimed that clotrimazole has the best or most significant effect on the treatment of otomycosis --- Explanation: Review supporting clotrimazole as the most effective topical treatment for otomycosis.

[PMID:38962337] [SUPPORT] The most common treatment was local ear debridement and use of topical antifungal creams. --- Explanation: Confirms topical antifungal creams as standard clinical practice.

[PMID:41019825] [SUPPORT] In the 12th week after treatment, 76.34% of the 10% povidone-iodine group and 85.26% of the Clotrimazole group had a good response to treatment (p = 0.248). --- Explanation: RCT showing clotrimazole achieves 85.26% response rate at 12 weeks, with povidone-iodine as a comparable alternative (76.34%, no significant difference).


CHEBI:3764

[PMID:38375517] [INDIRECT EVIDENCE] [SUPPORT] Eight studies had similar results and claimed that clotrimazole has the best or most significant effect on the treatment of otomycosis --- Explanation: Review supporting clotrimazole as the most effective topical treatment for otomycosis.

[PMID:38962337] [INDIRECT EVIDENCE] [SUPPORT] The most common treatment was local ear debridement and use of topical antifungal creams. --- Explanation: Confirms topical antifungal creams as standard clinical practice.

[PMID:41019825] [INDIRECT EVIDENCE] [SUPPORT] In the 12th week after treatment, 76.34% of the 10% povidone-iodine group and 85.26% of the Clotrimazole group had a good response to treatment (p = 0.248). --- Explanation: RCT showing clotrimazole achieves 85.26% response rate at 12 weeks, with povidone-iodine as a comparable alternative (76.34%, no significant difference).


CHEBI:6923


MAXO:0000058

[PMID:38375517] [SUPPORT] in the biomedical field, the re-emerging investigation attention is due to the statements of a number of mechanisms defending the use of acidifying agents to treat mycosis (of antifungal-resistant species). --- Explanation: Supports acidifying agents as an alternative treatment approach, especially for resistant cases.


CHEBI:15366

[PMID:38375517] [INDIRECT EVIDENCE] [SUPPORT] in the biomedical field, the re-emerging investigation attention is due to the statements of a number of mechanisms defending the use of acidifying agents to treat mycosis (of antifungal-resistant species). --- Explanation: Supports acidifying agents as an alternative treatment approach, especially for resistant cases.


CHEBI:33118


NCBITaxon:5052

[PMID:38578519] [SUPPORT] In the 452 clinical strains isolated from the external ear canal, 284 were identified as Aspergillus terreus (62.83%), 92 as Aspergillus flavus (20.35%), 55 as Aspergillus niger (12.17%). --- Explanation: Large clinical series identifying Aspergillus species distribution in otomycosis, with A. terreus as the most common in central China.

[PMID:40317309] [SUPPORT] Our fungal culture results revealed that, in 83 patients (84.69%), the otomycotic pathogen was Aspergillus --- Explanation: RCT confirming Aspergillus as the dominant pathogen in 84.69% of culture-positive otomycosis cases.

[PMID:38486086] [SUPPORT] Black Aspergillus species are the most common etiological agents of otomycosis, and pulmonary aspergillosis. --- Explanation: Study on azole resistance mechanisms in Aspergillus section Nigri, confirming black aspergilli as the most common otomycosis agents.

[PMID:37257666] [SUPPORT] Black aspergilli (section Nigri) are predominate etiologic agents of otomycosis, however, there is controversy in the exact differentiation of species. --- Explanation: Molecular study using calmodulin gene sequencing revealing A. welwitschiae (60.5%) and A. tubingensis (36.0%) as the true predominant species within section Nigri, rather than A. niger sensu stricto.

[PMID:37108955] [SUPPORT] A. niger is more frequently reported in less severe infections such as otomycosis. --- Explanation: Comprehensive review of non-fumigatus Aspergillus noting A. niger's association with otomycosis as a less severe infection compared to invasive aspergillosis.


NCBITaxon:5475

[PMID:38450054] [SUPPORT] Aspergillus spp. (average abundance 90.68%) was the dominant fungus involved in otomycosis secretion. --- Explanation: Microbiome study showing fungal community composition in otomycosis, with Aspergillus dominant and Candida as a secondary pathogen.

