MONDO:0008988

[PMID:20301631] [SUPPORT] Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). --- Explanation: GeneReviews directly lists vomiting in neonatal CTLN1 decompensation.


MONDO:0008988

[PMID:40218931] [SUPPORT] Neurological impairment occurred in 44% of patients, with worse neurological outcomes observed in patients with argininosuccinate lyase deficiency, arginase 1 deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria, EO presentations, pre-2014 diagnosis, and patients with higher levels of ammonia at diagnosis. --- Explanation: Registry data showing neurological impairment in 44% of UCD patients.


MONDO:0008988

[PMID:40218931] [SUPPORT] Neurological impairment occurred in 44% of patients --- Explanation: High rate of neurological impairment in UCD patients supports developmental delay as a common outcome.


MONDO:0008988

[PMID:20301631] [SUPPORT] Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. --- Explanation: GeneReviews describes increased ICP (intracranial pressure) as a direct consequence of hyperammonemia.


MONDO:0008988

[PMID:20301631] [SUPPORT] Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. --- Explanation: GeneReviews lists spasticity among the neurological manifestations of hyperammonemic crises.


MONDO:0008988

[PMID:20301631] [SUPPORT] Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. --- Explanation: Loss of consciousness progressing to coma is described as part of the hyperammonemic crisis cascade.


MONDO:0008988

[PMID:38054409] [SUPPORT] LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. --- Explanation: Growth improvement after liver transplant implies growth impairment during medical management.


MONDO:0008988


MONDO:0008988

[PMID:37485339] [INDIRECT EVIDENCE] [SUPPORT] Citrullinemia type I (CTLN1) is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the gene encoding the arginosuccinate synthetase (ASS1) enzyme. --- Explanation: Supports ASS1 molecular deficiency as the initiating defect.


MONDO:0008988

[PMID:39649700] [INDIRECT EVIDENCE] [SUPPORT] the patient exhibited significantly elevated blood ammonia levels (655 μmol/L; normal reference: 10-30 μmol/L) and increased citrulline concentrations (936 μmol/L; normal reference: 5-25 μmol/L) --- Explanation: Quantitative case data demonstrating the magnitude of ammonia and citrulline accumulation in severe CTLN1.


MONDO:0008988

[PMID:20301631] [INDIRECT EVIDENCE] [SUPPORT] Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. --- Explanation: GeneReviews entry describes the cascade from ammonia and glutamine accumulation to cerebral edema and neurological decline.


MONDO:0008988

[PMID:39649700] [INDIRECT EVIDENCE] [SUPPORT] the C-terminal helix domain of the mutant protein structure, which was an important structure for ASS1 protein to form protein tetramers, was indeed more unstable than that of the wild-type protein structure. --- Explanation: In silico analysis showing C-terminal helix instability disrupts ASS1 tetramerization.

[PMID:38927689] [INDIRECT EVIDENCE] [SUPPORT] The p.Arg265Cys variant leads to enzyme deficiency, whereas p.Gly390Arg renders the enzyme inactive. --- Explanation: Demonstrates that different ASS1 variants produce different degrees of enzyme impairment.


MONDO:0008988

[PMID:40218931] [INDIRECT EVIDENCE] [SUPPORT] Early-onset (EO) cases comprised 32.7%, and 10.6% were diagnosed through NBS. Global mortality was 14.9%, higher in carbamoylphosphate synthetase 1 deficiency (36.8%) and male OTCD patients (32.1%) compared to other defects --- Explanation: Registry data showing high mortality in early-onset UCDs, reflecting severity of metabolic crises.


MAXO:0000088

[PMID:38054409] [SUPPORT] LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy --- Explanation: Confirms that protein restriction is standard pre-transplant medical management for UCDs.


MAXO:0000058

[PMID:38054409] [SUPPORT] LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy --- Explanation: Confirms nitrogen scavenger therapy as part of standard medical management for UCDs prior to transplant.


MAXO:0000058

[PMID:20301631] [SUPPORT] Daily routine treatment in those who have not undergone a liver transplantation includes lifelong protein restriction in conjunction with a metabolic nutritionist; nitrogen scavenger medications; arginine supplementation; --- Explanation: GeneReviews directly states arginine supplementation is part of standard CTLN1 management.


MAXO:0000950

[PMID:20301631] [SUPPORT] Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. --- Explanation: GeneReviews emphasizes the need for prompt intervention during hyperammonemic crises.

[PMID:40218931] [SUPPORT] EO cases presented a higher mortality rate (35.8%) than late-onset (LO) cases (7.1%) --- Explanation: High mortality in early-onset cases underscores the importance of acute crisis management.


MAXO:0010039

[PMID:38054409] [SUPPORT] LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. --- Explanation: Severity-adjusted analysis demonstrating metabolic stability and growth benefit after liver transplant in UCDs.

[PMID:40218931] [SUPPORT] Among transplanted patients (20.6%), survival was 95.2%, with no significant neurological differences compared to non-transplanted patients. --- Explanation: Registry data showing high transplant survival but persistent neurological challenges.


MAXO:0000124

[PMID:40218931] [SUPPORT] Diagnosis through NBS improved survival and reduced neurological impairment compared to symptomatic diagnosis. --- Explanation: Registry evidence that newborn screening improves outcomes in UCDs.


MAXO:0000079

[PMID:37485339] [SUPPORT] Molecular genetic testing is critical for patient diagnosis. --- Explanation: Genetic testing is essential for CTLN1, supporting the role of genetic counseling.


MAXO:0000058

[PMID:39449289] [SUPPORT] LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency --- Explanation: Review documenting preclinical mRNA therapy development specifically for CTLN1.


HGNC.SYMBOL:ASS1 pathogenic variants

[PMID:39649700] [SUPPORT] the C-terminal helix domain of the mutant protein structure, which was an important structure for ASS1 protein to form protein tetramers, was indeed more unstable than that of the wild-type protein structure. --- Explanation: Structural analysis demonstrating how specific variants disrupt ASS1 tetramer stability.

[PMID:37485339] [SUPPORT] Both c.649_651del (p.P217del) and c.1048C>T (p.Q350*) showed a highly significant reduction in enzyme activity, while c.-4C>T had no effect. --- Explanation: Functional studies demonstrating variable residual activity across different ASS1 variant types.

[PMID:39449289] [SUPPORT] LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency --- Explanation: Review noting nonsense mutations in approximately 7-10% of ASS1, relevant for therapeutic targeting.


MONDO:0021055

[DOI:10.1038/s43018-024-00831-z] [SUPPORT] Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). --- Explanation: Supports hallmark high-burden colorectal polyposis.


MONDO:0021055

[PMID:37119510] [SUPPORT] Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment. --- Explanation: Supports very high CRC risk in classic FAP without definitive prevention.


MONDO:0021055

[PMID:35636921] [SUPPORT] Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. --- Explanation: Supports frequent and clinically significant duodenal disease in FAP.

[PMID:39046601] [SUPPORT] The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. --- Explanation: Adds population-level evidence for high duodenal disease burden and surveillance relevance.


MONDO:0021055

[DOI:10.1055/s-0043-1767707] [SUPPORT] Exceptionally, for patients with attenuated FAP, high-risk of desmoid, chemoprevention therapy, or other circumstances, surgery can be postponed. --- Explanation: Supports desmoid risk as a clinically relevant disease manifestation and management modifier.

[PMID:39729982] [SUPPORT] The rate of desmoid tumor development was 30.3% in 66 patients. --- Explanation: Adds quantitative cohort evidence for substantial desmoid susceptibility after colectomy.


MONDO:0021055

[DOI:10.3390/ijms25158189] [SUPPORT] Analyses of our cases and the mutations available in the literature with these manifestations revealed that mutations in the N-terminal region (amino acids 1–~1000) of the protein are more frequently associated with only osseous anomalies, whereas dental manifestations are more prevalent in mutations in the middle region (amino acids 1000–~2100). --- Explanation: Supports APC-associated osseous phenotypes including osteoma-predominant extracolonic disease.


MONDO:0021055

[DOI:10.3390/ijms25158189] [SUPPORT] Since dental abnormalities often precede intestinal polyposis, dentists have a crucial role in the early identification of patients at risk. --- Explanation: Supports dental anomalies as an early and clinically actionable phenotype in APC-associated disease.


MONDO:0021055

[PMID:31525261] [SUPPORT] The percentage of FAP patients with CHRPE was found to be 80.00%, whereas the percentage of at-risk patients with CHRPE was 31.12%. --- Explanation: Supports high prevalence of CHRPE in classic FAP and its practical value in screening at-risk cohorts.

[PMID:35321042] [SUPPORT] CHRPE was found to be a non-invasive, rapid, early phenotypical screening marker of FAP. --- Explanation: Supports diagnostic utility of CHRPE as an early phenotypic marker.


MONDO:0021055

[PMID:16411234] [SUPPORT] Sebaceous cysts were reported in 51% of the patients, and their APC mutations were evenly distributed in the gene with no particular hotspot. --- Explanation: Supports frequent cystic cutaneous manifestations in APC-associated FAP/Gardner-spectrum disease.


MONDO:0021055

[DOI:10.1055/s-0043-1767707] [INDIRECT EVIDENCE] [SUPPORT] Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum. --- Explanation: Supports APC germline mutation as the initiating pathogenic event in FAP.

[PMID:28668823] [INDIRECT EVIDENCE] [SUPPORT] Familial adenomatous polyposis (FAP) is a cancer syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene. --- Explanation: Adds independent support that germline APC mutation is the core inherited initiating event.


MONDO:0021055


MONDO:0021055

[DOI:10.3389/fgene.2024.1391851] [INDIRECT EVIDENCE] [SUPPORT] The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial APC mutation leads to the activation of the WNT signaling pathway and CIN. --- Explanation: Supports the APC-to-WNT mechanistic step in progression.


MONDO:0021055

[DOI:10.1038/s43018-024-00831-z] [INDIRECT EVIDENCE] [SUPPORT] Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. --- Explanation: Supports a broad, early molecular expansion program during precancer progression in FAP.


MONDO:0021055

[PMID:19822006] [INDIRECT EVIDENCE] [SUPPORT] Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life. --- Explanation: Supports adenoma initiation as a discrete early disease event.


MONDO:0021055

[DOI:10.1186/s12967-024-05305-5] [INDIRECT EVIDENCE] [SUPPORT] We found simultaneous hyperactivation of Wnt/β-catenin and PI3K/mTOR pathways in FAP-lesions compared to CRCs. --- Explanation: Directly supports concurrent WNT and PI3K/mTOR pathway hyperactivation in FAP lesions.


MONDO:0021055

[DOI:10.3389/fgene.2024.1391851] [INDIRECT EVIDENCE] [SUPPORT] Furthermore, a progressive increase in the HRD score (a measure of “genomic scars”) was observed from tubular adenomas to villous adenomas and ultimately to carcinomas. --- Explanation: Supports stepwise accumulation of genomic instability through progression stages.

[DOI:10.3389/fgene.2024.1391851] [INDIRECT EVIDENCE] [SUPPORT] Adenomas exhibited lower mutational rates than FAP-CRC and displayed recurrent alterations in well-known chromosomal instability (CIN) genes (APC, RAS, SMAD4 and TP53) and DNA damage repair genes (SUZ12, KMT2C, BCLAF1, RUNX1, and ARID1B), suggesting the presence of genomic instability. --- Explanation: Supports CIN and DNA repair disruption as central progression features.


