MONDO:0019391

[PMID:20301575] [SUPPORT] Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. --- Explanation: GeneReviews confirms short stature as one of the common physical abnormalities in FA.


MONDO:0019391

[PMID:20301575] [SUPPORT] physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies


MONDO:0019391

[PMID:20301575] [SUPPORT] physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies --- Explanation: Abnormal skin pigmentation, including café-au-lait spots, is among the physical abnormalities present in ~75% of FA patients.


MONDO:0019391

[PMID:20301575] [SUPPORT] Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA. --- Explanation: GeneReviews confirms elevated risk of solid tumors including head/neck and skin squamous cell carcinomas.


MONDO:0019391

[PMID:20301575] [PARTIAL] Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies --- Explanation: GeneReviews documents that physical abnormalities are present in approximately 75% of FA patients, including gastrointestinal anomalies.


MONDO:0019391


MONDO:0019391

[PMID:20301575] [PARTIAL] Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies --- Explanation: GeneReviews documents that physical abnormalities are present in approximately 75% of FA patients, including central nervous system anomalies.


MONDO:0019391

[PMID:20301575] [PARTIAL] Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies --- Explanation: GeneReviews documents that physical abnormalities are present in approximately 75% of FA patients, including craniofacial anomalies.


MONDO:0019391

[PMID:20301575] [SUPPORT] Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies --- Explanation: GeneReviews documents that physical abnormalities are present in approximately 75% of FA patients, including craniofacial anomalies.


MONDO:0019391

[PMID:20301575] [SUPPORT] skeletal malformations of the upper and/or lower limbs --- Explanation: GeneReviews confirms upper limb skeletal malformations as a common feature of FA.

[PMID:20301575] [SUPPORT] skeletal malformations of the upper and/or lower limbs --- Explanation: GeneReviews lists skeletal malformations of the upper and/or lower limbs among the physical abnormalities present in ~75% of FA patients.


MONDO:0019391

[PMID:20301575] [SUPPORT] skeletal malformations of the upper and/or lower limbs --- Explanation: GeneReviews confirms upper limb skeletal malformations as common in FA.

[PMID:16015582] [SUPPORT] all have radial ray anomalies and 12 of these 13 subjects show at least 1 other feature of FA --- Explanation: In FA patients with VACTERL phenotype, all had radial ray anomalies including thumb abnormalities.


MONDO:0019391

[PMID:20301575] [PARTIAL] skeletal malformations of the upper and/or lower limbs --- Explanation: GeneReviews lists skeletal malformations of the upper and/or lower limbs among the physical abnormalities present in ~75% of FA patients.


MONDO:0019391

[PMID:20301575] [SUPPORT] ophthalmic and genitourinary tract anomalies --- Explanation: GeneReviews lists ophthalmic anomalies including microphthalmia among FA congenital features.


MONDO:0019391

[PMID:20301575] [SUPPORT] ophthalmic and genitourinary tract anomalies --- Explanation: GeneReviews lists ophthalmic anomalies as part of the FA congenital phenotype spectrum.


MONDO:0019391

[PMID:20301575] [SUPPORT] Treatment of growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, and dermatologic manifestations as recommended by the subspecialty care provider. --- Explanation: GeneReviews lists cardiac anomalies as part of the FA clinical spectrum requiring subspecialty management.

[PMID:31558676] [SUPPORT] Patients with missense mutations had significantly less congenital heart disease (P=0.022). --- Explanation: Israeli cohort study found genotype-phenotype correlation for cardiac defects and mutation type.

[PMID:20301575] [SUPPORT] Treatment of growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, and dermatologic manifestations as recommended by the subspecialty care provider. --- Explanation: GeneReviews lists cardiac anomalies among the FA manifestations requiring subspecialty management.


MONDO:0019391

[PMID:31558676] [SUPPORT] Of the 18% of the patients with hearing loss, all had a conductive component --- Explanation: Israeli cohort documents 18% hearing loss prevalence with conductive component in FA patients.

[PMID:20301575] [SUPPORT] Hearing aids may be helpful for hearing loss as per otolaryngologist --- Explanation: GeneReviews recommends hearing evaluation and hearing aids as part of FA management.


MONDO:0019391

[PMID:20301575] [PARTIAL] Hearing aids may be helpful for hearing loss as per otolaryngologist --- Explanation: GeneReviews documents hearing loss among FA manifestations and recommends otolaryngology evaluation.


MONDO:0019391

[PMID:25575015] [SUPPORT] About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. --- Explanation: Consensus review documents hypothyroidism as a common endocrine abnormality in FA.


MONDO:0019391

[PMID:17426088] [SUPPORT] short stature and/or GH deficiency (51%) --- Explanation: NCI cohort study of 45 FA patients found GH deficiency in 51%, establishing it as a frequent phenotype.

[PMID:25575015] [SUPPORT] About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. --- Explanation: Consensus review identifies GH deficiency as a recognized endocrine abnormality in FA.


MONDO:0019391

[PMID:25575015] [SUPPORT] About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. --- Explanation: Consensus review identifies abnormal glucose/insulin metabolism as part of the FA endocrine phenotype.


MONDO:0019391

[PMID:25575015] [SUPPORT] About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. --- Explanation: Consensus review identifies pubertal delay and hypogonadism as prominent endocrine features of FA.


MONDO:0019391

[PMID:25575015] [SUPPORT] About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. --- Explanation: Impaired fertility is listed as a key endocrine abnormality in FA patients.


MONDO:0019391

[PMID:20301575] [SUPPORT] ophthalmic and genitourinary tract anomalies --- Explanation: GeneReviews lists genitourinary anomalies including genital anomalies as part of FA.

[PMID:31558676] [SUPPORT] Patients with downstream mutations were found to have significantly more skull anomalies (P<0.001), central nervous system (CNS) abnormalities (P=0.005) and genitourinary anomalies (P=0.03), compared with patients with core complex mutations. --- Explanation: Israeli cohort found genitourinary anomalies enriched in downstream FA gene mutations (FANCD1, FANCJ).


MONDO:0019391

[PMID:20301575] [SUPPORT] ophthalmic and genitourinary tract anomalies --- Explanation: GeneReviews lists genitourinary tract anomalies as part of the FA congenital phenotype spectrum.


MONDO:0019391


MONDO:0019391

[PMID:20301575] [SUPPORT] Treatment of growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, and dermatologic manifestations as recommended by the subspecialty care provider. --- Explanation: GeneReviews lists genital anomalies among the FA manifestations requiring subspecialty management.


MONDO:0019391

[PMID:31558676] [SUPPORT] More than half had café-au-lait spots (52.3%) followed by renal anomalies (39.6%). --- Explanation: Israeli cohort found renal anomalies in nearly 40% of FA patients.

[PMID:20301575] [SUPPORT] ophthalmic and genitourinary tract anomalies --- Explanation: GeneReviews lists genitourinary tract anomalies as part of the FA congenital spectrum.

[PMID:20301575] [SUPPORT] Treatment of growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, and dermatologic manifestations as recommended by the subspecialty care provider. --- Explanation: GeneReviews lists renal malformations among the FA manifestations requiring subspecialty management.


MONDO:0019391

[PMID:31558676] [SUPPORT] 20% were born small for the gestational age, and 57% fit criteria for short stature. --- Explanation: Israeli cohort documents 20% small for gestational age prevalence in FA.


MONDO:0019391

[PMID:31558676] [SUPPORT] Patients with splice site mutations had significantly more CNS anomalies and developmental delay, compared with the other patients (P=0.03 and P=0.038, respectively). --- Explanation: Israeli cohort found developmental delay associated with splice site mutations in FA.

[PMID:38146508] [SUPPORT] this FA-S cohort phenotype includes short stature, microcephaly, facial dysmorphisms, hypo/hyperpigmented lesions, intellectual disability, chromosomal sensitivity to crosslinking agents and predisposition to breast/ovarian cancer and/or childhood cancers --- Explanation: FA-S (BRCA1 biallelic) patients commonly present with intellectual disability.


MONDO:0019391

[PMID:20301575] [PARTIAL] Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies --- Explanation: GeneReviews documents that physical abnormalities are present in approximately 75% of FA patients, including central nervous system anomalies.


MONDO:0019391

[PMID:20301575] [SUPPORT] abnormal skin pigmentation --- Explanation: GeneReviews lists abnormal skin pigmentation among the physical abnormalities present in ~75% of FA patients.


MONDO:0019391

[PMID:17426088] [SUPPORT] Ninety-two percent of the patients 18 yr or older had osteopenia or osteoporosis. --- Explanation: Near-universal bone density loss in adult FA patients.


MONDO:0019391

[PMID:39568270] [SUPPORT] In our cohort, 93.5% of patients exhibited anomalies, primarily root abnormalities (69.6%), tooth rotation (54.3%), and tooth agenesis (26%). --- Explanation: Systematic review demonstrates very high prevalence of dental anomalies in FA patients.


MONDO:0019391

[PMID:31558676] [SUPPORT] 30% developed myelodysplastic syndrome (MDS), leukemia and/or solid tumors --- Explanation: Israeli cohort documents that 30% of FA patients developed MDS, leukemia, and/or solid tumors.

[PMID:31558676] [SUPPORT] The mean age of the first cancer was 18.5 years (SD 6.3 years) for patients with FANCA, relative to 5.2 years (SD 3.7 years) for patients with FANCC, FANCD1, FANCG and FANCJ mutations, with a statistically significant difference (P=0.001). --- Explanation: Demonstrates significantly earlier cancer onset in non-FANCA complementation groups.


MONDO:0019391

[PMID:38424108] [INDIRECT EVIDENCE] [SUPPORT] proteostasis deregulation itself is driven by excess sterile inflammatory activity in hematopoietic and stromal cells within the fetal liver, and dampened Type I interferon signaling similarly restores fetal Fancd2-/- long-term hematopoietic stem cells to wild type-equivalent numbers. --- Explanation: Demonstrates that inflammatory signaling drives HSC pool deficits in FA, and that dampening inflammation rescues HSC numbers.

[PMID:24037726] [INDIRECT EVIDENCE] [PARTIAL] the FA proteins might counteract aldehyde-induced genotoxicity in hematopoietic stem cells --- Explanation: Establishes that aldehydes cause genotoxicity in HSCs and FA proteins normally protect against this damage.


MONDO:0019391

[PMID:25237197] [INDIRECT EVIDENCE] [PARTIAL] Establishing the interaction network involving the FA proteins and their associated partners has revealed an intersection of FA with several DNA repair pathways, including homologous recombination, DNA mismatch repair, nucleotide excision repair, and translesion DNA synthesis. --- Explanation: Demonstrates that the FA pathway intersects with translesion DNA synthesis, establishing the mechanistic link.