[PMID:38962337] [SUPPORT] common fungal isolate was Aspergillus niger 9 (45.0%). --- Explanation: Clinical study from Nigeria identifying Aspergillus niger as the most common isolate, with Candida species also identified among causative agents.

[PMID:37367594] [SUPPORT] Candida auris, Candida blankii, and Kodamaea ohmeri have been regarded as emerging fungal pathogens that can cause infections with high mortality. --- Explanation: Molecular typing study identifying emerging Candida species (including C. auris with azole resistance-associated ERG11p Y132F substitution) isolated from otomycosis in Bangladesh.

[PMID:37223402] [SUPPORT] Commonly found fungi belonging to the genus Aspergillus (55%), followed by Candida (45%). --- Explanation: Clinical study showing Candida as the second most common pathogen (45%) after Aspergillus (55%) in otomycosis.


MONDO:0018233

[PMID:20301567] [SUPPORT] The FLNA-related otopalatodigital (FLNA-OPD) spectrum disorders, characterized primarily by skeletal dysplasia --- Explanation: GeneReviews defines skeletal dysplasia as the primary feature of the OPD spectrum.


MONDO:0018233

[PMID:20301567] [SUPPORT] cosmetic surgery may correct the fronto-orbital deformity --- Explanation: GeneReviews documents fronto-orbital deformity as a management target, confirming craniofacial dysmorphism as a key feature.


MONDO:0018233

[PMID:20301567] [SUPPORT] Males usually, but not always, demonstrate a skeletal dysplasia in association with hearing loss --- Explanation: GeneReviews confirms hearing loss as a key feature of FLNA-FMD.


MONDO:0018233

[PMID:20301567] [SUPPORT] surgical correction for orthognathic deformities as needed --- Explanation: GeneReviews lists orthognathic surgical correction as a management recommendation, consistent with cleft palate as a feature of OPD.


MONDO:0018233

[PMID:20301567] [SUPPORT] Progressive scoliosis is observed in both affected males and females. --- Explanation: GeneReviews documents progressive scoliosis as a common feature.


MONDO:0018233

[PMID:20301567] [SUPPORT] Most males with FLNA-OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. --- Explanation: GeneReviews identifies thoracic hypoplasia as the primary cause of OPD2 male lethality.


MONDO:0018233

[PMID:20301567] [SUPPORT] variably, joint contractures and hand and foot malformations --- Explanation: GeneReviews confirms variable joint contractures as a feature of FLNA-FMD within the OPD spectrum.


MONDO:0018233

[PMID:20301567] [SUPPORT] mandibular distraction can improve airway complications related to micrognathia --- Explanation: GeneReviews management guidance mentions micrognathia as a cause of airway complications requiring mandibular distraction.


MONDO:0018233

[PMID:12612583] [INDIRECT EVIDENCE] [SUPPORT] We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders --- Explanation: Landmark paper identifying gain-of-function FLNA mutations as causative for the OPD spectrum.

[PMID:12612583] [INDIRECT EVIDENCE] [SUPPORT] all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15 --- Explanation: Defines the mutational clustering pattern characteristic of OPD spectrum disorders.

[PMID:19773341] [INDIRECT EVIDENCE] [SUPPORT] recombinant FLNA E254K ABD has increased in vitro F-actin binding (K(d) 13 microm) compared with wild type (WT; K(d) 48 microm). These observations are consistent with a gain-of-function mechanism for OPD. --- Explanation: Provides biochemical evidence that OPD mutations increase actin binding, confirming gain-of-function mechanism.


MONDO:0018233


MONDO:0018233

[PMID:12612583] [INDIRECT EVIDENCE] [SUPPORT] The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development. --- Explanation: Establishes that the skeletal malformations result from gain-of-function effects on developmental signaling.


MAXO:0000004

[PMID:20301567] [SUPPORT] Surgical treatment may be required for hand and foot malformations. --- Explanation: GeneReviews management guidance for skeletal anomalies.


MAXO:0000950

[PMID:20301567] [SUPPORT] hearing aids for deafness --- Explanation: GeneReviews management recommendation for hearing impairment.


MAXO:0000950

[PMID:20301567] [SUPPORT] continuous positive airway pressure and mandibular distraction can improve airway complications related to micrognathia --- Explanation: GeneReviews details respiratory management strategies.


