MAXO:0000088

[PMID:39203843] [SUPPORT] In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 ratio), with medium-chain triglyceride supplementation at 10-25% of total energy --- Explanation: Provides quantitative dietary guidance for MCT supplementation.


MAXO:0000088

[PMID:39203843] [SUPPORT] In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% --- Explanation: Directly supports quantitative LCT restriction guidance.

[PMID:38651394] [SUPPORT] Patients who had a high C14:1 value at diagnosis were started on a diet with a lower percentage of energy from long-chain triglycerides. --- Explanation: Supports clinical practice of LCT restriction guided by C14:1 levels.


MAXO:0000058

[PMID:37960342] [SUPPORT] Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect. --- Explanation: Demonstrates heptanoate supports glucose homeostasis in VLCAD-deficient mice.

[PMID:39203843] [SUPPORT] Trihepatnoin is a new therapeutic option with a good safety and efficacy profile. --- Explanation: Expert review supports triheptanoin as a therapeutic option with good profile. Note "Trihepatnoin" is a typo in the original publication (correct spelling is triheptanoin).


MAXO:0000058

[PMID:20301763] [SUPPORT] Acute inpatient treatment: Administration of high-energy fluids (≥10% IV dextrose) --- Explanation: Directly supports emergency dextrose therapy during catabolic crises.

[PMID:39203843] [SUPPORT] The main measure in emergency hospital treatment is the administration of IV glucose. --- Explanation: Expert review confirms IV glucose as the primary emergency measure.


MAXO:0000088

[PMID:39203843] [SUPPORT] Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise. --- Explanation: Directly supports pre-exercise caloric loading as a management strategy.


MAXO:0000950

[PMID:20301763] [SUPPORT] standard treatment of cardiomyopathy; supportive developmental therapies as needed. --- Explanation: Supports organ-specific supportive management for cardiac complications.


MAXO:0000124


MAXO:0000079

[PMID:20301763] [SUPPORT] VLCAD deficiency is inherited in an autosomal recessive manner. --- Explanation: Autosomal recessive inheritance supports the role of genetic counseling.


hgnc:92

[PMID:20301763] [SUPPORT] The diagnosis of VLCAD deficiency is established in a proband with a specific pattern of abnormal acylcarnitine levels on biochemical testing and/or by identification of biallelic pathogenic variants in ACADVL by molecular genetic testing. --- Explanation: Directly supports ACADVL biallelic pathogenic variants as causal.


MONDO:0009395

[PMID:11836356] [SUPPORT] generalised bone overgrowth, predominantly in the skull and mandible --- Explanation: Skull and mandible overgrowth are the predominant features.


MONDO:0009395

[PMID:11836356] [SUPPORT] Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients --- Explanation: Facial nerve palsy is a major clinical complication in most patients.


MONDO:0009395

[PMID:11836356] [SUPPORT] facial nerve palsy, optic atrophy, and impaired hearing occur in most patients --- Explanation: Optic atrophy is a recognized complication from cranial nerve compression.


MONDO:0009395

[PMID:11836356] [PARTIAL] impaired hearing occur in most patients --- Explanation: Hearing impairment is a major clinical complication.


MONDO:0009395


MAXO:0000004


MAXO:0000079


HGNC.SYMBOL:SOST Regulatory Deletion

[PMID:11836356] [PARTIAL] we mapped both disease genes to the same region on chromosome 17q12-q21, supporting the hypothesis that van Buchem disease and sclerosteosis are caused by mutations in the same gene --- Explanation: Van Buchem disease and sclerosteosis map to the same locus, both involving SOST.

[PMID:11181578] [PARTIAL] Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients --- Explanation: Distinguishes Van Buchem from sclerosteosis by absence of hand malformations and tall stature.


MONDO:0018486

[PMID:24645145] [SUPPORT] palinopsia (trailing and afterimages), entoptic phenomena (floaters, blue field entoptic phenomenon, spontaneous photopsia, self-light of the eye), photophobia, and nyctalopia --- Explanation: Photophobia is one of the core additional symptoms present in VSS patients.

[PMID:31941797] [SUPPORT] Floaters, afterimages, and photophobia were the most reported additional visual symptoms. --- Explanation: Large cohort study confirms photophobia as one of the most commonly reported symptoms.


MONDO:0018486

[PMID:24645145] [SUPPORT] palinopsia (trailing and afterimages), entoptic phenomena (floaters, blue field entoptic phenomenon, spontaneous photopsia, self-light of the eye), photophobia, and nyctalopia (impaired night vision) --- Explanation: Nyctalopia (impaired night vision) is one of the core additional symptoms in VSS.

[PMID:38465699] [SUPPORT] Visual snow syndrome (VSS) is a disorder characterized by persistent visual disturbances, including the visual snow phenomenon, palinopsia, heightened perception of entoptic phenomena, impaired night vision, and photophobia. --- Explanation: Impaired night vision is listed as a core feature of VSS in recent review.


MONDO:0018486

[PMID:24816400] [SUPPORT] entopic phenomena arising from the optic apparatus itself (floaters, blue field entoptic phenomenon, photopsia, self-light of the eye) --- Explanation: Spontaneous photopsia is one of the entoptic phenomena in VSS.

[PMID:40129600] [SUPPORT] Visual Snow Syndrome (VSS) is characterized by the presence of dynamic, continuous, tiny dots in the entire visual field persisting for more than three months, with at least two associated symptoms- palinopsia, photopsia, photophobia, or nyctalopia. --- Explanation: Photopsia is listed as one of the core associated symptoms in VSS diagnostic criteria.


MONDO:0018486

[PMID:28723606] [SUPPORT] While most of these symptoms appear to be visual in nature, approximately 63% of patients studied also report continuous bilateral tinnitus. --- Explanation: About 63% of VSS patients report continuous bilateral tinnitus.

[PMID:31941797] [SUPPORT] Migraine and tinnitus had a very high prevalence and were independently associated with a more severe presentation of the syndrome. --- Explanation: Tinnitus is highly prevalent and associated with more severe VSS presentation.

[PMID:24816400] [SUPPORT] as well as the non-visual symptom tinnitus. --- Explanation: Tinnitus is recognized as a common non-visual symptom in VSS.

[PMID:31213497] [SUPPORT] Migraine, depression, anxiety, and tinnitus were common comorbid diseases. --- Explanation: Tinnitus is confirmed as a common comorbid condition in VSS.


MONDO:0018486

[PMID:31941797] [SUPPORT] Floaters, afterimages, and photophobia were the most reported additional visual symptoms. --- Explanation: Floaters are among the most commonly reported symptoms in VSS.

[PMID:24645145] [SUPPORT] entoptic phenomena (floaters, blue field entoptic phenomenon, spontaneous photopsia, self-light of the eye) --- Explanation: Floaters are part of the enhanced entoptic phenomena seen in VSS patients.


MONDO:0018486

[PMID:38465699] [INDIRECT EVIDENCE] [SUPPORT] Electrophysiological studies have revealed cortical hyperresponsivity in visual brain areas, imaging studies demonstrated microstructural and functional connectivity alterations in multiple cortical and thalamic regions and investigated glutamatergic and serotoninergic neurotransmission. --- Explanation: Recent studies confirm cortical hyperresponsivity and connectivity alterations in VSS.

[PMID:24816400] [INDIRECT EVIDENCE] [SUPPORT] The hypermetabolic lingual gyrus confirms a brain dysfunction in patients with "visual snow." --- Explanation: PET imaging demonstrates hypermetabolism in the lingual gyrus in visual snow patients.

[PMID:34570907] [INDIRECT EVIDENCE] [SUPPORT] Imaging and electrophysiological findings indicate a hyperexcitability of the primary and secondary visual areas of the brain possibly due to an impairment of inhibitory feedback mechanisms. --- Explanation: Review article confirms hyperexcitability in visual cortical areas with impaired inhibitory feedback.

[PMID:33008511] [INDIRECT EVIDENCE] [PARTIAL] Regarding pathophysiology, hyperexcitability of the visual cortex and a processing problem of higher order visual function are assumed, but the location is still in discussion. --- Explanation: Systematic review confirms visual cortex hyperexcitability as leading hypothesis for VSS pathophysiology.


MONDO:0018486


MONDO:0018486

[PMID:38465699] [INDIRECT EVIDENCE] [PARTIAL] These findings suggest that VSS might be a network disorder. --- Explanation: Recent research suggests VSS is a network disorder affecting multiple brain regions.

[PMID:34570907] [INDIRECT EVIDENCE] [PARTIAL] Imaging and electrophysiological findings hint toward network disorders involving the sensory networks and other large-scale networks involved in the management of attention and emotional processing. --- Explanation: Evidence points to network-level dysfunction involving sensory processing and attention networks.

[PMID:33008511] [INDIRECT EVIDENCE] [PARTIAL] In particular, it is unclear if the primary visual cortex, the visual association cortex or the thalamocortical pathway is involved. --- Explanation: The thalamocortical pathway is one of the candidate structures involved in VSS pathophysiology.


MAXO:0000058

[PMID:31213497] [SUPPORT] Lamotrigine was prescribed most frequently (26/58) and resulted in partial remission of symptoms in 5/26 (19.2%). No patients reported complete remission. --- Explanation: Lamotrigine provides partial symptom relief in about 19% of patients, though complete remission is rare.

[PMID:33008511] [SUPPORT] The best data is available for lamotrigine being effective in 8/36 (22.2%, including one total response and no worsening), followed by topiramate being effective in 2/13 (15.4%, no total response and one worsening). --- Explanation: Systematic review confirms lamotrigine has the best evidence for effectiveness in VSS.

[PMID:40129600] [SUPPORT] benzodiazepines and lamotrigine had the best effect (71.4% and 61.5% of patients had an improvement of VS symptoms on each medication, respectively). --- Explanation: Recent 2025 review shows lamotrigine among the most effective pharmacological treatments.

[PMID:28349350] [SUPPORT] Our preferred treatment options include: (1) oral lamotrigine with a slow increase from 25 mg daily to a maintenance dose of 200-300 mg daily in divided doses as tolerated --- Explanation: Expert recommendations support lamotrigine as a first-line pharmacological option.


CHEBI:6367

[PMID:31213497] [INDIRECT EVIDENCE] [SUPPORT] Lamotrigine was prescribed most frequently (26/58) and resulted in partial remission of symptoms in 5/26 (19.2%). No patients reported complete remission. --- Explanation: Lamotrigine provides partial symptom relief in about 19% of patients, though complete remission is rare.

