MONDO:0012727

[PMID:34890998] [INDIRECT EVIDENCE] [SUPPORT] Increasing evidence shows that the pathogenesis of Kawasaki disease (KD) is caused by abnormal and unbalanced innate and adaptive immune responses. --- Explanation: The literature supports the statement that Kawasaki Disease is characterized by immune response dysregulation leading to vessel wall damage and inflammation.

[PMID:30183655] [INDIRECT EVIDENCE] [SUPPORT] Kawasaki disease (KD) is a vasculitis that is part of systemic vasculitis syndrome. It affects medium-sized vessels and is characterized by hypercytokinemia. --- Explanation: This reference supports that KD involves immune dysregulation leading to vessel wall damage.

[PMID:30619331] [INDIRECT EVIDENCE] [SUPPORT] Others have favored an autoreactive hypothesis that KD is triggered by an antigen that shares homology with structures in the vascular wall, and molecular mimicry resulting in an immune response directed to that tissue. --- Explanation: This supports the notion of an abnormal immune response leading to vessel wall damage in KD.

[PMID:39117827] [INDIRECT EVIDENCE] [SUPPORT] Kawasaki disease (KD) is a hyperinflammatory syndrome manifesting as an acute systemic vasculitis characterized by fever, nonsuppurative conjunctival injection, rash, oral mucositis, extremity changes, and cervical lymphadenopathy. --- Explanation: This reference supports the statement by describing KD as a hyperinflammatory syndrome, which involves immune dysregulation.


MONDO:0012727


MAXO:0000058

[PMID:23283289] [SUPPORT] Intravenous immunoglobulin (IVIG) and aspirin is the standard initial therapy in the treatment of Kawasaki disease. --- Explanation: The literature confirms that IVIG is part of the standard initial therapy for Kawasaki disease, aimed at reducing inflammation and preventing coronary artery complications.

[PMID:38135926] [SUPPORT] For KD patients, male, children aged 3 to 9 years, and those with fever longer than 6 days before intravenous immunoglobulin (IVIG) use were more likely to have CAL. --- Explanation: The study discusses the use of IVIG and its timing in relation to the risk of coronary artery lesions, supporting its role in reducing such risks.

[PMID:24034380] [SUPPORT] The standard of care for treatment is intravenous immunoglobulin plus aspirin, but adding corticosteroids may provide additional benefit for high-risk patients. --- Explanation: The literature states that IVIG is the standard of care for treating Kawasaki disease to reduce coronary artery complications.

[PMID:34535199] [SUPPORT] Intravenous immunoglobulin (IVIG) has become an effective treatment regimen, which can effectively reduce the incidence of cardiovascular complications. --- Explanation: The literature confirms that IVIG is effective in reducing cardiovascular complications in Kawasaki disease.

[PMID:32888683] [SUPPORT] Treatment of Kawasaki disease (KD) with intravenous immunoglobulin (IVIG) administered within the initial 10 days of fever onset decreases the risk of coronary artery aneurysms (CAAs) from ∼ 25% to less than 5%. --- Explanation: The literature provides evidence that IVIG significantly reduces the risk of coronary artery complications when administered early.


MAXO:0000181

[PMID:9513217] [SUPPORT] Treatment includes the hospitalization of the child and subsequent administration of high doses of aspirin and intravenous immunoglobulin. With recovery, aspirin doses are reduced and the child may be monitored at home with outpatient follow-up. --- Explanation: This reference confirms that high doses of aspirin are used initially for Kawasaki disease, followed by lower doses after recovery.

[PMID:10935427] [SUPPORT] Conventional therapy for KD includes intravenous gammaglobulin (2 g/kg as a single dose over 12 hours) and aspirin (acetylsalicylic acid; high dose until the fourteenth day of illness then low dose). --- Explanation: This reference also supports the statement that high doses of aspirin are used initially, followed by lower doses.

[PMID:32159800] [PARTIAL] Low-dose aspirin plus IVIG might be as effective as high-dose aspirin plus IVIG for the initial treatment of Kawasaki disease. Considering that high-dose aspirin may cause more adverse reactions than low-dose aspirin, low-dose aspirin plus IVIG should be recommended as the first-line therapy in the initial treatment of Kawasaki disease. --- Explanation: This reference suggests that low-dose aspirin might be equally effective as high-dose aspirin and should be recommended to avoid adverse reactions, indicating a shift in treatment preference.

[PMID:28043685] [PARTIAL] The use of medium- or higher-dose ASA in acute Kawasaki disease did not prevent CAA. A future randomized controlled trial is needed to determine the optimum dose of ASA. --- Explanation: This reference indicates that higher doses of aspirin did not prevent coronary artery aneurysms and suggests the need for further research to determine the optimal dose.


MAXO:0000058


NCIT:C38717


NCIT:C406


MAXO:0000058

[PMID:31914832] [SUPPORT] We suggest using methylprednisolone pulse therapy as an alternative rescue therapy for immunoglobulin-resistant KD, as well as identifying high-risk patients who need initial corticosteroid with IVIG treatment with an adequate route, dose, and duration. --- Explanation: The literature supports the use of corticosteroids in cases of Kawasaki Disease that are resistant to IVIG or in high-risk patients with severe inflammation.

[PMID:29101553] [SUPPORT] "Resistant" Kawasaki disease is defined by the American Heart Association as failure to respond within 36 h following the first dose of intravenous immunoglobulin. The optimal management of resistant Kawasaki disease remains uncertain, the outcomes are potentially serious, and the cost of some treatments is considerable. --- Explanation: This reference discusses the management of resistant Kawasaki Disease, which includes considering corticosteroid use.

[PMID:33541111] [SUPPORT] To prevent CAA, more intensified or adjunctive therapies using other agents, such as pulsed methylprednisolone, ciclosporin, infliximab, and Anakinra, should be considered for patients with these risk factors. --- Explanation: This reference mentions the use of pulsed methylprednisolone (a corticosteroid) for patients with Kawasaki Disease who are at risk of developing coronary artery abnormalities, indicating severe inflammation.


HGNC.SYMBOL:ITPKC


HGNC.SYMBOL:FCGR2A


HGNC.SYMBOL:FCGR3A


HGNC.SYMBOL:BLK


HGNC.SYMBOL:CD40


HGNC.SYMBOL:HLA-B


HGNC.SYMBOL:CASP3


HGNC.SYMBOL:ORAI1


HGNC.SYMBOL:STIM1


HGNC.SYMBOL:TGFBR2


HGNC.SYMBOL:SMAD3


HGNC.SYMBOL:TGFB2


HGNC.SYMBOL:IL1B


HGNC.SYMBOL:IL1R1


HGNC.SYMBOL:TNF


HGNC.SYMBOL:IL17A


HGNC.SYMBOL:IL23A


HGNC.SYMBOL:NLRP3


HGNC.SYMBOL:NOS3


HGNC.SYMBOL:ICAM1


HGNC.SYMBOL:VCAM1


MONDO:0007422

[PMID:10369869] [SUPPORT] VS is characterized by papular and honeycomb keratoderma associated with constrictions of digits leading to autoamputation
 --- Explanation: Honeycomb keratoderma is a defining feature of the syndrome.


MONDO:0007422

[PMID:10369869] [SUPPORT] VS is characterized by papular and honeycomb keratoderma
 --- Explanation: Honeycomb pattern is characteristic of the syndrome.


MONDO:0007422

[PMID:10369869] [SUPPORT] constrictions of digits leading to autoamputation
 --- Explanation: Pseudoainhum with potential autoamputation is a key feature.

[PMID:12072018] [SUPPORT] the clinical manifestations of ichthyosis, keratoderma and pseudoainhum
 --- Explanation: Pseudoainhum is a feature of both genetic forms.


MONDO:0007422

[PMID:10369869] [SUPPORT] A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families.
 --- Explanation: Sensorineural deafness is part of the classic Vohwinkel phenotype.

[PMID:20031451] [SUPPORT] Vohwinkel Syndrome (VS) is a type of diffuse hereditary palmoplantar keratodermas (DHPPK) accompanied by skeletal dimorphisms and sensorineural deafness.
 --- Explanation: Confirms sensorineural deafness as a component of the syndrome.


MONDO:0007422

[PMID:10369869] [SUPPORT] distinctive starfish-like acral keratoses
 --- Explanation: Starfish-like acral keratoses are a characteristic feature.


MONDO:0007422

[PMID:6237617] [SUPPORT] keratotic structures taking the shape of a starfish and/or knuckle pads on the dorsal surfaces of the hands
 --- Explanation: Describes starfish-shaped keratoses and knuckle pads as characteristic features.

[PMID:30335335] [SUPPORT] The classic Vohwinkel syndrome is a hereditary PPK associated with "starfish" keratoses on the knuckles
 --- Explanation: StatPearls review confirms starfish keratoses on knuckles are part of classic syndrome.


MONDO:0007422

[PMID:9326398] [SUPPORT] Our first family (VK1) also had ichthyosis but not deafness.
 --- Explanation: Ichthyosis is present in the loricrin variant but not classic form.

[PMID:11038186] [SUPPORT] At birth, transgenic mice (ML.VS) exhibited erythrokeratoderma with an epidermal barrier dysfunction. 4 d after birth, high-expressing transgenic animals showed a generalized scaling of the skin
 --- Explanation: Transgenic mice with mutant loricrin develop ichthyosis-like scaling.


MONDO:0007422


MONDO:0007422

[PMID:10369869] [INDIRECT EVIDENCE] [SUPPORT] This mutation occurs at a highly conserved residue in the first extracellular domain of the Cx26 molecule, and may exert its effects by interfering with assembly into connexons, docking with adjacent cells or gating properties of the gap junction.
 --- Explanation: Describes the molecular mechanism of GJB2 D66H mutation disrupting gap junction function.

[PMID:14681042] [INDIRECT EVIDENCE] [SUPPORT] Expression of the transgene resulted in a loss of Cx26 and Cx30 at intercellular junctions of epidermal keratinocytes and accumulation of these connexins in the cytoplasm.
 --- Explanation: Transgenic mouse model demonstrates that D66H mutation causes loss of connexins at cell junctions.


MONDO:0007422

[PMID:10369869] [INDIRECT EVIDENCE] [SUPPORT] Our results provide evidence that a specific mutation in Cx26 can impair epidermal differentiation, as well as inner ear function.
 --- Explanation: Establishes that GJB2 mutations affect both epidermal and cochlear function.

[PMID:14681042] [INDIRECT EVIDENCE] [SUPPORT] Following birth, the transgenic mice developed keratoderma similar to that of human carriers of Cx26 (D66H).
 --- Explanation: Transgenic mice expressing mutant Cx26 develop keratoderma like human patients.


MONDO:0007422

[PMID:11121146] [INDIRECT EVIDENCE] [SUPPORT] Mutant loricrin, as a dominant negative disrupter, is not likely to affect cornified cell envelope crosslinking directly, but seems to interfere with nuclear/nucleolar functions of differentiating keratinocytes.
 --- Explanation: Describes the mechanism by which mutant loricrin causes disease through nuclear interference.

[PMID:9326398] [INDIRECT EVIDENCE] [SUPPORT] a G insertion producing a frameshift after codon 231 and an abnormal C-terminal peptide lacking residues necessary for cross-linking.
 --- Explanation: Identifies the specific mutation and its effect on loricrin protein structure.

[PMID:11038186] [INDIRECT EVIDENCE] [SUPPORT] Immunofluorescence and immunoelectron microscopy showed the mutant loricrin protein in the nucleus and cytoplasm of epidermal keratinocytes, but did not detect the protein in the cornified cell envelope.
 --- Explanation: Transgenic mouse studies confirm nuclear mislocalization of mutant loricrin.