MONDO:0019391

[PMID:25237197] [INDIRECT EVIDENCE] [PARTIAL] the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology. --- Explanation: The overlap of FA genes with breast cancer genes (BRCA1, BRCA2, PALB2) establishes the connection between FA and homologous recombination repair.


MONDO:0019391

[PMID:24037726] [INDIRECT EVIDENCE] [SUPPORT] We examined 64 Japanese FA patients, and found that the ALDH2 variant is associated with accelerated progression of BMF --- Explanation: Human clinical data showing that impaired aldehyde detoxification (ALDH2 variant) accelerates bone marrow failure in FA patients.

[PMID:25237197] [INDIRECT EVIDENCE] [SUPPORT] recent studies have shown a major involvement of the FA pathway in the tolerance of reactive aldehydes. --- Explanation: Establishes that the FA pathway is required for tolerance of aldehyde-induced DNA damage.


MONDO:0019391

[PMID:35596788] [INDIRECT EVIDENCE] [PARTIAL] At least 22 genes are associated with Fanconi anemia, constituting the Fanconi anemia DNA repair pathway. --- Explanation: Core complex genes form the upstream signaling arm of the FA pathway.


MONDO:0019391

[PMID:32106311] [INDIRECT EVIDENCE] [SUPPORT] This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. --- Explanation: FANCD2 monoubiquitination is the essential central step in ICL repair.


MONDO:0019391

[PMID:38424108] [INDIRECT EVIDENCE] [SUPPORT] proteostasis deregulation itself is driven by excess sterile inflammatory activity in hematopoietic and stromal cells within the fetal liver, and dampened Type I interferon signaling similarly restores fetal Fancd2-/- long-term hematopoietic stem cells to wild type-equivalent numbers. --- Explanation: Inflammatory signaling in the BM microenvironment drives HSC loss in FA.


MONDO:0019391


MONDO:0019391

[PMID:26369989] [INDIRECT EVIDENCE] [PARTIAL] The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development. --- Explanation: Midline predominance of anomalies supports developmental progenitor loss during embryogenesis.


MONDO:0019391

[PMID:31558676] [INDIRECT EVIDENCE] [PARTIAL] 30% developed myelodysplastic syndrome (MDS), leukemia and/or solid tumors --- Explanation: 30% malignancy rate reflects ongoing clonal evolution in FA HSCs.

[PMID:36736290] [INDIRECT EVIDENCE] [SUPPORT] Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia. --- Explanation: Longitudinal study of 335 FA patients showing chromosome 1q gain (containing MDM4) as the most common early clonal event, dampening p53 and driving clonal hematopoiesis.

[PMID:36167633] [INDIRECT EVIDENCE] [SUPPORT] Polyclonal evolution of Fanconi anemia to MDS and AML revealed at single cell resolution. --- Explanation: Single-cell DNA sequencing of FA patients transforming to MDS/AML revealed polyclonal patterns with sequential acquisition of UBASH3A, SF3B1, RUNX1, and IDH2 mutations.

[PMID:37391485] [INDIRECT EVIDENCE] [PARTIAL] we performed multiplexed gene editing of mutational hotspots in MDS-associated genes in human induced pluripotent stem cells (iPSCs) followed by hematopoietic differentiation. We observed aberrant self-renewal and impaired differentiation of HSPCs with enrichment of RUNX1 insertions and deletions (indels) --- Explanation: iPSC-based modeling demonstrates that RUNX1 mutations blunt the G1/S cell cycle checkpoint in FA, promoting transformation.


MONDO:0019391

[PMID:20301575] [INDIRECT EVIDENCE] [SUPPORT] Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA. --- Explanation: Confirms epithelial tissue susceptibility to malignancy in FA.

[PMID:36912284] [INDIRECT EVIDENCE] [PARTIAL] We developed the Fanconi Anemia Cancer Cell Line Resource (FA-CCLR) to foster new work on the origins, treatment and prevention of FA-associated carcinomas. The FA-CCLR consists of Fanconi-isogenic head and neck squamous cell carcinoma (HNSCC) cell line pairs generated from five individuals with FA-associated HNSCC, and five individuals with sporadic HNSCC. --- Explanation: Isogenic FA/sporadic HNSCC cell line pairs provide a platform to identify FA-dependent cancer phenotypes and test therapeutic strategies.

[PMID:36450981] [INDIRECT EVIDENCE] [PARTIAL] Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer. --- Explanation: Computational genomic analysis defined the primary structural variant signature of FA pathway deficiency in squamous cancers, enabling computational classification of FA-associated vs sporadic carcinomas.


MONDO:0019391

[PMID:17426088] [INDIRECT EVIDENCE] [SUPPORT] Endocrine abnormalities were present in 73%, including short stature and/or GH deficiency (51%), hypothyroidism (37%), midline brain abnormalities (17%) --- Explanation: Giri et al. documents 73% endocrine abnormality prevalence.

[PMID:26369989] [INDIRECT EVIDENCE] [SUPPORT] Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males) --- Explanation: Small pituitary in 68% provides anatomical basis for endocrine dysfunction.


MONDO:0019391

[PMID:26369989] [INDIRECT EVIDENCE] [SUPPORT] Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males) --- Explanation: 90% brain MRI abnormality rate with midline predominance.

[PMID:26369989] [INDIRECT EVIDENCE] [SUPPORT] Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy-Walker variant (n = 2) and cerebellar atrophy (n = 2). --- Explanation: Posterior fossa and corpus callosum anomalies reflect early CNS developmental impact.


MONDO:0019391

[PMID:32997960] [INDIRECT EVIDENCE] [SUPPORT] In addition to overexpression of p53 and TGF-β pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM). --- Explanation: scRNA-seq of primary FA patient HSPCs identifies MYC as a novel driver of BMF alongside known p53/TGF-beta pathways.

[PMID:32997960] [INDIRECT EVIDENCE] [SUPPORT] Inhibiting MYC expression with the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of FA patient HSPCs but rescued physiological and genotoxic stress in HSPCs from FA mice, showing that MYC promotes proliferation while increasing DNA damage. --- Explanation: BET inhibitor targeting MYC rescues genotoxic stress in FA mouse HSPCs, validating MYC as a therapeutic target.


MONDO:0019391

[PMID:33338401] [INDIRECT EVIDENCE] [SUPPORT] reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. --- Explanation: Demonstrates that transcriptional reprogramming during differentiation generates formaldehyde-induced DNA damage that specifically depletes FA-deficient progenitors.


MONDO:0019391

[PMID:33002135] [INDIRECT EVIDENCE] [SUPPORT] FANCA-deficient human HPCs underwent accelerated terminal differentiation driven by activation of p53/p21. We identified growth arrest specific 6 (GAS6) as a novel target of activated p53 in FANCA-deficient HPCs and modulate GAS6 signaling to rescue hematopoiesis in FANCA-deficient cells. --- Explanation: iPSC-derived FA model reveals p53/p21/GAS6 axis driving progenitor exhaustion and validates GAS6 as a therapeutic target.

[PMID:33512438] [INDIRECT EVIDENCE] [PARTIAL] disease model iPSCs displayed drastically defective cell expansion when stimulated into hematopoietic differentiation in vitro, displaying increased levels of DNA damage. The expansion defect was partially reversed by treatment with a new small molecule termed C1, which is an agonist of ALDH2 --- Explanation: ADH5/ALDH2-deficient iPSCs modeling FA-like aldehyde toxicity confirm hematopoietic differentiation defects and identify ALDH2 agonism as a rescue strategy.


MAXO:0000747

[PMID:20301575] [SUPPORT] hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of FA


MAXO:0000283

[PMID:20301575] [SUPPORT] Administration of oral androgens (e.g., oxymetholone) improves blood counts (red cell and platelets) in approximately 50% of individuals with FA


MAXO:0000283

[PMID:20301575] [SUPPORT] Treatment of growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, and dermatologic manifestations as recommended by the subspecialty care provider. --- Explanation: GeneReviews recommends treatment of growth deficiency as part of comprehensive FA management.


MAXO:0000950

[PMID:20301575] [SUPPORT] granulocyte colony-stimulating factor improves the neutrophil count in some individuals --- Explanation: GeneReviews confirms use of growth factors as part of supportive care for cytopenias.


MAXO:0000126

[PMID:20301575] [SUPPORT] oral examinations for tumors every six months beginning at age nine to ten years; annual nasolaryngoscopy beginning at age ten years --- Explanation: GeneReviews recommends regular oral and nasolaryngoscopic surveillance for early cancer detection.


MAXO:0000079

[PMID:20301575] [SUPPORT] Carrier testing for at-risk relatives (for autosomal recessive and X-linked FA) and prenatal and preimplantation genetic testing are possible if the pathogenic variant(s) in the family are known. --- Explanation: GeneReviews confirms the importance of genetic counseling for carrier testing and prenatal diagnosis.


MAXO:0001001

[PMID:37021532] [SUPPORT] gene therapy reverts the transcriptional signature of FA HSPC, which then resemble the transcriptional program of healthy donor HSPC --- Explanation: Single-cell RNA-seq of gene therapy-treated FA patients demonstrates molecular rescue of the FA HSPC transcriptional program.

[PMID:37021532] [SUPPORT] a down-regulated expression of TGF-β and p21, typically up-regulated in FA HSPC, and upregulation of DNA damage response and telomere maintenance pathways --- Explanation: Gene therapy corrects specific molecular defects in FA HSPCs as confirmed by scRNA-seq.


MAXO:0001001

[PMID:36371486] [SUPPORT] optimizing adenine base editor construct, vector type, guide RNA format, and delivery conditions leads to very effective genetic modification in multiple FA patient backgrounds --- Explanation: ABE8e base editing achieves effective correction across multiple FANCA mutation backgrounds.

[PMID:36371486] [SUPPORT] Optimized base editing restored FANCA expression, molecular function of the FA pathway, and phenotypic resistance to crosslinking agents --- Explanation: Base editing restores functional FA pathway activity in patient-derived HSPCs.


HGNC.SYMBOL:FANCA

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms FANCA is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:FANCB

[PMID:20301575] [SUPPORT] a hemizygous pathogenic variant in FANCB known to cause X-linked FA --- Explanation: GeneReviews confirms FANCB causes X-linked Fanconi anemia.


HGNC.SYMBOL:FANCC

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms FANCC is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:FANCE

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms FANCE is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:FANCF

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms FANCF is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:FANCG

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms FANCG is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:FANCL

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms FANCL is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:FANCM

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews lists FANCM among FA-associated genes; some ontology resources classify FANCM-related disease separately from canonical FA complementation groups.