[PMID:33008511] [INDIRECT EVIDENCE] [SUPPORT] The best data is available for lamotrigine being effective in 8/36 (22.2%, including one total response and no worsening), followed by topiramate being effective in 2/13 (15.4%, no total response and one worsening). --- Explanation: Systematic review confirms lamotrigine has the best evidence for effectiveness in VSS.

[PMID:40129600] [INDIRECT EVIDENCE] [SUPPORT] benzodiazepines and lamotrigine had the best effect (71.4% and 61.5% of patients had an improvement of VS symptoms on each medication, respectively). --- Explanation: Recent 2025 review shows lamotrigine among the most effective pharmacological treatments.

[PMID:28349350] [INDIRECT EVIDENCE] [SUPPORT] Our preferred treatment options include: (1) oral lamotrigine with a slow increase from 25 mg daily to a maintenance dose of 200-300 mg daily in divided doses as tolerated --- Explanation: Expert recommendations support lamotrigine as a first-line pharmacological option.


MAXO:0000058

[PMID:40129600] [SUPPORT] benzodiazepines and lamotrigine had the best effect (71.4% and 61.5% of patients had an improvement of VS symptoms on each medication, respectively). --- Explanation: Benzodiazepines show the highest improvement rate at 71.4% of patients.


MONDO:0008661

[PMID:37919864] [PARTIAL] Additionally, several small studies have found potential links to uveitis and glaucoma. --- Explanation: The literature mentions potential links between vitiligo and uveitis, but it does not provide a clear frequency of occurrence.

[PMID:30850197] [NO_EVIDENCE] Uveitis is by far the most common ocular manifestation of Behçet's disease --- Explanation: This reference discusses uveitis in the context of Behcet's disease, not vitiligo.

[PMID:15609264] [NO_EVIDENCE] Uveitis is probably a misnomer unless antigens within the uvea are the direct targets of the inflammatory process. --- Explanation: This reference discusses uveitis in the context of autoimmune diseases generally, without specific mention of vitiligo.


MONDO:0008661


MONDO:0008661

[PMID:33200838] [INDIRECT EVIDENCE] [SUPPORT] Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction...self-responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo...CD8(+) cytotoxic T lymphocytes finally execute the killing of melanocytes. --- Explanation: The literature describes the autoimmune-mediated destruction of melanocytes involving CD8+ T lymphocytes, consistent with the provided statement.

[PMID:31209143] [INDIRECT EVIDENCE] [SUPPORT] Vitiligo is an autoimmune skin disease mediated by autoreactive CD8(+) T cells that destroy the pigment-producing cells of the epidermis, melanocytes, leading to areas of depigmentation. --- Explanation: The reference confirms the autoimmune-mediated destruction mechanism, mentioning both CD8+ T lymphocytes and melanocytes.

[PMID:25184918] [INDIRECT EVIDENCE] [SUPPORT] The main histopathological finding in vitiligo is the total absence of functioning melanocytes in the lesions, while the inflammatory cells most commonly found on the edges of the lesions are CD4+ and CD8+ T lymphocytes. --- Explanation: The literature supports the involvement of CD8+ T lymphocytes and the destruction of melanocytes in vitiligo.

[PMID:35653192] [INDIRECT EVIDENCE] [SUPPORT] Vitiligo is an autoimmune skin disease characterized by the destruction of melanocytes by autoreactive CD8+ T cells. --- Explanation: This source directly mentions the destruction of melanocytes by CD8+ T cells.

[PMID:18460889] [INDIRECT EVIDENCE] [SUPPORT] Vitiligo is characterized by progressive skin depigmentation resulting from an autoimmune response targeting epidermal melanocytes...Type I cytokine-mediated immunity to melanocytes in vitiligo involves T cells reactive with melanosomal antigens... --- Explanation: The source elaborates on the autoimmune nature of vitiligo, involving T cells and targeting melanocytes.


MAXO:0000058

[PMID:19178066] [SUPPORT] Topical corticosteroids are one of the oldest and most useful treatments for dermatologic conditions... evidence of effectiveness exists only for select conditions, such as psoriasis, vitiligo... --- Explanation: The use of topical corticosteroids as a treatment for vitiligo is supported, indicating it as a common and effective treatment option.

[PMID:38477910] [SUPPORT] Evidence supports the use of... topical corticosteroids... as effective therapeutics for vitiligo... --- Explanation: The recommendations include topical corticosteroids as a first-line treatment for vitiligo in pediatric, adolescent, and young adult patients.

[PMID:33350506] [SUPPORT] The mainstay of treatment for unstable vitiligo has been topical agents (corticosteroids, calcineurin inhibitors)... --- Explanation: This article highlights topical corticosteroids as a primary treatment for vitiligo, supporting the statement.

[PMID:20445292] [SUPPORT] Topical therapy is employed as first-line treatment in localized vitiligo. Currently, several topical agents are available... corticosteroids... --- Explanation: Topical corticosteroids are mentioned as a first-line treatment, aligning with the provided statement.


MAXO:0000058


CHEBI:66919


MAXO:0000014

[PMID:27638438] [SUPPORT] Acting on multiple steps in vitiligo pathogenesis, narrowband ultraviolet B is one of the few therapies that can effectively induce stabilization and stimulate repigmentation. --- Explanation: The article supports the use of narrowband UVB for stimulating repigmentation in vitiligo.

[PMID:28317529] [SUPPORT] The most potent stimulus for repigmentation is the UV light. --- Explanation: This reference directly supports that UV light, including UVB, is a potent stimulus for repigmentation in vitiligo.

[PMID:20149899] [SUPPORT] There have been many treatments to cure vitiligo such as use of steroid creams, PUVA (psoralen and ultraviolet A light), narrow band UVB (ultraviolet B), various surgical techniques, vitamin D analogues and pseudocatalase. --- Explanation: It lists both PUVA and narrowband UVB as standard treatments for vitiligo.

[PMID:34806278] [PARTIAL] OBJECTIVE: To study whether the colorimeter and point counting technique can be used as objective methods in monitoring vitiligo lesions during treatment with Nb-UVB... --- Explanation: The study demonstrates the effectiveness of narrowband UVB in increasing the melanin index, indicating pigment production in vitiligo lesions.


MAXO:0000004

[PMID:38038734] [PARTIAL] For patients with stable vitiligo who have not achieved satisfactory results with medical treatments, the melanocyte-keratinocyte transplantation procedure (MKTP) is a viable option. --- Explanation: MKTP is a type of autologous non-cultured cellular grafting procedure used for treating stable vitiligo.

[PMID:37000977] [PARTIAL] Surgical therapies are effective methods to treat resistant stable vitiligo, with each method having advantages and disadvantages. --- Explanation: This study compares ultrathin skin grafting (UTSG) and suction blister epidermal grafting (SBEG), both of which are skin grafting methods used to treat stable vitiligo.

[PMID:34169570] [SUPPORT] Cultured epidermal autografts (CEA) are surgical therapeutic alternatives for patients with stable vitiligo resistant to conventional medical treatments. --- Explanation: CEA is mentioned as an option for treating stable vitiligo, indicating the use of skin grafting.

[PMID:22994670] [SUPPORT] A number of new therapeutic options for vitiligo have become available...One among them is the smashed skin grafting or simply smash grafting --- Explanation: This reference discusses smash grafting as a method used in vitiligo treatment.

[PMID:27274556] [PARTIAL] Medical treatments are usually reasonably effective for nonstable vitiligo patches; however, for vitiligo patches that have been stable for a substantial period of time, surgical intervention should be considered. --- Explanation: It supports the use of surgical interventions, including skin grafting, for stable vitiligo.


MAXO:0010039

[PMID:12709002] [PARTIAL] This surgical treatment gives its best results in segmental and focal vitiligo, even with large affected areas, and in at least 50% of patients with generalized vitiligo. --- Explanation: This implies that melanocyte-keratinocyte transplantation can be effective for stable vitiligo.

[PMID:26728804] [NO_EVIDENCE] Melanocyte-keratinocyte transplantation procedure: A few insights. --- Explanation: The procedure involves melanocyte transplantation which supports the statement for treating stable vitiligo.

[PMID:28445194] [SUPPORT] Cultured autologous melanocyte transplantation (CMT) is an effective treatment for stable vitiligo. --- Explanation: This confirms the use of melanocyte transplantation for stable vitiligo.

[PMID:35457678] [PARTIAL] Both the development of new techniques and modifications to the already available treatment of cell and tissue transplantation give hope to numerous patients around the world. --- Explanation: Surgical treatments including melanocyte transplantation are viable for stable vitiligo according to the literature.


MAXO:0000058

[PMID:3168334] [SUPPORT] When large areas of skin are involved or when the patient is unresponsive to therapy, serious consideration should be given to depigmentation with monobenzone (Benoquin). --- Explanation: This supports the use of monobenzone cream for removing remaining pigment in cases of extensive vitiligo.

[PMID:21054565] [SUPPORT] If vitiligo involves most of the body, it might be easier to depigment the normal remaining skin rather than to attempt repigmentation...Our review revealed that...Monobenzyl ether of hydroquinone (MBEH) is the most widely used depigmenting agent and has few side-effects. --- Explanation: The reference supports the use of monobenzone (MBEH) for depigmentation in extensive vitiligo cases.


CHEBI:34380

[PMID:3168334] [INDIRECT EVIDENCE] [SUPPORT] When large areas of skin are involved or when the patient is unresponsive to therapy, serious consideration should be given to depigmentation with monobenzone (Benoquin). --- Explanation: This supports the use of monobenzone cream for removing remaining pigment in cases of extensive vitiligo.

[PMID:21054565] [INDIRECT EVIDENCE] [SUPPORT] If vitiligo involves most of the body, it might be easier to depigment the normal remaining skin rather than to attempt repigmentation...Our review revealed that...Monobenzyl ether of hydroquinone (MBEH) is the most widely used depigmenting agent and has few side-effects. --- Explanation: The reference supports the use of monobenzone (MBEH) for depigmentation in extensive vitiligo cases.


HGNC.SYMBOL:NALP1

[PMID:17637824] [SUPPORT] This study confirms genetic association of generalized vitiligo with variation in NALP1, which contains at least two independent risk signals. --- Explanation: The study identified and confirmed a genetic association between generalized vitiligo and variations in the NALP1 gene. This supports the statement.