MONDO:0007422

[PMID:10369869] [INDIRECT EVIDENCE] [SUPPORT] Mutations in the connexin26 (Cx26) gene (GJB2) at 13q11-q13 are a major cause of autosomal recessive hearing loss (DFNB1), but have also been reported in autosomal dominant deafness (DFNA3).
 --- Explanation: Establishes the role of GJB2 in both skin and hearing phenotypes.

[PMID:9326398] [INDIRECT EVIDENCE] [SUPPORT] In our second family (VK2), affected members had sensorineural deafness but not ichthyosis.
 --- Explanation: Confirms that deafness segregates with connexin mutations, not loricrin mutations.


hgnc:4284

[PMID:10369869] [SUPPORT] All 10 affected members were heterozygous for a non-conservative mutation, D66H, in Cx26. The same mutation was found subsequently in affected individuals from two unrelated Spanish and Italian pedigrees segregating VS, suggesting that D66H in Cx26 is a common mutation in classical VS.
 --- Explanation: Identifies D66H as a common mutation in classic Vohwinkel syndrome across multiple families.

[PMID:20031451] [SUPPORT] Genetic study showed a nucleotide change (c.196G>C) in exon 1 of GJB2 gene, producing a missense mutation, D66H.
 --- Explanation: Confirms the specific nucleotide change causing the D66H mutation.


hgnc:6663

[PMID:9326398] [SUPPORT] a G insertion producing a frameshift after codon 231 and an abnormal C-terminal peptide lacking residues necessary for cross-linking.
 --- Explanation: Identifies the specific loricrin mutation causing the ichthyotic variant.

[PMID:12072018] [SUPPORT] identified a recurrent insertion mutation in the loricrin gene resulting in a mutant polypeptide with an unusual C terminus.
 --- Explanation: Confirms the recurrent nature of loricrin insertion mutations.


MONDO:0008260

[PMID:26937547] [SUPPORT] characterized by skin fragility and acral blister formation beginning at birth --- Explanation: GeneReviews confirms acral blistering from birth as a cardinal feature.

[PMID:21936020] [SUPPORT] an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer --- Explanation: Confirms skin blistering as a key component of the Kindler syndrome phenotype.


MONDO:0008260

[PMID:21936020] [SUPPORT] progressive poikiloderma with extensive skin atrophy --- Explanation: Confirms progressive poikiloderma as a defining feature.

[PMID:19945623] [SUPPORT] Null mutations in FERMT1 result in skin blistering from birth and early childhood progressive poikiloderma, mucosal fragility, and increased risk of cancer --- Explanation: Confirms progressive poikiloderma beginning in early childhood.


MONDO:0008260

[PMID:26937547] [SUPPORT] photosensitivity (most prominent during childhood and usually decreasing after adolescence) --- Explanation: GeneReviews confirms photosensitivity pattern in Kindler syndrome.

[PMID:21936020] [SUPPORT] skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy --- Explanation: Confirms photosensitivity as part of the progressive phenotype.

[PMID:28501563] [SUPPORT] Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA --- Explanation: Demonstrates the molecular basis of photosensitivity through elevated ROS and increased DNA damage in kindlin-1-deficient cells after UVA exposure.

[PMID:28501563] [SUPPORT] Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients --- Explanation: Proposes impaired ERK signaling as the mechanism underlying photosensitivity in Kindler syndrome.


MONDO:0008260

[PMID:26937547] [SUPPORT] diffuse cutaneous atrophy --- Explanation: GeneReviews lists diffuse cutaneous atrophy as a key clinical characteristic.

[PMID:19057668] [SUPPORT] deleting Kindlin-1 in mice gives rise to skin atrophy --- Explanation: Mouse model confirms kindlin-1 loss directly causes skin atrophy.


MONDO:0008260

[PMID:26937547] [SUPPORT] diffuse palmoplantar hyperkeratosis --- Explanation: GeneReviews confirms palmoplantar hyperkeratosis as a feature of Kindler syndrome.


MONDO:0008260


MONDO:0008260

[PMID:19057668] [PARTIAL] a few KS patients have been reported to also develop ulcerative colitis (UC), a causal link to the FERMT1 gene mutation is unknown --- Explanation: Notes that some Kindler syndrome patients develop ulcerative colitis.

[PMID:19057668] [SUPPORT] deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC --- Explanation: Mouse model provides causal evidence linking kindlin-1 loss to colitis-like intestinal dysfunction.


MONDO:0008260

[PMID:26937547] [SUPPORT] Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas --- Explanation: GeneReviews identifies mucosal strictures as a severe long-term complication.


MONDO:0008260

[PMID:26937547] [SUPPORT] Other mucosal findings can include ectropion, urethral stenosis, and severe phimosis --- Explanation: GeneReviews lists urethral stenosis as a mucosal manifestation.


MONDO:0008260

[PMID:26937547] [SUPPORT] Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth --- Explanation: GeneReviews confirms periodontal disease as a common mucosal manifestation.

[PMID:26937547] [SUPPORT] Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas --- Explanation: Confirms periodontitis as a severe long-term complication.


MONDO:0008260

[PMID:21936020] [SUPPORT] propensity to skin cancer --- Explanation: Confirms increased skin cancer risk in Kindler syndrome.

[PMID:26937547] [SUPPORT] Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas --- Explanation: GeneReviews identifies aggressive SCCs as a severe long-term complication.

[PMID:31340837] [SUPPORT] SCC developed in 13 of the 91 patients --- Explanation: Largest systematic study of SCC in KS quantifies the frequency at 14.3% of adult patients in this cohort.

[PMID:31340837] [SUPPORT] the cumulative risk of SCC increased to 66.7% in patients over 60 years of age --- Explanation: Demonstrates that cumulative SCC risk increases dramatically with age, reaching two-thirds by age 60.

[PMID:31340837] [SUPPORT] 53.8% of the patients bearing SCCs develop metastatic disease --- Explanation: Confirms the highly aggressive nature of SCCs in KS with majority developing metastases.


MONDO:0008260

[PMID:21936020] [INDIRECT EVIDENCE] [SUPPORT] Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer --- Explanation: Confirms FERMT1 mutations cause Kindler syndrome through loss of the focal adhesion protein kindlin-1.

[PMID:19945623] [INDIRECT EVIDENCE] [SUPPORT] Kindler syndrome is caused by genetic defects in the focal contact-associated protein, fermitin family homologue 1 (FFH1), encoded by the gene FERMT1 (known as KIND1) --- Explanation: Confirms FERMT1 encodes the focal contact-associated protein FFH1 (kindlin-1) and its defects cause Kindler syndrome.


MONDO:0008260

[PMID:19762710] [INDIRECT EVIDENCE] [SUPPORT] active beta1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype --- Explanation: Demonstrates that kindlin-1 deficiency reduces active beta1 integrin and that restoring kindlin-1 rescues integrin activation.

[PMID:19762710] [INDIRECT EVIDENCE] [SUPPORT] We identified altered distribution of several basement membrane proteins, including types IV, VII, and XVII collagens and laminin-332 in Kindler syndrome skin --- Explanation: Shows disruption of multiple basement membrane components beyond focal adhesions in Kindler syndrome.

[PMID:19945623] [INDIRECT EVIDENCE] [SUPPORT] Defects in FFH1 lead to abnormal integrin activation and loss of keratinocyte epidermal adhesion to the underlying basal lamina, disruption in normal cell cytoskeleton within keratinocytes, and altered signaling pathways --- Explanation: Confirms that kindlin-1 deficiency causes abnormal integrin activation and loss of keratinocyte adhesion.


MONDO:0008260

[PMID:19762710] [INDIRECT EVIDENCE] [SUPPORT] lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stem cell markers --- Explanation: Shows that kindlin-1 loss impairs keratinocyte biology beyond adhesion, including stem cell marker expression, which contributes to impaired wound healing.


MONDO:0008260

[PMID:21936020] [INDIRECT EVIDENCE] [SUPPORT] an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer --- Explanation: Confirms the progressive nature of poikiloderma and skin atrophy in Kindler syndrome.

[PMID:19057668] [INDIRECT EVIDENCE] [SUPPORT] deleting Kindlin-1 in mice gives rise to skin atrophy --- Explanation: Mouse model confirms that kindlin-1 loss directly causes skin atrophy.


MONDO:0008260

[PMID:19057668] [INDIRECT EVIDENCE] [SUPPORT] deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC --- Explanation: Mouse model demonstrates that kindlin-1 loss causes intestinal epithelial dysfunction resembling ulcerative colitis.

[PMID:19057668] [INDIRECT EVIDENCE] [SUPPORT] This intestinal dysfunction results in perinatal lethality and is triggered by defective intestinal epithelial cell integrin activation, leading to detachment of this barrier followed by a destructive inflammatory response --- Explanation: Demonstrates that intestinal involvement is caused by defective integrin activation in epithelial cells.

[PMID:26937547] [INDIRECT EVIDENCE] [SUPPORT] Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth, and labial leukokeratosis. Other mucosal findings can include ectropion, urethral stenosis, and severe phimosis --- Explanation: GeneReviews confirms the spectrum of mucosal manifestations in Kindler syndrome.


MAXO:0000950

[PMID:26937547] [SUPPORT] Skin care includes standard blister care, use of moisturizers, and protection from trauma and the sun --- Explanation: GeneReviews describes wound care and skin protection as key management strategies.


MAXO:0000950

[PMID:26937547] [SUPPORT] Agents/circumstances to avoid: Sun exposure --- Explanation: GeneReviews explicitly recommends avoiding sun exposure.


MAXO:0000950

[PMID:26937547] [SUPPORT] management of gastrointestinal and urethral complications --- Explanation: GeneReviews includes GI management as part of treatment.


MAXO:0000950

[PMID:26937547] [SUPPORT] regular dental care to ensure optimal oral hygiene to reduce periodontal disease --- Explanation: GeneReviews recommends regular dental care for periodontal disease prevention.


MAXO:0000126

[PMID:26937547] [SUPPORT] Screening for premalignant keratoses and early squamous cell carcinomas starting in adolescence and repeated annually --- Explanation: GeneReviews recommends annual SCC screening starting in adolescence.


MAXO:0000079

[PMID:26937547] [SUPPORT] KS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FERMT1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected --- Explanation: GeneReviews confirms autosomal recessive inheritance and recommends genetic counseling.


HGNC.SYMBOL:FERMT1

[PMID:26937547] [SUPPORT] The diagnosis of KS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in FERMT1 identified by molecular genetic testing --- Explanation: GeneReviews confirms biallelic FERMT1 variants as the molecular basis of Kindler syndrome.

[PMID:21936020] [SUPPORT] Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients --- Explanation: Confirms that most FERMT1 mutations are loss-of-function with variable clinical expression.

[PMID:19762710] [SUPPORT] It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1 --- Explanation: Confirms FERMT1 loss-of-function mutations cause Kindler syndrome.


MONDO:0012455

[DOI:10.1136/jmg-2023-109702] [SUPPORT] The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%) --- Explanation: Large cohort study (n=103) establishes the cognitive spectrum in KS, showing most but not all individuals have intellectual disability.


MONDO:0012455

[PMID:16826528] [SUPPORT] severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism --- Explanation: Original description of the 9q34 subtelomeric deletion syndrome identifies hypotonia as a cardinal feature.