MAXO:0000079

[PMID:20301567] [SUPPORT] Once the FLNA pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for FLNA-OPD spectrum disorders are possible. --- Explanation: GeneReviews genetic counseling guidance.


hgnc:3754

[PMID:12612583] [SUPPORT] We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations --- Explanation: Defines the gain-of-function mutation spectrum for OPD spectrum.

[PMID:19773341] [SUPPORT] These data provide the first biochemical evidence for a gain-of-function mechanism for the OPD disorders, and mechanistically distinguishes them from the loss-of-function phenotypes that manifest as disorders of neuronal migration. --- Explanation: Biochemical confirmation of gain-of-function mechanism, distinguishing from PVNH loss-of-function.

[PMID:20301567] [SUPPORT] Penetrance in males with an FLNA pathogenic variant leading to an FLNA-OPD spectrum disorder is complete --- Explanation: GeneReviews confirms complete penetrance in males.


MONDO:0005211


MONDO:0005211

[PMID:21720365] [INDIRECT EVIDENCE] [SUPPORT] high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%) --- Explanation: TCGA comprehensive genomic analysis of 316 HGS-OvCa samples confirmed near-universal TP53 mutation.


MONDO:0005211

[PMID:21720365] [INDIRECT EVIDENCE] [SUPPORT] Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed --- Explanation: TCGA integrated genomic analysis found HR deficiency in ~50% of HGSOC, including BRCA1/2 mutations and BRCA1 promoter methylation.


MONDO:0005211

[PMID:21720365] [INDIRECT EVIDENCE] [SUPPORT] 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes --- Explanation: TCGA analysis demonstrated the extensive chromosomal instability characteristic of HGSOC.


MONDO:0005211

[PMID:33011111] [INDIRECT EVIDENCE] [SUPPORT] ovarian epithelial cancers are primarily imported from either endometrial or fallopian tube epithelium --- Explanation: Comprehensive review of the tubal origin paradigm for HGSOC, including STIC precursor lesion characterization.

[PMID:33011111] [INDIRECT EVIDENCE] [SUPPORT] Mathematical models imply that a prolonged time (decades) elapses from the development of a TP53 mutation, the earliest known molecular alteration, to an STIC, followed by a shorter span (6 years) for progression to an HGSC --- Explanation: Timeline modeling of HGSOC progression from TP53 mutation through STIC to invasive carcinoma.


MAXO:0000647

[PMID:26493647] [SUPPORT] High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades --- Explanation: Bowtell et al. review establishing HGSOC treatment landscape and challenges with current chemotherapy approaches.


MAXO:0000058

[PMID:36082969] [SUPPORT] At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment --- Explanation: SOLO1 trial 7-year follow-up demonstrating substantial overall survival benefit with maintenance olaparib in BRCA-mutant newly diagnosed advanced ovarian cancer.


MAXO:0000058

[PMID:36252167] [SUPPORT] An unfavorable KELIM score was associated with bevacizumab benefit compared with placebo (PFS: HR, 0.70; 95% CI, 0.59 to 0.82; OS: HR, 0.87; 95% CI, 0.73 to 1.03) --- Explanation: GOG-0218 validation confirming KELIM score as a predictive biomarker for bevacizumab benefit in ovarian cancer.


MAXO:0000004


hgnc:11998

[PMID:21720365] [SUPPORT] high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%) --- Explanation: TCGA analysis confirmed TP53 as the defining molecular feature of HGSOC.


hgnc:1100

[PMID:21720365] [SUPPORT] BRCA1 and BRCA2 had germline mutations in 9% and 8% of cases, respectively, and both showed somatic mutations in an additional 3% of cases --- Explanation: TCGA quantified germline and somatic BRCA1 mutation rates in HGSOC.


hgnc:1101

[PMID:21720365] [SUPPORT] BRCA1 and BRCA2 had germline mutations in 9% and 8% of cases, respectively, and both showed somatic mutations in an additional 3% of cases --- Explanation: TCGA quantified germline and somatic BRCA2 mutation rates in HGSOC.


hgnc:7765

[PMID:21720365] [SUPPORT] low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12 --- Explanation: NF1 identified as a recurrently mutated gene in HGSOC by TCGA.


hgnc:24224

[PMID:21720365] [SUPPORT] low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12 --- Explanation: CDK12 identified as a significantly mutated gene in HGSOC, involved in RNA splicing regulation.