HGNC.SYMBOL:TYR

[PMID:20410501] [SUPPORT] We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase. --- Explanation: The study identified a significant association between generalized vitiligo and a genetic locus containing the TYR gene.

[PMID:32838589] [PARTIAL] The tyrosinase levels were significantly elevated in patients. The TT genotype was the most prevalent one in the patients... MiRNA 196a-2 C/T (11614913) gene polymorphism and the elevated serum tyrosinase levels might be related to the pathogenesis of vitiligo and may affect its therapeutic response. --- Explanation: Elevated serum tyrosinase levels in vitiligo patients suggest a genetic association involving the TYR gene with vitiligo.


HGNC.SYMBOL:PTPN22

[PMID:21515266] [SUPPORT] The PTPN22 locus is one of the strongest risk factors outside of the major histocompatability complex that associates with autoimmune diseases...vitiligo --- Explanation: The literature specifically mentions that PTPN22 is associated with vitiligo as part of its association with several autoimmune diseases.

[PMID:28164884] [PARTIAL] Several studies have demonstrated the association of protein tyrosine phosphatase, non-receptor type 22 +1858C-->T polymorphism with vitiligo... limited ethnic-based studies... In conclusion, protein tyrosine phosphatase, non-receptor type 22 +1858 T allele predisposes European individuals to vitiligo. --- Explanation: This source confirms the association but notes that the genetic association is specific to the European population and not found in the Asian population, suggesting partial support.


HGNC.SYMBOL:MC1R

[PMID:20197744] [SUPPORT] Genome-wide association studies (GWAS) have unveiled single nucleotide polymorphisms (SNPs) or genetic variants in MC1R, TPCN2, ASIP, KITLG, NCKX5, TYR, IRF4, OCA2, and TYRP1 pigmentation genes. --- Explanation: This reference provides evidence of an association between the MC1R gene and vitiligo.

[PMID:33757175] [SUPPORT] MC1R was found as a key gene in vitiligo and involved in the melanogenesis. --- Explanation: This reference identifies MC1R as a key gene involved in vitiligo, providing further support for its genetic association.


HGNC.SYMBOL:HLA-A

[PMID:17243956] [SUPPORT] Meta-analysis showed a significantly increased frequency of HLA-A2 in vitiligo among cases [OR = 2.07, 95% confidence interval (CI) 1.67-2.58]. --- Explanation: The meta-analysis strongly suggests an association between HLA-A2, a specific allele of HLA-A, and vitiligo.


HGNC.SYMBOL:HLA-DRB1

[PMID:34686989] [SUPPORT] In this study, we have evaluated the association and role of HLA-DRB4*01:01, -DRB1*07:01, and -DQB1*03:03:2 genes in different clinical subtypes of Vitiligo in the Iranian population. --- Explanation: The study discusses the association of different HLA-DRB1 allelic genes, including HLA-DRB1, with vitiligo.

[PMID:20526339] [SUPPORT] Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles... --- Explanation: The findings of the genome-wide association study indicate an association of HLA-DRB1 alleles with vitiligo.

[PMID:6600753] [SUPPORT] Association of HLA-DR4 with vitiligo. --- Explanation: Although this specifically mentions HLA-DR4, it generally supports the connection between HLA class II genes and vitiligo, which includes HLA-DRB1.


HGNC.SYMBOL:IFIH1

[PMID:22561518] [SUPPORT] IFIH1 (P = 4.91 × 10(-15)) --- Explanation: Large-scale GWAS meta-analysis identified IFIH1 as a vitiligo susceptibility locus at genome-wide significance, encoding an immunoregulatory protein involved in innate immune sensing.


HGNC.SYMBOL:BACH2

[PMID:22561518] [SUPPORT] BACH2 (P = 2.53 × 10(-8)) --- Explanation: GWAS meta-analysis identified BACH2 as a vitiligo susceptibility locus at genome-wide significance. BACH2 encodes an immunoregulatory transcription factor involved in immune cell development.


HGNC.SYMBOL:IRF4

[PMID:27723757] [PARTIAL] identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. --- Explanation: GWAS meta-analysis identified IRF4 as one of the 23 new vitiligo susceptibility loci at genome-wide significance (P = 8.86 × 10-16). IRF4 is a key transcription factor for both immune cells and melanocytes.


HGNC.SYMBOL:FOXP3

[PMID:33181260] [PARTIAL] FOXP3 mRNA and protein levels were significantly decreased (p < 0.001) in GV Tregs compared to controls --- Explanation: This study found that FOXP3 expression is significantly reduced in regulatory T cells of vitiligo patients, and identified FOXP3 promoter polymorphisms associated with disease susceptibility.


ECTO:0000006

[PMID:29124690] [PARTIAL] This chapter focuses on the use of ultraviolet light in vitiligo as an established therapeutic option. --- Explanation: The reference suggests that UV light is used to treat vitiligo, which implies it can promote repigmentation. However, it does not address the exacerbation of contrast.

[PMID:34245476] [PARTIAL] Targeted phototherapy with EL demonstrated better repigmenting efficacy than TUVB in vitiligo. --- Explanation: This reference supports UV exposure aiding in repigmentation but does not discuss exacerbating contrast.

[PMID:34806278] [PARTIAL] Patients received Nb-UVB three times per week for 6 months... 90% of lesions showed variable degrees of repigmentation and 10% showed increase in size, indicating increased activity of the disease. --- Explanation: UVB treatments result in repigmentation in most cases, though some lesions increased in size, indicating potential exacerbation.


ECTO:0000231

[PMID:36433836] [SUPPORT] In the binary logistic regression model, household chemicals/colored toothpaste use...and an occupational exposure to phenol/catechol derivatives were significantly associated with vitiligo (three to fourfold increase). --- Explanation: The study identifies phenol derivatives as significant risk factors for the development of vitiligo.

[PMID:33039241] [PARTIAL] Chemicals like Monobenzyl Ether of Hydroquinone (MBEH) and 4-Tertiary Butyl Phenol (4-TBP) have been widely recognized to induce clinical lesions that resemble vitiligo. --- Explanation: The study demonstrates that phenol-based compounds can induce vitiligo-like lesions.

[PMID:28317525] [SUPPORT] these chemicals have been used therapeutically in patients with severe vitiligo to depigment their remaining skin and improve their appearance...these chemicals appear to induce melanocyte autoimmunity --- Explanation: The study mentions the use of chemicals, including phenols, to induce vitiligo for therapeutic purposes, supporting the role of phenolic compounds in inducing or exacerbating vitiligo.


MONDO:0008667

[PMID:34818478] [SUPPORT] Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α). --- Explanation: Confirms high incidence of RCC in VHL disease due to VHL gene inactivation and constitutive HIF-2α activation.


MONDO:0008667


MONDO:0008667

[PMID:37980175] [INDIRECT EVIDENCE] [SUPPORT] von Hippel-Lindau (VHL) disease is characterized by biallelic inactivation of the VHL gene leading to abnormal or absent VHL protein function, and constitutive activation of hypoxia-inducible factors (HIF) that leads to pro-tumorigenic signaling. --- Explanation: Confirms that biallelic VHL inactivation (consistent with two-hit hypothesis) leads to constitutive HIF activation and pro-tumorigenic signaling.


MONDO:0008667

[PMID:19671042] [INDIRECT EVIDENCE] [SUPPORT] The von-Hippel Lindau tumor suppressor (pVHL) is the substrate recognition component of an E3 ubiquitin ligase and functions as a master regulator of HIF activity by targeting the hydroxylated HIF-alpha subunit for ubiquitylation and rapid proteasomal degradation under normoxic conditions. --- Explanation: Defines pVHL as the substrate recognition component of an E3 ubiquitin ligase that targets hydroxylated HIF-alpha for proteasomal degradation.

[PMID:15162797] [INDIRECT EVIDENCE] [SUPPORT] VHL tumor suppressor is a specific substrate-recognition component of the E3 ubiquitin complex, which regulates proteasomal degradation of the subunit of the hypoxia inducible transcription factor (HIF). Impaired VHL complex function leads to accumulation of HIF, overexpression of various HIF-induced gene products and formation of highly vascular neoplasia. --- Explanation: Confirms that impaired VHL function leads to HIF accumulation due to loss of proteasomal degradation.


MONDO:0008667

[PMID:11114720] [INDIRECT EVIDENCE] [SUPPORT] in VHL deficient cell lines, both HIF-alpha subunits are constitutively expressed, whereas re-introduction of a functional VHL gene restores the instability of HIF-1alpha and HIF-2alpha proteins under normoxic conditions. --- Explanation: Demonstrates that VHL deficiency leads to constitutive HIF-alpha expression even under normoxic conditions, and that VHL restoration can reverse this effect.


MONDO:0008667

[PMID:11114720] [INDIRECT EVIDENCE] [SUPPORT] In a previous study of hemangioblastomas, the most frequent manifestation of hereditary von Hippel-Lindau disease (VHL), we found elevated levels of vascular endothelial growth factor and HIF-2alpha mRNA in stromal cells of the tumors. --- Explanation: Demonstrates elevated VEGF levels in VHL-associated hemangioblastomas, linking HIF activation to VEGF overexpression.

[PMID:11114720] [INDIRECT EVIDENCE] [SUPPORT] The data presented here provide evidence for a role of the VHL protein in regulation of angiogenesis and erythropoiesis mediated by the HIF-1alpha and HIF-2alpha proteins. --- Explanation: Confirms VHL protein regulates angiogenesis through HIF-mediated mechanisms.


MONDO:0008667

[PMID:37980175] [INDIRECT EVIDENCE] [PARTIAL] immunohistochemical studies for markers such as paired box 8 (PAX-8), carbonic anhydrase 9 (CA9), and glucose transporter 1 (GLUT-1) have an important role in routine clinical practice and represent cost-effective diagnostic tools. --- Explanation: The use of GLUT-1 as a diagnostic marker for VHL-associated tumors reflects HIF-induced metabolic reprogramming with increased glucose uptake.


MAXO:0000126


MAXO:0000004


MAXO:0000058

[PMID:34818478] [SUPPORT] Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. --- Explanation: Phase 2 clinical trial demonstrates belzutifan efficacy and tolerability across VHL-associated tumor types.


NCIT:C135627

[PMID:34818478] [INDIRECT EVIDENCE] [SUPPORT] Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. --- Explanation: Phase 2 clinical trial demonstrates belzutifan efficacy and tolerability across VHL-associated tumor types.