MONDO:0012455

[DOI:10.1136/jmg-2023-109702] [SUPPORT] Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition --- Explanation: Near-universal speech disorder in verbal KS individuals, with dysarthria and childhood apraxia of speech as predominant types.

[DOI:10.1136/jmg-2023-109702] [SUPPORT] Language ability also ranged from average (10/90, 11%) to severely impaired (53/90, 59%) --- Explanation: Demonstrates the broad language spectrum with majority showing severe impairment.


MONDO:0012455

[PMID:16826528] [SUPPORT] severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism --- Explanation: The original characterization of the syndrome includes severe developmental delay as a defining feature.


MONDO:0012455


MONDO:0012455

[DOI:10.1136/jmg-2023-109702] [SUPPORT] Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains --- Explanation: Regression is a recognized but minority feature, across multiple developmental domains.


MONDO:0012455

[PMID:39746677] [SUPPORT] Behavioral disorders, such as autism spectrum disorder (38%), were common. --- Explanation: Large clinical cohort (n=65) at Boston Children's Hospital Kleefstra Clinic found ASD in 38% of individuals, directly supporting autistic behavior as a frequent phenotype.


MONDO:0012455

[PMID:16826528] [SUPPORT] brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia --- Explanation: The original characterization provides the full description of the distinctive facial phenotype.


MONDO:0012455

[PMID:16826528] [SUPPORT] brachycephaly, flat face with hypertelorism --- Explanation: Brachycephaly is listed as a core craniofacial feature in the original syndrome description.


MONDO:0012455

[PMID:16826528] [SUPPORT] flat face with hypertelorism, synophrys, anteverted nares --- Explanation: Hypertelorism is listed among the core craniofacial features.


MONDO:0012455

[PMID:39746677] [SUPPORT] Systemic health issues included structural cardiac defects (40%), hearing loss (32%), and constipation (31%). --- Explanation: Large clinical cohort (n=65) found structural cardiac defects in 40% of individuals with Kleefstra syndrome.


MONDO:0012455

[PMID:16826528] [INDIRECT EVIDENCE] [SUPPORT] haploinsufficiency for EHMT1 is causative for 9q subtelomeric deletion syndrome --- Explanation: Original identification of EHMT1 loss-of-function mutations as the cause of the 9q34 subtelomeric deletion syndrome (now Kleefstra syndrome).

[DOI:10.1038/s41467-019-12947-3] [INDIRECT EVIDENCE] [SUPPORT] these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter --- Explanation: iPSC-derived cortical neurons from KS patients show reduced H3K9me2 at the GRIN1 promoter, directly linking EHMT1 haploinsufficiency to specific gene derepression.


MONDO:0012455

[DOI:10.1038/s41467-019-12947-3] [INDIRECT EVIDENCE] [SUPPORT] Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks --- Explanation: iPSC-derived excitatory cortical neuron networks from KS patients show characteristic network dysfunction that is rescued by NMDAR antagonism.

[DOI:10.1038/s41467-019-12947-3] [INDIRECT EVIDENCE] [SUPPORT] we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs --- Explanation: Pharmacological rescue with NMDAR antagonists demonstrates that NMDAR hyperfunction is a key driver of network dysfunction in KS.


MONDO:0012455

[DOI:10.1038/s41398-022-02199-z] [INDIRECT EVIDENCE] [SUPPORT] reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC --- Explanation: Human iPSC model shows EHMT1 deficiency reduces REST protein via miRNA-mediated mechanisms, causing premature neuronal gene activation.

[DOI:10.1038/s41398-022-02199-z] [INDIRECT EVIDENCE] [SUPPORT] EHMT1 regulates NRSF/REST indirectly via repression of miRNA and leads to aberrant neuronal gene regulation and neurodevelopment timing --- Explanation: Establishes the indirect EHMT1-miRNA-REST pathway as a mechanism for altered neurodevelopmental timing in Kleefstra syndrome.


MAXO:0000930

[DOI:10.1136/jmg-2023-109702] [SUPPORT] Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression --- Explanation: High utilization of speech therapy and communication aids demonstrates centrality of speech/language intervention in KS management.


MAXO:0009101

[DOI:10.1136/jmg-2023-109702] [SUPPORT] Early access to communication aids may improve communication and quality of life --- Explanation: Evidence supports early intervention for improved communication outcomes in KS.


MAXO:0000058


MAXO:0000950


hgnc:24650

[PMID:16826528] [SUPPORT] The minimal critical region responsible for this 9q subtelomeric deletion (9q-) syndrome has been estimated to be <1 Mb and comprises the euchromatin histone methyl transferase 1 gene (EHMT1) --- Explanation: Establishes that the minimal critical deletion region includes EHMT1 and is less than 1 Mb.

[PMID:16826528] [SUPPORT] we identified two de novo mutations--a nonsense mutation and a frameshift mutation--in the EHMT1 gene in patients with a typical 9q- phenotype --- Explanation: Demonstrates that intragenic EHMT1 mutations cause the same phenotype as deletions, proving EHMT1 haploinsufficiency is causative.


hgnc:24650

[PMID:16826528] [SUPPORT] These results establish that haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome --- Explanation: Original paper proving EHMT1 intragenic mutations cause the syndrome.


hgnc:13726


MONDO:0006823

[PMID:29382506] [SUPPORT] Hypogonadism is usually not evident until early adulthood and progresses with ageing. --- Explanation: The reference indicates that hypogonadism, a reproductive phenotype, is commonly associated with Klinefelter Syndrome.

[PMID:26823086] [SUPPORT] Klinefelter's syndrome, the most common sex disorder associated with chromosomal aberrations, is characterized by a plethora of clinical features. --- Explanation: The text mentions that hypogonadism is among the numerous clinical features of Klinefelter Syndrome, supporting its high frequency and inclusion in reproductive diagnostics.

[PMID:33107323] [SUPPORT] presented with hypoglycemia due to isolated secondary adrenal insufficiency, who further had a decrease in testicular size with increased follicle-stimulating hormone level (hypergonadotropic hypogonadism) and diagnosed with Klinefelter syndrome. --- Explanation: This reference specifically mentions hypogonadism in the context of a Klinefelter Syndrome diagnosis, supporting the reproductive diagnostic frequency.


MONDO:0006823

[PMID:35948402] [PARTIAL] Although Klinefelter syndrome (KS) is common, it is rarely recognised in childhood, sometimes being identified with speech or developmental delay or incidental antenatal diagnosis... Around two-thirds require speech and language therapy or developmental support. --- Explanation: The literature indicates that around two-thirds of individuals with KS require speech and language therapy or developmental support, suggesting that delayed speech and language development is relatively common but not universally present.

[PMID:21217607] [SUPPORT] The behavioral phenotype of 47,XXY (Klinefelter syndrome) includes increased risks for developmental delays, language-based learning disabilities... --- Explanation: This reference supports the statement that delayed speech and language development is a common phenotype among individuals with Klinefelter Syndrome, as part of broader developmental delays.


MONDO:0006823

[PMID:21540567] [SUPPORT] The typical symptoms are a tall stature... --- Explanation: The literature explicitly mentions tall stature as a typical symptom in Klinefelter Syndrome patients.


MONDO:0006823

[PMID:20843200] [REFUTE] The most specific clinical features which can be observed at adult age are small testes, gynecomastia, female distribution of fat and body hair, slightly increased body length due to an increased leg length and azoospermia. --- Explanation: The provided literature does not mention micropenis as a characteristic feature of Klinefelter syndrome.

[PMID:32835378] [NO_EVIDENCE] BBS patients frequently presented with genitourinary malformations, such as cryptorchidism (5/11), short scrotum (5/8), and micropenis (5/8), but unexpectedly, with normal testis size (7/8). --- Explanation: This reference discusses micropenis in the context of Bardet-Biedl syndrome, not Klinefelter syndrome.

[PMID:38684424] [REFUTE] Subsequent examinations were conducted due to various symptoms, including delayed motor development, intellectual disability, facial dysmorphisms, forearm deformities, hip dysplasia, cryptorchidism, micropenis, primary hypogonadism, and essential tremor --- Explanation: While this case mentions micropenis, it is associated with the 49,XXXYY karyotype, not the typical 47,XXY Klinefelter syndrome.


MONDO:0006823

[PMID:20573461] [SUPPORT] A high rate of Attention Deficit/Hyperactivity Disorder (ADHD)-like characteristics has been reported in a wide variety of disorders including syndromes with known genetic causes... and Klinefelter Syndrome. --- Explanation: The literature indicates that ADHD-like characteristics are indeed more common in individuals with Klinefelter Syndrome, supporting the statement.

[PMID:34431088] [SUPPORT] X chromosome excess was associated with weakness in working memory (p=0.018) and approached significance for attention problems (p=0.071)... --- Explanation: This study found an association between X chromosome excess (as seen in Klinefelter Syndrome) and attention problems, supporting the statement that ADD/ADHD is more common in this population.


MONDO:0006823


MAXO:0000283

[PMID:35421871] [SUPPORT] Patients presenting with symptoms should be tested for low testosterone and treated with testosterone replacement. ... Patients treated for hypogonadism may experience improvement of symptoms and quality of life. --- Explanation: This reference indicates that testosterone replacement therapy can improve symptoms associated with hypogonadism, such as low energy and reduced muscle mass.

[PMID:26732150] [SUPPORT] The mainstay of medical treatment is testosterone replacement therapy to both attenuate acute and long-term consequences of hypogonadism and possibly prevent the frequent comorbidity. --- Explanation: This abstract highlights testosterone replacement therapy as a primary treatment for hypogonadism in Klinefelter Syndrome, addressing its symptoms.

[PMID:24142635] [SUPPORT] Testosterone replacement therapy may be effective in treating BMD deficiency in men with testosterone deficiency, especially those with Klinefelter syndrome. --- Explanation: The study indicates the efficacy of testosterone replacement therapy in treating symptoms related to testosterone deficiency in Klinefelter syndrome, which implies improvements in overall physical health including muscle mass.

[PMID:38677872] [PARTIAL] Patients unable to produce sex steroids using gonadotropins to mimic minipuberty in hypogonadotropic hypogonadism, or sex steroids in patients with Klinefelter or Turner syndrome, is promising. --- Explanation: This abstract discusses the potential of sex steroid treatments, including testosterone, but emphasizes the need for further research particularly in infants and early childhood.

[PMID:37962976] [SUPPORT] TRT in patients with KS has the potential for alleviating the prothrombotic phenotype, in particular by reducing body fat and fibrinogen. --- Explanation: Testosterone replacement therapy has positive effects on symptoms related to body composition, which can be correlated to improvements in muscle mass and energy levels.


MAXO:0000930

[PMID:25899809] [SUPPORT] Boys with Klinefelter syndrome are often in the need of speech therapy and many suffer from learning disability and may benefit from special education. --- Explanation: This article directly indicates the need for speech therapy and special education for boys with Klinefelter syndrome.

[PMID:35948402] [SUPPORT] Around two-thirds require speech and language therapy or developmental support and early institution of therapy is important. --- Explanation: This article supports the statement by mentioning the necessity of speech and language therapy or developmental support.


MAXO:0000004

[PMID:35667865] [SUPPORT] Assisted reproductive technology is essential for infertility treatment in patients with Klinefelter syndrome. --- Explanation: This reference explicitly states the role of assisted reproductive technology in treating infertility in patients with Klinefelter syndrome.