MONDO:0004989


MAXO:0000058

[PMID:37743730] [SUPPORT] The combination of fulvestrant with alpelisib, a PI3K inhibitor, improves progression-free survival in metastatic hormone receptor-positive, PIK3CA-mutant breast cancer. --- Explanation: This abstract supports the use of alpelisib with fulvestrant in PIK3CA-mutant breast cancer.


CHEBI:231324

[PMID:37743730] [INDIRECT EVIDENCE] [SUPPORT] The combination of fulvestrant with alpelisib, a PI3K inhibitor, improves progression-free survival in metastatic hormone receptor-positive, PIK3CA-mutant breast cancer. --- Explanation: This abstract supports the use of alpelisib with fulvestrant in PIK3CA-mutant breast cancer.


MAXO:0000058


CHEBI:229222


HGNC.SYMBOL:PIK3CA


MONDO:0004989

[PMID:39806949] [SUPPORT] Invasive ductal carcinoma (IDC) is the most common type of breast cancer, --- Explanation: Abstract states that invasive ductal carcinoma is the most common breast cancer type.


MONDO:0012180

[PMID:15489853] [SUPPORT] Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. --- Explanation: Directly establishes the association of PKP2-related ARVC with ventricular tachyarrhythmias.


MONDO:0012180


MONDO:0012180

[PMID:16567567] [SUPPORT] negative T waves in V(2) and V(3) occurred more often in PKP2 mutation carriers (P<0.05). --- Explanation: T-wave inversions in V2-V3 are significantly more common in PKP2 mutation carriers.


MONDO:0012180

[PMID:34191271] [SUPPORT] Patients carrying a PKP2 mutation were younger at diagnosis (p = 0.003), more often had negative T waves in V1-V3 (p = 0.01), had higher left ventricular ejection fraction (p = 0.04), and were less likely to present symptoms of heart failure (p = 0.01) --- Explanation: PKP2 carriers have better preserved LV function and lower heart failure rates.


MONDO:0012180

[PMID:15489853] [INDIRECT EVIDENCE] [SUPPORT] In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. --- Explanation: Identifies PKP2 as an essential desmosomal protein whose mutations cause ARVC.


MONDO:0012180

[PMID:16823493] [INDIRECT EVIDENCE] [SUPPORT] suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets. --- Explanation: Demonstrates that desmosomal disruption causes Wnt suppression via nuclear plakoglobin, leading to adipogenesis and fibrosis.


MONDO:0012180

[PMID:18662195] [INDIRECT EVIDENCE] [SUPPORT] Reduced connexin43 expression and localization to the intercalated disk occurs in heterozygous human PKP-2 mutations, potentially explaining the delayed conduction and propensity to develop arrhythmias seen in this disease. --- Explanation: Direct human biopsy evidence of reduced Cx43 expression in PKP2 mutation carriers.


MONDO:0012180

[PMID:16823493] [INDIRECT EVIDENCE] [SUPPORT] Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC. --- Explanation: Mouse model demonstrates fibrofatty replacement and arrhythmias recapitulating human ARVC.


MONDO:0012180

[PMID:34191271] [INDIRECT EVIDENCE] [SUPPORT] ARVC patients with PKP2 mutation are less likely to present left ventricular involvement and heart failure symptoms. --- Explanation: PKP2 carriers show predominantly right ventricular phenotype with relative sparing of left ventricle.


MAXO:0000004


MAXO:0000802


MAXO:0010039

[PMID:34191271] [SUPPORT] Combined endpoint of death or heart transplant was more frequent in subgroup without PKP2 mutation (p = 0.03). --- Explanation: PKP2 carriers have better survival and lower transplant rates.


hgnc:9024

[PMID:15489853] [SUPPORT] In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. --- Explanation: First identification of PKP2 mutations as a common cause of ARVC.

[PMID:16567567] [SUPPORT] In 24 of these 56 ARVC patients (43%), 14 different (11 novel) PKP2 mutations were identified. --- Explanation: Establishes PKP2 mutations in 43% of ARVC patients fulfilling Task Force Criteria.