MAXO:0000079


HGNC.SYMBOL:VHL


MONDO:0005116

[PMID:26288590] [SUPPORT] Prior to patients reporting symptoms of a malabsorption syndrome (chronic diarrhea/steatorhea, weight loss), they often suffer from non-specific symptoms. --- Explanation: Review lists chronic diarrhea as hallmark of Whipple disease malabsorption.


MONDO:0005116

[PMID:26288590] [SUPPORT] Prior to patients reporting symptoms of a malabsorption syndrome (chronic diarrhea/steatorhea, weight loss), they often suffer from non-specific symptoms. --- Explanation: Same review notes steatorrhea as part of the malabsorption syndrome.


MONDO:0005116

[PMID:26288590] [SUPPORT] The weight loss is on average 11 kg (range: 3-36 kg). --- Explanation: Quantifies typical weight loss in Whipple disease.


MONDO:0005116

[PMID:26288590] [SUPPORT] Patients report a migrating polyarthritis of the peripheral joints (ankles, shoulders, knees, wrists, hands) and of the axial system. --- Explanation: Describes typical migratory joint involvement.

[PMID:40204565] [SUPPORT] Joint involvement was similar, with initial episodic migratory arthritis (91 %) predominantly affecting large joints and lasting 2-7 days. --- Explanation: Cohort of isolated articular Whipple disease shows stereotyped migratory arthritis pattern.


MONDO:0005116

[PMID:26288590] [SUPPORT] Patients complain of headaches, cognitive dysfunctions, and eye motility disorders. --- Explanation: Review notes cognitive dysfunction among neurological features of Whipple disease.


MONDO:0005116

[PMID:26288590] [SUPPORT] Prior to patients reporting symptoms of a malabsorption syndrome (chronic diarrhea/steatorhea, weight loss), they often suffer from non-specific symptoms (polyarthralgia, fever, fatigue). --- Explanation: Notes fever among early systemic symptoms.


MONDO:0005116

[PMID:26288590] [SUPPORT] The clinical symptoms of WD include chronic diarrhea, malnutrition (weight loss), migratory polyarthralgia, abdominal pain, and/or enlarged lymph nodes. --- Explanation: Review lists abdominal pain among common clinical symptoms.


MONDO:0005116

[PMID:26288590] [SUPPORT] The clinical symptoms of WD include chronic diarrhea, malnutrition (weight loss), migratory polyarthralgia, abdominal pain, and/or enlarged lymph nodes. --- Explanation: Review notes lymphadenopathy as part of the systemic presentation.

[PMID:40398847] [SUPPORT] A supraclavicular lymph node excisional biopsy revealed complete architectural effacement by a diffuse foamy histiocytic infiltrate without granuloma formation or necrosis. --- Explanation: Case report shows lymph node involvement with foamy macrophages due to Whipple disease.


MONDO:0005116

[PMID:38414785] [SUPPORT] Whipple's disease (WD) is a multiple-system chronic disease caused by Tropheryma whipplei (T. whipplei) infection. The present study describes 3 cases of WD with clinical manifestations of cough, chest pain, headache, dyspnea, sputum, joint pain, abdominal pain, diarrhea and weight loss. --- Explanation: Case series documents pulmonary symptoms including dyspnea and chest pain.

[PMID:38414785] [SUPPORT] Chest computed tomography (CT) showed signs of plaques, nodules and pleural thickening; and bronchoscopic alveolar lavage fluid metagenomic-sequencing indicated that it was T. whipplei. --- Explanation: Imaging and BAL sequencing confirm pulmonary involvement due to T. whipplei.


MONDO:0005116

[PMID:38525769] [SUPPORT] We describe an atypical case of Whipple disease exclusively involving the spinal cord in an adolescent receiving immunosuppressive therapy for systemic lupus erythematosus. --- Explanation: Case report highlights spinal cord involvement as a presentation of Whipple disease.


MONDO:0005116

[PMID:26288590] [INDIRECT EVIDENCE] [SUPPORT] The disease is a chronic infection of the intestinal mucosa with the bacterium Tropheryma whipplei, which leads to a lymphostasis with an impaired absorption of the nutrition. --- Explanation: Review describes lymphatic obstruction and malabsorption from chronic infection.

[PMID:26288590] [INDIRECT EVIDENCE] [SUPPORT] Recent studies suggest that a host-specific dysfunction of the intestinal macrophages is responsible for the chronic infection with T. whipplei. --- Explanation: Highlights macrophage functional defect underlying persistent infection.


MONDO:0005116


MONDO:0005116

[PMID:40062480] [INDIRECT EVIDENCE] [SUPPORT] Half the world's population is exposed to T. whipplei, but only one in a million develop WD. This suggests that acquired or inborn errors of immunity (IEI) may underlie WD. --- Explanation: Genetic review links rare immune defects to disease susceptibility.

[PMID:40062480] [INDIRECT EVIDENCE] [SUPPORT] Anti-TNF treatment is a well established risk factor for flare-ups of WD. --- Explanation: Notes iatrogenic immune suppression as a trigger for disease activation.

[PMID:32896657] [INDIRECT EVIDENCE] [PARTIAL] About 60% were immunosuppressed. The most frequent clinical presentations were joint pain (16/22), weight loss (15/22) and/or digestive tract disorder (15/22). --- Explanation: Cohort shows high immunosuppression rate among confirmed Whipple disease cases.

[PMID:37727483] [INDIRECT EVIDENCE] [PARTIAL] The patient was admitted to the hospital due to recurrent diarrhea for 1 mo, shortness of breath, and 1 wk of fever, after 3 years of renal transplantation. --- Explanation: Post-transplant case illustrates Whipple disease emerging under chronic immunosuppression.


MONDO:0005116

[PMID:34093562] [INDIRECT EVIDENCE] [SUPPORT] Etanercept, adalimumab or certolizumab treatment of monocyte-derived macrophages from healthy subjects significantly increased bacterial replication in vitro without affecting uptake. --- Explanation: Demonstrates TNF inhibitors increase T. whipplei replication within macrophages.

[PMID:34093562] [INDIRECT EVIDENCE] [SUPPORT] TNFI aggravate/exacerbate latent or subclinical undiagnosed Whipple's disease by promoting a strong inflammatory response and apoptosis. --- Explanation: Study links TNF blockade to apoptosis-driven exacerbation of Whipple disease.


MAXO:0000058

[PMID:26288590] [SUPPORT] The German treatment recommendations include a two-week intravenous induction therapy with ceftriaxone, which is followed by a three-month oral maintenance therapy with trimethoprim/sulfamethoxazole. --- Explanation: Details standard ceftriaxone induction and TMP-SMX maintenance regimen.


CHEBI:29007

[PMID:26288590] [INDIRECT EVIDENCE] [SUPPORT] The German treatment recommendations include a two-week intravenous induction therapy with ceftriaxone, which is followed by a three-month oral maintenance therapy with trimethoprim/sulfamethoxazole. --- Explanation: Details standard ceftriaxone induction and TMP-SMX maintenance regimen.


CHEBI:45924


CHEBI:9332


MAXO:0000058

[PMID:26288590] [SUPPORT] A French group favors a combination of doxycycline and hydroxychloroquine for 1 year, followed by a lifelong administration of doxycycline. --- Explanation: Review reports alternative long-course doxycycline plus hydroxychloroquine approach.


CHEBI:50845

[PMID:26288590] [INDIRECT EVIDENCE] [SUPPORT] A French group favors a combination of doxycycline and hydroxychloroquine for 1 year, followed by a lifelong administration of doxycycline. --- Explanation: Review reports alternative long-course doxycycline plus hydroxychloroquine approach.


CHEBI:5801


NCBITaxon:2039


MONDO:0006058

[PMID:33394739] [SUPPORT] In most cases, a parent will identify an abdominal mass upon bathing or dressing their child, or a pediatrician will palpate a mass upon examining the child during a routine well-child visit. --- Explanation: Confirms abdominal mass as the most common presenting finding in Wilms tumor.


MONDO:0006058

[PMID:33394739] [SUPPORT] However, up to 35% of patients can present with either hematuria, hypertension, fever, or flank pain --- Explanation: Confirms hematuria as a presenting symptom in a subset of Wilms tumor patients.


MONDO:0006058

[PMID:33394739] [SUPPORT] However, up to 35% of patients can present with either hematuria, hypertension, fever, or flank pain --- Explanation: Confirms hypertension as a presenting symptom in Wilms tumor patients.


MONDO:0006058

[PMID:33394739] [SUPPORT] However, up to 35% of patients can present with either hematuria, hypertension, fever, or flank pain --- Explanation: Lists fever among presenting symptoms in Wilms tumor patients.


MONDO:0006058

[PMID:33394739] [SUPPORT] More than 15 different syndromes are associated with WT, including WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and a range of developmental delays) --- Explanation: Confirms aniridia as a feature of WAGR syndrome associated with Wilms tumor.


MONDO:0006058

[PMID:33394739] [SUPPORT] Beckwith-Wiedemann (embryonal tumors, macrosomia, macroglossia, hemihypertrophy, visceromegaly, omphalocele, neonatal hypoglycemia, and ear creases/pits) --- Explanation: Confirms hemihypertrophy as a feature of Beckwith-Wiedemann syndrome associated with Wilms tumor predisposition.


MONDO:0006058

[PMID:33394739] [SUPPORT] However, up to 35% of patients can present with either hematuria, hypertension, fever, or flank pain --- Explanation: Confirms flank pain as one of the presenting symptoms of Wilms tumor.


MONDO:0006058

[PMID:37916284] [INDIRECT EVIDENCE] [SUPPORT] In 1990, mutations of the Wilms' tumor-1 gene (WT1), encoding a transcription factor in the embryonic kidney, were found in 10-15% of Wilms' tumors; germline WT1 mutations were associated with hereditary syndromes involving glomerular and reproductive tract dysplasia. --- Explanation: Confirms WT1 mutation frequency in Wilms tumors and association with hereditary syndromes including WAGR and Denys-Drash.

[PMID:37916284] [INDIRECT EVIDENCE] [SUPPORT] WT1 functions at multiple stages of kidney development, including the transition from resting stem cells to committed nephron progenitor, which it primes to respond to WNT9b signals from the ureteric bud. --- Explanation: Details the role of WT1 in kidney development and nephron progenitor cell commitment.


