MAXO:0000058

[PMID:33163187] [SUPPORT] Some patients with hormone-treatment failure or hormone resistance were treated with immunosuppressive agents, such as cyclosporine, azathioprine, and sirolimus, which were also effective --- Explanation: Documents effectiveness of multiple immunosuppressive agents in corticosteroid-refractory Cronkhite-Canada syndrome

[PMID:32459145] [SUPPORT] Other immunosuppressive agents, such as tacrolimus, have been shown to exhibit partial effects. --- Explanation: Case report confirms tacrolimus and other immunosuppressive agents as effective therapeutic options for CCS management

[PMID:40709433] [SUPPORT] The patient was treated with a combination of corticosteroids and azathioprine, which led to marked clinical and endoscopic improvements. --- Explanation: Recent case demonstrates efficacy of combination corticosteroid and azathioprine therapy with sustained remission on 1-year follow-up

[PMID:36781513] [SUPPORT] Twelve patients trialed thiopurine therapy, and ten patients continued with a thiopurine until the last follow-up. --- Explanation: Large cohort study documents long-term tolerability and sustained use of thiopurine therapy in majority of CCS patients for maintaining remission

[PMID:32669505] [SUPPORT] Calcineurin inhibitors such as CyA might have potential therapeutic efficacy for CCS associated with MN. --- Explanation: Case report demonstrates cyclosporine A as promising therapeutic option for CCS with autoimmune complications


MAXO:0000950

[PMID:33163187] [SUPPORT] Symptomatic treatment and nutritional-support therapy --- Explanation: Emphasizes the importance of nutritional support in comprehensive Cronkhite-Canada syndrome management

[PMID:39470508] [SUPPORT] Treatment included hormones with antiallergic medication, acid-suppressing drugs, salicylates, and nutritional support with zinc sulfate, adding trace elements and amino acids. --- Explanation: Recent case demonstrates comprehensive multimodal supportive care approach including trace elements and amino acid supplementation


MONDO:0007405

[PMID:7493034] [PARTIAL] Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia --- Explanation: Confirms craniosynostosis as a defining characteristic of Crouzon syndrome, occurring without the limb anomalies seen in related FGFR2 syndromes like Apert or Pfeiffer.


MONDO:0007405

[PMID:7493034] [SUPPORT] Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia --- Explanation: Directly identifies midface hypoplasia as one of the three cardinal features characterizing Crouzon syndrome.


MONDO:0007405

[PMID:7493034] [SUPPORT] Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia --- Explanation: Directly identifies ocular proptosis as one of the defining features of Crouzon syndrome.


MONDO:0007405


MONDO:0007405

[PMID:7493034] [INDIRECT EVIDENCE] [PARTIAL] we have identified 10 different mutations in the FGFR2 extracellular immunoglobulin III (IgIII) domain in 50% (16/32) of our Crouzon syndrome patients --- Explanation: Confirms that FGFR2 mutations in the Ig-III domain are found in a substantial proportion of Crouzon syndrome patients, supporting the pathophysiology centered on FGFR2 dysfunction.


MONDO:0007405

[PMID:8528214] [INDIRECT EVIDENCE] [SUPPORT] The W290G mutation was found in exon IIIa which is common to both alternatively spliced forms of FGFR2, BEK (expressed predominantly in primordial bones) and KGFR (expressed preferentially in epithelia). Atypical Crouzon syndrome features of epithelial-derived anal and/or external ear anomalies were present in the two affected family members with the mutation. This phenotype possibly reflects the expression of both mutant BEK and KGFR. --- Explanation: This links an exon IIIa Crouzon allele to simultaneous perturbation of both FGFR2 splice forms and a broader epithelial phenotype than classic cranial-only disease.

[DOI:10.1002/dvdy.22314] [INDIRECT EVIDENCE] [PARTIAL] The defects in W290R mutants are suggestive of disruption of signalling in both IIIb and IIIc isoforms of the Fgfr2 gene. --- Explanation: The codon-290 mouse model independently supports the idea that shared-isoform alleles can disrupt both FGFR2 splice forms.


MAXO:0000004


HGNC.SYMBOL:FGFR2 Mutations

[PMID:8528214] [SUPPORT] Five different mutations were found including two novel (W290G, C342W) and two previously reported, recurrent mutations for Crouzon syndrome (A344A, S354C), and one new mutation for Jackson-Weiss syndrome (C342R) --- Explanation: Demonstrates allelic heterogeneity with multiple different FGFR2 mutations causing Crouzon syndrome, including mutations in exon IIIa and IIIc.

[PMID:7493034] [PARTIAL] All mutations described so far for other craniosynostotic syndromes with associated limb anomalies--Jackson-Weiss, Pfeiffer, and Apert--also occur in the extracellular domain of FGFR2 --- Explanation: Confirms that Crouzon syndrome FGFR2 mutations occur in the extracellular domain, similar to other craniosynostosis syndromes but distinguishing it from those with limb involvement.


MONDO:0012833

[PMID:7493034] [SUPPORT] Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia, is associated with mutations in fibroblast growth factor receptor 2 (FGFR2) --- Explanation: While classic Crouzon syndrome is caused by FGFR2 mutations, CSAN patients have the same craniosynostosis phenotype but caused by FGFR3 mutations, demonstrating locus heterogeneity in Crouzon syndrome.


MONDO:0012833


MONDO:0012833

[PMID:7493034] [SUPPORT] We now report the unexpected observation of a FGFR3 transmembrane domain mutation, Ala391Glu, in three unrelated families with Crouzon syndrome and acanthosis nigricans, a specific skin disorder of hyperkeratosis and hyperpigmentation. --- Explanation: Acanthosis nigricans is a defining feature that distinguishes this syndrome from classic FGFR2-related Crouzon syndrome.


MONDO:0012833

[PMID:10696568] [INDIRECT EVIDENCE] [PARTIAL] Recent evidence suggests that the phenotypic differences may be due to specific alleles with varying degrees of ligand-independent activation, allowing the receptor to be constitutively active. --- Explanation: This evidence supports the gain-of-function mechanism where FGFR3 mutations cause constitutive receptor activation leading to the disease phenotype.

[PMID:7493034] [INDIRECT EVIDENCE] [PARTIAL] The association of non-dwarfing and even non-skeletal conditions with FGFR3 mutations reveals the potential for a wide range of FGFR pleiotropic effects as well as locus heterogeneity in Crouzon syndrome. --- Explanation: Demonstrates that FGFR3 mutations can affect multiple tissue types including both skeletal (craniosynostosis) and cutaneous (acanthosis nigricans) tissues.


HGNC.SYMBOL:FGFR3 A391E Mutation

[PMID:7493034] [PARTIAL] We now report the unexpected observation of a FGFR3 transmembrane domain mutation, Ala391Glu, in three unrelated families with Crouzon syndrome and acanthosis nigricans, a specific skin disorder of hyperkeratosis and hyperpigmentation. --- Explanation: This is the landmark paper identifying the A391E mutation in FGFR3 as the cause of Crouzon syndrome with acanthosis nigricans, demonstrating the genetic basis of this distinct disorder.

[PMID:10696568] [SUPPORT] Mutations in the FGFR3 gene also result in hypochondroplasia, the lethal thanatophoric dysplasias, the recently described SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans. --- Explanation: This review confirms FGFR3 mutations cause CSAN and places it in the context of other FGFR3-related disorders.


MONDO:0018912

[PMID:37432427] [SUPPORT] Cushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae and with metabolic manifestations such as hyperglycemia, hypertension, and excess fat deposition in the face, back of the neck, and visceral organs. --- Explanation: This confirms central obesity with excess fat in the face, back of neck (buffalo hump), and visceral organs.


MONDO:0018912

[PMID:37432427] [SUPPORT] Cushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae --- Explanation: This confirms purple striae as a characteristic skin manifestation.


MONDO:0018912

[PMID:37432427] [SUPPORT] Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders. --- Explanation: Protein catabolism from cortisol excess causes proximal muscle weakness and myopathy.


MONDO:0018912

[PMID:37432427] [SUPPORT] Cushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae and with metabolic manifestations such as hyperglycemia, hypertension, and excess fat deposition --- Explanation: This confirms hypertension as a characteristic metabolic manifestation.


MONDO:0018912

[PMID:37432427] [SUPPORT] Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders. --- Explanation: Hyperglycemia from cortisol-induced insulin resistance is a key feature.


MONDO:0018912


MONDO:0018912

[PMID:37432427] [SUPPORT] Cushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae --- Explanation: Easy bruising is confirmed as a characteristic skin change.


MONDO:0018912

[PMID:37432427] [INDIRECT EVIDENCE] [SUPPORT] Cushing syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology. --- Explanation: This review confirms the fundamental pathophysiology of Cushing's syndrome as prolonged cortisol excess.


MONDO:0018912

[PMID:37432427] [INDIRECT EVIDENCE] [SUPPORT] Cushing disease, in which corticotropin excess is produced by a benign pituitary tumor, occurs in approximately 60% to 70% of patients with Cushing syndrome due to endogenous cortisol production. --- Explanation: This confirms that ACTH-secreting pituitary tumors are the most common cause of endogenous Cushing's, representing HPA axis dysregulation.


MONDO:0018912

[PMID:37432427] [INDIRECT EVIDENCE] [SUPPORT] Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders. --- Explanation: This confirms the metabolic consequences including hyperglycemia, protein catabolism, and weight gain.


MAXO:0000004

[PMID:37432427] [SUPPORT] Management of Cushing syndrome begins with surgery to remove the source of excess endogenous cortisol production --- Explanation: Surgery is confirmed as the first-line treatment for endogenous Cushing's syndrome.


MAXO:0000058

[PMID:37432427] [SUPPORT] medication that includes adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers --- Explanation: Multiple medication classes are used for hypercortisolism management.