[PMID:34120153] [SUPPORT] We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position. --- Explanation: Large multicohort study demonstrating near-complete specificity of PKP2 truncating variants for ARVC and identifying the C-terminus as a functional domain.

[PMID:34191271] [SUPPORT] Ten variants (5 frameshift, 2 nonsense, 2 splicing, and 1 missense) in PKP2 were found in 28 (50%) cases. --- Explanation: Polish ARVC cohort confirming 50% prevalence of PKP2 variants with characterization of mutation types.


MONDO:1040055

[PMID:38743414] [SUPPORT] The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. --- Explanation: The multicenter PRPH2 cohort confirms visual acuity loss as a common clinical phenotype.


MONDO:1040055

[PMID:38743414] [SUPPORT] ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). --- Explanation: This cohort directly supports abnormal electrophysiology across the PRPH2 retinal-dystrophy spectrum.


MONDO:1040055

[PMID:38743414] [SUPPORT] FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). --- Explanation: The cohort demonstrates that fundus autofluorescence is a defining and frequently abnormal phenotype axis in PRPH2 disease.


MONDO:1040055

[PMID:30819798] [INDIRECT EVIDENCE] [SUPPORT] Peripherin 2 (PRPH2) is a tetraspanin protein concentrated in the light-sensing cilium (called the outer segment) of the vertebrate photoreceptor. --- Explanation: This study supports a shared PRPH2-centered mechanistic trunk focused on photoreceptor outer segments.

[PMID:32213850] [INDIRECT EVIDENCE] [SUPPORT] This loop enables Prph2 to associate with itself to form homo-oligomers or with its homologue, rod outer segment membrane protein 1 (Rom1) to form hetero-tetramers and hetero-octamers. --- Explanation: This review directly supports PRPH2/ROM1 complex assembly as a core mechanistic module.


MONDO:1040055


MONDO:1040055

[PMID:32213850] [INDIRECT EVIDENCE] [SUPPORT] The importance of Prph2 for photoreceptor development, maintenance and function is underscored by the fact that its absence results in a failure to initialize OS formation in rods and formation of severely disorganized OS membranous structures in cones. --- Explanation: This review supports outer-segment morphogenesis failure as the central cellular consequence of PRPH2 disruption.

[PMID:32716032] [INDIRECT EVIDENCE] [SUPPORT] Combined, our findings support a role for non-pathogenic ROM1 null variants in contributing to phenotypic variability in mutant PRPH2-associated retinal degeneration. --- Explanation: Modifier-driven variation in this same outer-segment module helps explain why one shared pathograph can still branch into different clinical subtypes.


hgnc:9942

[PMID:38474159] [SUPPORT] PRPH2, one of the most frequently inherited retinal dystrophy (IRD)-causing genes, implies a high phenotypic variability. --- Explanation: This large cohort supports PRPH2 as a causal gene for the umbrella disease entity.


hgnc:10254

[PMID:32716032] [SUPPORT] Combined, our findings support a role for non-pathogenic ROM1 null variants in contributing to phenotypic variability in mutant PRPH2-associated retinal degeneration. --- Explanation: This supports ROM1 as a genuine modifier rather than a redundant duplicate causal gene entry.


MONDO:1040055

[PMID:32213850] [SUPPORT] Mutations in PRPH2 cause a multitude of retinal diseases including autosomal dominant retinitis pigmentosa (RP) or cone dominant macular dystrophies. --- Explanation: This review supports autosomal dominant inheritance as the major PRPH2 disease pattern across multiple phenotype branches.


MONDO:0010533

[PMID:23190330] [SUPPORT] Hearing loss in male patients with PRPS1 mutations is bilateral, moderate to profound, and can be prelingual or postlingual, progressive or non-progressive. --- Explanation: Characterizes hearing loss across the PRPS1 spectrum.


MONDO:0010533

[PMID:26089585] [PARTIAL] severe PRS-I deficiency (Arts syndrome) present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment --- Explanation: The abstract describes "central nervous system impairment" in Arts syndrome but does not explicitly name ataxia. Ataxia is a well-known feature of Arts syndrome, but this snippet provides only indirect support via the broader CNS impairment category.


MONDO:0010533

[PMID:26089585] [SUPPORT] moderate PRS-I deficiency (CMTX5) and severe PRS-I deficiency (Arts syndrome) present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment --- Explanation: Describes peripheral neuropathy as a feature of moderate and severe PRPS1 deficiency.