MONDO:0006058


MONDO:0006058

[PMID:25018051] [INDIRECT EVIDENCE] [SUPPORT] This has been illustrated by the findings that mutations of Wnt/β-catenin pathway-related WT1, β-catenin, and WTX together account for about one-third of Wilms tumor cases. --- Explanation: Confirms WTX as one of the key Wnt pathway genes mutated in Wilms tumor.


MONDO:0006058

[PMID:25018051] [INDIRECT EVIDENCE] [SUPPORT] This has been illustrated by the findings that mutations of Wnt/β-catenin pathway-related WT1, β-catenin, and WTX together account for about one-third of Wilms tumor cases. --- Explanation: Confirms CTNNB1 as one of the key Wnt pathway genes mutated in Wilms tumor.


MONDO:0006058

[PMID:37916284] [INDIRECT EVIDENCE] [SUPPORT] Loss of WT1 in nephrogenic rests may leave these premalignant clones with inadequate DNA repair enzymes and may disturb the epigenetic landscape. --- Explanation: Supports the concept that nephrogenic rests with WT1 loss are premalignant precursors of Wilms tumor.

[PMID:37385707] [INDIRECT EVIDENCE] [SUPPORT] Wilms tumor (WT), or nephroblastoma, is the most common primary malignant renal tumor of childhood. It is an embryonal tumor that develops from remnants of immature kidney. --- Explanation: Confirms Wilms tumor arises from embryonal remnants of immature kidney tissue.


MONDO:0006058

[PMID:25018051] [INDIRECT EVIDENCE] [SUPPORT] epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF2, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors. --- Explanation: Confirms loss of imprinting at IGF2 locus leading to biallelic overexpression in Wilms tumor development.

[PMID:33394739] [INDIRECT EVIDENCE] [SUPPORT] While only 3% of patients without LOH/LOI relapsed, 20% with LOH 11p15 and 25% with LOI 11p15 relapsed --- Explanation: Demonstrates the prognostic significance of 11p15 LOH/LOI in Wilms tumor, confirming its role in tumor biology.


MAXO:0000004

[PMID:33394739] [SUPPORT] The COG approach of upfront nephrectomy allows for immediate histologic diagnosis, molecular analysis, and accurate local staging assessment. --- Explanation: Confirms the role of nephrectomy as primary surgical approach in COG trials.

[PMID:37385707] [SUPPORT] Advances in multimodal therapy including surgery, chemotherapy, and radiation therapy given according to risk stratification have allowed most patients to achieve survival rates in excess of 90%. --- Explanation: Confirms the multimodal approach including surgery achieves >90% survival.


MAXO:0000647

[PMID:39034876] [SUPPORT] The most common drugs used were vincristine and actinomycin D (78%). Only 12 patients (28%) received anthracyclines. --- Explanation: Confirms vincristine and dactinomycin as backbone chemotherapy with anthracyclines reserved for higher-risk patients.

[PMID:33394739] [SUPPORT] Stepwise advances made by the National Wilms Tumor Study Group (NWTSG), which was succeeded by the Children's Oncology Group (COG), and the International Society of Pediatric Oncology (SIOP) Renal Tumor Study Group (RTSG) have not only improved survival to 90%, but have also decreased the burden of therapy --- Explanation: Confirms that stepwise refinement of chemotherapy has improved survival to 90%.


NCIT:C412

[PMID:39034876] [INDIRECT EVIDENCE] [SUPPORT] The most common drugs used were vincristine and actinomycin D (78%). Only 12 patients (28%) received anthracyclines. --- Explanation: Confirms vincristine and dactinomycin as backbone chemotherapy with anthracyclines reserved for higher-risk patients.

[PMID:33394739] [INDIRECT EVIDENCE] [SUPPORT] Stepwise advances made by the National Wilms Tumor Study Group (NWTSG), which was succeeded by the Children's Oncology Group (COG), and the International Society of Pediatric Oncology (SIOP) Renal Tumor Study Group (RTSG) have not only improved survival to 90%, but have also decreased the burden of therapy --- Explanation: Confirms that stepwise refinement of chemotherapy has improved survival to 90%.


NCIT:C933


NCIT:C456


MAXO:0000014

[PMID:32893998] [SUPPORT] The objectives for the treatment of Wilms tumor in both the Children's Oncology Group (COG) and the International Society of Paediatric Oncology (SIOP) have focused on improving cure rates and minimizing toxicity by limiting the use of radiation and doxorubicin. --- Explanation: Confirms radiation therapy is part of standard treatment while efforts focus on minimizing its use to reduce toxicity.


hgnc:12796

[PMID:37916284] [SUPPORT] In 1990, mutations of the Wilms' tumor-1 gene (WT1), encoding a transcription factor in the embryonic kidney, were found in 10-15% of Wilms' tumors; germline WT1 mutations were associated with hereditary syndromes involving glomerular and reproductive tract dysplasia. --- Explanation: Confirms WT1 mutation frequency and germline association with hereditary syndromes.


hgnc:2514

[PMID:25018051] [SUPPORT] This has been illustrated by the findings that mutations of Wnt/β-catenin pathway-related WT1, β-catenin, and WTX together account for about one-third of Wilms tumor cases. --- Explanation: Confirms CTNNB1 as one of the key mutated genes in Wilms tumor contributing to Wnt pathway activation.


hgnc:26837

[PMID:25018051] [SUPPORT] This has been illustrated by the findings that mutations of Wnt/β-catenin pathway-related WT1, β-catenin, and WTX together account for about one-third of Wilms tumor cases. --- Explanation: Confirms WTX (AMER1) as one of the key mutated genes in Wilms tumor.


HGNC.SYMBOL:Loss of 11p15 Imprinting

[PMID:25018051] [SUPPORT] epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF2, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors. --- Explanation: Confirms loss of imprinting at IGF2/11p15 locus in Wilms tumor development.


HGNC.SYMBOL:Chromosome 1q Gain

[PMID:33394739] [SUPPORT] gain of chromosome 1q is one of the most commonly observed cytogenetic abnormalities in WT, seen in as many as 30% of patients --- Explanation: Confirms 1q gain frequency and its status as a common cytogenetic abnormality in Wilms tumor.

[PMID:33394739] [SUPPORT] A retrospective analysis of more than 1000 patients in NWTS-5 demonstrated that 1q gain was associated with inferior EFS and OS across all tumor stages --- Explanation: Demonstrates prognostic significance of 1q gain across all stages.


HGNC.SYMBOL:Combined LOH 1p/16q

[PMID:33394739] [SUPPORT] Combined LOH 1p and 16q has limited impact as a prognostic marker because only 5% of favorable histology WT carry this molecular change. --- Explanation: Confirms frequency and prognostic relevance of combined 1p/16q LOH.


hgnc:11998

[PMID:33394739] [SUPPORT] careful analysis including copy number assessment and immunohistochemistry, as well as confirming that anaplasia was present in the portion of tumor undergoing mutation analysis, indicated that nearly all anaplastic WT have TP53 mutations if one looks hard enough --- Explanation: Confirms near-universal TP53 mutation in anaplastic Wilms tumors when thoroughly assessed.


HGNC.SYMBOL:DROSHA and DICER1 Mutations

[PMID:25018051] [SUPPORT] Recent investigations also revealed that mutations of Drosha and Dicer, the RNases required for miRNA generation, and Dis3L2, the 3'-5' exonuclease that normally degrades miRNAs and mRNAs, could cause predisposition to Wilms tumors, demonstrating that miRNA can play a pivotal role in Wilms tumor development. --- Explanation: Confirms mutations in miRNA processing enzymes as a mechanism of Wilms tumor predisposition.

[DOI:10.1158/1541-7786.mcr-23-0930] [SUPPORT] DROSHA mutations are correlated with de-repressing microRNA target genes that regulate differentiation and proliferation and a self-renewing, mesenchymal state. --- Explanation: Demonstrates the functional consequence of DROSHA mutations in Wilms tumor, linking them to a self-renewing mesenchymal state.


HGNC.SYMBOL:SIX1/SIX2 Mutations

[PMID:25670083] [SUPPORT] Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases) --- Explanation: Landmark genomic study directly demonstrating recurrent SIX1/SIX2 Q177R mutations in 18.1% of blastemal-type Wilms tumors.


MONDO:0006058

[PMID:27512769] [SUPPORT] Typically, WT comprises three histological components namely blastemal, epithelial and stromal. The proportion and the degree of maturation of these components vary significantly, making the histological appearance of each tumour unique. Classical triphasic WT rarely presents diagnostic difficulty for pathologists --- Explanation: Directly describes the triphasic histological composition of Wilms tumor with blastemal, epithelial, and stromal components.


MONDO:0006058

[PMID:33394739] [SUPPORT] careful analysis including copy number assessment and immunohistochemistry, as well as confirming that anaplasia was present in the portion of tumor undergoing mutation analysis, indicated that nearly all anaplastic WT have TP53 mutations if one looks hard enough --- Explanation: Confirms near-universal TP53 mutation in anaplastic Wilms tumors.


MONDO:0010200

[PMID:15205951] [PARTIAL] Resultant liver damage leads to steatosis, inflammation, cirrhosis, and, occasionally, fulminant liver failure. --- Explanation: Hepatic copper accumulation causes progressive liver damage including steatosis and inflammation, which manifest as hepatomegaly. Direct frequency data for hepatomegaly not available in this abstract.


MONDO:0010200

[PMID:35197085] [SUPPORT] Four patients (17%) presented with acute liver failure and fifteen (63%) individuals had cirrhosis at diagnosis. --- Explanation: Cohort data support cirrhosis as a common presenting hepatic phenotype in Wilson disease.

[PMID:38731973] [PARTIAL] Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. --- Explanation: End-stage liver disease including cirrhosis is a major complication requiring transplantation.


MONDO:0010200

[PMID:35197085] [SUPPORT] Four patients (17%) presented with acute liver failure and fifteen (63%) individuals had cirrhosis at diagnosis. --- Explanation: Supports acute hepatic failure as a recognized presenting hepatic manifestation in Wilson disease.


MONDO:0010200

[PMID:28433112] [SUPPORT] Most liver biopsy specimens show moderate to severe steatosis, variable degree of portal and/or lobular inflammation, and fibrosis eventually progressing to cirrhosis. --- Explanation: Liver biopsy findings of portal and lobular inflammation are consistent with hepatitis as a very frequent hepatic presentation.