MAXO:0000004

[PMID:37119510] [SUPPORT] Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment. --- Explanation: Supports colectomy as a core preventive intervention in classic FAP.

[DOI:10.1055/s-0043-1767707] [SUPPORT] Generally, proctocolectomy is recommended for FAP patients at the age of 20s. --- Explanation: Supports guideline-aligned timing of prophylactic surgery.


MAXO:0001184

[DOI:10.1055/s-0043-1770384] [SUPPORT] Cancer prevention in hereditary gastrointestinal predisposition syndromes relies primarily on intensive screening (e.g., colonoscopy) or prophylactic surgery (e.g., colectomy). --- Explanation: Supports intensive endoscopic screening as a core prevention strategy.

[PMID:37119510] [SUPPORT] While most patients undergo colectomy at an early age, ongoing screening and surveillance of the upper gastrointestinal tract and rectal pouch must continue throughout adulthood. --- Explanation: Supports lifelong endoscopic surveillance needs after surgical management.


MAXO:0000058

[DOI:10.1055/s-0043-1770384] [SUPPORT] The use of chemopreventive agents as an adjunct to these measures has long been studied both in the general population and in hereditary cancer patients, in whom the risk of malignancy, and therefore the potential risk reduction, is considerably greater. --- Explanation: Supports adjunctive chemoprevention strategy in hereditary cancer settings including FAP.

[DOI:10.1055/s-0043-1770384] [PARTIAL] However, to date only few compounds have been found to be effective, safe, and tolerable for widespread use. --- Explanation: Supports a cautious interpretation of chemoprevention efficacy and tolerability.


MAXO:0000058

[DOI:10.1186/s13023-024-03064-6] [SUPPORT] One-year metformin therapy for FAP is safe and effective, potentially mediated by modulating the intestinal flora. --- Explanation: Supports favorable efficacy/safety signal in one recent clinical study.

[PMID:33509804] [REFUTE] A 7-month metformin treatment (500 mg or 1,500 mg) did not reduce the number or size of polyps in the colorectum or duodenum of FAP patients as compared to placebo. --- Explanation: Supports conflicting trial evidence showing no significant lesion-regression endpoint benefit.


MAXO:0000058

[PMID:35636921] [SUPPORT] Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of -29.6% (95% CI, -39.6% to -19.7%; p<0.0001). --- Explanation: Supports clinical efficacy for reducing duodenal polyp burden.

[PMID:35636921] [PARTIAL] Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention. --- Explanation: Supports efficacy with important tolerability tradeoffs.


MAXO:0000058

[PMID:32905675] [PARTIAL] In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. --- Explanation: Supports limited incremental efficacy of combination therapy in the primary trial analysis.


MAXO:0000079

[DOI:10.3390/cimb46070385] [SUPPORT] The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants. --- Explanation: Supports inclusion of structured genetic counseling as a core management component.


hgnc:583

[DOI:10.1055/s-0043-1767707] [SUPPORT] Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum. --- Explanation: Supports APC as the germline causal driver of disease.


hgnc:11998

[DOI:10.3389/fgene.2024.1391851] [SUPPORT] TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas. --- Explanation: Supports a TP53-dominant transition mechanism in advanced progression.


MONDO:0021055

[DOI:10.1055/s-0043-1767707] [SUPPORT] Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum. --- Explanation: The abstract directly supports autosomal dominant APC-mediated inheritance in FAP.


MONDO:0005005


MONDO:0005005

[PMID:37085424] [INDIRECT EVIDENCE] [PARTIAL] These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1 --- Explanation: This comprehensive review confirms VHL as the primary genomic biomarker and driver mutation in ccRCC.


MONDO:0005005

[PMID:37085424] [INDIRECT EVIDENCE] [PARTIAL] These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1 --- Explanation: This review confirms PBRM1, SETD2, and BAP1 as recurrent genomic biomarkers in ccRCC contributing to epigenetic dysregulation.


MONDO:0005005

[PMID:38762484] [INDIRECT EVIDENCE] [SUPPORT] The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents dysregulated immunity and harmful immune responses. However, cancer cells exploit the PD-1/PD-L1 axis to cause immune escape in cancer development and progression. --- Explanation: Review describing how tumors including ccRCC exploit PD-1/PD-L1 signaling to suppress anti-tumor immunity, relevant to the highly immune-infiltrated ccRCC microenvironment.


MAXO:0000004


MAXO:0000058


CHEBI:38940


CHEBI:71219


CHEBI:66910


CHEBI:72317


NCIT:C135627


MAXO:0001002


HGNC.SYMBOL:VHL


HGNC.SYMBOL:PBRM1


HGNC.SYMBOL:BAP1


MONDO:0005005

[PMID:39196544] [SUPPORT] Clear cell RCC is the most common histologic subtype --- Explanation: Abstract reports clear cell RCC as the most common histologic subtype.


MONDO:0002926


MONDO:0002926

[PMID:9793401] [INDIRECT EVIDENCE] [PARTIAL] reciprocal translocation between the long arms of chromosomes 12 and 22 --- Explanation: Supports the characteristic t(12;22) translocation in clear cell sarcoma.


MAXO:0000014


MAXO:0000647


CHEBI:28748


HGNC.SYMBOL:EWSR1-ATF1 Fusion


MONDO:0002926

[PMID:11211309] [SUPPORT] sarcoma (also known as malignant melanoma of soft parts). --- Explanation: Abstract notes clear cell sarcoma is also known as malignant melanoma of soft parts.


MONDO:0007340

[PMID:10204840] [SUPPORT] Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes. --- Explanation: This directly supports clavicular abnormalities as a defining phenotype.


MONDO:0007340

[PMID:10204840] [SUPPORT] Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes. --- Explanation: This supports persistent patent sutures/fontanelles as core CCD features.


MONDO:0007340

[PMID:10204840] [SUPPORT] Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes. --- Explanation: This directly supports supernumerary dentition as a hallmark CCD feature.


MONDO:0007340

[PMID:25206109] [SUPPORT] prolonged retention of primary teeth and delayed eruption of permanent teeth were evident. --- Explanation: This provides direct clinical evidence for delayed permanent tooth eruption in CCD.


MONDO:0007340

[PMID:25206109] [SUPPORT] A-P view of the skull demonstrated widening of sutures and a few wormian bones --- Explanation: Full-text case imaging documents wormian bones in affected family members.


MONDO:0007340

[PMID:10204840] [SUPPORT] Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes. --- Explanation: This directly supports short stature as part of the characteristic CCD phenotype.


MONDO:0007340

[PMID:10204840] [INDIRECT EVIDENCE] [SUPPORT] Loss of both alleles (-/-) leads to a complete absence of bone owing to a lack of osteoblast differentiation. --- Explanation: This model-organism evidence directly supports RUNX2-dependent osteoblast differentiation as a causal mechanism.

[PMID:10204840] [INDIRECT EVIDENCE] [SUPPORT] CBFA1 controls differentiation of precursor cells into osteoblasts and is thus essential for membranous as well as endochondral bone formation. --- Explanation: This supports the dual intramembranous and endochondral ossification defects in RUNX2-related disease.


MONDO:0007340


MAXO:0000950

[PMID:25206109] [SUPPORT] Medical treatment is mainly directed at orthopedic and dental correction. --- Explanation: This directly supports supportive orthopedic/dental management in CCD.


hgnc:10472

[PMID:25206109] [SUPPORT] is a rare autosomal dominant skeletal dysplasia caused by CBAF1 gene --- Explanation: This report links the RUNX2 locus (historically CBFA1/CBAF1 notation) with autosomal dominant CCD.

[PMID:10204840] [SUPPORT] Mutations in the CBFA1 gene that presumably lead to synthesis of an inactive gene product were identified in patients with CCD. --- Explanation: This identifies pathogenic RUNX2/CBFA1 mutations in affected CCD patients.


MONDO:0007340

[PMID:10204840] [SUPPORT] Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes. --- Explanation: This sentence directly supports autosomal dominant inheritance and the core clinical spectrum.


MONDO:0000705

[PMID:28613708] [SUPPORT] This obligate anaerobic bacillus is recognized for its ability to produce toxins and is the leading cause of antibiotic-associated diarrhea worldwide. --- Explanation: StatPearls review states CDI is the leading cause of antibiotic-associated diarrhea.


MONDO:0000705

[PMID:37004449] [PARTIAL] A 40 years old male patient presented with abdominal pain and diarrhea of 10 days duration after he was diagnosed and managed as a case of Clostridium Difficile infection and amebiasis. --- Explanation: Case report notes abdominal pain with CDI presentation.


MONDO:0000705

[PMID:33402156] [PARTIAL] A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea, non-bilious vomiting, and subjective fevers. --- Explanation: CDI case report documents fever accompanying infection.


MONDO:0000705

[PMID:33402156] [PARTIAL] A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea, non-bilious vomiting, and subjective fevers. --- Explanation: Case report documents nausea among presenting symptoms in laboratory-confirmed CDI.


MONDO:0000705

[PMID:33402156] [PARTIAL] A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea, non-bilious vomiting, and subjective fevers. --- Explanation: Case report documents vomiting as part of CDI clinical presentation.


MONDO:0000705

[PMID:28613708] [SUPPORT] C difficile infections can range from an asymptomatic carrier to diarrhea, progressing to severe conditions such as pseudomembranous colitis and toxic megacolon with septic shock, often resulting in a high mortality rate. --- Explanation: Explicitly identifies pseudomembranous colitis as a severe CDI manifestation.


MONDO:0000705

[PMID:28613708] [SUPPORT] C difficile infections can range from an asymptomatic carrier to diarrhea, progressing to severe conditions such as pseudomembranous colitis and toxic megacolon with septic shock, often resulting in a high mortality rate. --- Explanation: Supports toxic megacolon as a severe, high-risk complication of CDI.


MONDO:0000705

[PMID:28613708] [SUPPORT] C difficile infections can range from an asymptomatic carrier to diarrhea, progressing to severe conditions such as pseudomembranous colitis and toxic megacolon with septic shock, often resulting in a high mortality rate. --- Explanation: Supports septic shock as a life-threatening complication in severe CDI.


MONDO:0000705

[PMID:28613708] [INDIRECT EVIDENCE] [SUPPORT] The most significant risk factor for C difficile infection is broad-spectrum antibiotics. Patients can be colonized with C difficile without symptoms, but antibiotic use disturbs the balance of gut flora, enabling C difficile overgrowth and infection. --- Explanation: StatPearls notes antibiotic-driven dysbiosis allows C. difficile overgrowth in the colon.


MONDO:0000705

[PMID:15831824] [INDIRECT EVIDENCE] [SUPPORT] Following expression and release from the bacterium, TcdA and TcdB translocate to the cytosol of target cells and inactivate small GTP-binding proteins, which include Rho, Rac, and Cdc42. Inactivation of these substrates occurs through monoglucosylation of a single reactive threonine. --- Explanation: Comprehensive review details the molecular mechanism of toxin action on Rho GTPases.