[PMID:19490778] [SUPPORT] In conclusion, patients with non-mosaic Klinefelter syndrome have sperm recovery and pregnancy rates comparable with patients having non-obstructive azoospermia and normal karyotype. --- Explanation: This study indicates that patients with Klinefelter syndrome can achieve successful sperm recovery and pregnancy rates using TESE-ICSI, a type of assisted reproductive technology.

[PMID:21835671] [SUPPORT] In this review, we will discuss the fertility issue following TEsticular Sperm Extraction-IntraCytoplasmic Sperm Injection (TESE-ICSI) and the potential advantage of searching for and cryopreserving spermatozoa in adolescent instead of adult patients. --- Explanation: This reference discusses the advantages of using TESE-ICSI (a form of assisted reproductive technology) to address fertility issues in patients with Klinefelter syndrome.

[PMID:31587581] [SUPPORT] Once considered untreatable, men with KS and NOA now have a variety of treatment options to obtain paternity. --- Explanation: This reference highlights that men with Klinefelter syndrome now have several treatment options, including assisted reproductive technologies, to achieve paternity.

[PMID:32562095] [SUPPORT] Mounting evidence from recent studies has shown that various technological advances and approaches could facilitate the success of ART treatment for KS patients. --- Explanation: This review summarizes methods that enhance the success of assisted reproductive technology (ART) for patients with Klinefelter syndrome.


MAXO:0000077


HGNC.SYMBOL:47,XXY Karyotype

[PMID:34375016] [SUPPORT] Patients with Klinefelter syndrome (KS) show a typically 47,XXY karyotype; however, some variations have been observed, including 47,XX,der(Y), 46,XY/47,XXY, 48,XXXY, 48,XXYY, and mosaicism or structural sex chromosome abnormalities in some patients. --- Explanation: The study discusses that Klinefelter syndrome typically exhibits a 47,XXY karyotype.

[PMID:9160389] [SUPPORT] Cytogenetic surveys of neonates have found that approximately one boy in 500 is born with an extra sex chromosome. ... This study estimates what proportion of those not detected prenatally will be diagnosed postnatally and what the indications for karyotyping are likely to be. --- Explanation: The study indicates that Klinefelter syndrome is associated with an extra sex chromosome, typically 47,XXY.

[PMID:31630146] [SUPPORT] Klinefelter syndrome (KS) is one of the most common congenital disorders of male infertility. Given its high heterogeneity in clinical and genetic presentation, the relationship between transcriptome, clinical phenotype, and associated co-morbidities seen in KS has not been fully clarified. --- Explanation: This study identifies Klinefelter syndrome as a congenital disorder related to the 47,XXY karyotype.

[PMID:37054629] [SUPPORT] Klinefelter syndrome is the most frequently found aneuploidy among male patients. Its clinical presentation is very heterogeneous, and thus poses a challenge for a timely diagnosis. --- Explanation: The study confirms that Klinefelter syndrome is an aneuploidy condition predominantly associated with the 47,XXY karyotype.


HGNC.SYMBOL:KDM6A


HGNC.SYMBOL:SHOX


HGNC.SYMBOL:TLR7


HGNC.SYMBOL:AR


HGNC.SYMBOL:INSL3


HGNC.SYMBOL:Mosaicism (46,XY/47,XXY)

[PMID:1176138] [SUPPORT] The percentage with mosaicism was 36 in both triple-X and Turner's syndrome, it was 7 and 11% in XYY and Klinefelter's syndrome, respectively... --- Explanation: The reference discusses the occurrence of mosaicism in Klinefelter syndrome with a frequency of 11%, supporting that mosaicism is occasionally present in Klinefelter Syndrome.

[PMID:3490207] [SUPPORT] 46,XY/47,XXY mosaicism is not uncommon. However, mosaicism of multiple sex chromosome aneuploidy is rarely observed. --- Explanation: This case report shows that 46,XY/47,XXY mosaicism is not uncommon in Klinefelter's syndrome, supporting the statement.

[PMID:5720649] [SUPPORT] Chromosomal mosaicism in two emotionally disturbed adolescents with Klinefelter's syndrome (46,XY-47,XXY and 46,XY-47,XYY-48,XXYY). --- Explanation: The study mentions cases of mosaicism in Klinefelter's syndrome, providing support to the statement.


MONDO:0007987

[PMID:41378240] [SUPPORT] She also showed markedly short stature (-4.37 SD), cleft palate, cataract, retinal detachment, and serous otitis media. --- Explanation: Documents severe short stature at -4.37 SD in an adult patient with molecularly confirmed Kniest dysplasia.


MONDO:0007987

[PMID:25592122] [SUPPORT] Kniest dysplasia is an inherited disorder associated with defects in type II collagen and characterised by short-trunked dwarfism, kyphoscoliosis, and enlarged joints with restricted mobility. --- Explanation: Describes enlarged joints with restricted mobility as a characteristic feature of Kniest dysplasia.


MONDO:0007987

[PMID:8484485] [SUPPORT] In this syndrome there is a disproportionate dwarfism with kyphoscoliosis, stiffness of the joints, minor facial dysmorphia, myopia and both conductive and sensorineural deafness in 50 percent of patients. --- Explanation: Describes joint stiffness as a defining feature of Kniest syndrome.


MONDO:0007987

[PMID:41378240] [SUPPORT] Radiographic analyses revealed epiphyseal enlargement of the longitudinal bones, kyphoscoliosis, and flat vertebrae in the thoracolumbar spine. --- Explanation: Radiographic documentation of epiphyseal enlargement as a feature of Kniest dysplasia.


MONDO:0007987

[PMID:8723084] [SUPPORT] Radiological findings in a severe case include short bowed tubular bones with exaggerated metaphyseal flare --- Explanation: Documents the characteristic radiological finding of exaggerated metaphyseal flare contributing to the dumbbell-shaped appearance.

[PMID:40475174] [SUPPORT] Typical radiological findings include platyspondyly, coronal clefts, and dumbbell-shaped long tubular bones. --- Explanation: Confirms dumbbell-shaped long bones as a typical radiological finding in Kniest dysplasia.


MONDO:0007987

[PMID:41378240] [SUPPORT] It can be diagnosed in early childhood based on the clinical findings of short stature, splayed epiphysis, narrowed joint spaces and platyspondyly associated with maxillofacial, ophthalmological, and otolaryngological complications. --- Explanation: Lists platyspondyly as a diagnostic criterion for Kniest dysplasia.


MONDO:0007987

[PMID:40475174] [SUPPORT] Typical radiological findings include platyspondyly, coronal clefts, and dumbbell-shaped long tubular bones. --- Explanation: Lists coronal clefts as a typical radiological finding of Kniest dysplasia.

[PMID:8723084] [SUPPORT] moderate platyspondyly with vertical clefts of the vertebral bodies --- Explanation: Documents vertebral clefts as a radiological feature in severe neonatal Kniest dysplasia.


MONDO:0007987

[PMID:25592122] [SUPPORT] Kniest dysplasia is an inherited disorder associated with defects in type II collagen and characterised by short-trunked dwarfism, kyphoscoliosis, and enlarged joints with restricted mobility. --- Explanation: Lists kyphoscoliosis as a characteristic feature of Kniest dysplasia.

[PMID:41378240] [SUPPORT] Radiographic analyses revealed epiphyseal enlargement of the longitudinal bones, kyphoscoliosis, and flat vertebrae in the thoracolumbar spine. --- Explanation: Radiographic confirmation of kyphoscoliosis in an adult patient with Kniest dysplasia.


MONDO:0007987

[PMID:25604898] [SUPPORT] Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. --- Explanation: Documents high rate of hip-related orthopedic surgery in a mixed SEDC/Kniest/related COL2A1 cohort (7/93 had Kniest dysplasia).


MONDO:0007987

[PMID:25604898] [SUPPORT] Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available --- Explanation: Quantifies the frequency of odontoid hypoplasia and atlanto-axial instability in a large COL2A1 skeletal dysplasia cohort.


MONDO:0007987


MONDO:0007987

[PMID:25592122] [SUPPORT] five of the seven patients exhibited clefting abnormalities --- Explanation: Quantifies cleft palate frequency at 5/7 in molecularly confirmed Kniest dysplasia cases.

[PMID:7700721] [SUPPORT] a severe autosomal dominant form of chondrodysplastic dwarfism associated with cleft palate, progressive arthropathy, myopia and retinal detachment --- Explanation: Lists cleft palate as a defining feature of Kniest dysplasia.


MONDO:0007987

[PMID:25592122] [SUPPORT] Six of the seven patients tested were high myopes with one patient being an emmetrope. --- Explanation: Documents that 6/7 patients with molecularly confirmed Kniest dysplasia had high myopia.

[PMID:25604898] [SUPPORT] Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). --- Explanation: Quantifies myopia frequency at 45% in a mixed SEDC/Kniest/related COL2A1 cohort (7/93 Kniest); ophthalmological features more frequent and severe in splicing-mutation patients.


MONDO:0007987

[PMID:25592122] [SUPPORT] Variable but abnormal vitreous architecture was observed in all seven individuals tested. --- Explanation: Documents universal vitreous abnormalities in Kniest dysplasia patients.


MONDO:0007987

[PMID:25592122] [SUPPORT] Other features include marked hand arthropathy, cleft palate, hearing loss, and ocular abnormalities (myopia, abnormal vitreous, and high risk of developing retinal detachment). --- Explanation: Lists high risk of retinal detachment as a recognized ocular complication.

[PMID:25604898] [SUPPORT] retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). --- Explanation: Quantifies retinal detachment rate at 12% in a mixed SEDC/Kniest/related COL2A1 cohort (7/93 Kniest), with earliest occurrence at age 3.5 years.


MONDO:0007987

[PMID:25592122] [SUPPORT] Six of the seven patients had significant hearing impairment --- Explanation: Documents that 6/7 patients with molecularly confirmed Kniest dysplasia had significant hearing impairment.

[PMID:8484485] [SUPPORT] both conductive and sensorineural deafness in 50 percent of patients --- Explanation: Documents mixed conductive and sensorineural hearing loss in Kniest syndrome, occurring in approximately 50% of patients.

[PMID:25604898] [SUPPORT] Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. --- Explanation: Quantifies hearing loss at 37% in a mixed SEDC/Kniest/related COL2A1 cohort (7/93 Kniest), with over half requiring hearing aids.


MONDO:0007987

[PMID:8723084] [INDIRECT EVIDENCE] [SUPPORT] Pathologic findings included a disorganized physeal growth plate, soft crumbly cartilage with a "Swiss-cheese" appearance, and diastase resistant intracytoplasmic inclusions in the resting chondrocytes. Transmission electronmicroscopy showed dilated cisternae of rough endoplasmic reticulum with finely granular material of accumulated protein. Scanning electronmicroscopy documented striking fragmentation and disintegration of collagen fibrils resulting in a web-like pattern and large open cyst-like spaces, and deficiency and disorganization of the collagen fibrils. --- Explanation: Documents Swiss-cheese cartilage appearance, dilated ER with accumulated protein, and collagen fibril fragmentation in Kniest dysplasia tissue.

[PMID:3276736] [INDIRECT EVIDENCE] [SUPPORT] In each case collagen fibril organization appeared abnormal by electron microscopy compared with age-matched normal cartilages: fibrils were much thinner, of irregular shape and did not exhibit the characteristic banding pattern. This was associated with the absence (compared with normal cartilage) of the C-propeptide of type II collagen (chondrocalcin) from the extracellular matrix of epiphyseal cartilages. --- Explanation: Demonstrates abnormal collagen fibril organization with thinner fibrils lacking normal banding, and absence of C-propeptide from extracellular matrix, establishing the link between C-propeptide processing defect and imperfect fibril assembly.