[PMID:28433112] [SUPPORT] Wilson disease may be microscopically misinterpreted as many other liver diseases, including viral or autoimmune hepatitis, alcoholic/nonalcoholic steatohepatitis, toxic liver injury, cryptogenic cirrhosis --- Explanation: Wilson disease liver pathology frequently mimics hepatitis patterns, confirming hepatitis-like presentation.


MONDO:0010200

[PMID:16709660] [SUPPORT] Diagnostic criteria for non-caeruloplasmin-bound serum copper, serum caeruloplasmin, 24-h urinary copper excretion, liver copper content, presence of Kayser-Fleischer rings and histological signs of chronic liver damage were reached in 86.6%, 88.2%, 87.1%, 92.7%, 66.3% and 73% of patients, respectively. --- Explanation: Large-cohort data confirm frequent Kayser-Fleischer ring detection in diagnosed Wilson disease.

[PMID:38731973] [SUPPORT] copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings --- Explanation: Confirms Kayser-Fleischer rings as a key clinical feature of Wilson's disease due to copper deposition in the eyes.


MONDO:0010200

[PMID:33474589] [SUPPORT] most common neurological manifestation was dystonia, followed by tremor and parkinsonism. --- Explanation: Cohort data directly identify tremor as a common neurologic manifestation.

[PMID:28433096] [SUPPORT] spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia --- Explanation: Supports tremor as part of the core neurologic phenotype spectrum.


MONDO:0010200

[PMID:33474589] [SUPPORT] most common neurological manifestation was dystonia, followed by tremor and parkinsonism. --- Explanation: Cohort data support dystonia as the most common neurologic manifestation in this series.

[PMID:28433096] [SUPPORT] spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia --- Explanation: Supports dystonia as a core feature of neurologic Wilson disease.


MONDO:0010200

[PMID:33474589] [SUPPORT] most common neurological manifestation was dystonia, followed by tremor and parkinsonism. --- Explanation: Cohort data directly report parkinsonism among predominant neurologic presentations.

[PMID:28433096] [SUPPORT] spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia --- Explanation: Supports parkinsonian-spectrum motor features in neurologic Wilson disease.


MONDO:0010200

[PMID:28433096] [SUPPORT] spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia --- Explanation: Supports bradykinesia as part of the neurologic movement phenotype spectrum.


MONDO:0010200

[PMID:28433096] [SUPPORT] spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia --- Explanation: Supports rigidity as part of the neurologic movement phenotype spectrum.


MONDO:0010200

[PMID:28433096] [SUPPORT] spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia --- Explanation: Supports chorea as part of the neurologic movement phenotype spectrum.


MONDO:0010200

[PMID:38731973] [SUPPORT] Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia --- Explanation: Dysarthria is explicitly listed as a neurological manifestation of Wilson disease.

[PMID:28433096] [SUPPORT] spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia --- Explanation: Confirms dysarthria among core neurologic Wilson disease features.


MONDO:0010200

[PMID:38731973] [SUPPORT] Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia --- Explanation: Ataxia is explicitly listed as a neurological manifestation of Wilson disease.


MONDO:0010200

[PMID:38731973] [SUPPORT] Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia --- Explanation: Dysphagia is explicitly listed as a neurological manifestation of Wilson disease.

[PMID:28433096] [SUPPORT] spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia --- Explanation: Confirms dysphagia among the core neurologic manifestations.


MONDO:0010200

[PMID:38731973] [SUPPORT] Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia --- Explanation: Supports writing impairment as part of the neurologic Wilson disease phenotype.


MONDO:0010200

[PMID:38731973] [SUPPORT] Among these are depression, psychosis, dysarthria, ataxia, writing problems --- Explanation: Depression is explicitly listed as a neuropsychiatric manifestation of Wilson disease.


MONDO:0010200

[PMID:38731973] [SUPPORT] Among these are depression, psychosis, dysarthria, ataxia, writing problems --- Explanation: Psychosis is explicitly listed as a neuropsychiatric manifestation of Wilson disease.


MONDO:0010200

[PMID:28433113] [PARTIAL] the cerebral copper content is not correlated with the severity of the neuropathologic abnormalities or with the neuropsychiatric symptomatology. --- Explanation: Reference to neuropsychiatric symptomatology in Wilson disease indirectly supports personality changes as a recognized psychiatric feature, though personality changes are not individually named in this abstract.


MONDO:0010200

[PMID:38731973] [SUPPORT] This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias --- Explanation: Cardiomyopathy is explicitly listed as a cardiac manifestation of Wilson disease due to copper deposition.


MONDO:0010200

[PMID:38731973] [SUPPORT] This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias --- Explanation: Cardiac arrhythmias are explicitly listed as a cardiac manifestation of Wilson disease.


MONDO:0010200

[PMID:38731973] [SUPPORT] This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction --- Explanation: Renal tubular dysfunction is explicitly listed as a renal manifestation of Wilson disease.


MONDO:0010200

[PMID:38731973] [SUPPORT] In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin --- Explanation: Coombs-negative hemolytic anemia is described as a key feature of Wilson disease.


MONDO:0010200

[PMID:38731973] [SUPPORT] This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis --- Explanation: Rhabdomyolysis is explicitly listed as a muscle manifestation in Wilson disease.


MONDO:0010200

[PMID:29110062] [SUPPORT] The pooled prevalencerates of osteopenia and osteoporosis in WD patients were 36.5% --- Explanation: Meta-analysis supports frequent low bone density and osteoporosis in Wilson disease populations.

[PMID:38731973] [SUPPORT] This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis --- Explanation: Osteoporosis is explicitly listed as a skeletal manifestation of Wilson disease.


MONDO:0010200

[PMID:29110062] [SUPPORT] The pooled prevalencerates of osteopenia and osteoporosis in WD patients were 36.5% --- Explanation: Meta-analysis supports osteopenia as a common bone phenotype in Wilson disease.


MONDO:0010200

[PMID:38731973] [SUPPORT] osteoporosis, osteomalacia, arthritis, and arthralgia --- Explanation: Osteomalacia is explicitly listed among musculoskeletal manifestations in Wilson disease.


MONDO:0010200

[PMID:38731973] [SUPPORT] osteoporosis, osteomalacia, arthritis, and arthralgia --- Explanation: Arthritis is listed as a musculoskeletal manifestation of Wilson disease.


MONDO:0010200

[PMID:38731973] [SUPPORT] osteoporosis, osteomalacia, arthritis, and arthralgia --- Explanation: Arthralgia is explicitly listed among musculoskeletal manifestations in Wilson disease.


MONDO:0010200

[PMID:38731973] [INDIRECT EVIDENCE] [SUPPORT] Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. --- Explanation: Confirms that impaired biliary copper excretion is the primary defect caused by ATP7B dysfunction.

[PMID:16382340] [INDIRECT EVIDENCE] [SUPPORT] ATP7B is the gene product of the WD gene located on chromosome 13 and resides in hepatocytes in the trans-Golgi network, transporting copper into the secretory pathway for incorporation into apoceruloplasmin and excretion into the bile. --- Explanation: Supports ATP7B localization to the trans-Golgi network with biliary excretion function.

[PMID:18395099] [INDIRECT EVIDENCE] [SUPPORT] Copper excess provokes a massive download of the ATP7B retained in the trans-Golgi network into the bile canalicular membrane. --- Explanation: Demonstrates copper-stimulated ATP7B trafficking to the canalicular membrane.


MONDO:0010200


MONDO:0010200

[PMID:16382340] [INDIRECT EVIDENCE] [SUPPORT] ATP7B is the gene product of the WD gene located on chromosome 13 and resides in hepatocytes in the trans-Golgi network, transporting copper into the secretory pathway for incorporation into apoceruloplasmin and excretion into the bile. --- Explanation: Supports that ATP7B loads copper into apoceruloplasmin in the secretory pathway.


MONDO:0010200

[PMID:16382340] [INDIRECT EVIDENCE] [SUPPORT] Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism, resulting in pathological accumulation of copper in many organs and tissues. --- Explanation: Supports multi-organ copper accumulation in Wilson disease.

[PMID:38731973] [INDIRECT EVIDENCE] [SUPPORT] Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. --- Explanation: Confirms hepatic copper overflow into systemic circulation.


MONDO:0010200

[PMID:38731973] [INDIRECT EVIDENCE] [SUPPORT] Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation --- Explanation: Demonstrates that excess copper generates ROS leading to oxidative stress and cellular injury.

[PMID:24517326] [INDIRECT EVIDENCE] [SUPPORT] On the contrary, however, when copper is massively deposited in mitochondria, severe structural and respiratory impairments are observed upon disease progression. This provokes reactive oxygen species and consequently causes the mitochondrial membranes to disintegrate, which triggers hepatocyte death. --- Explanation: Supports mitochondrial dysfunction, ROS generation, and hepatocyte death with copper overload.

[PMID:28433112] [INDIRECT EVIDENCE] [SUPPORT] Most liver biopsy specimens show moderate to severe steatosis, variable degree of portal and/or lobular inflammation, and fibrosis eventually progressing to cirrhosis. --- Explanation: Supports progression from hepatic injury to fibrosis and cirrhosis.

[PMID:30452922] [INDIRECT EVIDENCE] [SUPPORT] ATP7B-deficient hepatocytes, such as in those in patients with WD, activate autophagy in response to copper overload to prevent copper-induced apoptosis. --- Explanation: Demonstrates that human Wilson disease hepatocytes activate autophagy as a protective response to copper overload.

[PMID:30452922] [INDIRECT EVIDENCE] [SUPPORT] Hepatocytes in liver tissues from patients with WD and from Atp7b-/- mice and rats (but not controls) had multiple autophagosomes. --- Explanation: Atp7b-/- mice and rats confirm autophagosome accumulation in ATP7B-deficient hepatocytes, corroborating the human findings.

[PMID:33360697] [INDIRECT EVIDENCE] [PARTIAL] In general, the results reveal that Cu exposure can cause mitophagy through the PINK1/Parkin pathway in chicken livers, and that mitophagy might attenuate Cu-induced mitochondrial apoptosis. --- Explanation: Shows copper-induced mitophagy in chicken liver tissue (non-standard model), supporting mitochondrial quality control responses to copper overload.


MONDO:0010200

[PMID:28433113] [INDIRECT EVIDENCE] [SUPPORT] In Wilson disease (WD), brain cellular damage is thought to be due to copper deposition. Striatal lesions are the most characteristic lesions found in the brain of patients with neurologic symptoms, as emphasized in the initial reports of S.A.K. Wilson. --- Explanation: Supports copper deposition driving brain damage with characteristic striatal lesions.