[PMID:34837014] [INDIRECT EVIDENCE] [SUPPORT] The bacterium produces up to three toxins, which are considered the major virulence factors in C. difficile infection. These toxins promote inflammation, tissue damage and diarrhoea. --- Explanation: Review confirms toxins as major virulence factors causing disease pathology.


MONDO:0000705

[PMID:15831824] [INDIRECT EVIDENCE] [SUPPORT] By glucosylating small GTPases, TcdA and TcdB cause actin condensation and cell rounding, which is followed by death of the cell. --- Explanation: Review describes the cellular consequences of toxin-mediated GTPase inactivation.


MONDO:0000705

[PMID:15831824] [INDIRECT EVIDENCE] [SUPPORT] Furthermore, there have been major advances in defining the role of these toxins in modulating the inflammatory events involving the disruption of cell junctions, neuronal activation, cytokine production, and infiltration by polymorphonuclear cells. --- Explanation: Review details toxin-induced inflammatory cascade including neutrophil recruitment.


MONDO:0000705


MONDO:0000705

[PMID:34837014] [INDIRECT EVIDENCE] [PARTIAL] These toxins promote inflammation, tissue damage and diarrhoea. --- Explanation: Toxin activity drives the pseudomembrane-associated inflammation and diarrheal fluid loss that characterize severe CDI.


MAXO:0000058

[PMID:38508330] [SUPPORT] Effective infection management requires appropriate interpretation of diagnostic tests, as well as the use of vancomycin and fidaxomicin as first-line treatment. --- Explanation: Clinical review lists oral vancomycin among first-line agents for CDI management.


MAXO:0000058

[PMID:38726585] [SUPPORT] IDSA/SHEA shifted its preference for initial treatment to fidaxomicin over vancomycin and metronidazole due to its lower recurrence rate. --- Explanation: Guideline update highlights fidaxomicin as preferred initial therapy because of reduced recurrence.

[PMID:39282548] [SUPPORT] Management of CDI has evolved, with fidaxomicin emerging as a superior treatment option over vancomycin for initial and recurrent infections due to its reduction of recurrence rate. --- Explanation: Recent review reinforces fidaxomicin's superiority to vancomycin for initial and recurrent CDI.


MAXO:0000748

[PMID:38508330] [SUPPORT] Novel treatments such as Bezlotoxumab, fecal microbiota transplant, and live biotherapeutic products are proven effective in recurrent C. difficile infection and address dysbiosis. --- Explanation: Review notes FMT as effective for recurrent CDI in restoring microbiota.

[PMID:39282548] [SUPPORT] Faecal microbiota transplantation (FMT) is effective for recurrent CDI, restoring gut eubiosis. --- Explanation: Update article explicitly states FMT effectiveness for recurrent CDI by reestablishing gut balance.


MAXO:0000058

[PMID:39282548] [SUPPORT] Bezlotoxumab, a monoclonal antibody against C. difficile toxin B, has shown promise in reducing recurrence rates. --- Explanation: Review notes bezlotoxumab reduces CDI recurrence when used adjunctively with standard antibiotics.


MAXO:0000004

[PMID:39650985] [PARTIAL] In cases where pharmacological management has been ineffective, fecal microbiota transplantation and surgical intervention demonstrated success. --- Explanation: Case report highlights loop ileostomy with lavage as a surgical option after failed pharmacologic therapy in fulminant CDI.


NCBITaxon:1496

[PMID:39204246] [SUPPORT] Clostridioides difficile is the main causative agent of antibiotic-associated diarrhea (AAD) in hospitals in the developed world. --- Explanation: Directly establishes C. difficile as the core infectious agent for CDI.


MONDO:0005706

[PMID:26904326] [SUPPORT] Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy. --- Explanation: Identifies cough as one of the usual presenting symptoms of coccidioidomycosis.


MONDO:0005706

[PMID:24613568] [SUPPORT] Common symptoms (median, 5 weeks) included cough (47%), chest pain (44%), and dyspnea (39%). --- Explanation: Documents chest pain in 44% of patients with pleural coccidioidomycosis.

[PMID:26904326] [SUPPORT] Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy. --- Explanation: Confirms pleurisy (pleuritic chest pain) as a common symptom of coccidioidomycosis.


MONDO:0005706

[PMID:33262956] [SUPPORT] the host presents generic flu-like symptoms including headache, fever, body ache, coughing, and respiratory distress --- Explanation: Identifies fever as one of the flu-like symptoms of coccidioidomycosis.


MONDO:0005706

[PMID:21791226] [SUPPORT] His initial presentation included a non-productive cough, dyspnea, fatigue, night sweats, myalgias, and arthralgias. --- Explanation: Documents fatigue as a presenting symptom in a patient with disseminated coccidioidomycosis.

[PMID:26904326] [SUPPORT] Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy. --- Explanation: Confirms fatigue as a common symptom of coccidioidomycosis.


MONDO:0005706

[PMID:28857979] [SUPPORT] a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats --- Explanation: Documents night sweats as a presenting symptom in a patient with disseminated coccidioidomycosis.

[PMID:21791226] [SUPPORT] His initial presentation included a non-productive cough, dyspnea, fatigue, night sweats, myalgias, and arthralgias. --- Explanation: Confirms night sweats as part of the clinical presentation of disseminated coccidioidomycosis.


MONDO:0005706

[PMID:28857979] [SUPPORT] a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats --- Explanation: Documents weight loss as a presenting symptom in disseminated coccidioidomycosis.

[PMID:21791226] [SUPPORT] Pain progressed over the ensuing weeks, refractory to analgesics, and then accompanied by fevers, night sweats, and unintentional (15-pound) weight loss prompting further evaluation. --- Explanation: Documents significant unintentional weight loss in a patient with disseminated coccidioidomycosis.


MONDO:0005706

[PMID:38196429] [SUPPORT] A common triad of symptoms of coccidioidomycosis, also called "desert rheumatism," include fever, erythema nodosum, and arthralgia, often accompanied by a respiratory problem. --- Explanation: Erythema nodosum is identified as part of the classic symptom triad of coccidioidomycosis.

[PMID:38667927] [SUPPORT] some risk factors, such as ABO blood group, Filipino ancestry, or lack of erythema nodosum among black individuals, are repeated in the literature despite the lack of supporting studies or biologic plausibility. --- Explanation: Discusses erythema nodosum in the context of coccidioidomycosis risk assessment.


MONDO:0005706

[PMID:38196429] [SUPPORT] A common triad of symptoms of coccidioidomycosis, also called "desert rheumatism," include fever, erythema nodosum, and arthralgia, often accompanied by a respiratory problem. --- Explanation: Arthralgia is part of the classic desert rheumatism triad.


MONDO:0005706

[PMID:37233271] [SUPPORT] Cavitary lung disease may be found incidentally or when investigating symptoms such as cough or hemoptysis. --- Explanation: Identifies hemoptysis as a presenting symptom that prompts investigation of cavitary coccidioidomycosis.


MONDO:0005706

[PMID:24613568] [SUPPORT] Common symptoms (median, 5 weeks) included cough (47%), chest pain (44%), and dyspnea (39%). --- Explanation: Documents dyspnea in 39% of patients with pleural coccidioidomycosis.

[PMID:28857979] [SUPPORT] a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats --- Explanation: Documents dyspnea on exertion as a presenting symptom in disseminated coccidioidomycosis.


MONDO:0005706

[PMID:33262956] [SUPPORT] the host presents generic flu-like symptoms including headache, fever, body ache, coughing, and respiratory distress --- Explanation: Documents headache as part of the symptomatic presentation of coccidioidomycosis.


MONDO:0005706

[PMID:39189034] [SUPPORT] 41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement). --- Explanation: Documents meningitis as one of the most common extrapulmonary manifestations in critically ill patients.


MONDO:0005706

[PMID:39189034] [SUPPORT] 41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement). --- Explanation: Musculoskeletal disease, including osteomyelitis, is documented as a form of extrapulmonary dissemination.


MONDO:0005706

[PMID:37367586] [SUPPORT] One mechanism by which the host immune system attempts to control and eliminate Coccidioides is through granuloma formation. --- Explanation: Confirms granuloma formation as a key feature of coccidioidomycosis.


MONDO:0005706

[PMID:39452676] [INDIRECT EVIDENCE] [SUPPORT] Coccidioidomycosis is transmitted through the inhalation of fungal spores, arthroconidia, which can cause disease in susceptible mammalian hosts, including humans. --- Explanation: Confirms the inhalation route of arthroconidia transmission.

[PMID:33262956] [INDIRECT EVIDENCE] [SUPPORT] In the spherule state, Coccidioides secretes metalloproteinase 1 (Mep1) which digests an immunodominant antigen spherical outer wall glycoprotein (SOWgp) on the fungal surface --- Explanation: Describes spherule morphogenesis and the Mep1 metalloproteinase that digests SOWgp to evade immune detection.


MONDO:0005706


MONDO:0005706

[PMID:32358020] [INDIRECT EVIDENCE] [SUPPORT] the GCP-rCpa1 vaccine stimulates a robust Th17 immunity against Coccidioides infection through activation of the CARD9-associated Dectin-1 and Dectin-2 signal pathways. --- Explanation: Demonstrates that innate immune recognition of Coccidioides involves CARD9-associated Dectin-1 and Dectin-2 C-type lectin receptor signaling pathways.

[PMID:33262956] [INDIRECT EVIDENCE] [SUPPORT] Macrophages and neutrophils detect Coccidioides arthroconidia and immature spherules via receptors Dectin-1, Dectin-2, and Mincle interacting with SOWgp --- Explanation: Identifies the specific pattern recognition receptors (Dectin-1, Dectin-2, Mincle) and their fungal ligand (SOWgp) involved in innate immune recognition of Coccidioides.


MONDO:0005706

[PMID:38535182] [INDIRECT EVIDENCE] [SUPPORT] the host response to this organism is very effective at resolving the infection in most cases and immunizing to prevent second infections. People who are immunocompromised are much more likely to develop disseminated infection. --- Explanation: Confirms the effectiveness of cell-mediated immunity and the role of immunocompromise in dissemination.

[PMID:38667927] [INDIRECT EVIDENCE] [SUPPORT] Specific genetic variants, sex, and immune suppression by TNF inhibitors have been validated in later cohort studies, confirming the original hypotheses. --- Explanation: Validates genetic susceptibility factors and TNF-alpha blockade as risk factors, supporting the importance of the Th1/TNF-alpha axis.


MONDO:0005706

[PMID:37367586] [INDIRECT EVIDENCE] [SUPPORT] One mechanism by which the host immune system attempts to control and eliminate Coccidioides is through granuloma formation. --- Explanation: Directly supports granuloma formation as a key containment mechanism in coccidioidomycosis.

[PMID:33262956] [INDIRECT EVIDENCE] [SUPPORT] Host responses sometimes control infections through granuloma formation in the lung as fungi is walled off instead of destroyed --- Explanation: Confirms that granuloma formation in the lung is a containment mechanism where fungi are walled off rather than destroyed.


MAXO:0000058

[PMID:11074900] [SUPPORT] fluconazole and itraconazole were effective therapy for progressive forms of coccidioidomycosis. --- Explanation: Randomized double-blind trial confirms fluconazole as effective therapy for progressive coccidioidomycosis.