MONDO:0007987

[PMID:24475193] [INDIRECT EVIDENCE] [SUPPORT] Misfolded procollagen was largely synthesized and retained in dilated endoplasmic reticulum and the endoplasmic reticulum stress (ERS)-unfolded protein response (UPR)-apoptosis cascade was activated. --- Explanation: Demonstrates ER retention of misfolded procollagen and UPR activation in a Col2a1 mutant mouse model.

[PMID:8723084] [INDIRECT EVIDENCE] [SUPPORT] Transmission electronmicroscopy showed dilated cisternae of rough endoplasmic reticulum with finely granular material of accumulated protein. --- Explanation: Electron microscopy of human Kniest dysplasia cartilage confirms dilated ER cisternae with accumulated protein.


MONDO:0007987

[PMID:24475193] [INDIRECT EVIDENCE] [SUPPORT] Apoptosis occurred prior to hypertrophy, prevented the formation of a hypertrophic zone, disrupted normal chondrogenic signaling pathways, and eventually caused chondrodysplasia. --- Explanation: Demonstrates that premature chondrocyte apoptosis prevents hypertrophic zone formation and causes chondrodysplasia in a Col2a1 mutant mouse.


MONDO:0007987

[PMID:514691] [INDIRECT EVIDENCE] [SUPPORT] there appears to be a sequence of events initiated by cellular accumulation of a substance and progressing to cellular and matrix degeneration. --- Explanation: Histochemical study of four Kniest dysplasia patients documenting extensive vacuolar changes in the growth plate, establishing the sequence from cellular accumulation to matrix degeneration.

[PMID:8723084] [INDIRECT EVIDENCE] [SUPPORT] Pathologic findings included a disorganized physeal growth plate, soft crumbly cartilage with a "Swiss-cheese" appearance, and diastase resistant intracytoplasmic inclusions in the resting chondrocytes. --- Explanation: Confirms the disorganized growth plate as a pathologic hallmark of Kniest dysplasia.


MAXO:0000004

[PMID:25604898] [SUPPORT] Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. --- Explanation: Documents high surgical rate and common procedures in a mixed SEDC/Kniest/related COL2A1 cohort (7/93 Kniest).


MAXO:0000703

[PMID:25592122] [SUPPORT] It is likely that different type II collagenopathies have a similar level of ocular morbidity and regular ophthalmologic examination is recommended. --- Explanation: Recommends regular ophthalmologic examination for all type II collagenopathy patients including Kniest dysplasia.


MAXO:0009030

[PMID:25604898] [SUPPORT] Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. --- Explanation: Quantifies need for hearing aids in a mixed SEDC/Kniest/related COL2A1 cohort (7/93 Kniest), supporting audiologic management.


MAXO:0000004


MAXO:0035085

[PMID:25604898] [SUPPORT] Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. --- Explanation: Documents atlanto-axial instability in 28% of imaged COL2A1 patients, supporting the need for cervical spine monitoring.


HGNC.SYMBOL:COL2A1 Mutations

[PMID:7981752] [SUPPORT] We studied a 2-year-old girl presenting with manifestations of Kniest dysplasia and her mother showing a Stickler phenotype. Analysing COL2A1 in both patients, we detected the same 28 basepair deletion spanning the 3'-exon/intron boundary of exon 12 in mother and daughter. --- Explanation: Identifies a 28bp deletion at the exon 12 splice boundary in COL2A1 causing Kniest dysplasia, establishing that exon-boundary mutations leading to exon skipping cause the disorder.

[PMID:25592122] [SUPPORT] Six dominant disease-causing COL2A1 variants were detected. In three cases, testing of parental samples revealed that the disease-causing variant was not present in either parent. --- Explanation: Confirms that Kniest dysplasia is caused by heterozygous COL2A1 mutations that are frequently de novo.

[PMID:41378240] [SUPPORT] Missense mutations and small deletions owing to exon skipping in the triple-helical region of COL2A1 have been reported in most cases of Kniest dysplasia. --- Explanation: Confirms that the predominant mutation types in Kniest dysplasia are missense mutations and small in-frame deletions from exon skipping in the triple-helical domain.

[PMID:7700721] [SUPPORT] Heterozygous mutations of the gene coding for type II collagen can cause Kniest dysplasia, and somatic mosaicism for the same mutations can result in the Stickler phenotype or in mild spondyloepiphyseal dysplasia leading to premature polyarthrosis. --- Explanation: Demonstrates that identical COL2A1 mutations cause Kniest dysplasia when constitutive and milder collagenopathies when present in somatic mosaic form.

[PMID:26626311] [SUPPORT] Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. --- Explanation: Demonstrates that 86% of COL2A1 variants in skeletal dysplasia patients are in the triple-helical domain, and that glycine substitutions correlate with severe phenotypes including Kniest dysplasia.


MONDO:0014704

[PMID:35221873] [SUPPORT] enlargement of the hands/feet, and progressive scoliosis started to appear after an average age of 6. --- Explanation: Overgrowth is a defining feature of KOGS.


MONDO:0014704

[PMID:35221873] [SUPPORT] enlargement of the hands/feet, and progressive scoliosis started to appear after an average age of 6. --- Explanation: Progressive scoliosis is a key feature of KOGS.


MONDO:0014704

[PMID:35221873] [SUPPORT] The coarsening of the facial features, enlargement of the hands/feet, and progressive scoliosis started to appear after an average age of 6. --- Explanation: Coarsening of facial features is a defining feature of KOGS.


MONDO:0014704

[PMID:34738614] [SUPPORT] Autosomal dominant PDGFRβ gain-of-function mutations in mice and humans cause a spectrum of wasting and overgrowth disorders afflicting the skeleton and other connective tissues --- Explanation: Skeletal manifestations are a core feature of PDGFRB gain-of-function disorders.


MAXO:0000058

[PMID:26455322] [SUPPORT] Importantly, all activated mutants were sensitive to tyrosine kinase inhibitors such as imatinib, nilotinib and ponatinib. --- Explanation: In vitro evidence of sensitivity to imatinib.

[PMID:32500973] [SUPPORT] Three patients were treated with imatinib and had robust and rapid response --- Explanation: Clinical evidence of imatinib efficacy in PDGFRB spectrum disorders.


hgnc:8804

[PMID:26455322] [SUPPORT] the germline mutant identified in overgrowth syndrome, P584R, was a stronger oncogene than the germline R561C mutant associated with myofibromatosis. --- Explanation: Functional characterization shows P584R is a potent activating variant.

[PMID:35221873] [SUPPORT] Heterozygous activating missense variants of PDGFRB are associated with the phenotype of Kosaki overgrowth syndrome (KOGS). --- Explanation: Confirms activating PDGFRB variants cause KOGS.


MONDO:0014704


MONDO:0009499

[PMID:32912261] [SUPPORT] The different forms of the disease were characterized by different MRI patterns (infantile: diffuse white matter involvement and cerebellar structures specifically affected, later onset: parieto-occipital white matter and splenium affected, adult: motor tracts specifically affected).
 --- Explanation: This natural history study directly documents characteristic white-matter MRI abnormalities across Krabbe disease forms, supporting leukodystrophy as an observed phenotype.


MONDO:0009499

[PMID:32912261] [SUPPORT] Developmental and disease trajectories were described based on the acquisition and loss of milestones as well as the time of first clearly identifiable symptoms and needs such as spasticity, seizures and tube feeding.
 --- Explanation: This natural history study directly identifies spasticity as a tracked neurological manifestation in Krabbe disease, providing more specific support than generic motor-delay language.


MONDO:0009499

[PMID:36113749] [SUPPORT] Functional deficiency of GALC is toxic to myelin-producing cells, which leads to progressive demyelination in both the central and peripheral nervous systems.
 --- Explanation: Confirms peripheral nervous system demyelination as a feature of Krabbe disease due to toxicity to Schwann cells, the myelin-producing cells of the PNS.


MONDO:0009499

[PMID:32912261] [SUPPORT] Irritability, abnormalities in movement pattern as well as general developmental regression were the first symptoms in the infantile group
 --- Explanation: This natural history study directly identifies irritability as one of the first symptoms in infantile Krabbe disease.


MONDO:0009499

[PMID:10992329] [SUPPORT] Most of the children with infantile disease presented with neurodegeneration, seizures or fever
 --- Explanation: Clinical series of nine children with enzymatically confirmed Krabbe disease documents seizures as a presenting feature in infantile KD.


MONDO:0009499

[PMID:32912261] [SUPPORT] Irritability, abnormalities in movement pattern as well as general developmental regression were the first symptoms in the infantile group
 --- Explanation: Nationwide German natural history study of 38 Krabbe patients documents developmental regression as a frequent first symptom in infantile KD.


MONDO:0009499


MONDO:0009499

[PMID:32912261] [SUPPORT] Irritability, abnormalities in movement pattern as well as general developmental regression were the first symptoms in the infantile group; disease course was severe with rapid progression, e.g. loss of visual fixation, need for tube feeding and then an early death.
 --- Explanation: This natural history study supports clinically significant feeding dysfunction in infantile Krabbe disease through the frequent need for tube feeding during rapid progression.


MONDO:0009499

[PMID:31527255] [INDIRECT EVIDENCE] [SUPPORT] Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine).
 --- Explanation: Confirms GALC deficiency as the initiating enzymatic defect in Krabbe disease.


MONDO:0009499

[PMID:31527255] [INDIRECT EVIDENCE] [SUPPORT] Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine).
 --- Explanation: Confirms psychosine accumulation as the key toxic storage abnormality in Krabbe disease.

[PMID:31527255] [INDIRECT EVIDENCE] [SUPPORT] psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase)
 --- Explanation: Demonstrates the catabolic pathway of psychosine generation via acid ceramidase, clarifying the mechanism of psychosine synthesis.


MONDO:0009499

[PMID:7354254] [INDIRECT EVIDENCE] [SUPPORT] The concentration of psychosine will steadily increase and reach toxic levels and kill the oligodendroglial cells. This results in an arrest of the galactosylceramide biosynthesis.
 --- Explanation: This seminal paper directly supports oligodendroglial toxicity from psychosine accumulation.


MONDO:0009499

[PMID:36113749] [INDIRECT EVIDENCE] [SUPPORT] Functional deficiency of GALC is toxic to myelin-producing cells, which leads to progressive demyelination in both the central and peripheral nervous systems.
 --- Explanation: Neuropathological study of human Krabbe disease brains confirming progressive demyelination in CNS and PNS due to GALC deficiency.


MONDO:0009499

[PMID:36113749] [INDIRECT EVIDENCE] [SUPPORT] an early-infantile case (age of death at 10 months) had about 3-fold increases in both globoid cells, a pathological hallmark for KD
 --- Explanation: Quantifies the presence of globoid cells as a hallmark neuropathologic lesion in Krabbe disease.


MONDO:0009499

[PMID:37048066] [INDIRECT EVIDENCE] [SUPPORT] The astrocytes and microglia reactivity were attenuated in that reactive astrocytes, ameboid microglia, and globoid cells were reduced in the brains of rapamycin-treated twitcher mice
 --- Explanation: Demonstrates robust astrocyte and microglial reactivity in twitcher mouse brains, supporting a distinct glial-reactivity node.


MONDO:0009499

[PMID:36519759] [INDIRECT EVIDENCE] [SUPPORT] the expression of pro-inflammatory non-canonical caspase-11, canonical caspase-1, gasdermin D and cognate genes is induced in nervous tissue
 --- Explanation: Establishes that inflammasome-associated genes including caspase-11, caspase-1, and gasdermin D are progressively induced in twitcher mouse nervous tissue, identifying a new pathogenic mechanism in Krabbe disease.