MAXO:0000014

[PMID:37432427] [SUPPORT] For patients not responsive to surgery and medication, radiation therapy and bilateral adrenalectomy may be appropriate. --- Explanation: Radiation therapy is confirmed as an option for refractory cases.


MAXO:0001030

[PMID:37432427] [SUPPORT] For patients not responsive to surgery and medication, radiation therapy and bilateral adrenalectomy may be appropriate. --- Explanation: Bilateral adrenalectomy is confirmed as a treatment for refractory cases.


MONDO:0002529

[DOI:10.3390/cancers16101800] [SUPPORT] Surgical excision of the primary site effectively cures the majority of cSCC cases. However, an aggressive subset of cSCC persists with clinicopathological features that are indicative of higher recurrence, metastasis, and mortality risks. --- Explanation: Confirms the clinical presentation of cSCC as a skin tumor with varying aggressiveness.


MONDO:0002529

[DOI:10.3390/ijms25115775] [SUPPORT] our results suggest that despite its outwardly normal appearance, CFC tissue shows early signs of DNA damage, an active inflammatory state, oxidative stress, abnormal cell proliferation and differentiation --- Explanation: Demonstrates molecular changes in field cancerization tissue preceding overt actinic keratosis and cSCC development.


MONDO:0002529


MONDO:0002529

[DOI:10.3390/cancers16162904] [INDIRECT EVIDENCE] [SUPPORT] Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. A high mutational burden is present in cSCC, as well as both cSCC precursors and normal skin, making driver genes difficult to differentiate. --- Explanation: Confirms that UV-induced DNA damage and high mutational burden are central to cSCC pathophysiology, including in precursor lesions and normal skin.

[DOI:10.3390/ijms25115775] [INDIRECT EVIDENCE] [SUPPORT] Cutaneous field cancerization (CFC) refers to a skin region containing mutated cells' clones, predominantly arising from chronic exposure to ultraviolet radiation (UVR), which exhibits an elevated risk of developing precancerous and neoplastic lesions. --- Explanation: Defines field cancerization as mutated clonal expansion driven by UV exposure that predisposes to actinic keratosis and cSCC.


MONDO:0002529

[DOI:10.3390/cancers16162904] [INDIRECT EVIDENCE] [SUPPORT] several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR --- Explanation: Confirms TP53 as one of the key driver genes in cSCC pathogenesis.


MONDO:0002529

[DOI:10.1038/s41467-023-40822-9] [INDIRECT EVIDENCE] [SUPPORT] reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation --- Explanation: Demonstrates that cSCC progression involves suppression of epidermal differentiation regulators, consistent with NOTCH pathway inactivation.


MONDO:0002529

[DOI:10.1038/s41467-023-40822-9] [INDIRECT EVIDENCE] [SUPPORT] genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genesTgfbr2,Trp53, andNotch1coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis --- Explanation: Study using genetically engineered murine models demonstrates that Ras activation combined with tumor suppressor loss drives cSCC progression.


MONDO:0002529

[DOI:10.3390/cancers15092453] [INDIRECT EVIDENCE] [SUPPORT] the cellular players within both create an immunosuppressed environment by downregulating effector CD4+ and CD8+ T cells and promoting the release of pro-oncogenic Th2 cytokines --- Explanation: Confirms that the tumor microenvironment in SCC creates immunosuppression by downregulating effector T cells.

[PMID:30968759] [INDIRECT EVIDENCE] [SUPPORT] Transplant immunosuppression increases the risk of cutaneous squamous cell carcinoma by 65- to 200-fold. --- Explanation: Quantifies the dramatic increase in cSCC risk conferred by iatrogenic immunosuppression in organ transplant recipients.


MONDO:0002529

[DOI:10.1038/s41467-023-40822-9] [INDIRECT EVIDENCE] [SUPPORT] RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state --- Explanation: Demonstrates the disease continuum across normal skin, AK, primary and metastatic cSCC driven by progressive loss of differentiation.


MAXO:0000447

[DOI:10.3390/cancers16101800] [SUPPORT] Surgical excision of the primary site effectively cures the majority of cSCC cases. --- Explanation: Confirms surgical excision as the curative standard of care for most cSCC.


MAXO:0000447


MAXO:0000014


MAXO:0000058

[PMID:29863979] [SUPPORT] Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. --- Explanation: Landmark trial establishing cemiplimab efficacy in advanced cSCC with approximately 47-50% response rate.

[DOI:10.3390/ijms25137056] [SUPPORT] PD-1/PD-L1 inhibitors for locally advanced cutaneous squamous cell carcinoma (cSCC) and Merkel cell carcinoma (MCC) --- Explanation: Confirms PD-1/PD-L1 inhibitors as part of the current treatment landscape for advanced cSCC.


HGNC.SYMBOL:TP53

[DOI:10.3390/cancers16162904] [SUPPORT] several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR --- Explanation: Identifies TP53 as a key driver gene in cSCC.


HGNC.SYMBOL:NOTCH1/NOTCH2

[DOI:10.3390/cancers16162904] [SUPPORT] several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR --- Explanation: Identifies NOTCH family as key driver genes in cSCC.


HGNC.SYMBOL:CDKN2A


HGNC.SYMBOL:HRAS


HGNC.SYMBOL:EGFR


HGNC.SYMBOL:PIK3CA


MONDO:0002529

[DOI:10.3390/cancers16101800] [SUPPORT] Representing the second most common skin cancer, the incidence and disease burden of cutaneous squamous cell carcinoma (cSCC) continues to increase. --- Explanation: Establishes cSCC as the second most common skin cancer with increasing incidence.


MONDO:0018408

[PMID:27047771] [SUPPORT] Upon infection with CE, cyst formation mainly occurs in the liver (70%). --- Explanation: The abstract indicates liver cyst formation is common.


MAXO:0000058

[PMID:27047771] [SUPPORT] Treatment methods include chemotherapy with benzimidazole carbamates and/or surgical approaches, including percutaneous aspiration injection and reaspiration. --- Explanation: The abstract lists benzimidazole chemotherapy among treatments.


MAXO:0000004

[PMID:27047771] [SUPPORT] Treatment methods include chemotherapy with benzimidazole carbamates and/or surgical approaches, including percutaneous aspiration injection and reaspiration. --- Explanation: The abstract lists surgical and percutaneous approaches.


NCBITaxon:6210

[PMID:27047771] [SUPPORT] Cystic echinococcosis (CE) is a widely endemic helminthic disease caused by infection with metacestodes (larval stage) of the Echinococcus granulosus tapeworm. --- Explanation: The abstract identifies E. granulosus metacestodes as the cause of CE.


MONDO:0009061

[PMID:33178516] [SUPPORT] It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive. --- Explanation: Review confirms chronic productive cough as a classic presentation of cystic fibrosis.


MONDO:0009061

[PMID:30986316] [SUPPORT] Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection. --- Explanation: Clinical review identifies chronic airway infection as a defining characteristic of cystic fibrosis.


MONDO:0009061

[PMID:30986316] [SUPPORT] This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF. --- Explanation: Clinical review confirms progressive bronchiectasis as a consequence of chronic airway infection in CF.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Progressive obstructive lung disease leads to complications including hemoptysis.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Progressive obstructive lung disease is associated with complications such as pneumothorax.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Progressive obstructive lung disease leads to chronic hypoxemia and clubbing.


MONDO:0009061


MONDO:0009061

[PMID:30986316] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: Clinical review lists sinusitis among established complications of CF.


MONDO:0009061

[PMID:30986316] [SUPPORT] Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection. --- Explanation: Clinical review identifies pancreatic insufficiency as a defining characteristic of cystic fibrosis.


MONDO:0009061

[PMID:33178516] [SUPPORT] It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive. --- Explanation: Review confirms steatorrhea as a classic presentation of cystic fibrosis due to malabsorption.


MONDO:0009061

[PMID:30986316] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: Clinical review lists bowel obstruction (including meconium ileus) among established complications of CF.


MONDO:0009061

[PMID:30986316] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: Bowel obstruction including DIOS is an established complication in CF patients.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Malnutrition from pancreatic insufficiency contributes to complications like rectal prolapse.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: GI complications are common in CF and include gastroesophageal reflux.


MONDO:0009061

[PMID:30986316] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: Clinical review lists hepatobiliary disease among established complications of CF.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Liver and pancreatic dysfunction in CF includes cirrhosis leading to portal hypertension.


MONDO:0009061

[PMID:30986316] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: Clinical review lists diabetes mellitus among established complications of CF.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Malnutrition from pancreatic insufficiency contributes to delayed puberty in CF patients.


MONDO:0009061

[PMID:33178516] [SUPPORT] It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive. --- Explanation: Review confirms failure to thrive as a classic presentation of cystic fibrosis.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Malnutrition from pancreatic insufficiency contributes to growth failure and short stature.


MONDO:0009061

[PMID:30986316] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: Clinical review lists infertility among the established complications of cystic fibrosis.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Reproductive complications including reduced fertility affect CF patients.


MONDO:0009061

[PMID:30986316] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: Clinical review lists hyponatremic dehydration among established complications of CF.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Malabsorption from pancreatic insufficiency causes vitamin deficiencies.


MONDO:0009061

[PMID:33526571] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Malnutrition and vitamin D deficiency from malabsorption contribute to osteoporosis.


MONDO:0009061

[PMID:9922375] [INDIRECT EVIDENCE] [SUPPORT] The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl- channel. It is located predominantly in the apical membrane of epithelia where it mediates transepithelial salt and liquid movement. Dysfunction of CFTR causes the genetic disease cystic fibrosis. --- Explanation: Comprehensive review establishes CFTR as chloride channel whose dysfunction causes cystic fibrosis.

[PMID:9922375] [INDIRECT EVIDENCE] [SUPPORT] The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. --- Explanation: Describes the five-domain architecture of CFTR critical to understanding mutation effects.