CHEBI:46081

[PMID:11074900] [INDIRECT EVIDENCE] [SUPPORT] fluconazole and itraconazole were effective therapy for progressive forms of coccidioidomycosis. --- Explanation: Randomized double-blind trial confirms fluconazole as effective therapy for progressive coccidioidomycosis.


MAXO:0000058

[PMID:11074900] [SUPPORT] 50% of patients (47 of 94) and 63% of patients (61 of 97) responded to 8 months of treatment with fluconazole and itraconazole, respectively --- Explanation: Randomized double-blind trial of 198 patients showing itraconazole had a 63% response rate in nonmeningeal coccidioidomycosis.

[PMID:11074900] [SUPPORT] Patients with skeletal infections responded twice as frequently to itraconazole as to fluconazole. --- Explanation: Demonstrates itraconazole's particular efficacy in skeletal coccidioidomycosis compared to fluconazole.


CHEBI:6076

[PMID:11074900] [INDIRECT EVIDENCE] [SUPPORT] 50% of patients (47 of 94) and 63% of patients (61 of 97) responded to 8 months of treatment with fluconazole and itraconazole, respectively --- Explanation: Randomized double-blind trial of 198 patients showing itraconazole had a 63% response rate in nonmeningeal coccidioidomycosis.

[PMID:11074900] [INDIRECT EVIDENCE] [SUPPORT] Patients with skeletal infections responded twice as frequently to itraconazole as to fluconazole. --- Explanation: Demonstrates itraconazole's particular efficacy in skeletal coccidioidomycosis compared to fluconazole.


MAXO:0000058

[PMID:21791226] [SUPPORT] Treatment was initiated with liposomal amphotericin and posaconazole (400-mg bid) with fatty meals. --- Explanation: Documents use of liposomal amphotericin B as initial induction therapy for severe disseminated coccidioidomycosis.

[PMID:39189034] [SUPPORT] most (91%) received antifungal therapy during hospitalization. --- Explanation: Documents that the vast majority of critically ill patients received antifungal therapy.


CHEBI:2682

[PMID:21791226] [INDIRECT EVIDENCE] [SUPPORT] Treatment was initiated with liposomal amphotericin and posaconazole (400-mg bid) with fatty meals. --- Explanation: Documents use of liposomal amphotericin B as initial induction therapy for severe disseminated coccidioidomycosis.

[PMID:39189034] [INDIRECT EVIDENCE] [SUPPORT] most (91%) received antifungal therapy during hospitalization. --- Explanation: Documents that the vast majority of critically ill patients received antifungal therapy.


HGNC.SYMBOL:CLEC7A

[PMID:18418396] [SUPPORT] These results suggest that alternative splicing of the Dectin-1 gene contributes to susceptibility of C57BL/6 mice to coccidioidomycosis, and affects the cytokine responses of macrophages and mDCs to spherules. --- Explanation: Demonstrates that truncated Dectin-1 (Clec7a) splice variant in C57BL/6 mice contributes to coccidioidomycosis susceptibility.

[PMID:35071044] [SUPPORT] Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice. --- Explanation: Identifies Dectin-1 (CLEC7A) deficiency as a primary immunodeficiency associated with disseminated coccidioidomycosis.


HGNC.SYMBOL:CARD9

[PMID:32358020] [SUPPORT] The GCP-rCpa1 vaccine stimulates a robust Th17 immunity against Coccidioides infection through activation of the CARD9-associated Dectin-1 and Dectin-2 signal pathways. --- Explanation: Demonstrates that CARD9-associated signaling through Dectin-1 and Dectin-2 is required for protective Th17 immunity against Coccidioides.


HGNC.SYMBOL:STAT4

[PMID:35149520] [SUPPORT] All affected family members had a single heterozygous base change in STAT4, c.1877A>G, causing substitution of glycine for glutamate at AA626 (STAT4E626G/+ ). A knockin mouse, heterozygous for the substitution, developed more severe experimental coccidioidomycosis than did wild-type mice. --- Explanation: Identifies the STAT4 E626G mutation in a family with disseminated coccidioidomycosis and validates its effect in a mouse model.

[PMID:35149520] [SUPPORT] defective early induction of IFN-γ and adaptive responses by STAT4 prevents normal control of coccidioidomycosis in both mice and humans. --- Explanation: Confirms that STAT4 deficiency impairs IFN-gamma and adaptive immune responses critical for controlling coccidioidomycosis.


HGNC.SYMBOL:STAT3

[PMID:35071044] [SUPPORT] Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice. --- Explanation: Identifies STAT3 mutations as a primary immunodeficiency associated with disseminated coccidioidomycosis.

[PMID:35071044] [SUPPORT] Splenic dissemination was prevented in most vaccinated immunodeficient mice while all unvaccinated B6 mice and the Rag-1 KO mice displayed disseminated disease. --- Explanation: Demonstrates that unvaccinated mice with STAT3 and other PID-associated mutations develop disseminated disease, and that vaccination can mitigate this susceptibility.


HGNC.SYMBOL:IL12RB1

[PMID:21258095] [SUPPORT] We report a family with disseminated coccidioidomycosis due to a novel homozygous C186Y mutation in interleukin (IL)-12 receptor β1. This family confirms the centrality of the IL-12/IFN-γ axis to human immunity to Coccidioides spp. --- Explanation: Documents a family with IL12RB1 deficiency (C186Y mutation) presenting with disseminated coccidioidomycosis, confirming the gene's role in host defense.


NCBITaxon:5501

[PMID:39452676] [SUPPORT] Coccidioidomycosis is a disease caused by soil fungi of the genus Coccidioides, divided genetically into Coccidioides immitis (California isolates) and Coccidioides posadasii (isolates outside California). --- Explanation: Identifies C. immitis as one of two causative species, primarily associated with California isolates.

[PMID:39365073] [SUPPORT] Coccidioides immitis and Coccidioides posadasii are fungal pathogens that cause systemic mycoses and are prevalent in arid regions in the Americas. --- Explanation: Confirms both Coccidioides species as causative agents of systemic mycoses.


NCBITaxon:199306

[PMID:39452676] [SUPPORT] Coccidioidomycosis is a disease caused by soil fungi of the genus Coccidioides, divided genetically into Coccidioides immitis (California isolates) and Coccidioides posadasii (isolates outside California). --- Explanation: Identifies C. posadasii as the species found outside California.

[PMID:39365073] [SUPPORT] While C. immitis mainly occurs in California and Washington, C. posadasii is widely distributed across North and South America. --- Explanation: Confirms the geographic distribution of C. posadasii.


MONDO:0016006

[PMID:39179905] [SUPPORT] Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which-through largely unknown mechanisms-can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. --- Explanation: Explicitly names microcephaly as a clinical presentation of CSB.


MONDO:0016006

[PMID:39179905] [SUPPORT] Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which-through largely unknown mechanisms-can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. --- Explanation: Identifies intellectual disability as a core clinical manifestation in CSB.


MONDO:0016006

[PMID:39179905] [SUPPORT] Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which-through largely unknown mechanisms-can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. --- Explanation: Supports demyelination as a defining neurologic phenotype.


MONDO:0016006

[PMID:36190439] [SUPPORT] Cockayne syndrome has classically been linked to demyelinating polyneuropathies, whereas xeroderma pigmentosum has long been associated with axonal polyneuropathies. --- Explanation: Supports the peripheral demyelinating neuropathy phenotype in CS.


MONDO:0016006

[PMID:38674442] [SUPPORT] Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. --- Explanation: Identifies ataxia as a cardinal neurologic feature in ERCC6-related CS.


MONDO:0016006

[PMID:38674442] [SUPPORT] Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. --- Explanation: Supports spasticity as a common neurologic manifestation in CS.


MONDO:0016006


MONDO:0016006

[PMID:30988227] [SUPPORT] The clinical features of CS include photosensitivity, a characteristic senile face, significant developmental abnormalities, such as short stature, underweight, and microcephaly, progressive cachexia, severe visual impairment, and sensorineural deafness. --- Explanation: Explicitly lists photosensitivity as a core clinical feature of Cockayne syndrome.

[PMID:30988227] [SUPPORT] Unlike XP, in CS, skin cancer is not known to occur in areas of skin exposed to sunlight. --- Explanation: Confirms that despite photosensitivity, CS patients are not predisposed to skin cancers, distinguishing CS from xeroderma pigmentosum.


MONDO:0016006

[PMID:39473441] [SUPPORT] BACKGROUND: Cockayne syndrome (CS) is a rare, multisystem, autosomal recessive disorder characterized by cachectic dwarfism, nervous system abnormalities, and premature aging. --- Explanation: Supports growth impairment with cachectic dwarfism/short stature as a clinical hallmark.


MONDO:0016006

[PMID:30988227] [SUPPORT] The clinical features of CS include photosensitivity, a characteristic senile face, significant developmental abnormalities, such as short stature, underweight, and microcephaly, progressive cachexia, severe visual impairment, and sensorineural deafness. --- Explanation: Explicitly names "a characteristic senile face" as a clinical feature of CS, directly supporting the progeroid facial appearance phenotype.


MONDO:0016006

[PMID:40723898] [INDIRECT EVIDENCE] [SUPPORT] A branch of the nucleotide excision repair (NER) pathway, transcription-coupled repair (TCR or TC-NER) specifically operates on the template DNA strand of actively transcribed genes. --- Explanation: Defines the core repair pathway mechanistically affected in Cockayne syndrome biology.

[PMID:40332372] [INDIRECT EVIDENCE] [SUPPORT] TCR, a specialized sub-pathway of nucleotide excision repair, rapidly removes transcription-blocking lesions from the transcribed strand of active genes, thereby safeguarding transcription fidelity and cellular homeostasis. --- Explanation: Reinforces TC-NER as the critical pathway disrupted in CS, with consequences for transcription fidelity.

[PMID:38674442] [INDIRECT EVIDENCE] [SUPPORT] (1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). --- Explanation: Provides direct human clinical-genetic evidence that ERCC6 and ERCC8 are the main causal genes.


MONDO:0016006

[PMID:39179905] [INDIRECT EVIDENCE] [SUPPORT] In our models, CSB deficiency is associated with (i) impaired cellular migration due to defective autophagy as an explanation for clinical microcephaly --- Explanation: Directly links impaired migration via defective autophagy to microcephaly in CSB.

[PMID:39179905] [INDIRECT EVIDENCE] [SUPPORT] Of note, the impaired migration and oligodendrocyte maturation could both be partially rescued by pharmacological HDAC inhibition. --- Explanation: Demonstrates pharmacological rescue potential for the migration defect, suggesting a targetable pathway.


MONDO:0016006

[PMID:39179905] [INDIRECT EVIDENCE] [SUPPORT] altered neuronal network functionality and neurotransmitter GABA levels, which is suggestive of a disturbed GABA switch that likely impairs brain circuit formation and ultimately causes intellectual disability --- Explanation: Identifies disturbed GABA switch as a mechanism underlying intellectual disability in CSB.