HGNC.SYMBOL:UBE2T

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms UBE2T (FANCT) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:FANCD2

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms FANCD2 is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:FANCI

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms FANCI is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:SLX4

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms SLX4 (FANCP) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:BRCA2

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms BRCA2 (FANCD1) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:PALB2

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms PALB2 (FANCN) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:BRCA1

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms BRCA1 (FANCS) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:BRIP1

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms BRIP1 (FANCJ) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:ERCC4

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms ERCC4 (FANCQ) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:RAD51C

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms RAD51C (FANCO) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:RAD51

[PMID:20301575] [SUPPORT] a heterozygous pathogenic variant in RAD51 known to cause autosomal dominant FA --- Explanation: GeneReviews confirms RAD51 (FANCR) as the autosomal dominant FA subtype gene.


HGNC.SYMBOL:XRCC2

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms XRCC2 (FANCU) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:MAD2L2

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms MAD2L2/REV7 (FANCV) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:RFWD3

[PMID:20301575] [SUPPORT] biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA --- Explanation: GeneReviews confirms RFWD3 (FANCW) is one of the 21 genes causing autosomal recessive Fanconi anemia.


HGNC.SYMBOL:ALDH2

[PMID:24037726] [SUPPORT] the ALDH2 variant is associated with accelerated progression of BMF --- Explanation: Study of 64 Japanese FA patients showed ALDH2 deficiency accelerates bone marrow failure progression.


HGNC.SYMBOL:ADH5

[PMID:22081012] [SUPPORT] a synthetic lethal interaction in avian cells between ADH5, encoding the main formaldehyde-detoxifying enzyme, and the Fanconi anemia (FA) DNA-repair pathway --- Explanation: Demonstrates that ADH5 formaldehyde catabolism is essential in FA-deficient cells.


HGNC.SYMBOL:KMT2D


MONDO:0016068

[PMID:6507478] [SUPPORT] Fibrochondrogenesis is a rare, neonatally lethal rhizomelic chondrodysplasia distinguished from other forms of lethal dwarfism by broad long-bone metaphyses, pear-shaped vertebral bodies --- Explanation: Establishes rhizomelic short-limbed dwarfism as a defining feature.

[PMID:9475607] [SUPPORT] Fibrochondrogenesis is a very rare form of lethal short-limb dwarfism, with 8 cases described since it was first reported in 1978. --- Explanation: Confirms short-limb dwarfism as cardinal feature.


MONDO:0016068

[PMID:6507479] [SUPPORT] The long bones are short and dumbbell-shaped with metaphyseal flare. --- Explanation: Documents the characteristic dumbbell-shaped long bones with metaphyseal flaring.


MONDO:0016068

[PMID:6507479] [SUPPORT] The spine is platyspondylic with superior-inferior clefting defects, and the ribs are short and distally cupped. --- Explanation: Documents platyspondyly with clefting as a characteristic radiographic feature.

[PMID:22439129] [SUPPORT] We report a case of fibrochondrogenesis with severe pear-shaped platyspondyly --- Explanation: Confirms the characteristic pear-shaped platyspondyly pattern.


MONDO:0016068

[PMID:6507479] [SUPPORT] The spine is platyspondylic with superior-inferior clefting defects, and the ribs are short and distally cupped. --- Explanation: Documents short ribs with distal cupping as a characteristic finding.


MONDO:0016068

[PMID:22246659] [SUPPORT] The chest is small and leads to perinatal respiratory problems which usually, but not always, result in lethality --- Explanation: Directly describes the small chest and its role in lethality via respiratory compromise.


MONDO:0016068

[PMID:22246659] [SUPPORT] short long bones and short ribs with broad metaphyses, a flat midface, and vertebral bodies which show distinctive hypoplastic posterior ends --- Explanation: Explicitly describes the flat midface as a characteristic feature of fibrochondrogenesis.


MONDO:0016068

[PMID:9475607] [SUPPORT] the fetus showed severe micrognathia and a bifid tongue. --- Explanation: Documents severe micrognathia in a 17-week fetus with fibrochondrogenesis.


MONDO:0016068


MONDO:0016068

[PMID:22246659] [SUPPORT] The chest is small and leads to perinatal respiratory problems which usually, but not always, result in lethality --- Explanation: Describes the small chest causing respiratory insufficiency and lethality, consistent with pulmonary hypoplasia as the mechanism of death.


MONDO:0016068

[PMID:21668896] [SUPPORT] These patients show additional symptoms which include developmental delay, profound sensory-neural deafness, severe myopia and progressive severe skeletal abnormalities. --- Explanation: Documents profound sensorineural deafness in surviving fibrochondrogenesis patients.


MONDO:0016068

[PMID:21668896] [SUPPORT] These patients show additional symptoms which include developmental delay, profound sensory-neural deafness, severe myopia and progressive severe skeletal abnormalities. --- Explanation: Documents severe myopia in surviving fibrochondrogenesis patients.


MONDO:0016068

[PMID:21668896] [SUPPORT] These patients show additional symptoms which include developmental delay, profound sensory-neural deafness, severe myopia and progressive severe skeletal abnormalities. --- Explanation: Documents developmental delay in surviving patients.

[PMID:24127948] [SUPPORT] Two infants survived beyond 3 years of age, but both had severe global developmental delay. --- Explanation: Confirms severe global developmental delay in the rare survivors.


MONDO:0016068

[PMID:21035103] [INDIRECT EVIDENCE] [SUPPORT] Sequence analysis of COL11A1 in two genetically independent fibrochondrogenesis cases demonstrated that each was a compound heterozygote for a loss-of-function mutation on one allele and a mutation predicting substitution for a conserved triple-helical glycine residue on the other. --- Explanation: Identifies compound heterozygous COL11A1 mutations as the genetic event disrupting type XI collagen.

[PMID:22246659] [INDIRECT EVIDENCE] [SUPPORT] Fibrochondrogenesis is a severe, recessively inherited skeletal dysplasia shown to result from mutations in the gene encoding the proα1(XI) chain of type XI collagen, COL11A1. --- Explanation: Confirms COL11A1 as the causative gene and extends the genetic basis to COL11A2.


MONDO:0016068

[PMID:22246659] [INDIRECT EVIDENCE] [SUPPORT] The phenotypic similarities among these disorders likely arise from the contribution of the gene products affected in all three disorders to the cartilage collagen fibril. --- Explanation: Establishes that type XI collagen gene products contribute directly to the cartilage collagen fibril, and that fibril disruption underlies the shared phenotypic features.


MONDO:0016068

[PMID:6507479] [INDIRECT EVIDENCE] [SUPPORT] The growth-plate cartilage is grossly disorganized and has a densely fibrous collagenous matrix when examined by light and electron microscopy. --- Explanation: Documents the characteristic fibrous replacement of normal cartilage matrix that defines fibrochondrogenesis histopathologically.

[PMID:6507478] [INDIRECT EVIDENCE] [SUPPORT] Fibrochondrogenesis is a rare, neonatally lethal rhizomelic chondrodysplasia distinguished from other forms of lethal dwarfism by broad long-bone metaphyses, pear-shaped vertebral bodies, and by microscopic changes of cartilage with unique interwoven fibrous septa and fibroblastic dysplasia of chondrocytes. --- Explanation: Establishes the histopathological hallmarks including fibroblastic dysplasia of chondrocytes and interwoven fibrous septa.


hgnc:2186

[PMID:21035103] [SUPPORT] Sequence analysis of COL11A1 in two genetically independent fibrochondrogenesis cases demonstrated that each was a compound heterozygote for a loss-of-function mutation on one allele and a mutation predicting substitution for a conserved triple-helical glycine residue on the other. --- Explanation: Identifies the characteristic compound heterozygous pattern of COL11A1 mutations.

[PMID:21668896] [SUPPORT] Screening of the COL11A1 gene revealed two null homozygous mutations --- Explanation: Documents homozygous null COL11A1 mutations in consanguineous Emirati families.

[PMID:36397853] [SUPPORT] Whole-exome sequencing revealed a novel missense variant from G to A in exon 45 of 68 in the COL11A1 gene --- Explanation: Documents a novel homozygous COL11A1 glycine substitution in a consanguineous Iranian family.


hgnc:2187

[PMID:22246659] [SUPPORT] COL11A2, was located within a large region of homozygosity. Sequence analysis identified homozygosity for a splice donor mutation in intron 18. --- Explanation: Identifies a homozygous COL11A2 splice mutation in a consanguineous family.


MONDO:0016068

[PMID:21035103] [SUPPORT] Fibrochondrogenesis is a severe, autosomal-recessive, short-limbed skeletal dysplasia. --- Explanation: Establishes autosomal recessive inheritance as the primary mode for fibrochondrogenesis.

[PMID:15150788] [SUPPORT] This occurrence confirms autosomal recessive inheritance of fibrochondrogenesis. --- Explanation: Recurrence in siblings from a consanguineous couple confirms autosomal recessive inheritance.


MONDO:0016068

[PMID:22246659] [SUPPORT] heterozygosity for a de novo 9 bp deletion in exon 40 of COL11A2 was identified, indicating that there are autosomal dominant forms of fibrochondrogenesis. --- Explanation: Documents a de novo dominant COL11A2 mutation causing fibrochondrogenesis.


MONDO:0007606

[PMID:17572636] [SUPPORT] Individuals with fibrodysplasia ossificans progressiva are born with malformations of the great toes --- Explanation: Congenital toe malformation is described as a cardinal feature present from birth.


MONDO:0007606

[PMID:17572636] [SUPPORT] Individuals with fibrodysplasia ossificans progressiva are born with malformations of the great toes and develop a heterotopic skeleton during childhood --- Explanation: The development of a second skeleton is the defining feature of the disease.


MONDO:0007606

[PMID:26896819] [SUPPORT] causes skeletal deformities, movement impairment, and premature death --- Explanation: Movement impairment is a direct consequence of progressive ossification.


MONDO:0007606

[PMID:26896819] [PARTIAL] palovarotene maintained joint, limb, and body motion, providing clear evidence for its encompassing therapeutic potential as a treatment for FOP --- Explanation: The therapeutic goal of maintaining joint motion indicates joint stiffness and loss of motion are key disease features.


MONDO:0007606

[PMID:26896819] [PARTIAL] causes skeletal deformities, movement impairment, and premature death --- Explanation: Skeletal deformities including scoliosis result from progressive heterotopic ossification.