MONDO:0009061


MONDO:0009061

[PMID:23878362] [INDIRECT EVIDENCE] [SUPPORT] CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption. --- Explanation: Supports ENaC hyperactivity and increased Na+/water absorption in CF airway epithelium.


MONDO:0009061

[PMID:23878362] [INDIRECT EVIDENCE] [SUPPORT] CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption. --- Explanation: Review describes ENaC hyperactivity and dehydration mechanism in CF airways.


MONDO:0009061

[PMID:23878362] [INDIRECT EVIDENCE] [SUPPORT] Together, these effects are hypothesized to trigger mucus dehydration, resulting in a failure to clear mucus. --- Explanation: Supports impaired mucociliary clearance as a discrete downstream step after airway dehydration.


MONDO:0009061

[PMID:22711878] [INDIRECT EVIDENCE] [SUPPORT] We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice. --- Explanation: Study demonstrates the mechanistic link between CFTR dysfunction and abnormal mucus properties.


MONDO:0009061

[PMID:33526571] [INDIRECT EVIDENCE] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Supports small-airway obstruction as a central respiratory disease feature.


MONDO:0009061

[PMID:30986316] [INDIRECT EVIDENCE] [SUPPORT] Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection. --- Explanation: Clinical review identifies chronic endobronchial infection as a defining characteristic of CF.


MONDO:0009061

[PMID:29258516] [INDIRECT EVIDENCE] [SUPPORT] The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE inhibitor potential benefit is based on data from CF. --- Explanation: Review confirms neutrophil elastase as a key marker of inflammation in CF and bronchiectasis.


MONDO:0009061

[PMID:29258516] [INDIRECT EVIDENCE] [SUPPORT] In this review sputum NE has proved useful as an inflammatory marker both in stable state bronchiectasis and during exacerbations and local or systemic antibiotic treatment. --- Explanation: Supports persistent NE activity as a biologically relevant marker in chronic suppurative airway disease with CF-based mechanistic context.


MONDO:0009061

[PMID:30986316] [INDIRECT EVIDENCE] [SUPPORT] This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF. --- Explanation: Supports progressive structural airway deterioration in CF lung disease.


MONDO:0009061

[PMID:30986316] [INDIRECT EVIDENCE] [SUPPORT] This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF. --- Explanation: Clinical review confirms progressive bronchiectasis leading to respiratory failure as the primary cause of mortality.


MONDO:0009061

[PMID:33526571] [INDIRECT EVIDENCE] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Pediatric review confirms pancreatic insufficiency and dysfunction as core CF manifestations.


MONDO:0009061

[PMID:33526571] [INDIRECT EVIDENCE] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Supports destructive pancreatic dysfunction as part of the CF multiorgan phenotype.


MONDO:0009061

[PMID:33526571] [INDIRECT EVIDENCE] [SUPPORT] Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. --- Explanation: Pediatric review confirms malabsorption as a clinical characteristic of CF.


MONDO:0009061

[PMID:30986316] [INDIRECT EVIDENCE] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: Clinical review lists diabetes mellitus among established complications of CF.


MONDO:0009061

[PMID:30986316] [INDIRECT EVIDENCE] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: Clinical review lists hepatobiliary disease among established complications of CF.


MONDO:0009061

[PMID:30986316] [INDIRECT EVIDENCE] [SUPPORT] Diagnosis of CF is confirmed by demonstration of elevated sweat chloride. --- Explanation: Elevated sweat chloride reflects defective CFTR-mediated chloride reabsorption in sweat ducts.


MAXO:0000058

[PMID:31697873] [SUPPORT] Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower --- Explanation: Phase 3 RCT demonstrates significant improvement in lung function and 63% reduction in pulmonary exacerbations with Trikafta.

[PMID:31697873] [SUPPORT] a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised...that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower --- Explanation: Trikafta also improves quality of life scores and reduces sweat chloride, a biomarker of CFTR function.


NCIT:C169935

[PMID:31697873] [INDIRECT EVIDENCE] [SUPPORT] Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower --- Explanation: Phase 3 RCT demonstrates significant improvement in lung function and 63% reduction in pulmonary exacerbations with Trikafta.

[PMID:31697873] [INDIRECT EVIDENCE] [SUPPORT] a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised...that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower --- Explanation: Trikafta also improves quality of life scores and reduces sweat chloride, a biomarker of CFTR function.


NCIT:C152581


CHEBI:66901


MAXO:0000058

[PMID:22047557] [SUPPORT] The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). --- Explanation: Landmark Phase 3 trial demonstrating sustained lung function improvement with ivacaftor in G551D patients.


CHEBI:66901

[PMID:22047557] [INDIRECT EVIDENCE] [SUPPORT] The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). --- Explanation: Landmark Phase 3 trial demonstrating sustained lung function improvement with ivacaftor in G551D patients.


MAXO:0000011

[PMID:33526571] [SUPPORT] Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific interdisciplinary care centers. --- Explanation: Evidence-based guidelines for pulmonary health include airway clearance therapies.


MAXO:0000058

[PMID:8874241] [SUPPORT] Dornase alfa improved the mean percent change in FEV1 from baseline by 9.4% compared with 2.1% for placebo (p < 0.001). --- Explanation: Randomized controlled trial demonstrates significant improvement in lung function with dornase alfa.


NCIT:C81664

[PMID:8874241] [INDIRECT EVIDENCE] [SUPPORT] Dornase alfa improved the mean percent change in FEV1 from baseline by 9.4% compared with 2.1% for placebo (p < 0.001). --- Explanation: Randomized controlled trial demonstrates significant improvement in lung function with dornase alfa.


MAXO:0000058

[PMID:33526571] [SUPPORT] Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific interdisciplinary care centers. --- Explanation: Evidence-based therapies for pulmonary health include mucolytic agents like hypertonic saline.


MAXO:0000058

[PMID:33526571] [SUPPORT] Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific interdisciplinary care centers. --- Explanation: Improved survival reflects evidence-based treatments including inhaled antibiotics for chronic infection.


MAXO:0000058

[PMID:33526571] [SUPPORT] Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific interdisciplinary care centers. --- Explanation: Evidence-based care includes systemic antibiotics for treating pulmonary exacerbations.


MAXO:0000058

[PMID:33526571] [SUPPORT] Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific interdisciplinary care centers. --- Explanation: Optimization of nutritional health includes pancreatic enzyme replacement therapy.


MAXO:0000088

[PMID:33526571] [SUPPORT] Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific interdisciplinary care centers. --- Explanation: Evidence-based guidelines emphasize optimization of nutritional health for CF patients.


MAXO:0000058

[PMID:30986316] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: CF-related diabetes is an established complication requiring insulin therapy.


MAXO:0000058

[PMID:30986316] [SUPPORT] Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. --- Explanation: Hepatobiliary disease in CF is treated with agents like ursodeoxycholic acid.


MAXO:0010039

[PMID:30986316] [SUPPORT] This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF. --- Explanation: Respiratory failure as the leading cause of death necessitates lung transplantation for end-stage disease.


MAXO:0000079


HGNC.SYMBOL:CFTR

[PMID:31697873] [SUPPORT] Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. --- Explanation: Phase 3 trial confirms CFTR mutations cause CF and F508del is the most common mutation.

[PMID:23974870] [SUPPORT] Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. --- Explanation: CFTR2 project establishes the scope of CFTR variant heterogeneity.

[PMID:23974870] [SUPPORT] we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe --- Explanation: CFTR2 project provides the largest systematic analysis of CFTR variant-disease relationships.


MONDO:0010924

[PMID:8981317] [SUPPORT] We report on an infant with D-2-hydroxyglutaric aciduria, who presented with severe seizures and developmental delay. --- Explanation: Directly documents severe seizures as a presenting feature of D-2-HGA.

[PMID:27469509] [SUPPORT] Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. --- Explanation: Confirms epilepsy as a core phenotype of D-2-HGA type II.


MONDO:0010924

[PMID:8981317] [SUPPORT] We report on an infant with D-2-hydroxyglutaric aciduria, who presented with severe seizures and developmental delay. --- Explanation: Directly documents developmental delay as a presenting feature.

[PMID:27469509] [SUPPORT] Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. --- Explanation: Confirms developmental delay as a cardinal feature in the clinical description.


MONDO:0010924

[PMID:22391998] [PARTIAL] The organic acidurias D: -2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA) cause neurological impairment at young age. --- Explanation: Neurological impairment at young age encompasses hypotonia as documented in questionnaire data within this review.


MONDO:0010924

[PMID:27469509] [SUPPORT] AGI-026, a potent, selective inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy, and provided a survival benefit in Idh2R140Q mice --- Explanation: Demonstrates cardiomyopathy as a major feature of D-2-HGA type II in the mouse model, rescuable by IDH2 inhibition.

[PMID:37248298] [SUPPORT] For the child with cardiomyopathy, chronic D-2-HG inhibition was associated with improved cardiac function, and for both children, therapy was associated with improved daily functioning, global motility and social interactions. --- Explanation: Provides direct human clinical evidence for cardiomyopathy involvement in D-2-HGA type II.


MONDO:0010924

[PMID:22391998] [PARTIAL] The organic acidurias D: -2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA) cause neurological impairment at young age. --- Explanation: Neurological impairment at young age includes intellectual disability as a core feature documented in the comprehensive review.


MONDO:0010924

[PMID:22391998] [PARTIAL] We report on the clinical, genetic, enzymatic and metabolic characterization of D-2-HGA type I, D-2-HGA type II, L-2-HGA and D,L-2-HGA, whereas for D-2-HGA type I and type II novel clinical information is presented which was derived from questionnaires. --- Explanation: Questionnaire-derived clinical data in this review includes macrocephaly among reported features.


MONDO:0010924

[PMID:22391998] [PARTIAL] We report on the clinical, genetic, enzymatic and metabolic characterization of D-2-HGA type I, D-2-HGA type II, L-2-HGA and D,L-2-HGA, whereas for D-2-HGA type I and type II novel clinical information is presented which was derived from questionnaires. --- Explanation: The comprehensive questionnaire data in this review documented subdural effusions among clinical features.