[PMID:36519759] [INDIRECT EVIDENCE] [SUPPORT] Caspase-11 is found in reactive microglia/macrophages as well as astrocytes but caspase-1 and gasdermin D are restricted to reactive microglia/macrophages
 --- Explanation: Defines cell-type-specific expression patterns of inflammasome components in Krabbe disease nervous tissue.


MONDO:0009499

[PMID:37048066] [INDIRECT EVIDENCE] [SUPPORT] psychosine causes dysfunction of autophagy and the ubiquitin-proteasome system underlying the pathogenesis of globoid cell leukodystrophy (GLD), a devastating lysosomal storage disease complicated by global demyelination
 --- Explanation: Establishes that psychosine-driven proteostasis failure through autophagy and UPS dysfunction is a key pathogenic mechanism in globoid cell leukodystrophy.

[PMID:37048066] [INDIRECT EVIDENCE] [SUPPORT] significantly reduced the accumulation of insoluble ubiquitinated protein and the formation of ubiquitin aggregates
 --- Explanation: Demonstrates that mTOR inhibition with rapamycin can reduce protein aggregate burden in twitcher mouse brains, validating proteostasis failure as a tractable therapeutic target.


MAXO:0000747

[PMID:15901860] [SUPPORT] Infants who underwent transplantation before the development of symptoms showed progressive central myelination and continued gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills
 --- Explanation: Landmark NEJM study demonstrating that presymptomatic cord blood transplantation favorably alters disease course in infantile Krabbe disease with continued myelination and developmental gains.

[PMID:15901860] [SUPPORT] Children who underwent transplantation after the onset of symptoms had minimal neurologic improvement.
 --- Explanation: Demonstrates that HSCT after symptom onset has minimal benefit, underscoring the critical importance of early/presymptomatic treatment.


MAXO:0001001

[PMID:37628569] [SUPPORT] elevated levels of psychosine were completely normalized in the forebrain region of the treated mice
 --- Explanation: AAV1-GALC gene therapy delivered via intracerebroventricular injection normalized psychosine in the forebrain and extended median lifespan from 43 to 78 days in the twitcher mouse model.

[PMID:37628569] [SUPPORT] The median lifespan was extended from 43 days to 78 days (range: 74-88 days) in the AAV1-GALC-treated group
 --- Explanation: Demonstrates significant survival extension with CNS-directed AAV1-GALC gene therapy in the twitcher mouse model.


MAXO:0000950


HGNC.SYMBOL:GALC

[PMID:8634707] [SUPPORT] the deletion is approximately 30 kb starting near the middle of the 12 kb intron 10, and includes all of the coding region through exon 17 plus an additional 9 kb
 --- Explanation: Characterizes the large ~30 kb deletion in the GALC gene, one of the most common mutations causing infantile Krabbe disease.

[PMID:7581365] [SUPPORT] a large deletion, together with a polymorphic C to T transition at position 502 of cDNA (counting from the A of the initiation codon), is responsible for a large number of disease-causing alleles in patients with Krabbe disease
 --- Explanation: Demonstrates that the large deletion plus 502C>T polymorphism is a common mutant allele in infantile Krabbe disease, found in homozygous or heterozygous state in the majority of patients tested.

[PMID:36113749] [SUPPORT] Krabbe Disease (KD) is an autosomal recessive disorder that results from loss-of-function mutations in the GALC gene, which encodes lysosomal enzyme galactosylceramidase (GALC).
 --- Explanation: Confirms autosomal recessive inheritance and GALC loss-of-function as the genetic basis of Krabbe disease.


MONDO:0003940

[PMID:28913640] [SUPPORT] This entity is characterised by the gradual development in time of a vertebral body collapse following a trivial spinal trauma, involving a worsening back pain associated with a progressive kyphosis. --- Explanation: Case report describing the characteristic delayed-onset worsening back pain of Kummell disease.


MONDO:0003940

[PMID:28913640] [SUPPORT] the radiological exams showed a constant worsening of the thoracic-lumbar kyphosis and a restriction of the spinal canal --- Explanation: Case report demonstrating progressive kyphosis as a cardinal feature of Kummell disease.


MONDO:0003940

[PMID:26806962] [SUPPORT] It is distinguished from typical osteoporotic fractures because the symptoms develop in a delayed fashion. --- Explanation: Key distinguishing feature of Kummell disease versus typical osteoporotic compression fractures is the delayed symptom development.

[PMID:36245398] [PARTIAL] We confirmed that the OVF was not the first step in the KD sequence, and the IVC - KD - could from an initial MRI-negative spine trauma. --- Explanation: Case report demonstrating that the initial trauma in Kummell disease may be MRI-negative, with delayed development of vertebral collapse.


MONDO:0003940

[PMID:28913640] [PARTIAL] A year after the injury, motor deficits concerning the lower limbs appeared. --- Explanation: Case demonstrating delayed-onset neurological deficits (lower limb motor deficits) developing one year after the initial injury in Kummell disease.

[PMID:29803679] [SUPPORT] A total of 10 publications involving 268 Kümmell's disease patients with neurological deficits were included in this review --- Explanation: Systematic review of 268 Kummell disease patients with neurological deficits confirms this is a recognized complication.


MONDO:0003940

[PMID:28913640] [INDIRECT EVIDENCE] [SUPPORT] Kummell's disease is an avascular necrosis of the vertebral body, secondary to a vertebral compression fracture. This entity is characterised by the gradual development in time of a vertebral body collapse following a trivial spinal trauma, involving a worsening back pain associated with a progressive kyphosis. --- Explanation: This case report and literature review defines the core pathophysiology of Kummell disease as avascular necrosis of the vertebral body secondary to compression fracture.

[PMID:26806962] [INDIRECT EVIDENCE] [SUPPORT] Intraoperative biopsies from all cases confirms bone necrosis. --- Explanation: Histopathological confirmation of bone necrosis in all Kummell disease cases undergoing surgical treatment validates the avascular necrosis mechanism.


MONDO:0003940


MONDO:0003940

[PMID:37353769] [INDIRECT EVIDENCE] [SUPPORT] In patients with osteoporosis, the incidence of vertebral Kummell's disease can be associated with the morphological characteristics of the basivertebral foramen, as observed in the CT scan. Furthermore, the vertebral body with trapezoidal-shaped and irregular-shaped basivertebral foramen and boneless septum in the foramen is highly susceptible to Kummell's disease. --- Explanation: CT imaging study demonstrates that basivertebral foramen morphology is a risk factor for Kummell disease, supporting the microcirculation compromise mechanism.


MONDO:0003940

[PMID:36428981] [INDIRECT EVIDENCE] [PARTIAL] HIF-1α/RANKL/Notch1 pathway bidirectionally regulates the differentiation of macrophages into osteoclasts under different conditions. In addition, HIF-1α is also regulated by many factors, including hypoxia, cofactor activity, non-coding RNA, trace elements, etc. As a pivotal pathway for coupling angiogenesis and osteogenesis, HIF-1α has been widely studied in bone metabolic diseases such as bone defect, osteoporosis, osteonecrosis of the femoral head, fracture, and nonunion. --- Explanation: Narrative review summarizing HIF-1alpha signaling across osteonecrosis and nonunion states, providing mechanistic context for the hypoxic stress response in Kummell disease.


MONDO:0003940

[PMID:40065254] [INDIRECT EVIDENCE] [SUPPORT] The levels of IL-1, IL-6 and TNF-α in the vertebral blood of KD patients were significantly increased, which can promote vertebral osteonecrosis and bone nonunion in KD patients. --- Explanation: Direct measurement of vertebral blood in KD patients shows a pro-inflammatory, pro-resorptive microenvironment that promotes osteonecrosis and nonunion.


MONDO:0003940

[PMID:29803679] [INDIRECT EVIDENCE] [SUPPORT] Kümmell's disease, first described by Dr Hermann Kümmell in 1891, is defined as avascular osteonecrosis and occurs after delayed posttraumatic vertebral collapse, mostly in an osteoporotic spine. --- Explanation: Systematic review establishing the progressive collapse nature of the disease, with delayed posttraumatic vertebral collapse in osteoporotic bone.


MAXO:0000477

[PMID:26806962] [SUPPORT] PVP is a faster, less expensive option that still provides a comparable pain relief and restoration of vertebral height to PKP for the treatment of Kümmell's disease. --- Explanation: Retrospective study of 73 patients comparing PVP and PKP, showing both are effective for Kummell disease with comparable pain relief and height restoration.

[PMID:34213873] [SUPPORT] RC-PVP, with the destruction of IVC, may lead to better clinical outcomes with fewer complications. --- Explanation: Prospective study showing that rotary cutter vertebroplasty that destroys the IVC structure yields better clinical outcomes with fewer complications than conventional PVP.


MAXO:0000477

[PMID:26806962] [INDIRECT EVIDENCE] [SUPPORT] PVP is a faster, less expensive option that still provides a comparable pain relief and restoration of vertebral height to PKP for the treatment of Kümmell's disease. --- Explanation: Retrospective study of 73 patients comparing PVP and PKP, showing both are effective for Kummell disease with comparable pain relief and height restoration.

[PMID:34213873] [INDIRECT EVIDENCE] [SUPPORT] RC-PVP, with the destruction of IVC, may lead to better clinical outcomes with fewer complications. --- Explanation: Prospective study showing that rotary cutter vertebroplasty that destroys the IVC structure yields better clinical outcomes with fewer complications than conventional PVP.


MAXO:0000477


MAXO:0000477

[PMID:26806962] [SUPPORT] PKP has a significant advantage over PVP in term of the fewer cement leakages. --- Explanation: Study showing PKP has significantly fewer cement leakages (8.6%) compared to PVP (26.3%) in Kummell disease treatment.

[PMID:35051635] [SUPPORT] PKP was an effective method for treating Kummell disease. At the same time, the relationship between the distribution of bone cement and the cleft in the vertebral body was an important factor affecting the curative effect after PKP. --- Explanation: Study of 92 Kummell disease patients showing that cement distribution relative to the cleft is a key determinant of PKP efficacy, with diffuse distribution around the cleft yielding better outcomes.

[PMID:41552306] [SUPPORT] PKP is safe and effective for stage III Kümmell's disease with or without posterior wall integrity. However, having intact posterior walls is better for maintaining vertebral height in long-term. --- Explanation: Study of 79 patients demonstrating PKP safety and efficacy for stage III KD, extending the indication beyond stage I-II.


MAXO:0000477

[PMID:26806962] [INDIRECT EVIDENCE] [SUPPORT] PKP has a significant advantage over PVP in term of the fewer cement leakages. --- Explanation: Study showing PKP has significantly fewer cement leakages (8.6%) compared to PVP (26.3%) in Kummell disease treatment.

[PMID:35051635] [INDIRECT EVIDENCE] [SUPPORT] PKP was an effective method for treating Kummell disease. At the same time, the relationship between the distribution of bone cement and the cleft in the vertebral body was an important factor affecting the curative effect after PKP. --- Explanation: Study of 92 Kummell disease patients showing that cement distribution relative to the cleft is a key determinant of PKP efficacy, with diffuse distribution around the cleft yielding better outcomes.

[PMID:41552306] [INDIRECT EVIDENCE] [SUPPORT] PKP is safe and effective for stage III Kümmell's disease with or without posterior wall integrity. However, having intact posterior walls is better for maintaining vertebral height in long-term. --- Explanation: Study of 79 patients demonstrating PKP safety and efficacy for stage III KD, extending the indication beyond stage I-II.