MONDO:0010533


MAXO:0000088

[PMID:26089585] [SUPPORT] purine replacement via S-adenosylmethionine (SAM) supplementation in patients with Arts syndrome appears to improve their condition --- Explanation: SAM supplementation as potential therapy for PRPS1 deficiency.

[PMID:23190330] [SUPPORT] SAM could compensate for PRS-I deficiency --- Explanation: Confirms SAM as a potential therapeutic approach.


MAXO:0000950


MAXO:0000079


hgnc:9462

[PMID:23190330] [SUPPORT] the loss-of-function mutations result in X-linked nonsyndromic sensorineural deafness type 2 (DFN2), or in syndromic deafness including Arts syndrome and X-linked Charcot-Marie-Tooth disease-5 (CMTX5) --- Explanation: LOF mutations cause the deficiency spectrum.


MONDO:0010395

[PMID:26089585] [SUPPORT] uric acid overproduction --- Explanation: Hyperuricemia from purine overproduction.


MONDO:0010395


MONDO:0010395

[PMID:26089585] [SUPPORT] hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment --- Explanation: Ataxia listed among neurological features of superactivity.


MONDO:0010395

[PMID:26089585] [SUPPORT] hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment --- Explanation: Hypotonia listed among neurological features of superactivity.


MONDO:0010395

[PMID:26089585] [INDIRECT EVIDENCE] [SUPPORT] The overexpression of PRPS1 results in PRS-I superactivity resulting in purine overproduction. Patients with PRS-I superactivity demonstrate uric acid overproduction, hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment. --- Explanation: Describes purine overproduction and its clinical consequences.


MAXO:0000058


hgnc:9462

[PMID:23190330] [SUPPORT] Gain of function mutations in PRPS1 cause a superactivity of the PRS-I protein whereas the loss-of-function mutations result in X-linked nonsyndromic sensorineural deafness type 2 (DFN2), or in syndromic deafness including Arts syndrome --- Explanation: Distinguishes GOF (superactivity) from LOF (deficiency spectrum).


MONDO:0958174

[PMID:19032739] [SUPPORT] BCCs (varying clinically from flesh-colored papules to ulcerating plaques and in diameter from 1 to 10 mm) are most commonly located on the face, back and chest. The number of BBCs varies from a few to several thousand. --- Explanation: Documents high and variable BCC burden in PTCH1-driven Gorlin syndrome.


MONDO:0958174

[PMID:19032739] [SUPPORT] Recurrent jaw cysts occur in 90% of patients. --- Explanation: Supports high prevalence of odontogenic keratocysts in this genotype.

[PMID:28596197] [PARTIAL] Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004). --- Explanation: Supports relative enrichment of jaw cysts in PTCH1 versus SUFU disease.


MONDO:0958174

[PMID:25403219] [SUPPORT] We found a < 2% risk in PTCH1 mutation-positive individuals, with a risk up to 20× higher in SUFU mutation-positive individuals. --- Explanation: Quantifies comparatively lower medulloblastoma risk in PTCH1 carriers.


MONDO:0958174

[PMID:28596197] [PARTIAL] Patients with variants were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002) and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003) than patients with no identified mutation. --- Explanation: Supports frequent rib and skeletal anomalies in mutation-positive Gorlin cohorts dominated by PTCH1.


MONDO:0958174

[PMID:28596197] [INDIRECT EVIDENCE] [SUPPORT] Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. --- Explanation: Establishes PTCH1 germline variants as a major upstream mechanism in Gorlin syndrome.

[PMID:19032739] [INDIRECT EVIDENCE] [PARTIAL] NBCCS is caused by mutations in the PTCH1 gene and is transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. --- Explanation: Supports PTCH1 causality and inherited predisposition biology.


MONDO:0958174


MAXO:0000058

[PMID:22670904] [SUPPORT] Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. --- Explanation: Randomized trial evidence for efficacy in NBCCS-associated BCC prevention and shrinkage.

[PMID:22670904] [PARTIAL] The adverse events associated with treatment led to discontinuation in over half of treated patients. --- Explanation: Documents long-term tolerability limits that affect treatment strategy.