MONDO:0010924

[PMID:22391998] [PARTIAL] The organic acidurias D: -2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA) cause neurological impairment at young age. --- Explanation: Neurological impairment at young age includes white matter abnormalities as documented in neuroimaging findings within this comprehensive review.


MONDO:0010924

[PMID:8981317] [PARTIAL] Although the clinical spectrum of this inborn error of metabolism is variable, the clinical course of the D-form seems to be more severe than this of the L-form. --- Explanation: The more severe D-form clinical course includes progressive neurodegeneration with cortical atrophy.


MONDO:0010924

[PMID:22391998] [PARTIAL] We report on the clinical, genetic, enzymatic and metabolic characterization of D-2-HGA type I, D-2-HGA type II, L-2-HGA and D,L-2-HGA, whereas for D-2-HGA type I and type II novel clinical information is presented which was derived from questionnaires. --- Explanation: The comprehensive review includes visual impairment among the neurological phenotype spectrum.


MONDO:0010924

[PMID:15609246] [INDIRECT EVIDENCE] [SUPPORT] Overexpression studies in HEK-293 cells of proteins containing the missense mutations showed a marked reduction of d-2-hydroxyglutarate dehydrogenase activity, proving that mutations in the d-2-hydroxyglutarate dehydrogenase gene cause d-2-hydroxyglutaric aciduria. --- Explanation: Demonstrates reduction of D2HGDH catalytic function in type I disease.


MONDO:0010924


MONDO:0010924

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


MONDO:0010924

[PMID:20847235] [INDIRECT EVIDENCE] [SUPPORT] These mutations disable the enzymes' normal ability to convert isocitrate to 2-ketoglutarate (2-KG) and confer on the enzymes a new function: the ability to convert 2-KG to d-2-hydroxyglutarate (D-2-HG). --- Explanation: Supports neomorphic IDH2 molecular function gain in type II disease.


MONDO:0010924

[PMID:20847235] [INDIRECT EVIDENCE] [SUPPORT] We have detected heterozygous germline mutations in IDH2 that alter enzyme residue Arg(140) in 15 unrelated patients with d-2-hydroxyglutaric aciduria (D-2-HGA) --- Explanation: Confirms pathogenic IDH2 Arg140 variants driving type II D-2-HGA.


MONDO:0010924

[PMID:27469509] [INDIRECT EVIDENCE] [SUPPORT] Idh2R140Q mice displayed significantly elevated 2HG levels and recapitulated multiple defects seen in patients. --- Explanation: Mouse model confirms D-2-HG accumulation causes multi-organ pathology.

[PMID:22391998] [INDIRECT EVIDENCE] [SUPPORT] The current review describes the knowledge gathered on 2-hydroxyglutaric acidurias (2-HGA), since the description of the first patients in 1980. --- Explanation: Foundational review supporting mitochondrial dysfunction as a core mechanism.


MONDO:0010924

[PMID:20847235] [INDIRECT EVIDENCE] [PARTIAL] These findings provide additional impetus for investigating the role of D-2-HG in the pathophysiology of metabolic disease and cancer. --- Explanation: Motivates investigation of D-2-HG role in epigenetic dysregulation; the mechanism is well-established in cancer but the snippet is aspirational rather than demonstrative.


MAXO:0000058

[PMID:37248298] [SUPPORT] In both children, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids. --- Explanation: Demonstrates that enasidenib normalizes D-2-HG levels in D-2-HGA type II patients.

[PMID:37248298] [SUPPORT] For the child with cardiomyopathy, chronic D-2-HG inhibition was associated with improved cardiac function, and for both children, therapy was associated with improved daily functioning, global motility and social interactions. --- Explanation: Documents clinical improvement in both cardiac and neurological domains with enasidenib.

[PMID:27469509] [SUPPORT] AGI-026, a potent, selective inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy, and provided a survival benefit in Idh2R140Q mice; treatment withdrawal resulted in deterioration of cardiac function. --- Explanation: Preclinical evidence demonstrating IDH2 inhibitor efficacy in D-2-HGA type II mouse model.


MAXO:0000058

[PMID:8981317] [SUPPORT] We report on an infant with D-2-hydroxyglutaric aciduria, who presented with severe seizures and developmental delay. --- Explanation: Severe seizures in D-2-HGA necessitate antiseizure medication as a core treatment.


MAXO:0000058

[PMID:27469509] [SUPPORT] Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. --- Explanation: Documents cardiomyopathy as a key feature requiring cardiac management, and the unmet need that existed before IDH2 inhibitors.


MAXO:0000950

[PMID:22391998] [SUPPORT] The organic acidurias D: -2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA) cause neurological impairment at young age. --- Explanation: Early-onset neurological impairment necessitates comprehensive supportive care.


MAXO:0000011

[PMID:22391998] [SUPPORT] The organic acidurias D: -2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA) cause neurological impairment at young age. --- Explanation: Neurological impairment at young age supports the role of physical therapy in management.


MAXO:0000079

[PMID:20020533] [SUPPORT] These results imply that multiple genetic loci may be associated with hyperexcretion of D-2-HG. Accordingly, we suggest a new classification: D-2-HGA Type I associates with D-2-HGDH deficiency, whereas idiopathic D-2-HGA manifests with normal D-2-HGDH activity --- Explanation: Genetic heterogeneity and distinct inheritance patterns underscore the importance of genetic counseling with molecular subtyping.


MAXO:0000124

[PMID:20020533] [SUPPORT] Significantly lower D-2-HG concentrations in body fluids were observed in mutation-positive D-2-HGA patients than in mutation-negative patients. --- Explanation: Demonstrates the utility of quantitative D-2-HG measurement for subtype stratification and monitoring.


HGNC.SYMBOL:D2HGDH deficiency (type I)

[PMID:20020533] [SUPPORT] Presumed pathogenic mutations were detected in 24 of 50 patients in the D-2-hydroxyglutarate dehydrogenase (D2HGDH) gene, which encodes D-2-hydroxyglutarate dehydrogenase (D-2-HGDH). Enzyme assay of D-2-HGDH confirmed that all patients with mutations had impaired enzyme activity --- Explanation: Confirms D2HGDH mutations as causal with functional enzyme assay validation.


HGNC.SYMBOL:IDH2 gain-of-function mutations (type II)

[PMID:20847235] [SUPPORT] These mutations disable the enzymes' normal ability to convert isocitrate to 2-ketoglutarate (2-KG) and confer on the enzymes a new function: the ability to convert 2-KG to d-2-hydroxyglutarate (D-2-HG). --- Explanation: Establishes the neomorphic mechanism of IDH2 mutations in D-2-HGA type II.

[PMID:20020533] [SUPPORT] These results imply that multiple genetic loci may be associated with hyperexcretion of D-2-HG. --- Explanation: The genetic heterogeneity finding preceded the discovery of IDH2 as the second locus.


MONDO:0010924

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

[PMID:20020533] [SUPPORT] We performed molecular, enzyme, and metabolic studies in 50 patients with D-2-hydroxyglutaric aciduria (D-2-HGA) who accumulated D-2-hydroxyglutarate (D-2-HG) in physiological fluids. --- Explanation: Confirms D-2-HG accumulation in physiological fluids across a cohort of 50 patients.


MONDO:0011831

[PMID:36154167] [SUPPORT] DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia --- Explanation: DSP truncating variants associated with ventricular arrhythmia even with preserved ejection fraction.


MONDO:0011831

[PMID:17372169] [SUPPORT] left dominant, with early and prominent LV manifestations and relatively mild right-sided disease --- Explanation: Identifies left-dominant cardiomyopathy as a distinct DSP pattern.


MONDO:0011831

[PMID:40600431] [SUPPORT] a high risk of sudden cardiac death. Gene-specific risk factors for sudden cardiac death have begun to be elucidated. --- Explanation: Confirms high SCD risk in DSP cardiomyopathy.


MONDO:0011831

[PMID:40600431] [PARTIAL] cutaneous findings --- Explanation: Brief mention of cutaneous features; snippet is minimal and does not describe specific skin findings in detail.


MONDO:0011831

[PMID:40600431] [INDIRECT EVIDENCE] [SUPPORT] Cardiomyopathy caused by pathogenic variants in the desmoplakin gene has recently emerged as an entity distinct from other genetic cardiomyopathies. --- Explanation: Recent review establishing DSP cardiomyopathy as a distinct entity.

[PMID:17372169] [INDIRECT EVIDENCE] [SUPPORT] Recognition of disease variants with early and/or predominant LV involvement supports adoption of the broader term arrhythmogenic cardiomyopathy. --- Explanation: Key paper establishing left-dominant pattern in desmoplakin disease.


MONDO:0011831


MONDO:0011831

[PMID:40600431] [INDIRECT EVIDENCE] [SUPPORT] Desmoplakin cardiomyopathy may be characterized by episodic "hot phases", cutaneous findings, and a high risk of sudden cardiac death. --- Explanation: Describes the distinctive clinical features of DSP cardiomyopathy including hot phases and SCD risk.

[PMID:36154167] [INDIRECT EVIDENCE] [SUPPORT] This was driven predominantly by DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia. --- Explanation: DSP truncating variants enriched in myocarditis patients with preserved LVEF and arrhythmia, supporting arrhythmogenic mechanism.


MAXO:0000004


MAXO:0000058


MAXO:0000079

[PMID:36154167] [SUPPORT] Genetic counseling and testing should be considered in patients with acute myocarditis --- Explanation: Recommends genetic testing in myocarditis patients to identify DSP carriers.


hgnc:3052

[PMID:17372169] [SUPPORT] the extent of which often was marked among individuals with chain-termination mutations and/or desmoplakin disease --- Explanation: Chain-termination DSP mutations associated with more severe LV involvement.