MONDO:0007606

[PMID:26896819] [NO_EVIDENCE] causes skeletal deformities, movement impairment, and premature death --- Explanation: Snippet does not directly mention thoracic insufficiency or restrictive ventilatory physiology.


MONDO:0007606

[PMID:17572636] [INDIRECT EVIDENCE] [SUPPORT] Protein modeling predicts that substitution with histidine, and only histidine, creates a pH-sensitive switch within the activation domain of the receptor that leads to ligand-independent activation of ACVR1 in fibrodysplasia ossificans progressiva. --- Explanation: This study explains the unique molecular mechanism of the R206H mutation creating pH-dependent receptor dysregulation.


MONDO:0007606


MONDO:0007606

[PMID:20463014] [INDIRECT EVIDENCE] [SUPPORT] The R206H mutant showed a decreased binding affinity for FKBP1A/FKBP12, a known safeguard molecule against the leakage of transforming growth factor (TGF)-beta or BMP signaling --- Explanation: Loss of FKBP1A binding is a key mechanism allowing leaky BMP signaling.


MONDO:0007606

[PMID:26896819] [INDIRECT EVIDENCE] [PARTIAL] Most FOP patients carry an activating mutation in a bone morphogenetic protein (BMP) type I receptor gene, ACVR1(R206H), that promotes ectopic chondrogenesis and osteogenesis and, in turn, HO --- Explanation: Supports mutant ACVR1-driven ectopic osteochondrogenesis, but does not directly establish Activin A neomorphic signaling.


MONDO:0007606

[PMID:26896819] [INDIRECT EVIDENCE] [SUPPORT] Fibrodysplasia ossificans progressiva (FOP), a rare and as yet untreatable genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification (HO) in humans --- Explanation: Establishes FOP as the most severe form of heterotopic ossification.


MONDO:0007606

[PMID:26896819] [INDIRECT EVIDENCE] [NO_EVIDENCE] Fibrodysplasia ossificans progressiva (FOP), a rare and as yet untreatable genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification (HO) in humans --- Explanation: Snippet establishes severe progressive HO in FOP but does not directly provide evidence for immune-cell inflammatory triggering mechanisms.


MAXO:0000058

[PMID:26896819] [PARTIAL] palovarotene maintained joint, limb, and body motion, providing clear evidence for its encompassing therapeutic potential as a treatment for FOP. --- Explanation: The study demonstrates palovarotene's therapeutic efficacy in preserving mobility in FOP mouse models.

[PMID:26896819] [PARTIAL] palovarotene restored long bone growth, maintained growth plate function, and protected growing mutant neonates --- Explanation: Demonstrates palovarotene's ability to preserve skeletal development while preventing heterotopic ossification.


CHEBI:188559

[PMID:26896819] [INDIRECT EVIDENCE] [PARTIAL] palovarotene maintained joint, limb, and body motion, providing clear evidence for its encompassing therapeutic potential as a treatment for FOP. --- Explanation: The study demonstrates palovarotene's therapeutic efficacy in preserving mobility in FOP mouse models.

[PMID:26896819] [INDIRECT EVIDENCE] [PARTIAL] palovarotene restored long bone growth, maintained growth plate function, and protected growing mutant neonates --- Explanation: Demonstrates palovarotene's ability to preserve skeletal development while preventing heterotopic ossification.


MAXO:0000058

[PMID:26896819] [PARTIAL] Fibrodysplasia ossificans progressiva (FOP), a rare and as yet untreatable genetic disorder of progressive extraskeletal ossification --- Explanation: The article notes FOP was untreatable, highlighting the limited efficacy of symptomatic treatments like corticosteroids.


MAXO:0000079

[PMID:17572636] [PARTIAL] Individuals with fibrodysplasia ossificans progressiva are born with malformations of the great toes and develop a heterotopic skeleton during childhood because of an identical heterozygous mutation --- Explanation: Identification of the causative mutation enables genetic counseling and potential prenatal diagnosis.


MAXO:0000058

[PMID:26896819] [PARTIAL] Most FOP patients carry an activating mutation in a bone morphogenetic protein (BMP) type I receptor gene, ACVR1(R206H), that promotes ectopic chondrogenesis and osteogenesis and, in turn, HO --- Explanation: Establishes the molecular rationale for anti-Activin A therapy targeting the aberrant signaling through mutant ACVR1.


NCIT:C170022

[PMID:26896819] [INDIRECT EVIDENCE] [PARTIAL] Most FOP patients carry an activating mutation in a bone morphogenetic protein (BMP) type I receptor gene, ACVR1(R206H), that promotes ectopic chondrogenesis and osteogenesis and, in turn, HO --- Explanation: Establishes the molecular rationale for anti-Activin A therapy targeting the aberrant signaling through mutant ACVR1.


HGNC.SYMBOL:ACVR1

[PMID:17572636] [SUPPORT] Substitution of adenine for guanine at nucleotide 617 replaces an evolutionarily conserved arginine with histidine at residue 206 of ACVR1 in all classically affected individuals, making this one of the most highly conserved disease-causing mutations in the human genome. --- Explanation: The R206H mutation is identified as the causative mutation in all classic FOP cases and is highly conserved.

[PMID:29097342] [SUPPORT] Most patients with fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of heterotopic ossification, have the same causative mutation in ACVR1, R206H. --- Explanation: Confirms R206H as the predominant mutation while noting variant cases.


MONDO:0005546

[PMID:21684692] [SUPPORT] Fibromyalgia (FM) is a condition of chronic generalized musculoskeletal pain that is thought to be a disorder of central pain sensitization. --- Explanation: Defines chronic widespread pain as the cardinal feature of fibromyalgia and links it to central sensitization mechanism.

[PMID:21684692] [PARTIAL] The defining symptom of FM is pain and GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia. --- Explanation: Identifies pain as the defining symptom with supporting animal model evidence for hyperalgesia mechanism.


MONDO:0005546

[PMID:29684996] [SUPPORT] FM is characterized by chronic widespread pain, fatigue, aching, joint stiffness, depression, cognitive dysfunction and non-restorative sleep. --- Explanation: Identifies fatigue as one of the core clinical manifestations of fibromyalgia alongside pain and other symptoms.


MONDO:0005546

[PMID:29684996] [SUPPORT] FM is characterized by chronic widespread pain, fatigue, aching, joint stiffness, depression, cognitive dysfunction and non-restorative sleep. --- Explanation: Documents non-restorative sleep as a core feature of fibromyalgia clinical presentation.

[PMID:21684692] [PARTIAL] FM is associated with poor sleep, specifically disrupted non-rapid eye movement (NREM) sleep, and the pharmacological induction of NREM sleep is associated with the activation of GAD-containing neurons in the preoptic hypothalamus. --- Explanation: Links sleep disturbance in fibromyalgia to GABAergic neurotransmission dysfunction in sleep-regulating brain regions.


MONDO:0005546


MONDO:0005546

[PMID:29684996] [SUPPORT] FM is characterized by chronic widespread pain, fatigue, aching, joint stiffness, depression, cognitive dysfunction and non-restorative sleep. --- Explanation: Identifies depression as a characteristic psychiatric comorbidity in fibromyalgia.

[PMID:21684692] [PARTIAL] Stress, depression, and anxiety, which are often comorbid with FM, decrease GAD activity. --- Explanation: Links depression in fibromyalgia to decreased GAD enzyme activity affecting neurotransmitter balance.


MONDO:0005546

[PMID:21684692] [PARTIAL] Stress, depression, and anxiety, which are often comorbid with FM, decrease GAD activity. --- Explanation: Documents anxiety as a common comorbidity in fibromyalgia associated with altered GABAergic function.


MONDO:0005546

[PMID:29684996] [SUPPORT] FM is characterized by chronic widespread pain, fatigue, aching, joint stiffness, depression, cognitive dysfunction and non-restorative sleep. --- Explanation: Identifies joint stiffness as one of the characteristic clinical manifestations of fibromyalgia.


MONDO:0005546

[PMID:7526868] [INDIRECT EVIDENCE] [SUPPORT] CSF SP levels were 3-fold higher in FMS patients than in normal controls (P < 0.001) --- Explanation: Elevated substance P in cerebrospinal fluid directly supports central sensitization mechanism with increased excitatory nociceptive signaling.

[PMID:21684692] [INDIRECT EVIDENCE] [PARTIAL] Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the conversion of glutamate to GABA and decreased expression or activity of this enzyme could result in an imbalance of excitatory and inhibitory neurotransmission in the ascending and descending pain pathways. --- Explanation: Proposes mechanism for excitatory/inhibitory imbalance underlying central sensitization via altered GAD activity affecting glutamate-GABA balance.

[PMID:33494476] [INDIRECT EVIDENCE] [PARTIAL] Fibromyalgia is the most common of the central sensitivity syndromes affecting 2-5% of the adult population in the United States. This pain amplification syndrome has enormous societal impact --- Explanation: Establishes fibromyalgia as a prototypical central sensitivity syndrome with augmented pain processing.


MONDO:0005546

[PMID:21684692] [INDIRECT EVIDENCE] [PARTIAL] A number of neurotransmitters in the ascending and descending pain pathways have been implicated in FM including glutamate and GABA. --- Explanation: Identifies neurotransmitter dysfunction in descending pain pathways as a key mechanism in fibromyalgia pathophysiology.

[PMID:21684692] [INDIRECT EVIDENCE] [PARTIAL] GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia. --- Explanation: Animal model evidence supporting the role of impaired inhibitory neurotransmission in pain amplification.


MONDO:0005546

[PMID:22126705] [INDIRECT EVIDENCE] [SUPPORT] We report elevated cerebrospinal fluid and serum concentrations of interleukin-8, but not interleukin-1beta, in FM patients. This profile is in accordance with FM symptoms being mediated by sympathetic activity rather than dependent on prostaglandin associated mechanisms and supports the hypothesis of glia cell activation in response to pain mechanisms. --- Explanation: Direct evidence of central inflammation in fibromyalgia via elevated CSF IL-8 levels, supporting glial cell activation hypothesis.

[PMID:22126705] [INDIRECT EVIDENCE] [PARTIAL] Activation of glia cells resulting in intrathecal elevation of cytokines and chemokines has been hypothesized in chronic pain syndromes such as fibromyalgia. --- Explanation: Establishes theoretical framework linking glial activation to intrathecal cytokine elevation in fibromyalgia pathophysiology.

[PMID:29684996] [INDIRECT EVIDENCE] [PARTIAL] Mast cells are involved in FM by releasing proinflammatory cytokines, chemokines, chemical mediators, and PGD2. TNF is a cytokine generated by MCs and its level is higher in FM. --- Explanation: Identifies mast cell-mediated inflammation as a contributor to low-grade chronic neuroinflammation in fibromyalgia.