MONDO:0016006

[PMID:39179905] [INDIRECT EVIDENCE] [SUPPORT] altered neuronal network functionality and neurotransmitter GABA levels, which is suggestive of a disturbed GABA switch that likely impairs brain circuit formation and ultimately causes intellectual disability --- Explanation: Demonstrates altered neuronal network functionality in CSB-deficient neural models.


MONDO:0016006

[PMID:39179905] [INDIRECT EVIDENCE] [SUPPORT] (iii) impaired oligodendrocyte maturation as a possible cause of the demyelination observed in children with CSB. --- Explanation: Directly links oligodendrocyte maturation failure to clinical demyelination.


MONDO:0016006

[PMID:39611850] [INDIRECT EVIDENCE] [SUPPORT] Gene expression analysis revealed alterations in two main pathways. This involves the activation of arachidonic acid metabolism and the repression of the NRF2 pathway in affected individuals with CS. --- Explanation: Identifies NRF2 pathway repression as a key oxidative stress defect in CS fibroblasts.

[PMID:39611850] [INDIRECT EVIDENCE] [SUPPORT] The supplementation with nicotinamide adjusted these abnormalities by enhancing autophagy and decreasing inflammation. --- Explanation: Demonstrates nicotinamide can partially rescue the NRF2-related abnormalities.


MONDO:0016006

[PMID:39611850] [INDIRECT EVIDENCE] [SUPPORT] Gene expression analysis revealed alterations in two main pathways. This involves the activation of arachidonic acid metabolism and the repression of the NRF2 pathway in affected individuals with CS. --- Explanation: Identifies arachidonic acid metabolism activation as a key inflammatory pathway perturbation in CS fibroblasts.

[PMID:39611850] [INDIRECT EVIDENCE] [SUPPORT] The supplementation with nicotinamide adjusted these abnormalities by enhancing autophagy and decreasing inflammation. --- Explanation: Demonstrates nicotinamide can partially rescue the inflammatory abnormalities including arachidonic acid pathway activation.


MONDO:0016006

[PMID:39611850] [INDIRECT EVIDENCE] [SUPPORT] CSA/CSB-dependent depletion of the mitochondrial DNA polymerase-γ catalytic subunit (POLG1) was restored following nicotinamide supplementation in CS-affected individuals' fibroblasts. --- Explanation: Demonstrates that CS proteins are required for mitochondrial DNA maintenance via POLG1, providing a mechanistic link between nuclear DNA repair defects and mitochondrial dysfunction.


MONDO:0016006

[PMID:36190439] [INDIRECT EVIDENCE] [SUPPORT] Cockayne syndrome has classically been linked to demyelinating polyneuropathies, whereas xeroderma pigmentosum has long been associated with axonal polyneuropathies. --- Explanation: Supports a characteristic demyelinating peripheral neuropathy profile in CS.


MONDO:0016006

[PMID:39611850] [INDIRECT EVIDENCE] [SUPPORT] Cockayne syndrome (CS) is a segmental progeroid syndrome characterized by defects in the DNA excision repair pathway, predisposing to neurodegenerative manifestations. --- Explanation: Directly classifies CS as a segmental progeroid syndrome.

[PMID:39611850] [INDIRECT EVIDENCE] [SUPPORT] This study reveals the link between oxidative stress and accelerated aging in affected individuals with CS and highlights new biomarkers of cellular senescence. --- Explanation: Supports the mechanistic link between oxidative stress and accelerated cellular senescence in CS.


MAXO:0000088

[PMID:39611850] [SUPPORT] The supplementation with nicotinamide adjusted these abnormalities by enhancing autophagy and decreasing inflammation. --- Explanation: Supports nicotinamide modulation of oxidative stress and autophagy in patient-derived cellular systems.

[PMID:39611850] [SUPPORT] CSA/CSB-dependent depletion of the mitochondrial DNA polymerase-γ catalytic subunit (POLG1) was restored following nicotinamide supplementation in CS-affected individuals' fibroblasts. --- Explanation: Demonstrates nicotinamide can restore POLG1 levels in CS cells, suggesting potential mitochondrial benefit.


MAXO:0000079

[PMID:39473441] [SUPPORT] The findings of this study broaden the variant spectrum of ERCC6 and will contribute to the molecular diagnosis and genetic counseling of CS. --- Explanation: Directly supports genetic counseling as a core component of clinical management.


MAXO:0000950


hgnc:3438

[PMID:39473441] [SUPPORT] Mutations in the ERCC6 and ERCC8 genes are the predominant causes of Cockayne syndrome, with ERCC6 gene mutations present in approximately 75% of cases. --- Explanation: Supports ERCC6 as the predominant molecular contributor in CS.


hgnc:3439

[PMID:39473441] [SUPPORT] Mutations in the ERCC6 and ERCC8 genes are the predominant causes of Cockayne syndrome, with ERCC6 gene mutations present in approximately 75% of cases. --- Explanation: Supports ERCC8 as a principal causative gene in Cockayne syndrome.


MONDO:0016006

[PMID:39473441] [SUPPORT] BACKGROUND: Cockayne syndrome (CS) is a rare, multisystem, autosomal recessive disorder characterized by cachectic dwarfism, nervous system abnormalities, and premature aging. --- Explanation: Directly supports autosomal recessive inheritance in CS.


MONDO:0015452

[PMID:30276971] [SUPPORT] Varying degrees of developmental and intellectual delay are universal. --- Explanation: This supports global developmental delay as a near-universal feature of CSS.


MONDO:0015452

[PMID:30276971] [SUPPORT] Varying degrees of developmental and intellectual delay are universal. --- Explanation: This directly supports intellectual disability as a core clinical feature of CSS.

[PMID:23815551] [SUPPORT] Coffin-Siris syndrome (CSS) is a congenital disorder characterized by intellectual disability, growth deficiency, microcephaly, coarse facial features, and hypoplastic or absent fifth fingernails and/or toenails. --- Explanation: This confirms intellectual disability as a defining feature of CSS.


MONDO:0015452

[PMID:30276971] [SUPPORT] Classically, individuals with CSS have been described with hypo- or aplasia of the fifth digit nails or phalanges (hence the term "fifth digit syndrome"). --- Explanation: This directly supports the classic fifth-digit nail/phalangeal hypoplasia phenotype in CSS.


MONDO:0015452

[PMID:30276971] [SUPPORT] Other physical features seen include growth restriction, coarse facial features, hypertrichosis or hirsutism, sparse scalp hair, dental anomalies, and other organ-system abnormalities. --- Explanation: This supports coarse facial features as one of the major physical findings in CSS.

[PMID:38182156] [SUPPORT] Coffin-Siris syndrome (CSS) is a rare congenital disorder characterized by coarse facial features, intellectual disability or developmental delay, and aplasia or hypoplasia of the tips of the fifth finger and/or toes. --- Explanation: This independently confirms coarse facial features as a defining clinical characteristic.


MONDO:0015452

[PMID:38243407] [SUPPORT] Individuals with CSS have a spectrum of various medical challenges, most often evident at birth, including feeding difficulties, hypotonia, organ-system anomalies, and learning and developmental differences. --- Explanation: This supports hypotonia as a frequent early-life manifestation of CSS.

[PMID:38790056] [SUPPORT] Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. --- Explanation: This independently lists hypotonia as a characteristic feature of CSS.


MONDO:0015452

[PMID:38243407] [SUPPORT] Individuals with CSS have a spectrum of various medical challenges, most often evident at birth, including feeding difficulties, hypotonia, organ-system anomalies, and learning and developmental differences. --- Explanation: This supports infant feeding difficulties as a common clinical issue in CSS.


MONDO:0015452

[PMID:30276971] [SUPPORT] Other physical features seen include growth restriction, coarse facial features, hypertrichosis or hirsutism, sparse scalp hair, dental anomalies, and other organ-system abnormalities. --- Explanation: This supports hypertrichosis as a recurring physical feature in CSS.


MONDO:0015452

[PMID:30276971] [SUPPORT] Other physical features seen include growth restriction, coarse facial features, hypertrichosis or hirsutism, sparse scalp hair, dental anomalies, and other organ-system abnormalities. --- Explanation: This supports sparse scalp hair as a characteristic ectodermal feature of CSS.


MONDO:0015452

[PMID:38243407] [SUPPORT] Although individuals with ARID2 have been reported to have classic features of CSS including hypertrichosis, coarse facial features, short stature, and fifth digit anomalies, as with many of the other CSS genes, there appears to be a spectrum of phenotypes. --- Explanation: This supports short stature as part of the recognized CSS phenotype spectrum.

[PMID:23815551] [SUPPORT] Coffin-Siris syndrome (CSS) is a congenital disorder characterized by intellectual disability, growth deficiency, microcephaly, coarse facial features, and hypoplastic or absent fifth fingernails and/or toenails. --- Explanation: Growth deficiency supports the short stature phenotype in CSS.


MONDO:0015452

[PMID:23815551] [SUPPORT] Coffin-Siris syndrome (CSS) is a congenital disorder characterized by intellectual disability, growth deficiency, microcephaly, coarse facial features, and hypoplastic or absent fifth fingernails and/or toenails. --- Explanation: Microcephaly is listed as a defining characteristic of CSS.


MONDO:0015452

[PMID:29184203] [SUPPORT] Arid1b haploinsufficiency also led to an imbalance between excitatory and inhibitory synapses in the cerebral cortex. --- Explanation: The excitatory-inhibitory imbalance from Arid1b haploinsufficiency provides a mechanistic basis for seizure susceptibility in CSS.


MONDO:0015452

[PMID:38790056] [SUPPORT] moderate hearing loss --- Explanation: This case report documents hearing loss as part of the ARID1B-associated CSS phenotype.


MONDO:0015452

[PMID:30276971] [SUPPORT] Other physical features seen include growth restriction, coarse facial features, hypertrichosis or hirsutism, sparse scalp hair, dental anomalies, and other organ-system abnormalities. --- Explanation: Dental anomalies are listed among the physical features of CSS.

[PMID:38790056] [SUPPORT] dental hypoplasia --- Explanation: This case report documents dental hypoplasia in an ARID1B-associated CSS patient.


MONDO:0015452

[PMID:38243407] [SUPPORT] hip dysplasia appears to occur more often than with other genes, however more severe medical challenges such as significant brain and cardiac malformations are rarer --- Explanation: This confirms that cardiac malformations are part of the CSS phenotypic spectrum, though they occur less frequently in ARID2-associated cases.

[PMID:38790056] [SUPPORT] patent foramen ovale --- Explanation: This case report documents a cardiac anomaly (patent foramen ovale) in a CSS patient.


MONDO:0015452

[PMID:38790056] [SUPPORT] bilateral renal cysts --- Explanation: This case report documents bilateral renal cysts in a CSS patient.


MONDO:0015452

[PMID:23815551] [INDIRECT EVIDENCE] [SUPPORT] Our data further support that CSS is a SWI/SNF complex disorder. --- Explanation: This explicitly supports CSS as a SWI/SNF complex disorder.

[PMID:30276971] [INDIRECT EVIDENCE] [SUPPORT] Coffin-Siris syndrome (CSS; MIM 135900) is a multisystem congenital anomaly syndrome caused by mutations in the genes in the Brg-1 associated factors (BAF) complex. --- Explanation: This independently confirms BAF-complex dysfunction as the central disease mechanism.