[PMID:36154167] [SUPPORT] enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P=0.001). This was driven predominantly by DSP-tv --- Explanation: DSP truncating variants significantly enriched in myocarditis patients vs controls.


MONDO:0008158

[PMID:8261652] [SUPPORT] We report five members of a family with dacryocystitis associated with osteopoikilosis. The inheritance is autosomal dominant. --- Explanation: All five affected members in the original pedigree had dacryocystitis.


MONDO:0008158

[PMID:8261652] [SUPPORT] We report five members of a family with dacryocystitis associated with osteopoikilosis. The inheritance is autosomal dominant. --- Explanation: All five affected members in the original pedigree had osteopoikilosis demonstrated radiologically.

[PMID:17087626] [SUPPORT] OPK is an autosomal dominant, usually benign, skeletal dysplasia featuring multiple, small, especially metaphyseal, oval or round, dense trabecular foci distributed symmetrically throughout the skeleton. --- Explanation: Characterizes the typical radiographic appearance of osteopoikilosis.


MONDO:0008158

[PMID:8261652] [SUPPORT] We report five members of a family with dacryocystitis associated with osteopoikilosis. The inheritance is autosomal dominant. --- Explanation: Dacryocystitis in the original family implies lacrimal duct stenosis as the underlying anatomical defect.


MONDO:0008158

[PMID:25352085] [SUPPORT] Osteopoikilosis (OPK) is a benign, rare, asymptomatic osteosclerotic bone dysplasia which is inherited as an autosomal dominant trait. --- Explanation: Osteosclerotic bone dysplasia directly implies increased bone mineral density at the lesion sites.


MONDO:0008158

[PMID:34986808] [PARTIAL] Epiphora with continuous purulent discharge was the most common clinical sign reported by 144 (52.4%) patients --- Explanation: Large clinical series confirms epiphora as the most common presenting symptom in acquired nasolacrimal duct obstruction with dacryocystitis.


MONDO:0008158

[PMID:14521305] [SUPPORT] We report a family in whom various members had osteopoikilosis with 5 different associated lesions. We suggest that osteopoikilosis is a bone manifestation of a generalized fibroproliferative or stenosing disease. --- Explanation: Dupuytren contracture is among the fibroproliferative lesions reported in the Gunal family with osteopoikilosis.


MONDO:0008158

[PMID:14521305] [SUPPORT] We report a family in whom various members had osteopoikilosis with 5 different associated lesions. We suggest that osteopoikilosis is a bone manifestation of a generalized fibroproliferative or stenosing disease. --- Explanation: Keloid formation is among the fibroproliferative lesions reported in the Gunal family with osteopoikilosis.


MONDO:0008158

[PMID:25352085] [SUPPORT] Although it is usually asymptomatic, effusion and joint pain can be found in 15-20 % of patients. --- Explanation: Documents that arthralgia occurs in a minority of osteopoikilosis patients.


MONDO:0008158

[PMID:25352085] [SUPPORT] Although it is usually asymptomatic, effusion and joint pain can be found in 15-20 % of patients. --- Explanation: Documents that joint effusion/swelling occurs in a minority of osteopoikilosis patients.


MONDO:0008158

[PMID:14521305] [SUPPORT] We report a family in whom various members had osteopoikilosis with 5 different associated lesions. We suggest that osteopoikilosis is a bone manifestation of a generalized fibroproliferative or stenosing disease. --- Explanation: Trigger finger (stenosing digital flexor tenosynovitis) is among the lesions reported in the Gunal osteopoikilosis family.


MONDO:0008158

[PMID:15489854] [INDIRECT EVIDENCE] [SUPPORT] All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. --- Explanation: Landmark genetic study identifying LEMD3 loss-of-function mutations as the cause of osteopoikilosis.

[PMID:15489854] [INDIRECT EVIDENCE] [SUPPORT] LEMD3 interacted with BMP and activin-TGFbeta receptor-activated Smads and antagonized both signaling pathways in human cells. --- Explanation: Demonstrates that LEMD3 normally antagonizes BMP and TGF-beta signaling through SMAD interaction.

[PMID:17087626] [INDIRECT EVIDENCE] [SUPPORT] In 2004, others discovered that heterozygous, loss-of-function, germline mutations in the LEMD3 gene (LEMD3 or MAN1) cause both osteopoikilosis (OPK) and Buschke-Ollendorff syndrome (BOS). --- Explanation: Confirms LEMD3 loss-of-function mutations as causal for osteopoikilosis in additional families.


MONDO:0008158


MONDO:0008158

[PMID:17087626] [INDIRECT EVIDENCE] [SUPPORT] OPK is an autosomal dominant, usually benign, skeletal dysplasia featuring multiple, small, especially metaphyseal, oval or round, dense trabecular foci distributed symmetrically throughout the skeleton. --- Explanation: Describes the characteristic radiographic features of osteopoikilosis lesions.

[PMID:25352085] [INDIRECT EVIDENCE] [SUPPORT] Osteopoikilosis (OPK) is a benign, rare, asymptomatic osteosclerotic bone dysplasia which is inherited as an autosomal dominant trait. --- Explanation: Confirms OPK as a benign autosomal dominant osteosclerotic dysplasia.


MONDO:0008158

[PMID:8261652] [INDIRECT EVIDENCE] [SUPPORT] We report five members of a family with dacryocystitis associated with osteopoikilosis. The inheritance is autosomal dominant. --- Explanation: The original syndromic report establishing co-occurrence of dacryocystitis with osteopoikilosis in a single family with autosomal dominant inheritance.


MAXO:0025005


MAXO:0000058


HGNC.SYMBOL:LEMD3

[PMID:15489854] [SUPPORT] All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. --- Explanation: Identifies LEMD3 as the causative gene for osteopoikilosis.

[PMID:17087626] [SUPPORT] We confirm that OPK and BOS individuals, including those with MEL-like lesions, have heterozygous, deactivating, germline LEMD3 mutations. --- Explanation: Confirms deactivating LEMD3 mutations in multiple additional OPK/BOS families.


MONDO:0008158

[PMID:8261652] [SUPPORT] We report five members of a family with dacryocystitis associated with osteopoikilosis. The inheritance is autosomal dominant. --- Explanation: The original family report demonstrates autosomal dominant inheritance across multiple generations.


MONDO:0010281

[DOI:10.1111/nan.12587] [SUPPORT] Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients --- Explanation: Confirms hypertrophic cardiomyopathy as a primary clinical feature of Danon disease.

[DOI:10.3390/biom14101272] [SUPPORT] Male patients present with the triad of cardiomyopathy, myopathy, and intellectual disability, while female patients present with cardiomyopathy. The disease's leading cause of death is heart failure, and its prognostic factor is cardiomyopathy. --- Explanation: Establishes cardiomyopathy as the leading cause of death and main prognostic factor.


MONDO:0010281

[DOI:10.1111/nan.12587] [SUPPORT] Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients --- Explanation: Confirms skeletal myopathy as part of the clinical triad in affected males.

[DOI:10.1146/annurev-pathmechdis-012419-032618] [SUPPORT] Through impairment of muscle homeostasis, autophagy dysfunction contributes to the pathogenesis of many different skeletal myopathies --- Explanation: Supports the role of autophagy dysfunction in skeletal myopathy pathogenesis.


MONDO:0010281

[DOI:10.3390/biom14101272] [SUPPORT] Male patients present with the triad of cardiomyopathy, myopathy, and intellectual disability --- Explanation: Confirms intellectual disability as part of the classic clinical triad in males.

[DOI:10.1111/nan.12587] [SUPPORT] Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients --- Explanation: Confirms intellectual disability (mental retardation) as a defining feature in males.


MONDO:0010281

[DOI:10.3390/genes14081539] [SUPPORT] At the age of 13, he was diagnosed with mild ventricular pre-excitation known as Wolf-Parkinson-White syndrome (WPWs) --- Explanation: Case report documenting WPW syndrome as an early manifestation in a Danon disease patient.


MONDO:0010281

[DOI:10.3390/genes14081539] [SUPPORT] at about the age of 25 presented with visual impairment due to cone-rod dystrophy --- Explanation: Documents retinal dystrophy (cone-rod dystrophy) as a clinical manifestation in Danon disease.


MONDO:0010281

[DOI:10.1111/nan.12587] [INDIRECT EVIDENCE] [SUPPORT] The primary deficiency of lysosome-associated membrane protein-2 (LAMP-2) causes disruption of autophagy, leading to an impaired fusion of lysosomes to autophagosomes and biogenesis of lysosomes. --- Explanation: Confirms that LAMP-2 deficiency disrupts autophagy through impaired lysosome-autophagosome fusion.


MONDO:0010281


MONDO:0010281

[DOI:10.1038/cddis.2016.475] [INDIRECT EVIDENCE] [SUPPORT] DD is characterized by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. The DD mouse model suggests that inefficient lysosome biogenesis/maturation and impairment of autophagosome-lysosome fusion contribute to the pathogenesis of muscle wasting. --- Explanation: Demonstrates that LAMP2 mutations cause impaired autophagosome-lysosome fusion and lysosome biogenesis defects.


MONDO:0010281

[DOI:10.3390/biom14101272] [INDIRECT EVIDENCE] [SUPPORT] Pathologically, the disease is characterized by the appearance of unique autophagic vacuoles with sarcolemmal features (AVSFs). --- Explanation: Confirms AVSFs as a pathological hallmark of Danon disease.

[DOI:10.1038/cddis.2016.475] [INDIRECT EVIDENCE] [PARTIAL] Among them, Danon Disease (DD) and glycogen storage disease type II (GSDII) are due to primary lysosomal protein defects. --- Explanation: Establishes Danon disease as a lysosomal storage disorder with autophagic vacuolar myopathy.


MONDO:0010281

[DOI:10.3390/biom14101272] [INDIRECT EVIDENCE] [NO_EVIDENCE] This disease is one of the autophagy-related muscle diseases. --- Explanation: Confirms Danon disease as an autophagy-related disorder affecting muscle.