MONDO:0005546

[PMID:7980669] [INDIRECT EVIDENCE] [SUPPORT] Patients with FM had low 24-hour urinary free cortisol, but normal peak and elevated trough plasma cortisol levels, compared with normal subjects. --- Explanation: Documents specific HPA axis abnormalities including low urinary cortisol and elevated trough levels supporting HPA dysregulation mechanism.

[PMID:15157948] [INDIRECT EVIDENCE] [SUPPORT] There was a significant delay in the rate of decline from acrophase to nadir for cortisol levels in patients with FMS (P <.01). --- Explanation: Demonstrates altered circadian cortisol rhythm with delayed decline indicating loss of HPA axis resiliency.

[PMID:7980669] [INDIRECT EVIDENCE] [SUPPORT] These data support the view that HPA axis function is perturbed in patients with FM. --- Explanation: Concludes that HPA axis perturbations are a characteristic feature of fibromyalgia pathophysiology.


MONDO:0005546

[PMID:39062116] [INDIRECT EVIDENCE] [NO_EVIDENCE] These include central sensitization, associated with an increase in the release of both excitatory and inhibitory neurotransmitters; peripheral sensitization, involving alterations in peripheral nociceptor signaling; and inflammatory and immune mechanisms that develop concurrently with the aforementioned processes. --- Explanation: Snippet supports peripheral sensitization broadly but does not directly provide evidence for small-fiber structural pathology or reduced IENFD.


MONDO:0005546

[PMID:21905019] [INDIRECT EVIDENCE] [SUPPORT] Evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4. --- Explanation: Large-scale genetic study identifies TAAR1, RGS4, CNR1, and GRIA4 as genes with evidence of association with fibromyalgia in replication cohort.


MAXO:0000058


CHEBI:36796


CHEBI:135005


CHEBI:64356


CHEBI:42797


CHEBI:2666


MAXO:0000011


MAXO:0000077


MAXO:0000010


HGNC.SYMBOL:COMT


HGNC.SYMBOL:SLC6A4


HGNC.SYMBOL:HTR2A


HGNC.SYMBOL:TAAR1


HGNC.SYMBOL:RGS4


HGNC.SYMBOL:CNR1


HGNC.SYMBOL:GRIA4


HGNC.SYMBOL:TRPV2


HGNC.SYMBOL:TRPV3


MONDO:0006552

[PMID:6402527] [SUPPORT] The eruption consists of pruritic papules, papulopustules, nodules, and urticarial lesions on the trunk and extremities. --- Explanation: Directly supports papular morphology and common distribution.


MONDO:0006552

[PMID:22639852] [SUPPORT] In addition, several Gram-negative bacterial, fungal, parasitic, and viral pathogens can cause follicular papules and pustules. --- Explanation: Supports pustules as a core lesion type across infectious etiologies.

[PMID:18715292] [SUPPORT] Clinically, the lesions present with follicular pustules, lack of ostia, diffuse and perifollicular erythema, follicular tufting, and, oftentimes, hemorrhagic crusts and erosions. --- Explanation: Provides subtype-specific clinical evidence for pustules in folliculitis decalvans.


MONDO:0006552

[PMID:6402527] [SUPPORT] The eruption consists of pruritic papules, papulopustules, nodules, and urticarial lesions on the trunk and extremities. --- Explanation: Confirms itch as a frequent symptom in symptomatic follicular eruptions.


MONDO:0006552

[PMID:2307901] [SUPPORT] The condition is characterized by painful, papulopustular skin lesions often accompanied by low-grade fever, malaise, and other systemic symptoms. --- Explanation: Supports fever as a contextual phenotype in Pseudomonas-associated folliculitis.


MONDO:0006552

[PMID:41146582] [SUPPORT] Folliculitis decalvans (FD) and Tufted Hair Folliculitis (THF) present with recurrent episodes of follicular inflammation, pustules and crusting, predominantly of the scalp, leading to scarring alopecia. --- Explanation: Supports alopecia as a clinically important sequela in scarring folliculitis subtypes.

[PMID:36716709] [SUPPORT] Folliculitis decalvans (FD) is a rare primary neutrophilic scarring alopecia whose etiology has not been completely elucidated yet. --- Explanation: Provides independent support that scarring alopecia is a defining phenotype of folliculitis decalvans.


MONDO:0006552

[PMID:22639852] [INDIRECT EVIDENCE] [SUPPORT] There are various infectious and non-infectious causes of folliculitis, and the most common causative agent is Staphylococcus aureus. --- Explanation: Supports S. aureus as an upstream and common etiologic mechanism.


MONDO:0006552

[DOI:10.3390/antibiotics12030557] [INDIRECT EVIDENCE] [SUPPORT] The immune response to S. aureus SSTIs involves initial responders such as keratinocytes and neutrophils, which are supported by dendritic cells and T-lymphocytes later during infection. --- Explanation: Supports keratinocyte participation as an early cellular event in skin infection pathophysiology.


MONDO:0006552


MONDO:0006552

[DOI:10.3390/antibiotics12030557] [INDIRECT EVIDENCE] [SUPPORT] The immune response to S. aureus SSTIs involves initial responders such as keratinocytes and neutrophils, which are supported by dendritic cells and T-lymphocytes later during infection. --- Explanation: Supports neutrophil-centric immune amplification in staphylococcal folliculitis mechanisms.


MONDO:0006552

[PMID:6402527] [INDIRECT EVIDENCE] [SUPPORT] Skin biopsies showed an acute, suppurative folliculitis and dermal abscess formation. --- Explanation: Histopathology confirms the suppurative inflammatory stage.


MONDO:0006552

[PMID:22639852] [INDIRECT EVIDENCE] [SUPPORT] In addition, several Gram-negative bacterial, fungal, parasitic, and viral pathogens can cause follicular papules and pustules. --- Explanation: Supports a pathogen-diverse upstream entry point into folliculitis pathophysiology.


MONDO:0006552

[PMID:10321942] [INDIRECT EVIDENCE] [SUPPORT] The gram-negative organisms most frequently cultivated from nares, facial skin, and pustules were Klebsiella spp., Escherichia coli, Enterobacter spp., and Proteus spp. --- Explanation: Supports a discrete pathogen-overgrowth stage in gram-negative folliculitis.


MONDO:0006552

[PMID:8989930] [INDIRECT EVIDENCE] [SUPPORT] Demodex mites were found in 42% of follicles with inflammation, but in just 10% of the follicles without inflammation. --- Explanation: Supports Demodex colonization as a candidate upstream event in follicular inflammation.


MONDO:0006552

[PMID:36912427] [INDIRECT EVIDENCE] [SUPPORT] Malassezia is a lipophilic yeast that is a part of the human mycobiome. --- Explanation: Establishes baseline commensal follicular colonization by Malassezia.


MONDO:0006552

[PMID:1671328] [INDIRECT EVIDENCE] [SUPPORT] These observations demonstrate that HIV-associated eosinophilic folliculitis is a unique HIV-related cutaneous disorder that is characterized by a culture-negative, chronic, pruritic folliculitis and a characteristic histopathologic picture. --- Explanation: Defines an immunologic, eosinophilic folliculitis mechanism distinct from pyogenic bacterial disease.


MONDO:0006552

[PMID:36716709] [INDIRECT EVIDENCE] [SUPPORT] CONCLUSION: FD hair follicles have a specific heterogenous follicular bacterial microbiota signature. --- Explanation: Supports the presence of subtype-specific follicular dysbiosis in folliculitis decalvans.


MONDO:0006552

[PMID:36716709] [INDIRECT EVIDENCE] [SUPPORT] BACKGROUND: Folliculitis decalvans (FD) is a rare primary neutrophilic scarring alopecia whose etiology has not been completely elucidated yet. --- Explanation: Supports a distinct chronic neutrophilic scarring-inflammatory stage in FD.

[PMID:18715292] [INDIRECT EVIDENCE] [SUPPORT] Histology displays a mainly neutrophilic inflammatory infiltrate in early lesions and additionally lymphocytes and plasma cells in advanced lesions. --- Explanation: Adds direct histologic support for neutrophil-dominant early FD inflammation with chronic inflammatory progression.


MAXO:0000058

[PMID:22639852] [SUPPORT] Therefore, topical and/or systemic antibacterial treatment is recommended, but this involves the risk of being misused for months or even years. --- Explanation: Review supports antibacterial treatment use while cautioning against prolonged empiric misuse.

[DOI:10.3390/antibiotics12030557] [SUPPORT] Treatment for S. aureus SSTIs is usually oral therapy, with parenteral therapy reserved for severe presentations; it ranges from cephalosporins and penicillin agents such as oxacillin, which is generally used for methicillin-sensitive S. aureus (MSSA), to vancomycin for methicillin-resistant S. aureus (MRSA). --- Explanation: Adds contemporary treatment-stratification evidence for staphylococcal folliculitis-spectrum infections.


MAXO:0000058

[PMID:27581777] [SUPPORT] Treatment consisted of topical application of 2% ketoconazole cream or 100 mg oral itraconazole based on symptom severity and patients' preferences. --- Explanation: Documents real-world topical and oral antifungal regimens.

[PMID:27581777] [SUPPORT] The results were "improved" and the treatment was "effective" in all patients. --- Explanation: Supports clinical effectiveness of both antifungal strategies in this cohort.


MAXO:0000058

[PMID:41146582] [SUPPORT] Combination therapy with systemic antibiotics, topical, local and/or other systemic agents may provide the best outcome and longest DoE for FD/THF patients, with a greater role for biologic agents and laser therapy in their management. --- Explanation: Systematic review supports multimodal treatment strategy for chronic scarring folliculitis variants.

[PMID:29864465] [SUPPORT] Treatment with rifampicin and clindamycin, tetracyclines, and intralesional steroids was the most effective. --- Explanation: Multicenter long-term follow-up study provides specific evidence for effective combination regimens in folliculitis decalvans.

[clinicaltrials:NCT07268534] [SUPPORT] Short-term efficacy rate of antibiotics is around 50-60%, but unfortunately, recurrences/relapses are occurring 5 to 7 months on average after stopping antibiotics, requiring their reintroduction/long-term use and potentially less efficacy/ecological harms. --- Explanation: Supports limitations of antibiotic-only strategies and the need for alternative or adjunctive management approaches in FD.


MAXO:0000058

[PMID:1671328] [SUPPORT] A clinical response was noted to astemizole, to ultraviolet light in the B range, and to topical clobetasol propionate. --- Explanation: Supports specific adjunctive therapies in eosinophilic folliculitis context.