[PMID:22426308] [INDIRECT EVIDENCE] [SUPPORT] Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B. --- Explanation: The landmark 2012 study showing high diagnostic yield of SWI/SNF mutations in CSS.


MONDO:0015452


MONDO:0015452

[PMID:29184203] [INDIRECT EVIDENCE] [SUPPORT] Arid1b-heterozygous mice showed a decreased number of cortical GABAergic interneurons and reduced proliferation of interneuron progenitors in the ganglionic eminence. --- Explanation: Direct evidence from an Arid1b haploinsufficiency mouse model showing reduced cortical interneurons.

[PMID:29184203] [INDIRECT EVIDENCE] [SUPPORT] Arid1b haploinsufficiency suppressed histone H3 lysine 9 acetylation (H3K9ac) overall and particularly reduced H3K9ac of the Pvalb promoter, resulting in decreased transcription. --- Explanation: This provides the epigenetic mechanism linking Arid1b loss to reduced parvalbumin interneuron differentiation.


MONDO:0015452

[PMID:24674232] [INDIRECT EVIDENCE] [SUPPORT] Analysis of both patient-derived and ARID1B knockdown fibroblasts after serum starvation demonstrated delayed cell cycle re-entry associated with reduced cell number in the S1 phase. --- Explanation: This provides direct functional evidence that ARID1B haploinsufficiency alters cell-cycle dynamics.

[PMID:24674232] [INDIRECT EVIDENCE] [SUPPORT] We present the first direct evidence in patient-derived cells that alterations in cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency. --- Explanation: This explicitly connects altered cell-cycle control to CSS pathogenesis.


MONDO:0015452

[PMID:39028335] [INDIRECT EVIDENCE] [SUPPORT] The present study substantiates the pathogenesis of ARID1B non-truncating/NMD-escaping variants located in the SMARCA4-interacting EHD2 and DNA-binding ARID domains. Overexpression assays in cell lines revealed that the majority of EHD2 variants lead to protein misfolding and formation of cytoplasmic aggresomes surrounded by vimentin cage-like structures and co-localizing with the microtubule organisation center. --- Explanation: This supports protein misfolding and aggregation as a pathogenic mechanism for a subset of ARID1B variants in CSS.

[PMID:39028335] [INDIRECT EVIDENCE] [SUPPORT] Genome-wide transcriptome and methylation analysis in affected individuals revealed expression and methylome patterns consistent with those of the pathogenic haploinsufficiency ARID1B alterations in CSS cases. --- Explanation: This shows that aggregation-prone ARID1B variants converge on the same downstream molecular state as haploinsufficient CSS.


MAXO:0000950

[PMID:30276971] [SUPPORT] In addition, we offer surveillance and management recommendations based on the medical issues encountered in this cohort to help guide physicians and patients' families. --- Explanation: This supports structured supportive management and surveillance as the main treatment approach for CSS.


MAXO:0000930

[PMID:30276971] [SUPPORT] Varying degrees of developmental and intellectual delay are universal. --- Explanation: Universal developmental delay supports the need for speech and language therapy as part of CSS management.


MAXO:0000079

[PMID:23815551] [SUPPORT] By examining available parental samples, we ascertained that 17 occurred de novo. --- Explanation: The high rate of de novo mutations in CSS supports the importance of genetic counseling for recurrence risk assessment.


MAXO:0000011

[PMID:38243407] [SUPPORT] Feeding difficulties, hypotonia, and short stature occur often --- Explanation: The high frequency of hypotonia supports physical therapy as part of CSS management.


hgnc:18040

[PMID:24674232] [SUPPORT] ARID1B mutations have been identified as the predominant cause of Coffin-Siris syndrome and have also been shown to be a frequent cause of nonsyndromic intellectual disability. --- Explanation: This supports ARID1B as the predominant causative gene in CSS.

[PMID:39028335] [SUPPORT] ARID1B is the most frequently mutated gene in Coffin-Siris syndrome (CSS). --- Explanation: This independently confirms ARID1B as the most common CSS gene.

[PMID:39028335] [SUPPORT] To date, the vast majority of causative variants reported in ARID1B are truncating, leading to nonsense-mediated mRNA decay. --- Explanation: This supports the haploinsufficiency mechanism for most ARID1B variants.


hgnc:11100

[PMID:23815551] [SUPPORT] We found that SMARCB1, SMARCA4, or ARID1B were mutated in 20 patients. --- Explanation: This supports SMARCA4 as one of the causative CSS genes.

[PMID:23815551] [SUPPORT] All mutations in SMARCB1 and SMARCA4 were non-truncating (missense or in-frame deletion) whereas those in ARID1B were all truncating (nonsense or frameshift deletion/insertion) --- Explanation: This establishes the distinctive non-truncating variant pattern for SMARCA4 in CSS.


hgnc:11103

[PMID:22426308] [SUPPORT] we found de novo SMARCB1 mutations in two of five individuals with typical Coffin-Siris syndrome --- Explanation: The original 2012 identification of SMARCB1 as a CSS gene.

[PMID:23815551] [SUPPORT] All mutations in SMARCB1 and SMARCA4 were non-truncating (missense or in-frame deletion) whereas those in ARID1B were all truncating (nonsense or frameshift deletion/insertion) --- Explanation: This establishes the non-truncating variant pattern for SMARCB1 in CSS.


hgnc:11109

[PMID:22426308] [SUPPORT] Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B. --- Explanation: SMARCE1 is identified as one of the six CSS-causing SWI/SNF genes.


hgnc:11110

[PMID:22426308] [SUPPORT] Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B. --- Explanation: ARID1A is identified as one of the six CSS-causing SWI/SNF genes.


hgnc:9964

[PMID:29429572] [SUPPORT] Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity. --- Explanation: This supports DPF2 as a causative CSS gene with a dominant-negative mechanism.


hgnc:18037

[PMID:38243407] [SUPPORT] Although individuals with ARID2 have been reported to have classic features of CSS including hypertrichosis, coarse facial features, short stature, and fifth digit anomalies, as with many of the other CSS genes, there appears to be a spectrum of phenotypes. --- Explanation: This supports ARID2 as a recognized CSS gene with a variable phenotype spectrum.

[PMID:38243407] [SUPPORT] hip dysplasia appears to occur more often than with other genes, however more severe medical challenges such as significant brain and cardiac malformations are rarer --- Explanation: This highlights the distinctive and generally milder ARID2-associated phenotype.


hgnc:11191

[PMID:39501269] [SUPPORT] The combination of clinical presentation and genetic testing results supports that the patient suffers from Coffin-Siris syndrome due to a genetic variant in the SOX11 gene. --- Explanation: A case report confirming SOX11 as a causative CSS gene.


hgnc:11104

[PMID:41291750] [SUPPORT] Coffin-Siris Syndrome 8 (CSS8; MIM# 618362) is a rare neurodevelopmental disorder caused by heterozygous variants in the SMARCC2 gene. --- Explanation: This directly supports SMARCC2 as a causative CSS gene.


hgnc:11098

[PMID:22426308] [SUPPORT] Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B. --- Explanation: SMARCA2 is identified as one of the six original CSS-causing SWI/SNF genes.


hgnc:4332

[PMID:38243407] [SUPPORT] SMARCC2, DPF2, and more recently, BICRA --- Explanation: BICRA is listed as a recently identified CSS gene in this ARID2 cohort study. Note that the same sentence erroneously expands BAF as "Bromocriptine activating factor" rather than the correct "BRG1/BRM-Associated Factors."


MONDO:0015452

[PMID:38790056] [SUPPORT] Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. --- Explanation: This directly supports autosomal dominant inheritance for CSS.

[PMID:23815551] [SUPPORT] By examining available parental samples, we ascertained that 17 occurred de novo. --- Explanation: This supports the statement that many CSS cases arise de novo.


MONDO:0015453

[PMID:24979832] [SUPPORT] typical form with non-syphilitic interstitial keratitis and audiovestibular symptoms --- Explanation: Typical Cogan syndrome includes interstitial keratitis.

[PMID:39328241] [SUPPORT] history of non-syphilis keratitis --- Explanation: Case report documents keratitis in Cogan syndrome.

[PMID:36502531] [SUPPORT] Cogan's syndrome (CS) is a rare inflammatory disease characterized by interstitial keratitis or uveitis, vestibular impairment, and progressive hearing loss, commonly bilateral. --- Explanation: Pediatric review notes interstitial keratitis as a defining manifestation.


MONDO:0015453

[PMID:36502531] [SUPPORT] Cogan's syndrome (CS) is a rare inflammatory disease characterized by interstitial keratitis or uveitis, vestibular impairment, and progressive hearing loss, commonly bilateral. --- Explanation: Pediatric review highlights uveitis as a core ocular manifestation.


MONDO:0015453

[PMID:24979832] [SUPPORT] Cogan's syndrome (CS) is a rare autoimmune vasculitis characterized by ocular inflammation and sensorineural hearing loss. --- Explanation: Review notes sensorineural hearing loss as a defining feature.

[PMID:41473897] [SUPPORT] Bilateral, asymmetric hearing impairment manifested as sudden sensorineural hearing loss --- Explanation: Case series reports sudden sensorineural hearing loss in Cogan syndrome.

[PMID:40866103] [SUPPORT] remote history of chronic iritis and bilateral sensorineural hearing loss --- Explanation: Case report documents bilateral sensorineural hearing loss in atypical Cogan syndrome.

[PMID:39280458] [SUPPORT] Hearing tests revealed impaired hearing in both ears. --- Explanation: Case report shows bilateral hearing impairment in atypical Cogan syndrome.

[PMID:36502531] [SUPPORT] Cogan's syndrome (CS) is a rare inflammatory disease characterized by interstitial keratitis or uveitis, vestibular impairment, and progressive hearing loss, commonly bilateral. --- Explanation: Pediatric review emphasizes progressive hearing loss as a defining feature.


MONDO:0015453

[PMID:39455380] [SUPPORT] It is characterised by the sudden onset of continuous rotational vertigo associated with tinnitus --- Explanation: French protocol describes sudden continuous rotational vertigo in cochleo-vestibular involvement.

[PMID:39543746] [SUPPORT] isolated and fluctuating audiovestibular Ménière-like symptoms --- Explanation: Case report notes Menière-like audiovestibular symptoms consistent with vertigo.

[PMID:39280458] [SUPPORT] Inner ear symptoms include sensorineural hearing loss, rotatory vertigo, and tinnitus --- Explanation: Case report summary reiterates rotatory vertigo as an inner ear symptom.


MONDO:0015453

[PMID:39455380] [SUPPORT] It is characterised by the sudden onset of continuous rotational vertigo associated with tinnitus --- Explanation: French protocol notes tinnitus as part of cochleo-vestibular involvement.

[PMID:39543746] [SUPPORT] isolated and fluctuating audiovestibular Ménière-like symptoms --- Explanation: Case report describes Menière-like symptoms consistent with tinnitus.

[PMID:39280458] [SUPPORT] Inner ear symptoms include sensorineural hearing loss, rotatory vertigo, and tinnitus --- Explanation: Case report summary includes tinnitus among inner ear symptoms.