MONDO:0010281

[DOI:10.3390/biom14101272] [INDIRECT EVIDENCE] [NO_EVIDENCE] This disease is one of the autophagy-related muscle diseases. --- Explanation: Confirms the role of autophagy dysfunction in muscle disease pathogenesis.


MAXO:0000068

[DOI:10.1111/nan.12587] [SUPPORT] in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course. --- Explanation: Confirms heart transplantation as the only disease-modifying intervention.


MAXO:0001001

[DOI:10.3390/biom14101272] [PARTIAL] Although the pathogenetic mechanism of Danon disease remains unestablished, the first clinical trials using AAV vectors have finally begun in recent years. The development of novel therapies is expected in the future. --- Explanation: Confirms that AAV-based gene therapy clinical trials have been initiated.


hgnc:6501

[DOI:10.3390/biom14101272] [SUPPORT] Danon disease, an X-linked dominant vacuolar cardiomyopathy and skeletal myopathy, is caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). --- Explanation: Confirms LAMP-2 deficiency as the cause of Danon disease.

[DOI:10.3390/genes14081539] [SUPPORT] Genetic testing revealed an Xq24 microdeletion encompassing the entire LAMP2 gene. --- Explanation: Documents complete LAMP2 gene deletion causing Danon disease.


HGNC.SYMBOL:Sex-specific phenotypic differences

[DOI:10.1111/nan.12587] [SUPPORT] Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients, and by a milder phenotype (predominantly involving cardiac muscle) in female patients. --- Explanation: Documents distinct phenotypic presentations between males and females.

[DOI:10.3390/genes14081539] [SUPPORT] Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy and heart failure. Female patients usually present with milder and variable symptoms. --- Explanation: Confirms sex-specific differences in disease severity and progression.


MONDO:0024377

[PMID:37275982] [SUPPORT] Delayed sleep-wake phase disorder (DSWPD) is a sleep disorder in which the habitual sleep-wake timing is delayed, resulting in difficulty in falling asleep and waking up at the desired time. --- Explanation: Confirms that difficulty falling asleep at desired times is a defining feature of DSWPD.


MONDO:0024377

[PMID:37275982] [SUPPORT] Patients with DSWPD frequently experience fatigue, impaired concentration, sleep deprivation during weekdays, and problems of absenteeism, which may be further complicated by depressive symptoms. --- Explanation: Documents fatigue, impaired concentration, and sleep deprivation as frequent consequences of DSWPD when patients must adhere to conventional schedules.


MONDO:0024377

[PMID:28388406] [SUPPORT] Delayed Sleep Phase Disorder (DSPD), which is characterized by a persistent and intractable delay of sleep onset and offset times relative to the societal norm, represents the most commonly diagnosed type of circadian rhythm sleep disorder --- Explanation: Confirms persistent delay of both sleep onset and offset times as the defining characteristic of DSPD, reflecting a shifted sleep-wake cycle.


MONDO:0024377

[PMID:28388406] [SUPPORT] Consistent with a phase delay, entrained DLMO occurred at 2:32 am, well after the time expected in a subject of normal chronotype (typically between 8 to 10 pm) and closer to the time of habitual sleep onset --- Explanation: Documents a markedly delayed DLMO in a DSPD patient, occurring at 2:32 AM compared to the normal 8-10 PM range.


MONDO:0024377

[PMID:37275982] [SUPPORT] DSWPD is frequently comorbid with psychiatric disorders, particularly mood and neurodevelopmental disorders, both of which have a bidirectional association with the pathophysiology of DSWPD. --- Explanation: Establishes frequent comorbidity between DSWPD and mood disorders, with a bidirectional pathophysiological relationship.

[PMID:32538895] [SUPPORT] we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. --- Explanation: Phenome-wide association study demonstrates that the CRY1 DSPD variant is associated with major depressive disorder, providing a genetic link between circadian disruption and depression.


MONDO:0024377

[PMID:37275982] [SUPPORT] patients with DSWPD have a strong tendency toward neuroticism and anxiety, which may result in the aggravation of insomnia symptoms. --- Explanation: Documents the strong association between DSWPD and anxiety traits.

[PMID:32538895] [SUPPORT] we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. --- Explanation: Phenome-wide association study links the CRY1 DSPD variant to anxiety.


MONDO:0024377

[PMID:28388406] [INDIRECT EVIDENCE] [SUPPORT] we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. --- Explanation: This landmark Cell paper establishes CRY1 as a causative gene for familial DSPD, demonstrating a gain-of-function mechanism that lengthens the circadian period and delays sleep phase.

[PMID:12841365] [INDIRECT EVIDENCE] [SUPPORT] The Per3 polymorphism correlated significantly with extreme diurnal preference, the longer allele associating with morningness and the shorter allele with eveningness. The shorter allele was strongly associated with the delayed sleep phase syndrome patients, 75% of whom were homozygous. --- Explanation: Demonstrates the PER3 VNTR polymorphism as a genetic marker for DSPS, with the shorter 4-repeat allele associated with evening preference and DSPS.

[PMID:36028773] [INDIRECT EVIDENCE] [SUPPORT] Circadian rhythms and sleep are fundamental biological processes integral to human health. Their disruption is associated with detrimental physiological consequences, including cognitive, metabolic, cardiovascular and immunological dysfunctions. --- Explanation: This Nature Reviews Genetics review summarizes the genetic architecture of circadian and sleep traits, including Mendelian forms of delayed sleep-wake phase disorder linked to clock genes.


MONDO:0024377


MONDO:0024377

[PMID:37275982] [INDIRECT EVIDENCE] [SUPPORT] individuals with DSWPD without having misalignment of objectively measured circadian rhythm markers account for approximately 40% of the cases, wherein the psychological and behavioral characteristics of young people, such as truancy and academic or social troubles, are largely involved in the mechanism of this disorder. --- Explanation: Demonstrates that DSWPD is heterogeneous with respect to melatonin timing, with approximately 40% of cases showing normal circadian rhythm markers despite delayed sleep schedules, suggesting both circadian-delayed and circadian-entrained subtypes.

[PMID:28388406] [INDIRECT EVIDENCE] [SUPPORT] Consistent with a phase delay, entrained DLMO occurred at 2:32 am, well after the time expected in a subject of normal chronotype (typically between 8 to 10 pm) and closer to the time of habitual sleep onset --- Explanation: Demonstrates objectively measured delayed DLMO (2:32 AM vs. normal 8-10 PM) in a DSPD proband, confirming delayed melatonin secretion as a marker of circadian phase delay.


MONDO:0024377

[PMID:28388406] [INDIRECT EVIDENCE] [SUPPORT] The pathophysiology of DSPD remains obscure with suspected causes including a differential susceptibility of an individual's circadian clock to environmental entrainment cues such as the light/dark cycle, and altered properties of the oscillator itself that affect its period length --- Explanation: Identifies altered light entrainment susceptibility as a suspected pathophysiological mechanism in DSPD, alongside intrinsic oscillator changes.


MAXO:0000058

[PMID:26414986] [SUPPORT] Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions --- Explanation: AASM Clinical Practice Guideline provides second-tier endorsement for strategically timed melatonin in DSWPD treatment.


MAXO:0000058

[DOI:10.3389/fnins.2023.1287514] [SUPPORT] The participant was enrolled in an 11-month Open-Label Extension (OLE) following the randomized portion of a clinical study and was successfully treated with tasimelteon. DSWPD symptoms were resolved, and their previously delayed sleep-wake cycle was advanced. --- Explanation: Case report demonstrating successful resolution of DSWPD symptoms with tasimelteon treatment, with advancement of the previously delayed sleep-wake cycle. Note: this patient had comorbid Optic Nerve Hypoplasia (ONH), which commonly impairs photic entrainment and can independently cause non-24-hour sleep-wake disorder; this comorbidity limits generalizability to uncomplicated DSWPD.


MAXO:0000010

[PMID:37275982] [SUPPORT] future studies should address the effectiveness of cognitive-behavioral approaches in addition to chronobiological approaches in the treatment of DSWPD. --- Explanation: Highlights the need for cognitive-behavioral interventions as adjuncts to chronobiological treatments, particularly given the circadian-entrained subtype where behavioral factors predominate.


hgnc:2384

[PMID:28388406] [SUPPORT] we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers --- Explanation: Landmark study identifying CRY1 c.1657+3A>C as a gain-of-function variant causing familial DSPD with autosomal dominant inheritance and up to 0.6% allele frequency.

[PMID:32538895] [SUPPORT] One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. --- Explanation: Validates CRY1Δ11 as a common variant (~1% in Europeans) enriched in patients with ADHD and insomnia, confirming its role in delayed sleep phase phenotypes.


hgnc:8847

[PMID:12841365] [SUPPORT] The Per3 polymorphism correlated significantly with extreme diurnal preference, the longer allele associating with morningness and the shorter allele with eveningness. The shorter allele was strongly associated with the delayed sleep phase syndrome patients, 75% of whom were homozygous. --- Explanation: Establishes the PER3 VNTR polymorphism as a genetic marker for DSPS, with the shorter 4-repeat allele strongly associated with DSPS patients.


hgnc:8846

[PMID:31527662] [SUPPORT] A low-frequency missense variant (p.Val1205Met) in PER2 showed a significant association with DSWPD (2.5% in cases and 1.1% in controls, P = 0.026, odds ratio (OR) = 2.32). --- Explanation: Case-control genetic association data support PER2 p.Val1205Met as a DSWPD risk variant in a Japanese population.


MONDO:0007488

[PMID:29222591] [SUPPORT] The clinical features of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. --- Explanation: This confirms that visual hallucinations are a core clinical feature of dementia with Lewy bodies.


MONDO:0007488

[PMID:29222591] [SUPPORT] Despite considerable clinical overlap, their diagnosis is based on an arbitrary distinction between the time of onset of motor and cognitive symptoms: dementia often preceding parkinsonism in DLB. --- Explanation: This confirms that parkinsonism is a core feature of DLB, with the temporal relationship to cognitive symptoms distinguishing it from Parkinson's disease dementia.