NCBITaxon:1280

[PMID:22639852] [SUPPORT] There are various infectious and non-infectious causes of folliculitis, and the most common causative agent is Staphylococcus aureus. --- Explanation: The review identifies S. aureus as the most common causative pathogen.

[PMID:15482221] [SUPPORT] S. aureus is one of the most common causes of skin infection, giving rise to folliculitis, furunculosis, carbuncles, ecthyma, impetigo, cellulitis and abscesses. --- Explanation: Additional clinical review evidence supports S. aureus as a major folliculitis pathogen.


NCBITaxon:287

[PMID:6402527] [SUPPORT] A family of three and a neighbor developed Pseudomonas folliculitis after using a home hot tub from which P. aeruginosa was cultured. --- Explanation: Human outbreak evidence supports P. aeruginosa as an etiologic agent in exposure-associated folliculitis.

[PMID:3955486] [SUPPORT] Outbreaks of community-acquired Pseudomonas aeruginosa folliculitis have recently been described in association with health spa whirlpools. --- Explanation: Independent outbreak evidence supports P. aeruginosa as a recurrent etiologic pathogen in water-associated folliculitis.


NCBITaxon:55193

[PMID:36912427] [SUPPORT] Malassezia folliculitis appears when the benign colonization of the hair follicles, by the Malassezia yeasts, becomes symptomatic with pruritic papules and pustules. --- Explanation: Position statement directly describes Malassezia-associated folliculitis mechanism and clinical morphology.


NCBITaxon:188544

[PMID:8989930] [SUPPORT] Demodex mites were found in 42% of follicles with inflammation, but in just 10% of the follicles without inflammation. --- Explanation: Supports association between Demodex mites and human follicular inflammation.


NCBITaxon:79923

[PMID:19597009] [SUPPORT] An estimated 750 million people are at risk of infections with food-borne trematodes, which comprise liver flukes (Clonorchis sinensis, Fasciola gigantica, Fasciola hepatica, Opisthorchis felineus, and Opisthorchis viverrini), lung flukes (Paragonimus spp.), and intestinal flukes (e.g., Echinostoma spp., Fasciolopsis buski, and the heterophyids). --- Explanation: The abstract lists C. sinensis among the major liver flukes.


NCBITaxon:46835

[PMID:19597009] [SUPPORT] An estimated 750 million people are at risk of infections with food-borne trematodes, which comprise liver flukes (Clonorchis sinensis, Fasciola gigantica, Fasciola hepatica, Opisthorchis felineus, and Opisthorchis viverrini), lung flukes (Paragonimus spp.), and intestinal flukes (e.g., Echinostoma spp., Fasciolopsis buski, and the heterophyids). --- Explanation: The abstract lists F. gigantica among the major liver flukes.


NCBITaxon:6192

[PMID:19597009] [SUPPORT] An estimated 750 million people are at risk of infections with food-borne trematodes, which comprise liver flukes (Clonorchis sinensis, Fasciola gigantica, Fasciola hepatica, Opisthorchis felineus, and Opisthorchis viverrini), lung flukes (Paragonimus spp.), and intestinal flukes (e.g., Echinostoma spp., Fasciolopsis buski, and the heterophyids). --- Explanation: The abstract lists F. hepatica among the major liver flukes.


NCBITaxon:147828

[PMID:19597009] [SUPPORT] An estimated 750 million people are at risk of infections with food-borne trematodes, which comprise liver flukes (Clonorchis sinensis, Fasciola gigantica, Fasciola hepatica, Opisthorchis felineus, and Opisthorchis viverrini), lung flukes (Paragonimus spp.), and intestinal flukes (e.g., Echinostoma spp., Fasciolopsis buski, and the heterophyids). --- Explanation: The abstract lists O. felineus among the major liver flukes.


NCBITaxon:6198

[PMID:19597009] [SUPPORT] An estimated 750 million people are at risk of infections with food-borne trematodes, which comprise liver flukes (Clonorchis sinensis, Fasciola gigantica, Fasciola hepatica, Opisthorchis felineus, and Opisthorchis viverrini), lung flukes (Paragonimus spp.), and intestinal flukes (e.g., Echinostoma spp., Fasciolopsis buski, and the heterophyids). --- Explanation: The abstract lists O. viverrini among the major liver flukes.


NCBITaxon:34503

[PMID:19597009] [SUPPORT] An estimated 750 million people are at risk of infections with food-borne trematodes, which comprise liver flukes (Clonorchis sinensis, Fasciola gigantica, Fasciola hepatica, Opisthorchis felineus, and Opisthorchis viverrini), lung flukes (Paragonimus spp.), and intestinal flukes (e.g., Echinostoma spp., Fasciolopsis buski, and the heterophyids). --- Explanation: The abstract lists Paragonimus species as lung flukes.


NCBITaxon:27847

[PMID:19597009] [SUPPORT] An estimated 750 million people are at risk of infections with food-borne trematodes, which comprise liver flukes (Clonorchis sinensis, Fasciola gigantica, Fasciola hepatica, Opisthorchis felineus, and Opisthorchis viverrini), lung flukes (Paragonimus spp.), and intestinal flukes (e.g., Echinostoma spp., Fasciolopsis buski, and the heterophyids). --- Explanation: The abstract lists Echinostoma species among intestinal flukes.


MONDO:0010383

[PMID:22483044] [SUPPORT] Fragile X is the most common known inherited cause of intellectual disability and autism --- Explanation: Review confirms intellectual disability as a cardinal feature of Fragile X syndrome.


MONDO:0010383

[PMID:22483044] [PARTIAL] Fragile X is the most common known inherited cause of intellectual disability and autism --- Explanation: Review confirms autism as a common feature of Fragile X syndrome.


MONDO:0010383

[PMID:8190590] [SUPPORT] Macroorchidism is one of the most well-described clinical characteristics of men with fragile X syndrome --- Explanation: Study confirms macroorchidism as a well-described clinical feature of Fragile X syndrome.


MONDO:0010383

[PMID:8190590] [NO_EVIDENCE] Clinical assessments were performed on 73 boys, 2.2 to 10.2 years, in whom fragile X either had been diagnosed or who had been referred for fragile X evaluations --- Explanation: This methods statement does not provide direct evidence for elongated face phenotype.


MONDO:0010383

[PMID:8190590] [NO_EVIDENCE] Clinical assessments were performed on 73 boys, 2.2 to 10.2 years, in whom fragile X either had been diagnosed or who had been referred for fragile X evaluations --- Explanation: This methods statement does not provide direct evidence for large ears/macrotia.


MONDO:0010383

[PMID:22483044] [NO_EVIDENCE] Fragile X is the most common known inherited cause of intellectual disability and autism, and it typically results from transcriptional silencing of FMR1 and loss of the encoded protein, FMRP --- Explanation: Snippet supports FMR1/FMRP disease mechanism and autism/intellectual disability, but does not directly mention hyperactivity.


MONDO:0010383


MONDO:0010383

[PMID:24346713] [INDIRECT EVIDENCE] [SUPPORT] Most FXS cases occur due to the expansion of the CGG trinucleotide repeats in the 5' un-translated region of FMR1, which leads to hypermethylation and in turn silences the expression of FMRP --- Explanation: Review confirms CGG repeat expansion leads to FMRP silencing in Fragile X syndrome.


MONDO:0010383

[PMID:24346713] [INDIRECT EVIDENCE] [SUPPORT] In the absence of FMRP, the basal protein translation is enhanced and not responsive to neuronal stimulation. The altered protein translation may contribute to functional abnormalities in certain aspects of synaptic plasticity --- Explanation: Review confirms FMRP absence leads to altered synaptic protein synthesis and plasticity.

[PMID:22483044] [INDIRECT EVIDENCE] [SUPPORT] FMRP is an mRNA-binding protein that functions at many synapses to inhibit local translation stimulated by metabotropic glutamate receptors (mGluRs) 1 and 5. --- Explanation: Review confirms FMRP normally inhibits synaptic protein translation.


HGNC.SYMBOL:FMR1

[PMID:24346713] [SUPPORT] Fragile X syndrome (FXS) is caused by mutations in the fragile X mental retardation 1 (FMR1) gene. --- Explanation: Review confirms FMR1 gene mutations cause Fragile X syndrome.


MONDO:0100339

[PMID:23859346] [SUPPORT] his description remains at the core of the classical clinical phenotype of gait and limb ataxia, poor balance and coordination, leg weakness, sensory loss, areflexia, impaired walking, dysarthria, dysphagia, eye movement abnormalities, scoliosis, foot deformities, cardiomyopathy and diabetes. --- Explanation: Comprehensive description of the classical Friedreich ataxia phenotype with ataxia as the core feature.


MONDO:0100339

[PMID:23859346] [SUPPORT] gait and limb ataxia, poor balance and coordination, leg weakness, sensory loss, areflexia, impaired walking, dysarthria, dysphagia --- Explanation: Dysarthria is part of the classical phenotype.


MONDO:0100339


MONDO:0100339

[PMID:23859346] [SUPPORT] his description remains at the core of the classical clinical phenotype of gait and limb ataxia, poor balance and coordination, leg weakness, sensory loss, areflexia, impaired walking, dysarthria, dysphagia, eye movement abnormalities, scoliosis, foot deformities, cardiomyopathy and diabetes. --- Explanation: Cardiomyopathy is listed as part of the classical Friedreich ataxia phenotype.


MONDO:0100339

[PMID:23859346] [SUPPORT] scoliosis, foot deformities, cardiomyopathy and diabetes. --- Explanation: Scoliosis is part of the classical phenotype.


MONDO:0100339

[PMID:23859346] [SUPPORT] Early-onset cases tend to have more rapid progression and a higher frequency of non-neurological features such as diabetes, cardiomyopathy, scoliosis and pes cavus. --- Explanation: Pes cavus is more frequent in early-onset cases.


MONDO:0100339

[PMID:23859346] [SUPPORT] scoliosis, foot deformities, cardiomyopathy and diabetes. --- Explanation: Diabetes is part of the classical phenotype description.


MONDO:0100339

[PMID:14653404] [INDIRECT EVIDENCE] [SUPPORT] the unstable GAA expansion that underlies FA causes a deficiency of the mitochondrial protein frataxin, leading to potentially harmful oxidative injury associated with excessive iron deposits in mitochondria. In addition, pathogenesis may involve a primary defect in synthesis of iron-sulfur cluster containing enzymes. --- Explanation: Confirms frataxin deficiency, mitochondrial iron accumulation, and iron-sulfur cluster assembly defect as the pathogenic mechanism.