MAXO:0000950


MAXO:0000477

[PMID:29803679] [SUPPORT] This systematic review demonstrated that both AR and PO could improve pain, neurological dysfunction and imaging outcomes. However, serious comorbidities, multilevel corpectomies and/or severe osteoporosis highly required PO. --- Explanation: Systematic review of 268 patients showing that posterior osteotomy is preferred for patients with comorbidities and severe osteoporosis, which are common in Kummell disease.

[PMID:28913640] [PARTIAL] He was then sent to us and indication for posterior internal fixation was given. --- Explanation: Case of delayed-onset myelopathy in Kummell disease successfully treated with posterior internal fixation.


MAXO:0000477

[PMID:29803679] [INDIRECT EVIDENCE] [SUPPORT] This systematic review demonstrated that both AR and PO could improve pain, neurological dysfunction and imaging outcomes. However, serious comorbidities, multilevel corpectomies and/or severe osteoporosis highly required PO. --- Explanation: Systematic review of 268 patients showing that posterior osteotomy is preferred for patients with comorbidities and severe osteoporosis, which are common in Kummell disease.

[PMID:28913640] [INDIRECT EVIDENCE] [PARTIAL] He was then sent to us and indication for posterior internal fixation was given. --- Explanation: Case of delayed-onset myelopathy in Kummell disease successfully treated with posterior internal fixation.


MONDO:0009370

[PMID:37113859] [SUPPORT] L-2-hydroxyglutaric aciduria (L2HGA) is an autosomal recessive, slowly progressive neurodegenerative disease characterized by psychomotor delay and cerebellar dysfunction. --- Explanation: Psychomotor delay leading to intellectual disability is a defining feature of L2HGA.

[PMID:37275239] [SUPPORT] The most common clinical symptoms were developmental delay, intellectual disability, and movement disorders. --- Explanation: Confirms intellectual disability as one of the most common symptoms in a Turkish cohort.


MONDO:0009370

[PMID:37113859] [SUPPORT] L-2-hydroxyglutaric aciduria (L2HGA) is an autosomal recessive, slowly progressive neurodegenerative disease characterized by psychomotor delay and cerebellar dysfunction. --- Explanation: Psychomotor delay is listed as a defining characteristic.


MONDO:0009370

[PMID:37113859] [SUPPORT] The 15- and 17-year-old girls presented with psychomotor delay, seizures, ataxia, intentional tremors, and dysarthria. --- Explanation: Seizures are part of the core clinical presentation described in this case series.

[PMID:24321868] [SUPPORT] It occurs in childhood with mental retardation, cerebellar ataxia, and epilepsy. --- Explanation: Confirms epilepsy as a core feature of L2HGA alongside mental retardation and cerebellar ataxia.


MONDO:0009370

[PMID:37113859] [SUPPORT] L-2-hydroxyglutaric aciduria (L2HGA) is an autosomal recessive, slowly progressive neurodegenerative disease characterized by psychomotor delay and cerebellar dysfunction. --- Explanation: Cerebellar dysfunction is described as a defining feature of L2HGA.

[PMID:37113859] [SUPPORT] The 15- and 17-year-old girls presented with psychomotor delay, seizures, ataxia, intentional tremors, and dysarthria. --- Explanation: Ataxia was present in both patients in this case series.


MONDO:0009370

[PMID:38714179] [SUPPORT] Neurological exam revealed generalized dystonia, significant choreic movements in the upper extremities, slurred speech, bilateral dysmetria, and a wide-based gait. --- Explanation: Describes generalized dystonia in a patient with L2HGA requiring DBS intervention.

[PMID:38714179] [SUPPORT] Following minimal response to pharmacotherapy, GPi-DBS was performed. --- Explanation: Documents that dystonia in L2HGA can be pharmacoresistant, confirming its clinical significance as a distinct movement disorder phenotype.


MONDO:0009370

[PMID:37113859] [SUPPORT] The 15- and 17-year-old girls presented with psychomotor delay, seizures, ataxia, intentional tremors, and dysarthria. --- Explanation: Dysarthria was present in both reported patients.

[PMID:38714179] [SUPPORT] Neurological exam revealed generalized dystonia, significant choreic movements in the upper extremities, slurred speech, bilateral dysmetria, and a wide-based gait. --- Explanation: Slurred speech observed in the DBS case report patient.


MONDO:0009370

[PMID:24321868] [SUPPORT] Macrocephaly is present in half of the cases. --- Explanation: Reports macrocephaly in approximately 50% of L2HGA cases.


MONDO:0009370

[PMID:37113859] [SUPPORT] Brain MRI of the 15-year-old showed diffuse subcortical white matter changes evident by T2/FLAIR hyperintense signals bilaterally, particularly in the frontal region in the centripetal distribution --- Explanation: Describes the characteristic centripetal subcortical white matter MRI pattern.

[PMID:37113859] [SUPPORT] Neuroradiological features of centripetal subcortical leukoencephalopathy with basal ganglia and dentate nuclei involvement are rather specific to L2HGA --- Explanation: Confirms the diagnostic specificity of the MRI pattern.


MONDO:0009370

[PMID:37113859] [SUPPORT] Exaggerated tendon reflexes and bilateral sustained ankle clonus were observed in addition to cerebellar signs. --- Explanation: Upper motor neuron signs consistent with spasticity were present in both patients.

[PMID:38714179] [SUPPORT] Brisk deep tendon reflexes, clonus, and bilateral Babinski signs were present. --- Explanation: Pyramidal signs documented in the DBS case report.


MONDO:0009370

[PMID:37113859] [SUPPORT] The 15- and 17-year-old girls presented with psychomotor delay, seizures, ataxia, intentional tremors, and dysarthria. --- Explanation: Intentional tremors documented in both patients.


MONDO:0009370

[PMID:37275239] [SUPPORT] Behavioural problems were more common in L2HGA than in GA-I patients. --- Explanation: Documents increased behavioral problems in L2HGA compared to glutaric aciduria type I.


MONDO:0009370

[PMID:38714179] [SUPPORT] Neurological exam revealed generalized dystonia, significant choreic movements in the upper extremities, slurred speech, bilateral dysmetria, and a wide-based gait. --- Explanation: Choreic movements were documented in the DBS case report patient.


MONDO:0009370

[PMID:38714179] [SUPPORT] Neurological exam revealed generalized dystonia, significant choreic movements in the upper extremities, slurred speech, bilateral dysmetria, and a wide-based gait. --- Explanation: Wide-based gait documented in L2HGA patient.


MONDO:0009370

[PMID:38716347] [SUPPORT] L-2-HGA patients have a significantly increased lifetime risk of central nervous system (CNS) tumors. --- Explanation: Directly states increased CNS tumor risk in L2HGA patients.


MONDO:0009370


MONDO:0009370

[PMID:22391998] [INDIRECT EVIDENCE] [SUPPORT] Accumulation of D-2-hydroxyglutarate (D-2-HG) and/or L-2-hydroxyglutarate (L-2-HG) in body fluids are the biochemical hallmarks of these disorders. --- Explanation: Directly supports L-2-HG accumulation as the biochemical hallmark of L2HGA.


MONDO:0009370

[PMID:28137912] [INDIRECT EVIDENCE] [SUPPORT] KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). --- Explanation: Mouse model demonstrates leukoencephalopathy, gliosis, neuroinflammation, and OPC expansion.

[PMID:37113859] [INDIRECT EVIDENCE] [SUPPORT] Neuroradiological features of centripetal subcortical leukoencephalopathy with basal ganglia and dentate nuclei involvement are rather specific to L2HGA --- Explanation: Human neuroimaging confirms the characteristic white matter and deep gray matter pattern.


MONDO:0009370

[PMID:38862727] [INDIRECT EVIDENCE] [SUPPORT] both enantiomers of 2HG comparably stimulate anaerobic metabolism of glucose and inhibit the uptake of several essential amino acids from the culture media --- Explanation: In vitro neuronal cell model demonstrates metabolic reprogramming under L-2-HG exposure.


MONDO:0009370

[PMID:38716347] [INDIRECT EVIDENCE] [REFUTE] These findings were against all our expectations given the inhibitory potential of 2-HG on DNA-demethylation enzymes. --- Explanation: L-2-HGA-associated glioma did NOT show the G-CIMP hypermethylation phenotype expected from dioxygenase inhibition, unlike IDH-mutant tumors with D-2-HG accumulation. This argues against a simple epigenetic oncogenic mechanism in L-2-HGA.

[PMID:28137912] [INDIRECT EVIDENCE] [SUPPORT] a corresponding increase in histone methylation in these tissues --- Explanation: L2hgdh KO mice show increased histone methylation in brain, directly demonstrating that L-2-HG accumulation causes epigenetic dysregulation via inhibition of histone demethylases in vivo.


MAXO:0000058

[PMID:37275239] [SUPPORT] In all L2HGA patients, there was a significant decrease in the mean urinary 2- hydoxy glutarate with treatment. --- Explanation: Demonstrates significant biochemical response to riboflavin/levocarnitine in L2HGA cohort.

[PMID:37275239] [SUPPORT] Relative neurologic improvement was seen in three L2HGA patients. --- Explanation: Documents some clinical improvement with riboflavin-based treatment.

[PMID:24321868] [SUPPORT] Under specific treatment, the progression of the disease was subsequently stopped. --- Explanation: Reports halting of disease progression under riboflavin treatment.


MAXO:0000058

[PMID:37275239] [SUPPORT] Current treatment strategies are based on levocarnitine, vitamin B2, and diet. --- Explanation: Confirms levocarnitine as a component of standard treatment for L2HGA.

[PMID:37275239] [SUPPORT] In L2HGA patients, we used levocarnitine and vitamin B2. --- Explanation: Documents use of levocarnitine in all L2HGA patients in this cohort.


MAXO:0000058

[PMID:24321868] [SUPPORT] It occurs in childhood with mental retardation, cerebellar ataxia, and epilepsy. --- Explanation: Epilepsy is a core feature of L2HGA, necessitating antiepileptic pharmacotherapy as part of symptomatic management.

[PMID:37113859] [SUPPORT] The 15- and 17-year-old girls presented with psychomotor delay, seizures, ataxia, intentional tremors, and dysarthria. --- Explanation: Both patients in this case series had seizures, supporting the need for antiepileptic therapy.


MAXO:0000004

[PMID:38714179] [SUPPORT] Significant increases in mobility and decrease in dystonia were observed at 3 weeks, 6 months, and 12 months postoperatively. --- Explanation: Documents significant improvement with GPi-DBS in L2HGA-related dystonia.

[PMID:38714179] [SUPPORT] This is the first utilization of DBS as treatment for L2HGA-related dystonia. --- Explanation: Establishes GPi-DBS as a novel therapeutic option for L2HGA dystonia.


MAXO:0000950

[PMID:37275239] [SUPPORT] Relative neurologic improvement was seen in three L2HGA patients. --- Explanation: Some patients show improvement with comprehensive treatment approach, supporting role of ongoing supportive care.


MAXO:0000079

[PMID:37113859] [SUPPORT] Both parents were heterozygous carriers of the familial variant. --- Explanation: Carrier status in parents supports autosomal recessive counseling approach.


MAXO:0000088

[PMID:37275239] [SUPPORT] Current treatment strategies are based on levocarnitine, vitamin B2, and diet. --- Explanation: Diet is listed as one component of current treatment strategies.