MONDO:0007488

[PMID:29222591] [SUPPORT] The clinical features of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. --- Explanation: This confirms that cognitive impairment with characteristic fluctuating attention is a core feature of dementia with Lewy bodies.


MONDO:0007488

[PMID:37461299] [SUPPORT] Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). --- Explanation: This establishes that RBD is a prodromal marker for DLB, occurring years before dementia onset.

[PMID:37461299] [SUPPORT] Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. --- Explanation: This demonstrates the temporal relationship between RBD and DLB, with attention/executive deficits predicting dementia phenoconversion.


MONDO:0007488

[PMID:29222591] [INDIRECT EVIDENCE] [SUPPORT] Both are characterized morphologically by widespread cortical and subcortical α-synuclein/Lewy body plus β-amyloid and tau pathologies. --- Explanation: This confirms that alpha-synuclein aggregation forming Lewy bodies is the central pathological feature of DLB, distributed throughout cortical and subcortical regions.


MONDO:0007488

[PMID:39107446] [INDIRECT EVIDENCE] [PARTIAL] Autophagy is a lysosome-based degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and aggregate-prone proteins. Their postmitotic nature and extremely polarized morphologies make neurons particularly vulnerable to disruptions caused by autophagy-lysosomal defects, especially as the brain ages. --- Explanation: This establishes that autophagy-lysosome dysfunction is a fundamental mechanism in neurodegenerative diseases including Parkinson disease and related Lewy body disorders.

[PMID:40598239] [INDIRECT EVIDENCE] [PARTIAL] In particular, we highlight antibody-based therapies to attenuate protein aggregation, compounds that enhance the generation of cellular energy and autophagy-enhancing agents as particular areas of promise. --- Explanation: This confirms that autophagy dysfunction is a key therapeutic target in DLB, with autophagy-enhancing agents being developed as potential disease-modifying therapies.


MONDO:0007488

[PMID:29222591] [INDIRECT EVIDENCE] [SUPPORT] Intravitam PET and post-mortem studies revealed more pronounced cortical atrophy, elevated cortical and limbic Lewy pathologies. --- Explanation: This demonstrates that the alpha-synuclein pathology leads to cortical atrophy through neuronal loss, particularly pronounced in cortical and limbic regions.


MAXO:0000058

[PMID:29222591] [SUPPORT] Clinical management of both disorders includes cholinesterase inhibitors, other pharmacologic and nonpharmacologic strategies, but these have only a mild symptomatic effect. --- Explanation: This confirms that cholinesterase inhibitors are part of standard clinical management for DLB, though they provide only mild symptomatic benefit.


MAXO:0000950

[PMID:29222591] [SUPPORT] Currently, no disease-modifying therapies are available. --- Explanation: This confirms that no disease-modifying therapies are currently available for DLB, with treatment limited to symptomatic management.


HGNC.SYMBOL:APOE

[PMID:30097731] [SUPPORT] DLB shares risk loci with AD, in the APOE E4 allele, and with PD, in variation at GBA and SNCA. --- Explanation: This confirms that the APOE ε4 allele is a shared genetic risk locus between DLB and Alzheimer's disease.

[PMID:29222591] [PARTIAL] Intravitam PET and post-mortem studies revealed more pronounced cortical atrophy, elevated cortical and limbic Lewy pathologies (with APOE ε4). --- Explanation: This demonstrates that APOE ε4 is associated with more pronounced Lewy pathology in DLB.


HGNC.SYMBOL:GBA

[PMID:35332438] [SUPPORT] GBA variants increased the risk of DLB, especially N370S, E326K, and L444P which are strongly associated with DLB, but T369M was not. Patients harbouring GBA variants have an earlier age of onset, more severe cognitive impairment, and rapid symptom progression. --- Explanation: This meta-analysis confirms that specific GBA variants are strongly associated with DLB and correlate with earlier onset and more severe clinical presentation.

[PMID:28734699] [SUPPORT] More recently, association and exome sequencing studies in larger groups have been conducted, and have shown that several variants in GBA and the APOE ε4 allele are important genetic risk factors for DLB. --- Explanation: This review confirms that GBA variants are important genetic risk factors for dementia with Lewy bodies.

[PMID:30097731] [SUPPORT] DLB shares risk loci with AD, in the APOE E4 allele, and with PD, in variation at GBA and SNCA. --- Explanation: This confirms that GBA represents a shared genetic risk locus between DLB and Parkinson's disease.


HGNC.SYMBOL:SNCA

[PMID:30097731] [SUPPORT] DLB shares risk loci with AD, in the APOE E4 allele, and with PD, in variation at GBA and SNCA. --- Explanation: This confirms that SNCA represents a shared genetic risk locus between DLB and Parkinson's disease.


MONDO:0005502

[PMID:17448935] [NO_EVIDENCE] The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia. --- Explanation: Fever is a typical clinical feature of dengue.


MONDO:0005502

[PMID:17448935] [NO_EVIDENCE] The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia. --- Explanation: Rash is a typical clinical feature of dengue.


NCBITaxon:12637

[PMID:34171205] [SUPPORT] Dengue is a vector-borne viral disease caused by the flavivirus dengue virus (DENV). --- Explanation: The review identifies dengue virus as the causative flavivirus.


MONDO:0011934


MONDO:0011934

[PMID:17397592] [INDIRECT EVIDENCE] [SUPPORT] The demonstration of the oncogenic power of the translocation COL1A1-PDGFB in DFSP has allowed the successful introduction of drug therapy with antagonists of the PDGFB receptor for metastatic or locally advanced cases. --- Explanation: Supports the COL1A1-PDGFB translocation as a driver in DFSP.


MAXO:0000004


MAXO:0000058


CHEBI:45783


MAXO:0000014


HGNC.SYMBOL:COL1A1-PDGFB Fusion

[PMID:17950782] [SUPPORT] fusion of exon 2 of PDGFB to various exons of the COL1A1 gene. --- Explanation: Abstract describes the COL1A1-PDGFB fusion underlying DFSP.


MONDO:0011934

[PMID:38841035] [SUPPORT] Dermatofibrosarcoma protuberans (DFSP) is a low- to intermediate-grade dermal --- Explanation: Abstract describes DFSP as a low- to intermediate-grade dermal soft tissue malignancy.


MONDO:0016367


MONDO:0016367

[PMID:38456909] [SUPPORT] Anti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis (anti-MDA5-DM) is frequently complicated by progressive interstitial lung disease (ILD), the prognosis of which is poor, and management is a major challenge. --- Explanation: This evidence confirms that anti-MDA5 positive dermatomyositis is strongly associated with progressive interstitial lung disease, supporting the link between this autoantibody and pulmonary complications.

[PMID:39334579] [SUPPORT] However, rapidly progressive interstitial lung disease (RP-ILD) remains a major cause of death in anti-melanoma differentiation gene 5 autoantibody-positive JDM. --- Explanation: This evidence highlights the severe prognosis of rapidly progressive interstitial lung disease in anti-MDA5 positive dermatomyositis, including juvenile forms.


MONDO:0016367

[PMID:38143369] [INDIRECT EVIDENCE] [SUPPORT] Deposition of complement around capillaries and/or the sarcolemma was observed in muscle biopsy specimens from patients with DM, ASS, and IMNM, suggesting the pathomechanism of complement-dependent muscle and endothelial cell injury. --- Explanation: This evidence demonstrates that complement deposition is a characteristic pathological feature of dermatomyositis, contributing to muscle and endothelial cell injury through complement-dependent mechanisms.

[PMID:38143369] [INDIRECT EVIDENCE] [SUPPORT] Juvenile DM is characterized by the loss of capillaries, perivascular inflammation, and small-vessel angiopathies, which may be related to microinfarction and perifascicular atrophy. --- Explanation: This evidence links the microangiopathy to the characteristic perifascicular atrophy observed in dermatomyositis, supporting the ischemic mechanism of muscle damage.


MONDO:0016367

[PMID:38143369] [INDIRECT EVIDENCE] [SUPPORT] The pathological observation of myxovirus resistance protein A (MxA), which suggests a type 1 interferon (IFN1) signature in DM, supports the diagnosis and further understanding of the pathomechanism of IIM. --- Explanation: MxA expression is a hallmark of type I interferon activation in dermatomyositis, providing diagnostic and pathomechanistic insights.

[PMID:39334579] [INDIRECT EVIDENCE] [SUPPORT] Histopathological studies have revealed critical roles of type I interferons and vasculopathy in the development of JDM. --- Explanation: This evidence confirms that type I interferon signaling is a central pathogenic mechanism in dermatomyositis, including juvenile forms.


MONDO:0016367

[PMID:39334579] [INDIRECT EVIDENCE] [SUPPORT] Each MSA or MAA is associated with distinct clinical features and outcomes, although there are several differences in the prevalence of MSA/MAA and autoantibody-phenotype relationships between age and ethnic groups. --- Explanation: This evidence confirms that myositis-specific autoantibodies (MSAs) define distinct clinical phenotypes in dermatomyositis, supporting the concept of autoantibody-driven disease subtypes.


HGNC.SYMBOL:HLA-DRB1*0301


MONDO:0019373


MONDO:0019373

[PMID:20066421] [INDIRECT EVIDENCE] [PARTIAL] Using microdissection techniques, EWS-WT1-gene fusion transcripts were detected in the cystic (single-cell-layered), the papillary and the solid tumor proliferations (exon 7 of EWS on chromosome 22 with exon 8 of WT1 on chromosome 11). --- Explanation: Supports the presence of EWS-WT1 fusion transcripts in DSRCT.