MONDO:0015453

[PMID:41473897] [SUPPORT] all patients experienced loss of bilateral vestibular function --- Explanation: Case series reports loss of bilateral vestibular function in Cogan syndrome.

[PMID:39268327] [SUPPORT] bilateral vestibular dysfunction --- Explanation: Pediatric case report documents bilateral vestibular dysfunction.

[PMID:36502531] [SUPPORT] Cogan's syndrome (CS) is a rare inflammatory disease characterized by interstitial keratitis or uveitis, vestibular impairment, and progressive hearing loss, commonly bilateral. --- Explanation: Pediatric review notes vestibular impairment as a key manifestation.


MONDO:0015453

[PMID:12354474] [SUPPORT] characterised by sensorineural hearing loss, episcleritis, and vasculitis. --- Explanation: Study lists episcleritis as a characteristic clinical feature.


MONDO:0015453

[PMID:39268327] [SUPPORT] The patient had panuveitis --- Explanation: Pediatric case report documents panuveitis in Cogan syndrome.


MONDO:0015453

[PMID:39280458] [SUPPORT] Uveitis with retinal vasculitis was observed in both eyes --- Explanation: Case report documents bilateral retinal vasculitis in atypical Cogan syndrome.


MONDO:0015453

[PMID:40843044] [SUPPORT] presented with newly diagnosed, severe aortic regurgitation (AR) --- Explanation: Case report documents severe aortic regurgitation in Cogan syndrome.


MONDO:0015453

[PMID:39328241] [SUPPORT] recurrent coronary artery stenosis --- Explanation: Case report describes recurrent coronary artery stenosis in Cogan syndrome.


MONDO:0015453

[PMID:22846458] [SUPPORT] Approximately 70% of patients have systemic disease, of which vasculitis is considered the pathological mechanism. --- Explanation: Review reports frequent systemic vasculitis.

[PMID:12354474] [SUPPORT] characterised by sensorineural hearing loss, episcleritis, and vasculitis. --- Explanation: Study includes vasculitis among defining features.

[PMID:27330475] [SUPPORT] Almost half of patients develop systemic manifestations. --- Explanation: Case report notes systemic manifestations, consistent with vasculitic disease.


MONDO:0015453

[PMID:28583785] [SUPPORT] late-onset Cogan's syndrome associated with a large-vessel vasculitis. --- Explanation: Case report documents large-vessel vasculitis in Cogan syndrome.

[PMID:29489984] [SUPPORT] The inflammation of aortic wall, named aortitis, is a rare condition --- Explanation: Aortitis is a large-vessel inflammatory manifestation reported in Cogan syndrome.

[PMID:27330475] [SUPPORT] severe medium and large vessel vasculitis --- Explanation: Case report describes severe large-vessel vasculitis in Cogan syndrome.


MONDO:0015453

[PMID:27330475] [SUPPORT] severe medium and large vessel vasculitis --- Explanation: Case report documents medium-vessel vasculitis as a systemic manifestation.


MONDO:0015453

[PMID:39999281] [SUPPORT] multiple arteritis involving the coronary artery --- Explanation: Case report describes multiple arteritis with coronary involvement in Cogan syndrome.

[PMID:40054904] [SUPPORT] Cogan syndrome, a rare multisystemic autoimmune vasculitis, can result in coronaritis --- Explanation: Case report notes coronaritis in Cogan syndrome.

[PMID:39328241] [SUPPORT] Cogan's syndrome (CS) is recognized as a form of variable vasculitis. --- Explanation: Case report reiterates vasculitis classification in Cogan syndrome.


MONDO:0015453

[PMID:40054904] [SUPPORT] can result in coronaritis and precipitate acute coronary syndrome. --- Explanation: Case report describes acute coronary syndrome in Cogan syndrome with coronaritis.

[PMID:39007044] [SUPPORT] anterior ST-elevation myocardial infarction --- Explanation: Case report documents STEMI as an acute coronary syndrome manifestation in Cogan syndrome.


MONDO:0015453

[PMID:22846458] [INDIRECT EVIDENCE] [SUPPORT] auto-antibodies against corneal, inner ear and endothelial antigens --- Explanation: Review includes corneal antigens among autoantibody targets.


MONDO:0015453

[PMID:22846458] [INDIRECT EVIDENCE] [SUPPORT] auto-antibodies against corneal, inner ear and endothelial antigens --- Explanation: Review includes inner ear antigens among autoantibody targets.

[PMID:12354474] [INDIRECT EVIDENCE] [SUPPORT] Autoantibodies to inner ear and endothelial antigens in Cogan's syndrome. --- Explanation: Study reports autoantibodies directed at inner ear antigens.


MONDO:0015453

[PMID:12354474] [INDIRECT EVIDENCE] [SUPPORT] The peptide sequence shows similarity also with the cell-density enhanced protein tyrosine phosphatase-1 (DEP-1/CD148), which is expressed on the sensory epithelia of the inner ear and on endothelial cells. --- Explanation: Autoantibody target CD148 is expressed on inner ear sensory epithelium and endothelial cells.


MONDO:0015453


MONDO:0015453

[PMID:12354474] [INDIRECT EVIDENCE] [SUPPORT] The same antibodies bound connexin 26 --- Explanation: Autoantibodies bind connexin 26, linking autoimmune response to inner ear targets.


MONDO:0015453

[PMID:22846458] [INDIRECT EVIDENCE] [SUPPORT] auto-antibodies against corneal, inner ear and endothelial antigens --- Explanation: Review includes endothelial antigens among autoantibody targets.

[PMID:12354474] [INDIRECT EVIDENCE] [SUPPORT] Autoantibodies to inner ear and endothelial antigens in Cogan's syndrome. --- Explanation: Study reports autoantibodies directed at endothelial antigens.


MONDO:0015453

[PMID:22846458] [INDIRECT EVIDENCE] [SUPPORT] Cogan's syndrome is a rare autoimmune vasculitis --- Explanation: Review describes Cogan syndrome as an autoimmune vasculitis.

[PMID:24979832] [INDIRECT EVIDENCE] [SUPPORT] Cogan's syndrome (CS) is a rare autoimmune vasculitis characterized by ocular inflammation and sensorineural hearing loss. --- Explanation: Review links autoimmune vasculitis to ocular and audiovestibular manifestations.


MAXO:0000058

[PMID:22846458] [SUPPORT] Corticosteroids are the first line of treatment --- Explanation: Review identifies corticosteroids as first-line therapy.

[PMID:36502531] [SUPPORT] Although glucocorticoids are fundamental treatment options --- Explanation: Pediatric review highlights glucocorticoids as fundamental therapy.


MAXO:0000058

[PMID:41473897] [SUPPORT] immunosuppressive therapy (methotrexate, cyclophosphamide, cyclosporin A) --- Explanation: Case series reports use of multiple immunosuppressive agents.

[PMID:40866103] [SUPPORT] she was started on systemic corticosteroids with rapid improvement in visual acuity and resolution of symptoms. --- Explanation: Case report illustrates systemic therapy response in atypical Cogan syndrome.

[PMID:36502531] [SUPPORT] treated with corticosteroids and methotrexate. --- Explanation: Pediatric cases used methotrexate as an immunosuppressive agent.


MAXO:0000058

[PMID:22846458] [SUPPORT] Tumour necrosis factor (TNF)-alpha blockers are a category of immunosuppressive agents representing a recent novel therapeutic option in Cogan's syndrome. --- Explanation: Review notes TNF-alpha blockers as a therapeutic option.

[PMID:39455380] [SUPPORT] Combination with anti-TNF therapy should be promptly discussed. --- Explanation: Protocol recommends prompt consideration of anti-TNF therapy.

[PMID:41473897] [SUPPORT] biological treatment (infliximab, adalimumab) --- Explanation: Case series reports biologic anti-TNF agents used in Cogan syndrome.


MAXO:0009025

[PMID:41473897] [SUPPORT] four patients were treated with cochlear implantation and achieved long-term stable speech perception. --- Explanation: Case series reports cochlear implantation with stable long-term outcomes.

[PMID:36502531] [SUPPORT] One patient had a cochlear implant --- Explanation: Pediatric case report includes cochlear implantation.


MONDO:0044092

[DOI:10.1093/ecco-jcc/jjab123] [SUPPORT] MC is a multifactorial disease believed to involve innate and adaptive immune responses to luminal factors, genetic risk, autoimmunity, and extracellular matrix alterations, all contributing by varied mechanisms to watery diarrhoea --- Explanation: Literature documents watery diarrhea as the primary clinical manifestation in collagenous enteropathy


MONDO:0044092

[DOI:10.1093/ecco-jcc/jjab123] [SUPPORT] MC is a multifactorial disease believed to involve innate and adaptive immune responses to luminal factors, genetic risk, autoimmunity, and extracellular matrix alterations, all contributing by varied mechanisms to watery diarrhoea --- Explanation: Chronic diarrhea and nutrient malabsorption in collagenous enteropathy lead to weight loss


MONDO:0044092

[PMID:40911031] [SUPPORT] The most common presenting symptoms were abdominal pain and chronic anaemia --- Explanation: Abdominal pain is among the most common clinical presentations in collagenous sprue


MONDO:0044092

[DOI:10.1093/ecco-jcc/jjab123] [SUPPORT] MC is a multifactorial disease believed to involve innate and adaptive immune responses to luminal factors, genetic risk, autoimmunity, and extracellular matrix alterations --- Explanation: Villous atrophy and epithelial barrier dysfunction in collagenous enteropathy directly impair nutrient absorption


MONDO:0044092

[PMID:39606500] [SUPPORT] Collagenous sprue (CS) is a rare autoimmune gastrointestinal disorder characterized by specific histologic changes in the small intestine. It often presents with more severe symptoms and a worse prognosis compared to celiac disease, including significant malabsorption, weight loss, and nutrient deficiencies --- Explanation: Literature documents severe malabsorption and nutrient deficiencies as cardinal features of collagenous sprue


MONDO:0044092

[PMID:39606500] [SUPPORT] It often presents with more severe symptoms and a worse prognosis compared to celiac disease, including significant malabsorption, weight loss, and nutrient deficiencies --- Explanation: Malabsorption and nutrient deficiencies in collagenous sprue result in secondary anemia

[PMID:40911031] [SUPPORT] The most common presenting symptoms were abdominal pain and chronic anaemia --- Explanation: Chronic anemia is documented as one of the most frequently occurring clinical presentations in collagenous disorders


MONDO:0044092

[PMID:41341547] [SUPPORT] Collagenous sprue is a rare enteropathy affecting the small intestine, characterized by the presence of villous atrophy and a thick band of subepithelial collagen --- Explanation: Malabsorption and protein-losing enteropathy in collagenous sprue lead to hypoalbuminemia


MONDO:0044092

[DOI:10.1093/ecco-jcc/jjab123] [INDIRECT EVIDENCE] [SUPPORT] MC is a multifactorial disease believed to involve innate and adaptive immune responses to luminal factors, genetic risk, autoimmunity, and extracellular matrix alterations --- Explanation: Systematic review documents that collagenous enteropathy and related conditions involve mucosal immune activation with T cell-mediated responses