[PMID:31179301] [INDIRECT EVIDENCE] [SUPPORT] Most severe neuropathologic abnormalities, including tissue rarefaction, reactive astrogliosis, myelin palor, and presence of iron-laden macrophages, are typically present in the putamen while other basal ganglia, thalami, and brainstem are usually less affected. --- Explanation: Supports reactive astrogliosis and basal ganglia/putamen involvement.

[PMID:39334421] [INDIRECT EVIDENCE] [PARTIAL] At 3-5 months of age, these mice started to display neurological deficits in motor coordination and cognitive dysfunction, accompanied by increased expression of inflammatory cytokines in the central nervous system. Microglia in the striatum and cortex exhibit significant activation, shorter processes, and decreased branch points. --- Explanation: Demonstrates CNS inflammatory cytokines and microglial activation in a Wilson disease mouse model.


MONDO:0010200

[PMID:38731973] [INDIRECT EVIDENCE] [PARTIAL] Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death --- Explanation: Establishes cuproptosis as a copper-dependent cell death mechanism in Wilson disease.

[PMID:41006805] [INDIRECT EVIDENCE] [SUPPORT] Moreover, abnormal lipoylation of the copper-dependent proteins metal-binding domain of ferredoxin 1 and dihydrolipoamide transacetylase causes mitochondrial protein oligomer buildup and tricarboxylic acid cycle dysfunction, reinforcing an "oxidative damage-inflammation-fibrosis" vicious cycle. --- Explanation: Supports lipoylation-related mitochondrial proteotoxic stress and TCA cycle dysfunction consistent with cuproptosis.


MONDO:0010200

[PMID:38731973] [INDIRECT EVIDENCE] [SUPPORT] In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles --- Explanation: Demonstrates that ferroptosis may contribute to liver injury in Wilson disease due to iron accumulation.


MAXO:0001224

[PMID:38731973] [SUPPORT] Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. --- Explanation: Establishes D-penicillamine as first-line chelation therapy with evidence for improved prognosis.

[PMID:37116715] [PARTIAL] NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW. --- Explanation: Large cohort data show treatment-associated neurological worsening can occur, supporting close neurologic monitoring during chelation.


MAXO:0001224

[PMID:35887738] [SUPPORT] The two salts of trientine were effective in treating patients with WD. --- Explanation: Directly supports trientine efficacy in treated Wilson disease cohorts.


MAXO:0000058

[PMID:37741465] [SUPPORT] reduction of copper absorption in the gut (zinc therapy) --- Explanation: Confirms zinc therapy works by reducing intestinal copper absorption.


CHEBI:62984

[PMID:37741465] [INDIRECT EVIDENCE] [SUPPORT] reduction of copper absorption in the gut (zinc therapy) --- Explanation: Confirms zinc therapy works by reducing intestinal copper absorption.


MAXO:0000088

[PMID:38731973] [PARTIAL] copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain --- Explanation: Establishes that dietary intake is a source of copper, supporting dietary restriction as an adjunctive treatment approach.


MAXO:0001224

[PMID:37741465] [PARTIAL] Current treatment protocols are limited to either sequestration of copper via chelation or reduction of copper absorption in the gut --- Explanation: Tetrathiomolybdate represents an emerging chelation approach that tightly complexes copper.


CHEBI:30703

[PMID:37741465] [INDIRECT EVIDENCE] [PARTIAL] Current treatment protocols are limited to either sequestration of copper via chelation or reduction of copper absorption in the gut --- Explanation: Tetrathiomolybdate represents an emerging chelation approach that tightly complexes copper.


MAXO:0001175

[PMID:38731973] [SUPPORT] Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. --- Explanation: Confirms liver transplantation as curative treatment that replaces the defective gene.


hgnc:870

[PMID:37741465] [SUPPORT] Inactivating mutations of the copper-transporting P-type ATPase, ATP7B, result in Wilson's disease, an autosomal recessive disorder --- Explanation: Establishes ATP7B mutations as the causative genetic defect in Wilson's disease with autosomal recessive inheritance.

[PMID:15205951] [SUPPORT] Thus far, more than 200 mutations of the WD gene have been detected, causing impairment of ATP7B function and, ultimately, copper accumulation. --- Explanation: Confirms large number of ATP7B mutations causing Wilson disease.


MONDO:0010200

[PMID:37741465] [SUPPORT] Inactivating mutations of the copper-transporting P-type ATPase, ATP7B, result in Wilson's disease, an autosomal recessive disorder --- Explanation: Directly states autosomal recessive inheritance for Wilson disease.


MONDO:0006018

[PMID:8150635] [SUPPORT] This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia. --- Explanation: The abstract lists recurrent high fever as a typical symptom of Wissler-Fanconi syndrome.


MONDO:0006018

[PMID:8150635] [SUPPORT] This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia. --- Explanation: The abstract lists polymorphous exanthemas as a typical symptom of Wissler-Fanconi syndrome.


MONDO:0006018

[PMID:8150635] [SUPPORT] This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia. --- Explanation: The abstract lists arthralgia as a typical symptom of Wissler-Fanconi syndrome.


MONDO:0006018

[PMID:8150635] [SUPPORT] This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia. --- Explanation: The abstract lists leukocytosis as a typical symptom of Wissler-Fanconi syndrome.


MONDO:0006018

[PMID:3572917] [PARTIAL] We describe a case of persistent microscopic hematuria as initial finding in incomplete Still's disease or Wissler-Fanconi syndrome. --- Explanation: The case report documents microscopic hematuria as a presenting sign.


MONDO:0006018

[PMID:27843372] [PARTIAL] A middle-aged female presented to the emergency department with shortness of breath and chest pain associated with fever, polyarthritis, and had a chronic polymorphic rash on the back and lower extremities. --- Explanation: The case report documents polyarthritis as part of the clinical presentation.


MONDO:0006018

[PMID:3092775] [PARTIAL] The long-term evolution is marked by recurrent febrile exacerbations, sometimes complicated by pericardo-myocarditis which usually resolves without sequellae. --- Explanation: The abstract notes pericardo-myocarditis as a complication during the course of disease.


MONDO:0006018

[PMID:3092775] [PARTIAL] The long-term evolution is marked by recurrent febrile exacerbations, sometimes complicated by pericardo-myocarditis which usually resolves without sequellae. --- Explanation: The abstract reports pericardo-myocarditis as a complication of Wissler-Fanconi syndrome.


MONDO:0006018

[PMID:3092775] [SUPPORT] The authors report a case with chronic pericardo-myocarditis progressing over a 7 year period to refractory congestive cardiac failure. --- Explanation: The case report documents progression to refractory congestive heart failure.


MAXO:0000221

[PMID:27843372] [PARTIAL] A combination of nonsteroidal anti-inflammatory drugs and steroids achieved complete remission. --- Explanation: The case report documents remission with NSAID therapy.


NCIT:C680

[PMID:27843372] [INDIRECT EVIDENCE] [PARTIAL] A combination of nonsteroidal anti-inflammatory drugs and steroids achieved complete remission. --- Explanation: The case report documents remission with NSAID therapy.


MAXO:0000640

[PMID:27843372] [PARTIAL] A combination of nonsteroidal anti-inflammatory drugs and steroids achieved complete remission. --- Explanation: The case report notes complete remission with steroids plus NSAIDs.

[PMID:1210460] [PARTIAL] In the present case the disease could successfully be controlled using imuran in combination with corticosteroids. --- Explanation: The abstract indicates corticosteroids were part of successful therapy.


MAXO:0000058

[PMID:27843372] [PARTIAL] A combination of naproxen, dapsone, and prednisolone therapy resulted in significant improvement of the patient’s arthralgias and rash. --- Explanation: The case report documents improvement with dapsone as part of combination therapy.


MAXO:0000058

[PMID:1210460] [PARTIAL] In the present case the disease could successfully be controlled using imuran in combination with corticosteroids. --- Explanation: The abstract reports successful control with azathioprine (imuran) plus steroids.


MONDO:0010619

[PMID:31104833] [SUPPORT] X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment --- Explanation: Phase 3 trial confirms rickets and lower extremity bowing as cardinal pediatric features of XLH.

[PMID:11062477] [SUPPORT] characterized by low serum phosphorus concentrations, rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses --- Explanation: Rickets listed as core clinical feature of phosphate wasting disorders.


MONDO:0010619

[PMID:29947083] [SUPPORT] Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities --- Explanation: Short stature confirmed as characteristic adult XLH feature.

[PMID:11062477] [SUPPORT] rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses --- Explanation: Short stature listed as core clinical feature.


MONDO:0010619

[PMID:29947083] [SUPPORT] short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia --- Explanation: Lower limb deformities confirmed as characteristic feature in adults with XLH.

[PMID:29460029] [SUPPORT] Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent --- Explanation: Confirms that lower limb bowing frequently requires surgical correction in adult XLH patients.


MONDO:0010619

[PMID:29947083] [SUPPORT] accelerated osteoarthritis, dental abscesses, and enthesopathy --- Explanation: Dental abscesses confirmed as characteristic adult XLH feature.

[PMID:29460029] [SUPPORT] Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common --- Explanation: 63% prevalence of dental disease in adult XLH cohort.

[PMID:11062477] [SUPPORT] rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses --- Explanation: Dental abscesses listed as core clinical feature of phosphate wasting disorders.


MONDO:0010619

[PMID:29947083] [SUPPORT] dental abscesses, and enthesopathy --- Explanation: Enthesopathy confirmed as characteristic adult XLH feature.

[PMID:29460029] [PARTIAL] Joint replacement and decompressive laminectomy were observed in those older than 40 years --- Explanation: Progressive enthesopathy leads to need for joint replacement and spinal surgery in older adults.


MONDO:0010619

[PMID:29460029] [SUPPORT] X-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia --- Explanation: XLH confirmed as the most common hereditary cause of hypophosphatemia.

[PMID:29947083] [SUPPORT] leading to lifelong renal phosphate wasting and hypophosphatemia --- Explanation: Lifelong hypophosphatemia confirmed as the biochemical hallmark.


MONDO:0010619


MONDO:0010619

[PMID:29947083] [INDIRECT EVIDENCE] [SUPPORT] inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia --- Explanation: Directly describes the FGF23-mediated phosphate wasting mechanism in XLH.