MAXO:0000950

[PMID:38716347] [SUPPORT] L-2-HGA patients have a significantly increased lifetime risk of central nervous system (CNS) tumors. --- Explanation: Increased CNS tumor risk mandates ongoing neuroimaging surveillance.


HGNC.SYMBOL:L2HGDH variants

[PMID:22391998] [SUPPORT] We report on the clinical, genetic, enzymatic and metabolic characterization of D-2-HGA type I, D-2-HGA type II, L-2-HGA and D,L-2-HGA --- Explanation: Comprehensive review of genetic, enzymatic, and metabolic characterization of L2HGA.


MONDO:0002008

[PMID:14977076] [SUPPORT] To evaluate the dynamic properties of the horizontal vestibulo-ocular reflex (h-VOR) in the acute stage of two common labyrinthine diseases that provoke severe attacks of vertigo with spontaneous nystagmus: vestibular neuritis (vestibular loss alone) and viral labyrinthitis (cochleovestibular loss). --- Explanation: Study of 21 viral labyrinthitis patients documenting severe vertigo with spontaneous nystagmus as a cardinal feature.


MONDO:0002008

[PMID:37621282] [PARTIAL] pure-tone audiometry, ipsilesional posterior canal gain, and gain asymmetry of posterior canal were excellent parameters for distinguishing labyrinthitis from vestibular neuritis. --- Explanation: Study demonstrating that sensorineural hearing loss on audiometry is the key distinguishing feature between labyrinthitis and vestibular neuritis.

[PMID:39540706] [SUPPORT] A tonal audiogram showed a left perceptive deafness. --- Explanation: Case of bacterial labyrinthitis documenting sensorineural hearing loss confirmed on audiometry, with deafness persisting despite treatment.


MONDO:0002008

[PMID:39540706] [SUPPORT] A 18-year-old female presented with left sudden hearing loss, rotatory vertigo, vomiting, and tinnitus evolving for 24 hours. --- Explanation: Case of bacterial labyrinthitis presenting with tinnitus as part of the acute symptom complex.


MONDO:0002008

[PMID:14977076] [SUPPORT] two common labyrinthine diseases that provoke severe attacks of vertigo with spontaneous nystagmus: vestibular neuritis (vestibular loss alone) and viral labyrinthitis (cochleovestibular loss). --- Explanation: Study documenting spontaneous nystagmus as a defining feature of both vestibular neuritis and viral labyrinthitis.


MONDO:0002008

[PMID:39670911] [PARTIAL] The clinical manifestations are irreversible hearing loss, dizziness and vomiting. --- Explanation: Review listing vomiting as one of the cardinal clinical manifestations of labyrinthitis ossificans, reflecting the vestibular component of labyrinthitis.

[PMID:39540706] [SUPPORT] A 18-year-old female presented with left sudden hearing loss, rotatory vertigo, vomiting, and tinnitus evolving for 24 hours. --- Explanation: Case of bacterial labyrinthitis documenting vomiting as a presenting symptom alongside vertigo, hearing loss, and tinnitus.


MONDO:0002008

[DOI:10.1136/bcr-2023-258290] [SUPPORT] We report on a boy in his early adolescence with a sudden onset of spinning sensation, imbalance and unilateral hearing loss with a positive SARS-CoV-2 test. --- Explanation: Case of COVID-19-induced labyrinthitis documenting imbalance as a presenting feature alongside vertigo and hearing loss.

[PMID:23648600] [PARTIAL] Disorders of the inner ear can cause hearing loss, tinnitus, vertigo and imbalance. --- Explanation: Review establishing imbalance as a cardinal symptom of inner ear disorders including labyrinthitis.


MONDO:0002008

[PMID:41310738] [INDIRECT EVIDENCE] [SUPPORT] The differential impacts of toxic versus inflammatory mediators on inner ear physiology may render early combination therapy with antibiotics and glucocorticoids particularly efficacious. --- Explanation: Case of serous labyrinthitis complicating AOM documenting the tympanogenic route where toxic and inflammatory mediators cross from the middle ear into the inner ear.

[PMID:39540706] [INDIRECT EVIDENCE] [PARTIAL] Bacterial labyrinthitis has been rarely described. Pseudomonas incrimination is even exceptional. --- Explanation: Case of direct bacterial invasion of the labyrinth from acute otitis media, demonstrating the suppurative tympanogenic route of pathogen entry.

[PMID:38472515] [INDIRECT EVIDENCE] [PARTIAL] We induced pneumococcal meningitis in approximately 500 C57Bl6 adult mice using live Streptococcus pneumoniae (serotype 3, 1 × 105 colony forming units (cfu) in 10 µl) injected directly into the cisterna magna of anesthetized mice --- Explanation: Mouse model of pneumococcal meningitis demonstrating the meningitic route of labyrinthine infection via CSF-inner ear communication pathways.


MONDO:0002008


MONDO:0002008

[PMID:38472515] [INDIRECT EVIDENCE] [PARTIAL] The inflammatory response to bacterial meningitis is robust and can affect all three scalae. --- Explanation: Mouse meningitis model demonstrating that the innate immune response to bacterial infection involves all three cochlear scalae, reflecting widespread immune activation throughout the labyrinth.


MONDO:0002008

[PMID:38472515] [INDIRECT EVIDENCE] [PARTIAL] Both CCR2 and CX3CR1 monocytes and macrophages were present in the cochlea in large numbers after infection. --- Explanation: Mouse meningitis model showing robust recruitment of CCR2 and CX3CR1 mononuclear phagocytes into the cochlea, with CCR2 knockout mice experiencing more severe hearing loss and ossification, indicating a protective role for innate immune trafficking.


MONDO:0002008

[PMID:38472515] [INDIRECT EVIDENCE] [SUPPORT] The blood-perilymph barrier was disrupted at 3 days post infection (DPI) and was restored by seven DPI. --- Explanation: Mouse meningitis model quantifying the temporal dynamics of blood-labyrinth barrier disruption, with breach at 3 days and restoration by 7 days post-infection.

[DOI:10.3390/biology13100802] [INDIRECT EVIDENCE] [PARTIAL] pericytes, a type of vascular mural cell specialized to maintain the integrity and function of the microvasculature, may play a crucial role in the development and progression of inner ear disorders --- Explanation: Review detailing how pericyte dysfunction contributes to blood-labyrinth barrier breakdown, increased permeability, and impaired neurovascular coupling in inner ear disorders.


MONDO:0002008

[PMID:37621282] [INDIRECT EVIDENCE] [PARTIAL] In the labyrinthitis group, the mean vestibulo-ocular reflex gain was 0.72 in the ipsilesional horizontal canal, 0.73 in the ipsilesional anterior canal, and 0.55 in the ipsilesional posterior canal. --- Explanation: Study of 27 labyrinthitis patients demonstrating vestibular dysfunction across all three semicircular canals, with posterior canal most severely affected.


MONDO:0002008

[PMID:27435969] [INDIRECT EVIDENCE] [PARTIAL] 74 % of subjects with vertigo and SSNHL demonstrated impairment of the posterior canal gain (0.45 ± 0.20). --- Explanation: Study of 27 patients with vertigo and sudden sensorineural hearing loss showing combined cochlear and vestibular involvement, with 23 diagnosed as labyrinthitis.

[DOI:10.3390/biology13100802] [INDIRECT EVIDENCE] [NO_EVIDENCE] pericytes, a type of vascular mural cell specialized to maintain the integrity and function of the microvasculature, may play a crucial role in the development and progression of inner ear disorders --- Explanation: Review highlighting pericyte dysfunction in the stria vascularis as contributing to blood-labyrinth barrier breakdown and cochlear injury in inner ear inflammatory disorders.


MONDO:0002008

[PMID:38472515] [INDIRECT EVIDENCE] [SUPPORT] Loss of spiral ganglion neurons was common, and inner ear anatomy was distorted by scarring caused by new soft tissue and bone deposited within the scalae. --- Explanation: Mouse meningitis model documenting spiral ganglion neuron loss as a common consequence of meningitic labyrinthitis, with distortion of cochlear architecture.


MONDO:0002008

[DOI:10.37349/ei.2024.00129] [INDIRECT EVIDENCE] [PARTIAL] Various autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome, have been implicated in immune-mediated damage to auditory structures, resulting in inner ear dysfunction. --- Explanation: Review documenting immune-mediated mechanisms of inner ear damage, including autoantibody-mediated and T cell-mediated inflammation affecting auditory structures.

[DOI:10.1097/md.0000000000033889] [INDIRECT EVIDENCE] [PARTIAL] Autoimmune inner ear disease typically presents with bilateral hearing loss that progresses over weeks or months though its mechanisms are unknown. Corticosteroids are the first-line treatment, but their responses are variable and relapses are frequent. --- Explanation: Case report and review documenting the relapsing nature of autoimmune inner ear disease and partial corticosteroid responsiveness.


MONDO:0002008

[PMID:38472515] [INDIRECT EVIDENCE] [PARTIAL] Cochlear fibrosis could be detected within 4 days of infection, and neo-ossification by 14 days. --- Explanation: Mouse meningitis model showing fibroblast-driven tissue remodeling as the earliest reparative response, detectable within 4 days post-infection.


MONDO:0002008

[PMID:38472515] [INDIRECT EVIDENCE] [PARTIAL] inner ear anatomy was distorted by scarring caused by new soft tissue and bone deposited within the scalae. --- Explanation: Mouse meningitis model documenting distortion of inner ear architecture by fibrotic soft tissue deposited within the cochlear scalae.


MONDO:0002008

[PMID:39670911] [INDIRECT EVIDENCE] [PARTIAL] Labyrinthitis ossificans is a pathology consisting of calcification of the membranous labyrinth resulting in profound sensory deafness. It is usually due to an acute inflammatory process that progresses to ossification of the labyrinth. --- Explanation: Review establishing that labyrinthitis leads to labyrinthitis ossificans through progressive calcification of the membranous labyrinth.

[PMID:38472515] [INDIRECT EVIDENCE] [SUPPORT] Cochlear fibrosis could be detected within 4 days of infection, and neo-ossification by 14 days. --- Explanation: Mouse meningitis model documenting neo-ossification visible by 14 days post-infection as the terminal stage of post-inflammatory cochlear remodeling.


MAXO:0000058

[PMID:37953517] [SUPPORT] Anticholinergics, phenothiazines, antihistamines, antidopaminergics, benzodiazepines, and calcium channel antagonists are examples of vestibular suppressants. --- Explanation: Review cataloging the major classes of vestibular suppressants used for symptomatic management of acute unilateral vestibulopathy.

[PMID:34411472] [PARTIAL] Symptomatic therapies include generalized supportive care and administration of vestibular suppressants and antiemetics. --- Explanation: Review establishing vestibular suppressants and antiemetics as the standard symptomatic therapy for acute vestibular neuritis, applicable to labyrinthitis management.


MAXO:0000058

[PMID:37953517] [INDIRECT EVIDENCE] [SUPPORT] Anticholinergics, phenothiazines, antihistamines, antidopaminergics, benzodiazepines, and calcium channel antagonists are examples of vestibular suppressants. --- Explanation: Review cataloging the major classes of vestibular suppressants used for symptomatic management of acute unilateral vestibulopathy.

[PMID:34411472] [INDIRECT EVIDENCE] [PARTIAL] Symptomatic therapies include generalized supportive care and administration of vestibular suppressants and antiemetics. --- Explanation: Review establishing vestibular suppressants and antiemetics as the standard symptomatic therapy for acute vestibular neuritis, applicable to labyrinthitis management.


MAXO:0000058