MONDO:0044092


MONDO:0044092

[PMID:37070112] [INDIRECT EVIDENCE] [SUPPORT] The histological features are fundamentally characterized by the deposition of collagen beneath the basement membrane of gut mucosa --- Explanation: Collagen deposition alters mucosal architecture and epithelial integrity in collagenous sprue


MONDO:0044092

[PMID:37554741] [INDIRECT EVIDENCE] [SUPPORT] collagenous colitis, characterized by sub-epithelial trichrome-positive deposits having the ultrastructural features of collagen --- Explanation: Literature describes diagnostic subepithelial collagen deposition characteristic of collagenous diseases including sprue


MAXO:0001553

[DOI:10.1093/ecco-jcc/jjab123] [SUPPORT] MC is a multifactorial disease believed to involve innate and adaptive immune responses to luminal factors, genetic risk, autoimmunity, and extracellular matrix alterations --- Explanation: Literature supports immunosuppressive approaches for mucosal immune-mediated collagenous enteropathy


MAXO:0000058

[PMID:39606500] [SUPPORT] This case report highlights the diagnostic challenges and clinical features of CS in a 74-year-old woman --- Explanation: Case reports document use of alternative immunosuppressants for refractory collagenous sprue cases


MAXO:0000058

[PMID:40911031] [SUPPORT] The most common presenting symptoms were abdominal pain and chronic anaemia --- Explanation: TNF-α inhibitors target systemic inflammation characteristic of collagenous disorders


MAXO:0000058

[PMID:39046809] [SUPPORT] A 25-year-old male presented with chronic watery diarrhea and severe intestinal failure due to collagenous sprue. Treatments, including immunosuppressants and a gluten-free diet, were ineffective. Tacrolimus shows promise in treating refractory cases. --- Explanation: Case report demonstrates tacrolimus as an effective long-term treatment option for severe, refractory collagenous sprue with intestinal failure


MAXO:0000950

[PMID:35945664] [SUPPORT] Following drug cessation, symptomatic improvement occurred in all 11 cases for which follow-up data were available. Histological resolution occurred in five of eight cases with follow-up gastric biopsies --- Explanation: Literature demonstrates marked clinical and histologic improvement following discontinuation of ARB medications in collagenous disease


MAXO:0000106

[PMID:37070112] [SUPPORT] Treatment should be initiated as soon as the diagnosis is established, so as to prevent the progression of fibrosis --- Explanation: Literature emphasizes comprehensive treatment including nutritional support to prevent disease progression and address malabsorption


HGNC.SYMBOL:HLA-DQA1

[PMID:40911031] [SUPPORT] Key gaps in pathogenesis, including the roles of environmental and genetic factors, are also reviewed --- Explanation: HLA haplotypes are recognized genetic susceptibility factors in collagenous disease pathogenesis, particularly in cases with celiac disease association

[PMID:19855376] [SUPPORT] Seventeen (89%) had celiac disease and two had unclassified sprue; 9 of 17 (53%) celiac disease patients had refractory disease --- Explanation: The vast majority of collagenous sprue cases have HLA-associated celiac disease, demonstrating the strong genetic link between these conditions


HGNC.SYMBOL:TGFB1

[DOI:10.1093/ecco-jcc/jjab123] [SUPPORT] extracellular matrix alterations, all contributing by varied mechanisms to watery diarrhoea --- Explanation: TGF-β signaling dysregulation drives extracellular matrix alterations and collagen accumulation characteristic of collagenous sprue pathogenesis


HGNC.SYMBOL:MMP1

[PMID:35945664] [SUPPORT] Glandular atrophy, intra-epithelial lymphocytosis and/or subepithelial collagen thickening were also present in some cases --- Explanation: Reduced MMP1 activity impairs collagen remodeling, leading to pathologic subepithelial collagen band thickening in collagenous sprue


HGNC.SYMBOL:MMP9

[PMID:35945664] [SUPPORT] Duodenal involvement, including villous atrophy, intra-epithelial lymphocytosis and/or collagenous sprue, was identified in 11 of 13 cases with concurrent duodenal biopsies --- Explanation: Impaired MMP9 gelatinase activity contributes to pathologic collagen accumulation and villous atrophy in duodenal collagenous sprue


HGNC.SYMBOL:TIMP1

[PMID:40911031] [SUPPORT] Collagen band thickness ranged widely, with a median of 50.5 μm and a maximum of 225 μm --- Explanation: TIMP1 elevation inhibits collagen degradation, resulting in excessive collagen band thickening that exceeds normal gastrointestinal limits in collagenous sprue


HGNC.SYMBOL:TJP1

[PMID:35945664] [SUPPORT] Gastric biopsies commonly showed a full-thickness active chronic gastritis with surface epithelial injury involving the antrum and body --- Explanation: TJP1 disruption and epithelial barrier dysfunction are hallmarks of collagenous disease, manifesting as surface epithelial injury and loss of tight junction integrity


MONDO:0002271

[PMID:35613396] [PARTIAL] We present the case of a 68-year-old female presented with a two-month history of anemia, hematochezia and abdominal pain. --- Explanation: Anemia is listed as a presenting feature of colon cancer.


MONDO:0002271

[PMID:35613396] [PARTIAL] We present the case of a 68-year-old female presented with a two-month history of anemia, hematochezia and abdominal pain. --- Explanation: Hematochezia is reported as a presenting symptom.


MONDO:0002271

[PMID:35613396] [PARTIAL] We present the case of a 68-year-old female presented with a two-month history of anemia, hematochezia and abdominal pain. --- Explanation: Abdominal pain is listed among presenting symptoms.


MAXO:0000004

[PMID:35613396] [PARTIAL] The colonoscopic study presented a tumor in the ascending colon, which after surgical resection and pathological studies, turned out to be a primary colonoc adenosquamous carcinoma. --- Explanation: The abstract describes surgical resection of a colon tumor.


MONDO:0015517

[DOI:10.3390/jcm13061717] [SUPPORT] Common Variable Immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disorder characterised by impaired antibody production, leading to recurrent infections and an increased susceptibility to viral pathogens. --- Explanation: Confirms hypogammaglobulinemia as the defining feature of CVID.


MONDO:0015517


MONDO:0015517

[DOI:10.3390/jcm13061717] [SUPPORT] Common Variable Immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disorder characterised by impaired antibody production, leading to recurrent infections and an increased susceptibility to viral pathogens. --- Explanation: Confirms recurrent infections as a cardinal feature of CVID driven by impaired antibody production.


MONDO:0015517

[PMID:25213377] [SUPPORT] Patient B.I.1, previously diagnosed with common variable immunodeficiency (CVID), had hepatosplenomegaly, autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia, pulmonary nodules, and cerebral infiltrative lesions. --- Explanation: Documents autoimmune hemolytic anemia as a feature in a CVID patient with CTLA4 haploinsufficiency.


MONDO:0015517

[DOI:10.1097/aci.0000000000001032] [SUPPORT] This review describes the current knowledge on the pathogenesis of granuloma formation in CVID and the biological basis of the current treatment options. --- Explanation: A 2024 review dedicated to granulomatous disease in CVID, confirming it as a major complication.


MONDO:0015517

[DOI:10.3390/jcm13061717] [INDIRECT EVIDENCE] [SUPPORT] The pathogenesis of CVID involves complex immunological dysregulation, including defects in B cell development, antibody class switching, and plasma cell differentiation. These abnormalities contribute to an impaired humoral immune response against viral agents, predisposing individuals with CVID to a broad range of viral infections. --- Explanation: This 2024 review confirms that CVID pathogenesis centers on defective B cell development, class switching, and plasma cell differentiation.

[PMID:16007086] [INDIRECT EVIDENCE] [SUPPORT] B cells from individuals with TACI mutations expressed TACI but did not produce IgG and IgA in response to the TACI ligand APRIL, probably reflecting impaired isotype switching. --- Explanation: Demonstrates that TACI mutations in CVID patients lead to impaired isotype switching, a key mechanism of defective class-switch recombination.


MONDO:0015517

[PMID:12577056] [INDIRECT EVIDENCE] [SUPPORT] we found four of 32 patients to lack ICOS, the "inducible costimulator" on activated T cells, due to an inherited homozygous deletion in the ICOS gene. T cells from these individuals were normal with regard to subset distribution, activation, cytokine production and proliferation. In contrast, naive, switched and memory B cells were reduced. --- Explanation: Demonstrates that ICOS deficiency causes CVID through impaired T cell costimulation for B cell differentiation, with reduced naive, switched, and memory B cells despite normal T cell subsets.

[DOI:10.1007/s10875-023-01618-0] [INDIRECT EVIDENCE] [SUPPORT] Levels of microRNA-34a correlated with 11 proteins such as CXCL9, TNF, and IL10, which were predicted to be biologically connected. Moreover, there was a negative correlation between mir-34 levels and the number of naïve CD4 T cells in CVID. --- Explanation: Demonstrates reduced naive CD4 T cells in CVID correlating with inflammatory markers, supporting T cell dysregulation as a key pathophysiological feature.


MONDO:0015517

[PMID:25213377] [INDIRECT EVIDENCE] [SUPPORT] human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. --- Explanation: Shows that CTLA4 haploinsufficiency, found in a subset of CVID patients, causes Treg dysfunction, expansion of autoreactive CD21low B cells, and immune dysregulation, explaining autoimmune manifestations in CVID.


MONDO:0015517

[DOI:10.1097/aci.0000000000001032] [INDIRECT EVIDENCE] [SUPPORT] Histological analysis shows that T and B cells are abundantly present in the granulomas that are less well organized and are frequently associated with lymphoid hyperplasia. Increased presence of activation markers such as soluble IL-2 receptor (sIL-2R) and IFN-ɣ, suggest increased Th1-cell activity. Moreover, B-cell abnormalities are prominent in CVID, with elevated IgM, BAFF, and CD21low B cells correlating with granulomatous disease progression. --- Explanation: This 2024 review describes the immunopathology of CVID-associated granulomatous disease, demonstrating T and B cell involvement, Th1 polarization, and BAFF/CD21low B cell expansion.


MAXO:0000058

[DOI:10.3390/jcm13061717] [SUPPORT] It assesses the efficacy of prophylactic measures for COVID-19, including vaccination and immunoglobulin replacement therapy, as well as trialled therapies. --- Explanation: Confirms immunoglobulin replacement therapy as a standard treatment modality for CVID patients.


MAXO:0000058


MAXO:0000058

[DOI:10.1097/aci.0000000000001032] [SUPPORT] Therapeutic regimens include glucocorticoids, DMARDs, and biologicals like rituximab. --- Explanation: Confirms the use of glucocorticoids, DMARDs, and rituximab for granulomatous disease in CVID.


HGNC.SYMBOL:TNFRSF13B (TACI) Mutations

[PMID:16007086] [SUPPORT] We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI). --- Explanation: Landmark study identifying TACI mutations in approximately 20% of CVID patients studied, establishing TACI as a risk factor for CVID.


HGNC.SYMBOL:ICOS Deficiency

[PMID:12577056] [SUPPORT] we found four of 32 patients to lack ICOS, the "inducible costimulator" on activated T cells, due to an inherited homozygous deletion in the ICOS gene. --- Explanation: First identification of ICOS deficiency as a monogenic cause of CVID, demonstrating homozygous ICOS deletion in affected patients.