[PMID:7550339] [INDIRECT EVIDENCE] [SUPPORT] impaired phosphate uptake in the kidney, which is likely to be caused by abnormal regulation of sodium phosphate cotransport in the proximal tubules --- Explanation: Early evidence linking PHEX to renal proximal tubule phosphate transport defect.

[PMID:11062477] [INDIRECT EVIDENCE] [PARTIAL] We identified missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23 --- Explanation: Discovery of FGF23 as the phosphaturic factor, providing the mechanistic link between PHEX and phosphate wasting.


MONDO:0010619

[PMID:29947083] [INDIRECT EVIDENCE] [PARTIAL] fractures, and pseudofractures due to osteomalacia --- Explanation: Pseudofractures and fractures reflect defective mineralization (osteomalacia) in adults with XLH.


MAXO:0000004

[PMID:29460029] [SUPPORT] Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40 years --- Explanation: Confirms frequent need for osteotomy and joint replacement in adult XLH patients.


HGNC.SYMBOL:PHEX Mutations

[PMID:7550339] [SUPPORT] By positional cloning, we have isolated a candidate gene from the HYP region in Xp22.1. This gene exhibits homology to a family of endopeptidase genes --- Explanation: Original cloning of the PHEX gene from Xp22.1 with endopeptidase homology.

[PMID:7550339] [SUPPORT] Intragenic non-overlapping deletions from four different families and three mutations (two splice sites and one frameshift) have been detected in HYP patients --- Explanation: Early evidence of diverse mutation types in PHEX causing XLH.

[PMID:29460029] [SUPPORT] XLH is associated with a large number of private mutations; 37 different mutations in the PHEX gene were identified in this cohort --- Explanation: 37 distinct PHEX mutations in a single cohort confirms extensive allelic heterogeneity.

[PMID:11062477] [SUPPORT] Inactivating mutations of the gene PHEX, encoding a member of the neutral endopeptidase family of proteins, are responsible for XLH --- Explanation: Confirms inactivating PHEX mutations as the cause of XLH.


MONDO:0033365

[PMID:39413657] [SUPPORT] Developmental and epileptic encephalopathy 56 (DEE-56) is caused by pathogenic variants in YWHAG and is characterized by early-onset epilepsy and neurodevelopmental delay. --- Explanation: Directly supports early-onset epilepsy as a defining clinical feature of DEE56.

[PMID:39413657] [SUPPORT] Early-onset seizures, particularly febrile seizures, were common, with various seizure types reported. --- Explanation: Supports the breadth of the seizure phenotype and the prominence of febrile seizures in this syndrome.


MONDO:0033365

[PMID:38491959] [SUPPORT] Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. --- Explanation: Supports intellectual disability as one of the most frequent non-seizure manifestations in reported YWHAG cohorts.

[PMID:39413657] [SUPPORT] Individuals with YWHAG variants exhibited variable psychomotor delay, with the majority experiencing mild intellectual disability. --- Explanation: Supports the developmental-delay to mild-intellectual-disability spectrum in the larger pooled cohort.


MONDO:0033365

[PMID:38491959] [SUPPORT] Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. --- Explanation: Supports behavioral abnormality as a very frequent non-seizure feature in the largest dedicated YWHAG cohort.

[PMID:39413657] [SUPPORT] Comorbidities such as autism spectrum disorders and attention deficit-hyperreactivity disorder were observed in a proportion of individuals. --- Explanation: Supports the specific spectrum of reported behavioral comorbidities in DEE56.


MONDO:0033365

[PMID:39413657] [SUPPORT] Movement disorders were present in a subset of individuals, primarily manifesting as ataxia and tremor. --- Explanation: Supports ataxia as a recurrent but non-obligate neurologic comorbidity.


MONDO:0033365

[PMID:28777935] [INDIRECT EVIDENCE] [SUPPORT] We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy --- Explanation: Establishes YWHAG as the causal disease gene upstream of the downstream neuronal phenotypes represented in this entry.

[PMID:38491959] [INDIRECT EVIDENCE] [SUPPORT] A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains --- Explanation: Supports severity enrichment for ligand-binding-domain missense alleles, including the mechanistically important Arg132 region.

[PMID:40152536] [INDIRECT EVIDENCE] [SUPPORT] Our findings suggest that the disruption of the stability of the highly conserved internal core of the YWHAG protein may be one mechanism leading to functional impairment, distinct from the previously proposed pathogenic models of dimer formation defects and/or impaired binding to phosphopeptide ligands. --- Explanation: Supports that pathogenic YWHAG variants can impair function through structural destabilization in addition to altered ligand-binding behavior.


MONDO:0033365


MONDO:0033365

[DOI:10.64898/2026.04.01.715876] [INDIRECT EVIDENCE] [SUPPORT] The widespread alterations in the transcriptome of mutant neurons revealed a biphasic dysregulation in the core genes and modulators associated with the ROCK pathway that resulted in maturation-dependent changes to cytoskeletal protein stability and calcium phenotypes. --- Explanation: Directly supports a ROCK-associated signaling/remodeling layer upstream of the cytoskeletal and calcium phenotypes in the YWHAG p.Arg132Cys cortical neuron model.


MONDO:0033365

[DOI:10.64898/2026.04.01.715876] [INDIRECT EVIDENCE] [SUPPORT] Exposure of YWHAGR132C/+ neurons to Trypsin-EDTA revealed underlying cytoskeletal instability, which was partially reversed by lovastatin treatment. --- Explanation: Directly supports latent cytoskeletal fragility in mutant cortical neurons and its partial lovastatin responsiveness.


MONDO:0033365

[DOI:10.64898/2026.04.01.715876] [INDIRECT EVIDENCE] [SUPPORT] Direct inhibition of ROCK with Y27632 further increased the calcium baseline compared to the isogenic control. Further, lovastatin partially rescued the elevated calcium baseline. --- Explanation: Directly supports elevated baseline calcium as a distinct homeostatic phenotype that is modified by ROCK inhibition and partially improved by lovastatin.


MONDO:0033365

[DOI:10.64898/2026.04.01.715876] [INDIRECT EVIDENCE] [SUPPORT] The YWHAGR132C/+ iPSC-derived neurons exhibited early cytoskeletal phenotypes, coupled with an elevated calcium baseline, lower frequency of calcium spikes, and reduced network activity. --- Explanation: Directly supports reduced spontaneous calcium signaling and network activity as a phenotype distinct from the elevated baseline-calcium state.

[DOI:10.64898/2026.04.01.715876] [INDIRECT EVIDENCE] [SUPPORT] Further, lovastatin partially rescued the elevated calcium baseline, but not the frequency or amplitude of calcium spikes. --- Explanation: Directly supports the partial decoupling between baseline calcium homeostasis and activity-dependent calcium signaling in mutant neurons.


hgnc:12852

[PMID:38491959] [SUPPORT] A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains --- Explanation: Supports the specific association between ligand-binding-domain missense alleles and the more severe DEE end of the YWHAG spectrum.

[PMID:40152536] [SUPPORT] Our findings suggest that the disruption of the stability of the highly conserved internal core of the YWHAG protein may be one mechanism leading to functional impairment --- Explanation: Supports a second molecular mechanism in which pathogenic alleles impair YWHAG by destabilizing the protein core.


MONDO:0033365

[PMID:28777935] [SUPPORT] We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy --- Explanation: The original discovery cohort identified de novo heterozygous YWHAG variants as the disease-associated inheritance pattern for early-onset epileptic encephalopathy.


MONDO:0006019

[PMID:40036381] [SUPPORT] In the primary stage, patients develop a, usually painless, papilloma or ulcer, often on the lower extremities, which is highly contagious. --- Explanation: The abstract describes ulcer formation in primary yaws.


MAXO:0000058

[PMID:40036381] [SUPPORT] Though yaws can be treated with benzathine penicillin, oral azithromycin has become the preferred treatment due to its ease of administration. --- Explanation: The abstract notes oral azithromycin as the preferred treatment.


NCBITaxon:168

[PMID:40036381] [SUPPORT] Yaws, a neglected tropical disease caused by Treponema pallidum subsp. pertenue, primarily affects children in impoverished rural areas. --- Explanation: The abstract identifies T. pallidum subsp. pertenue as the cause of yaws.


MONDO:0014848

[PMID:37215500] [PARTIAL] global development delay complicated with postnatal growth retardation for more than 1 year --- Explanation: Case report explicitly documents global developmental delay as a presenting feature in an infant with YHFS.


MONDO:0014848

[PMID:37215500] [SUPPORT] extremely severe mental retardation --- Explanation: Severe intellectual disability is a core feature documented in YHFS cases.

[PMID:33444416] [SUPPORT] variants of TELO2 have been linked to an intellectual disability disorder, the You-Hoover-Fong syndrome --- Explanation: Intellectual disability is recognized as the defining feature of the syndrome.


MONDO:0014848

[PMID:37215500] [PARTIAL] microcephaly --- Explanation: Microcephaly is explicitly listed as a clinical feature in YHFS.


MONDO:0014848

[PMID:37215500] [PARTIAL] congenital cataract --- Explanation: Congenital cataracts are documented in YHFS; surgical correction improved visual responses.


MONDO:0014848


MONDO:0014848

[PMID:37215500] [PARTIAL] abnormal hearing --- Explanation: Abnormal hearing is documented in YHFS cases.


MONDO:0014848

[PMID:37215500] [PARTIAL] congenital atrial septal defect --- Explanation: Congenital heart defects including ASD are documented in YHFS.


MONDO:0014848

[PMID:33444416] [INDIRECT EVIDENCE] [PARTIAL] the human counterpart of CLK-2/TEL2, TELO2, has been also implicated in the NMD, suggesting a conserved role of CLK-2/TEL2 proteins in mRNA surveillance --- Explanation: Demonstrates that TELO2 plays a conserved role in nonsense-mediated mRNA decay, linking the genetic defect to cellular dysfunction.


MAXO:0000950


MAXO:0000004

[PMID:37215500] [PARTIAL] After bilateral cataract surgery, the infant obtained better visual acuity and showed more responses and interactions with her parents --- Explanation: Demonstrates benefit of cataract surgery for improving visual function and patient engagement.


HGNC.SYMBOL:TELO2 mutations

[PMID:37215500] [PARTIAL] two compound heterozygous mutations, including a likely pathogenic TELO2 variant, c.2245A > T (p.K749X) from her mother and an uncertain variant, c.2299C > T (p.R767C) from her father --- Explanation: Documents novel compound heterozygous TELO2 variants causing YHFS.