[PMID:31456208] [INDIRECT EVIDENCE] [SUPPORT] This protein is essential for mitochondrial function by the involvement of iron-sulfur cluster biogenesis. The effects of its deficiency also include disruption of cellular, particularly mitochondrial, iron homeostasis, i.e., relatively more iron accumulated in mitochondria and less iron presented in cytosol. --- Explanation: Confirms frataxin's role in iron-sulfur cluster biogenesis and mitochondrial iron accumulation upon deficiency.


MAXO:0000950

[PMID:29053830] [SUPPORT] Management of Freidreich's ataxia is currently focussed on symptomatic management, delivered by the multidisciplinary team. --- Explanation: Confirms that current management is multidisciplinary and symptomatic.


MAXO:0000058


MAXO:0001001

[PMID:29053830] [SUPPORT] Phase II clinical trials in agents that address the abberrant silencing of the frataxin gene need to be translated into large placebo-controlled Phase III trials to help establish their therapeutic potential. --- Explanation: Confirms ongoing clinical development of frataxin-restoring therapies.


MAXO:0000079


HGNC.SYMBOL:FXN

[PMID:14653404] [SUPPORT] the unstable GAA expansion that underlies FA causes a deficiency of the mitochondrial protein frataxin --- Explanation: Confirms GAA expansion as the causative mutation leading to frataxin deficiency.

[PMID:23859346] [SUPPORT] Inheritance is autosomal recessive with the vast majority of cases showing an unstable intronic GAA expansion in both alleles of the frataxin gene on chromosome 9q13. --- Explanation: Confirms autosomal recessive inheritance with homozygous GAA expansion in FXN.


MONDO:0017276

[PMID:26473392] [SUPPORT] GRN patients were older at death and more likely to present with non-fluent aphasia. --- Explanation: This demonstrates that non-fluent aphasia is a characteristic presenting feature in patients with GRN mutations causing frontotemporal dementia.


MONDO:0017276

[PMID:26473392] [SUPPORT] They showed more psychotic symptoms and irrational behaviour, yet were more often reported clinically as socially appropriate and warm. --- Explanation: This highlights the complex and sometimes paradoxical personality changes in C9orf72-related FTD, where patients may retain apparent social warmth despite significant behavioral dysfunction.


MONDO:0017276


MONDO:0017276

[PMID:19664364] [INDIRECT EVIDENCE] [SUPPORT] TDP-43 is typically a nuclear protein, and its aggregation and cytoplasmic translocation are thought to represent major steps in the pathogenesis of FTLD due to TDP-43 proteinopathy (FTLD-TDP). --- Explanation: This confirms that TDP-43 aggregation and mislocalization are central to the pathogenesis of FTLD-TDP, a major subtype of frontotemporal dementia.


MONDO:0017276

[PMID:26473392] [INDIRECT EVIDENCE] [SUPPORT] MAPT patients were younger than other groups, and showed more frequent behavioural disinhibition, repetitive and stereotyped behaviours, semantic impairment and temporal predominance of atrophy. --- Explanation: This demonstrates the genotype-specific patterns of brain atrophy and their relationship to clinical phenotypes in frontotemporal dementia.


MONDO:0017276

[PMID:30711676] [INDIRECT EVIDENCE] [PARTIAL] We observed that biological changes and intracortical facilitation transmission abnormalities significantly antecede the emergence of clinical symptoms of at least 3 decades. --- Explanation: Supports long presymptomatic neurobiological change in genetic FTD, but does not directly quantify neuronal death in the quoted text.


MAXO:0000950


HGNC.SYMBOL:MAPT

[PMID:26473392] [SUPPORT] MAPT patients were younger than other groups, and showed more frequent behavioural disinhibition, repetitive and stereotyped behaviours, semantic impairment and temporal predominance of atrophy. --- Explanation: This confirms the distinct clinical and anatomical phenotype associated with MAPT mutations in frontotemporal dementia.


HGNC.SYMBOL:GRN

[PMID:26473392] [SUPPORT] GRN patients were older at death and more likely to present with non-fluent aphasia. --- Explanation: This demonstrates the characteristic clinical presentation of GRN-related FTD with language deficits.

[PMID:30711676] [SUPPORT] Presymptomatic carriers of GRN and C9orf72 mutations, the most frequent genetic causes of frontotemporal lobar degeneration, represent the optimal target population for the development of disease-modifying drugs. --- Explanation: This confirms GRN as one of the two most common genetic causes of FTD.


HGNC.SYMBOL:C9orf72

[PMID:26473392] [SUPPORT] C9orf72 patients alone showed a co-occurrence of ALS. They showed more psychotic symptoms and irrational behaviour, yet were more often reported clinically as socially appropriate and warm. --- Explanation: This highlights the distinctive clinical features of C9orf72-related FTD including the frequent association with ALS and unique behavioral profile.

[PMID:30711676] [SUPPORT] Presymptomatic carriers of GRN and C9orf72 mutations, the most frequent genetic causes of frontotemporal lobar degeneration, represent the optimal target population for the development of disease-modifying drugs. --- Explanation: This confirms C9orf72 as one of the most common genetic causes of FTD.


MONDO:0100595

[DOI:10.1159/000499184] [SUPPORT] The most frequent <i>S. aureus</i> infections include impetigo, folliculitis, furuncles, furunculosis, abscesses, hidradenitis suppurativa, and mastitis. --- Explanation: Furuncles are explicitly listed as frequent S. aureus clinical manifestations within recurrent furunculosis context.


MONDO:0100595

[PMID:22803835] [SUPPORT] PVL is associated with follicular infections in general, having its strongest association with furunculosis and its recurrence. --- Explanation: Supports recurrent abscess phenotype linked to PVL-positive furunculosis.

[PMID:17479931] [SUPPORT] From January 1998 through December 2004, 42 cases and 59 relapses of furunculosis were identified by active case finding. --- Explanation: Documents repeated relapses as a defining recurrent phenotype.


MONDO:0100595

[PMID:38518792] [INDIRECT EVIDENCE] [SUPPORT] Because S aureus infections commonly arise from asymptomatic colonisation, decolonisation is considered a key approach for their prevention. --- Explanation: Supports asymptomatic colonization as the upstream reservoir for infection episodes.

[PMID:22803835] [INDIRECT EVIDENCE] [SUPPORT] Nasal carriage of S. aureus is the primary risk factor for recurrent furunculosis and occurs in 60% of individuals. --- Explanation: Supports reservoir colonization as a central mechanism in recurrence.


MONDO:0100595


MONDO:0100595

[PMID:22803835] [INDIRECT EVIDENCE] [SUPPORT] PVL is associated with follicular infections in general, having its strongest association with furunculosis and its recurrence. --- Explanation: Supports PVL as a key virulence driver of recurrent furunculosis.

[PMID:23973399] [INDIRECT EVIDENCE] [SUPPORT] The study revealed a high prevalence of luk-PV gene among methicillin-susceptible strains and a statistically significant correlation between the presence of this gene and presenting with an abscess. --- Explanation: Correlates PVL gene carriage with abscess phenotype in human carriers.


MONDO:0100595

[DOI:10.3390/pathogens14090923] [INDIRECT EVIDENCE] [SUPPORT] In 90% of cases, S. aureus strains possessed the following virulence genes: clfA, clfB, spa, cna, eap, hlgA, hlgB, hlg, hld, bap, bbp, ebpS, fib, fnbA, fnbB, and pvl. --- Explanation: Demonstrates high prevalence of adhesion-associated virulence repertoire in chronic furunculosis isolates.


MONDO:0100595

[DOI:10.3390/pathogens14090923] [INDIRECT EVIDENCE] [SUPPORT] Biofilm production was confirmed using the crystal violet method. --- Explanation: Provides direct experimental support for biofilm-forming capability in the chronic furunculosis isolate set.


MONDO:0100595

[DOI:10.3390/pathogens14090923] [INDIRECT EVIDENCE] [SUPPORT] It has been demonstrated that MSSA possesses a similar set of virulence genes to MRSA and that MSSA is responsible for most cases of chronic osteomyelitis and furunculosis. --- Explanation: Supports MSSA as a persistent, high-virulence reservoir in chronic furunculosis.

[DOI:10.3390/pathogens14090923] [INDIRECT EVIDENCE] [SUPPORT] The findings indicate that S. aureus possesses numerous virulence factors that play a key role in the processes of adhesion to and proliferation within host cells. --- Explanation: Supports ongoing host persistence potential that can sustain chronic recurrence dynamics.


MONDO:0100595

[DOI:10.3390/antibiotics12030557] [INDIRECT EVIDENCE] [SUPPORT] The immune response to S. aureus SSTIs involves initial responders such as keratinocytes and neutrophils, which are supported by dendritic cells and T-lymphocytes later during infection. --- Explanation: Supports early innate phase dominated by keratinocytes and neutrophils.


MONDO:0100595

[DOI:10.3390/antibiotics12030557] [INDIRECT EVIDENCE] [SUPPORT] The immune response to S. aureus SSTIs involves initial responders such as keratinocytes and neutrophils, which are supported by dendritic cells and T-lymphocytes later during infection. --- Explanation: Supports the later adaptive phase involving dendritic cells and T cells.


MONDO:0100595

[DOI:10.1159/000499184] [INDIRECT EVIDENCE] [SUPPORT] Immunological and inflammatory processes of chronic furunculosis are based on the pathogenicity of <i>S. aureus</i> as well as innate and acquired immunity. --- Explanation: Explicitly supports immune-pathogenesis coupling in recurrent furunculosis.


MAXO:0000058

[DOI:10.3390/antibiotics12030557] [SUPPORT] Treatment for S. aureus SSTIs is usually oral therapy, with parenteral therapy reserved for severe presentations; it ranges from cephalosporins and penicillin agents such as oxacillin, which is generally used for methicillin-sensitive S. aureus (MSSA), to vancomycin for methicillin-resistant S. aureus (MRSA). --- Explanation: Supports antibiotic treatment strategy and escalation by severity/resistance profile.


MAXO:0000058

[PMID:17479931] [SUPPORT] Nasally colonized persons, persons who had current furuncles or who had experienced relapsing furuncles since 2002, and their family members underwent stringent decolonization measures using mupirocin nasal ointment and disinfecting wash solution. --- Explanation: Documents practical outbreak-control use of mupirocin plus antiseptic washing in recurrent furunculosis.

[PMID:38518792] [SUPPORT] Current decolonisation procedures include antibiotic-based and antiseptic-based eradication of S aureus from the nose and skin. --- Explanation: Supports decolonization as a prevention/treatment adjunct focused on reservoir eradication.