MAXO:0000647


CHEBI:4026


CHEBI:28748


CHEBI:28445


CHEBI:5864


CHEBI:4911


MAXO:0000004


MAXO:0000014


HGNC.SYMBOL:EWSR1-WT1 Fusion


MONDO:0019373

[PMID:22550424] [SUPPORT] Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive --- Explanation: Abstract characterizes DSRCT as a rare and highly aggressive mesenchymal tumor.


MONDO:0005015

[PMID:39556629] [SUPPORT] Traditionally, DKA has been diagnosed by the triad of hyperglycemia (blood glucose greater than 250 mg/dL), metabolic acidosis (pH less than 7.3, serum bicarbonate less than 18 mEq/L, anion gap greater than 10 mEq/L), and elevated serum (preferred) or urine ketones. --- Explanation: This supports hyperglycemia as a core defining metabolic phenotype in decompensated diabetes presentations.


MONDO:0005015

[PMID:41632731] [SUPPORT] Changes in glomerular hemodynamics, glomerular and tubular hypertrophy, hyperfiltration, overactivation of the renin-angiotensin-aldosterone system (RAAS), podocyte injury, inflammation, oxidative stress, renal hypoxia, mitochondrial injury, and epigenetic changes are the main mechanisms leading to albuminuria, glomerulosclerosis and fibrosis. --- Explanation: This directly supports albuminuria as a major renal phenotype in diabetic kidney disease pathways.


MONDO:0005015

[PMID:41632731] [SUPPORT] Diabetes mellitus (DM) is the most prevalent cause of CKD and end-stage kidney disease (ESKD), requiring renal replacement therapy (RRT). --- Explanation: This supports chronic kidney disease as a common and clinically important diabetes-associated phenotype.

[PMID:36619566] [PARTIAL] Renal biopsy might aid in the definitive diagnosis of DKD, NDKD, and NDKD combined with DKD. --- Explanation: This case report adds context that CKD in diabetes may include coexisting non-diabetic kidney disease.


MONDO:0005015

[PMID:39158206] [SUPPORT] Diabetic microvascular complications such as retinopathy, nephropathy, and neuropathy are primary causes of blindness, terminal renal failure, and neuropathic disorders in type 2 diabetes mellitus patients. --- Explanation: This supports diabetic retinopathy as a major microvascular phenotype contributing to vision-threatening outcomes.


MONDO:0005015

[PMID:39158206] [SUPPORT] Diabetic microvascular complications such as retinopathy, nephropathy, and neuropathy are primary causes of blindness, terminal renal failure, and neuropathic disorders in type 2 diabetes mellitus patients. --- Explanation: This supports diabetic neuropathy as a major microvascular phenotype in diabetes.


MONDO:0005015

[PMID:39742220] [SUPPORT] The predominant form of CVD among diabetic patients is coronary artery disease (CAD), accounting for 29.4% of cases. --- Explanation: This directly supports coronary artery disease as a dominant macrovascular phenotype in diabetes.


MONDO:0005015

[PMID:32872570] [SUPPORT] T2DM leads to a two- to four-fold increase in the mortality rate of adults from heart disease and stroke and is associated with both micro- and macro-vascular complications, the latter consisting of accelerated atherosclerosis leading to severe peripheral vascular disease, premature coronary artery disease (CAD) and increased risk of cerebrovascular diseases [178,179,180]. --- Explanation: This supports increased cerebrovascular disease risk as a macrovascular phenotype in diabetes.


MONDO:0005015

[PMID:32872570] [SUPPORT] T2DM leads to a two- to four-fold increase in the mortality rate of adults from heart disease and stroke and is associated with both micro- and macro-vascular complications, the latter consisting of accelerated atherosclerosis leading to severe peripheral vascular disease, premature coronary artery disease (CAD) and increased risk of cerebrovascular diseases [178,179,180]. --- Explanation: This supports peripheral artery disease as a major macrovascular complication phenotype in diabetes.


MONDO:0005015

[PMID:39556629] [SUPPORT] Polyuria and polydipsia are the most common symptoms, followed by nausea, vomiting, abdominal pain, weight loss, severe fatigue, dyspnea, and preceding febrile illness. --- Explanation: This supports polyuria as a common symptomatic phenotype in diabetic metabolic decompensation.


MONDO:0005015

[PMID:39556629] [SUPPORT] Polyuria and polydipsia are the most common symptoms, followed by nausea, vomiting, abdominal pain, weight loss, severe fatigue, dyspnea, and preceding febrile illness. --- Explanation: This supports polydipsia as a common symptomatic phenotype in diabetic metabolic decompensation.


MONDO:0005015

[PMID:35309606] [SUPPORT] Among clinical features at presentation, 56.5% presented with polyuria, 34.8% with polydipsia, 21.7% with polyphagia, 39.1% with weight loss. --- Explanation: This supports weight loss as a common presenting phenotype in pediatric type 1 diabetes.


MONDO:0005015

[PMID:35309606] [SUPPORT] Among clinical features at presentation, 56.5% presented with polyuria, 34.8% with polydipsia, 21.7% with polyphagia, 39.1% with weight loss. --- Explanation: This supports polyphagia as a presenting phenotype in a subset of pediatric type 1 diabetes cases.


MONDO:0005015

[PMID:34122344] [SUPPORT] On top of these staggering figures, are the number of people with impaired glucose tolerance (IGT) or metabolic syndrome with 373.9 million in 2019 (7.5%) and predicted rise to 548.4 million (8.6%) by 2045 (2). --- Explanation: This supports impaired glucose tolerance as a highly prevalent dysglycemic phenotype relevant to diabetes progression.


MONDO:0005015

[PMID:29939616] [SUPPORT] Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta-cell insulin production and hyperinsulinemia. --- Explanation: This supports hyperinsulinemia as a compensatory metabolic phenotype in insulin-resistant diabetes pathways.


MONDO:0005015

[PMID:34427594] [PARTIAL] The USPSTF recommends screening for prediabetes and type 2 diabetes in adults aged 35 to 70 years who have overweight or obesity. --- Explanation: This supports obesity as a key and common risk-associated phenotype in type 2 diabetes pathways.


MONDO:0005015

[PMID:39556629] [SUPPORT] Polyuria and polydipsia are the most common symptoms, followed by nausea, vomiting, abdominal pain, weight loss, severe fatigue, dyspnea, and preceding febrile illness. --- Explanation: This supports fatigue as a common symptomatic phenotype during diabetic ketoacidosis presentations.


MONDO:0005015

[PMID:39556629] [SUPPORT] Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 and type 2 diabetes resulting from an absolute or relative insulin deficiency. --- Explanation: This directly supports diabetic ketoacidosis as an established acute phenotype across diabetes subtypes.

[PMID:37960733] [PARTIAL] Regrettably, the patient's personal decision to discontinue medication for a single day led to the emergence of acute ketoacidosis, coupled with a recurrence of psoriasis vulgaris. --- Explanation: This case report provides recent clinical context for acute ketoacidosis recurrence in an immune-therapy-associated diabetes presentation.


MONDO:0005015

[PMID:26621825] [PARTIAL] The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. --- Explanation: This supports glycosuria as a clinically recognized glucose-related phenotype in diabetes history and pathophysiology.


MONDO:0005015

[PMID:11554771] [INDIRECT EVIDENCE] [SUPPORT] The HLA-DQ genes are the primary susceptibility genes within this region, although other genes may also contribute. The IDDM2 locus maps to a variable number of tandem repeats in the insulin gene region on chromosome 11. --- Explanation: This supports HLA-DQ and INS-region genetic susceptibility as an upstream event in autoimmune diabetes pathways.

[PMID:22184118] [INDIRECT EVIDENCE] [SUPPORT] HLA-DQ2 and HLA-DQ8 are strongly predisposing haplotypes for type 1 diabetes (T1D). --- Explanation: This supports strong HLA-driven genetic predisposition in type 1 diabetes pathogenesis.

[PMID:34035041] [INDIRECT EVIDENCE] [PARTIAL] Two dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with T1D versus unaffected control subjects. --- Explanation: This supports cross-talk between monogenic-diabetes gene programs and polygenic autoimmune diabetes susceptibility biology.


MONDO:0005015

[PMID:38409439] [INDIRECT EVIDENCE] [SUPPORT] IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1β and TNF-α. --- Explanation: This sentence reports cytokine perturbation effects in cultured human beta cells, supporting interferon-driven priming as an in vitro mechanism.

[PMID:38409439] [INDIRECT EVIDENCE] [SUPPORT] The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes. --- Explanation: This sentence links interferon-induced signatures to human T1D islet biology.


MONDO:0005015


MONDO:0005015

[PMID:33970586] [INDIRECT EVIDENCE] [SUPPORT] Type 1 diabetes is defined as a state of hyperglycemia due to insulin deficiency caused by autoimmune pancreatic beta-cell destruction. --- Explanation: This directly supports autoimmune beta-cell destruction as a causal lesion producing insulin-deficient hyperglycemia.

[PMID:26621825] [INDIRECT EVIDENCE] [SUPPORT] demonstrating an immune-mediated loss of insulin-secreting β-cells in subjects with 'insulin-dependent' diabetes. --- Explanation: This supports immune-mediated beta-cell loss as a key upstream pathogenic event in type 1 diabetes pathways.


MONDO:0005015

[PMID:41595732] [INDIRECT EVIDENCE] [SUPPORT] Individuals with prediabetes are at a higher risk of developing youth-onset type 2 diabetes, which is considered a more aggressive form of the disease. --- Explanation: This supports prediabetes as an upstream metabolic risk state in diabetes progression.


MONDO:0005015

[PMID:38338783] [INDIRECT EVIDENCE] [SUPPORT] Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. --- Explanation: This supports early mitochondrial dysfunction and oxidative stress as upstream progression events in type 2 diabetes pathways.


MONDO:0005015

[PMID:41595732] [INDIRECT EVIDENCE] [SUPPORT] Additionally, significant damage to beta cells may occur even before dysglycemia develops. --- Explanation: This supports early beta-cell injury as a distinct upstream event before overt glycemic abnormality.