NCBITaxon:1280

[PMID:22803835] [SUPPORT] The majority of furuncles in the U.S.A. are caused by CA-MRSA, while elsewhere in the world they are caused by methicillin-sensitive S. aureus. --- Explanation: Uses the abstract conclusion to support that S. aureus lineages are the principal causes of furunculosis.

[DOI:10.3390/antibiotics12030557] [SUPPORT] The pathogenic bacterium Staphylococcus aureus is the most common pathogen isolated in skin-and-soft-tissue infections (SSTIs) in the United States. --- Explanation: Furunculosis is a staphylococcal SSTI phenotype and this supports S. aureus as the dominant causative pathogen.


MONDO:0018116

[PMID:1561928] [SUPPORT] Galactosemia in newborns and infants is associated with the following symptoms: jaundice, hepatomegaly, failure to thrive, feeding difficulties, hypoglycemia, convulsions, lethargy, amino-aciduria, cataracts, hepatic cirrhosis, ascites, and mental retardation. --- Explanation: Clinical review documenting jaundice as a key symptom in galactosemic infants.


MONDO:0018116

[PMID:1561928] [SUPPORT] Galactosemia in newborns and infants is associated with the following symptoms: jaundice, hepatomegaly, failure to thrive, feeding difficulties, hypoglycemia, convulsions, lethargy, amino-aciduria, cataracts, hepatic cirrhosis, ascites, and mental retardation. --- Explanation: Clinical review documenting hepatomegaly as a key symptom in galactosemic infants.


MONDO:0018116

[PMID:1561928] [SUPPORT] Galactosemia in newborns and infants is associated with the following symptoms: jaundice, hepatomegaly, failure to thrive, feeding difficulties, hypoglycemia, convulsions, lethargy, amino-aciduria, cataracts, hepatic cirrhosis, ascites, and mental retardation. --- Explanation: Clinical review documenting failure to thrive as a key symptom in galactosemic infants.


MONDO:0018116

[PMID:3043741] [SUPPORT] Any single deficient enzyme can result in cataract through the accumulation of galactitol in the lens. --- Explanation: Review article confirming that galactitol accumulation in the lens causes cataract formation in all forms of galactosemia.


MONDO:0018116

[PMID:1561928] [SUPPORT] If the preliminary evaluation indicates galactosemia, there is high risk for E. coli sepsis and death. --- Explanation: Clinical review emphasizing the high risk of E. coli sepsis in infants with galactosemia.


MONDO:0018116

[PMID:1561928] [SUPPORT] Galactosemia in newborns and infants is associated with the following symptoms: jaundice, hepatomegaly, failure to thrive, feeding difficulties, hypoglycemia, convulsions, lethargy, amino-aciduria, cataracts, hepatic cirrhosis, ascites, and mental retardation. --- Explanation: Clinical review documenting mental retardation (intellectual disability) as a symptom in galactosemia.


MONDO:0018116

[PMID:21347587] [SUPPORT] Impairment of speech affects a significant number of patients with galactosemia, appears in early childhood, and persists into adulthood. --- Explanation: Cross-sectional human cohort data directly support speech impairment as a common long-term phenotype in classic galactosemia.


MONDO:0018116

[PMID:20978943] [SUPPORT] Primary or premature ovarian insufficiency (POI) is the most common long-term complication experienced by girls and women with classic galactosemia; more than 80% and perhaps more than 90% are affected despite neonatal diagnosis and careful lifelong dietary restriction of galactose. --- Explanation: Review documenting that POI affects more than 80-90% of females with classic galactosemia despite dietary treatment.


MONDO:0018116

[PMID:23400815] [SUPPORT] Thirty-one patients showed evidence of motor dysfunction including: tremor (23 patients), dystonia (23 patients), cerebellar signs (6 patients), and pyramidal signs (4 patients). --- Explanation: This adult classical galactosemia cohort directly documents tremor as a frequent component of the motor phenotype.


MAXO:0000088

[PMID:20978943] [SUPPORT] more than 80% and perhaps more than 90% are affected despite neonatal diagnosis and careful lifelong dietary restriction of galactose --- Explanation: Review confirming that dietary restriction of galactose is the standard treatment, though long-term complications persist.


MAXO:0000930

[PMID:34665663] [SUPPORT] The BBC appears to be a viable intervention to support the speech and expressive language development of children with GC. --- Explanation: This intervention study provides direct human evidence that targeted speech-language therapy can support speech and language development in children with classic galactosemia.


HGNC.SYMBOL:GALT variants (Classic galactosemia)

[PMID:11113841] [SUPPORT] The most prevalent mutation, Q188R, had a significant effect of genotype category (Q188R/Q188R, Q188R/Other, Other/Other) on POF --- Explanation: Clinical study demonstrating that Q188R is the most prevalent GALT mutation and has significant phenotypic effects.


HGNC.SYMBOL:GALK1 variants (Galactokinase deficiency)

[PMID:3043741] [SUPPORT] Galactosemia is a disorder caused by a deficiency of any one of three possible enzymes involved in the metabolism of galactose: galactokinase, transferase or epimerase. --- Explanation: Review article documenting galactokinase as one of three enzyme deficiencies causing galactosemia.


HGNC.SYMBOL:GALE variants (Epimerase deficiency)

[PMID:3043741] [SUPPORT] Galactosemia is a disorder caused by a deficiency of any one of three possible enzymes involved in the metabolism of galactose: galactokinase, transferase or epimerase. --- Explanation: Review article documenting epimerase as one of three enzyme deficiencies causing galactosemia.


MONDO:0004950


MONDO:0004950

[PMID:12446738] [INDIRECT EVIDENCE] [SUPPORT] the tyrosine-phosphorylated form of CagA specifically binds to and activates SHP-2 phosphatase, thereby inducing morphological transformation of gastric epithelial cells (hummingbird phenotype) --- Explanation: This study demonstrates the molecular mechanism of CagA-SHP-2 interaction and downstream oncogenic signaling in gastric epithelial cells.


MONDO:0004950

[PMID:26668499] [INDIRECT EVIDENCE] [PARTIAL] This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. --- Explanation: Abstract describes the gastric precancerous cascade with atrophic gastritis, intestinal metaplasia, and dysplasia.


MAXO:0000058

[PMID:32205420] [SUPPORT] In healthy individuals, eradication therapy reduced incidence of gastric cancer (RR=0.54; 95% CI 0.40 to 0.72, NNT=72) and reduced mortality from gastric cancer (RR=0.61; 95% CI 0.40 to 0.92, NNT=135) --- Explanation: Meta-analysis of 10 RCTs demonstrating that H. pylori eradication therapy significantly reduces gastric cancer incidence and mortality.


MAXO:0000004


MAXO:0000647

[PMID:36919950] [SUPPORT] Patients treated with FLOT showed a statistically significant longer median overall survival of 57.8 vs 28.9 months (HR: 0.554, 95% CI: 0.317-0.969, P = .036) --- Explanation: Real-world cohort study demonstrating FLOT4 perioperative chemotherapy significantly improves overall survival in gastric cancer patients.


MAXO:0000058


CHEBI:231601


HGNC.SYMBOL:CDH1

[PMID:26182300] [SUPPORT] By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). --- Explanation: Large cohort study of 75 CDH1 mutation-positive families providing precise cancer risk estimates for hereditary diffuse gastric cancer syndrome.


HGNC.SYMBOL:TP53


HGNC.SYMBOL:RHOA


HGNC.SYMBOL:ARID1A


NCBITaxon:210

[PMID:39004993] [PARTIAL] Gastric cancer is one of the major causes of cancer-related deaths worldwide, and infection with Helicobacter pylori and EBV, smoking and a salt-heavy diet have been shown to be risk factors for the development of gastric cancer. --- Explanation: This abstract identifies H. pylori infection as a risk factor for gastric cancer, supporting the infectious etiology noted here.


MONDO:0004950

[PMID:40647518] [PARTIAL] with adenocarcinoma being the most  --- Explanation: Abstract notes adenocarcinoma as the predominant histologic type in a gastric cancer cohort.


MONDO:0001126


MONDO:0007186


MONDO:0007186

[PMID:38177402] [INDIRECT EVIDENCE] [SUPPORT] GERD starts in the stomach, where the refluxate material is produced. Following the trajectory of reflux, the failure of the antireflux barrier, primarily the lower oesophageal sphincter and the crural diaphragm, enables the refluxate to reach the oesophageal lumen, triggering oesophageal or extra-oesophageal symptoms. --- Explanation: This review describes the failure of the antireflux barrier, particularly the lower esophageal sphincter, as a core mechanism allowing refluxate to enter the esophagus and cause symptoms.

[PMID:38177402] [INDIRECT EVIDENCE] [PARTIAL] Alterations of the oesophageal mucosal integrity, such as macroscopic oesophagitis or microscopic changes, determine the perception of symptoms. --- Explanation: Supports symptom effects of mucosal injury in GERD, but only indirectly supports LES dysfunction specifically.


MONDO:0007186

[PMID:38177402] [INDIRECT EVIDENCE] [SUPPORT] Reflux clearance mechanisms such as primary and secondary peristalsis and the arrival of bicarbonate-rich saliva are critical to prevent mucosal damage. --- Explanation: This highlights the importance of clearance mechanisms in preventing mucosal damage from refluxate exposure in GERD.

[PMID:38177402] [INDIRECT EVIDENCE] [SUPPORT] It is now recognized that different GERD phenotypes have different degrees of reflux, severity of mucosal integrity damage and type, and severity of symptoms. --- Explanation: This review recognizes that mucosal integrity damage varies across GERD phenotypes and contributes to symptom severity.


MONDO:0007186

[PMID:38177402] [INDIRECT EVIDENCE] [SUPPORT] Reflux clearance mechanisms such as primary and secondary peristalsis and the arrival of bicarbonate-rich saliva are critical to prevent mucosal damage. --- Explanation: This directly supports the role of impaired clearance mechanisms in prolonging refluxate exposure and increasing mucosal damage in GERD.


MONDO:0007186

[PMID:38449873] [INDIRECT EVIDENCE] [SUPPORT] The IVW method's findings suggested protective roles against GERD for the Family Clostridiales Vadin BB60 group (P = 0.027), Genus Lachnospiraceae UCG004 (P = 0.026), Genus Methanobrevibacter (P = 0.026), and Phylum Actinobacteria (P = 0.019). In contrast, Class Mollicutes (P = 0.037), Genus Anaerostipes (P = 0.049), and Phylum Tenericutes (P = 0.024) emerged as potential GERD risk factors. --- Explanation: This Mendelian randomization study establishes causal relationships between specific gut microbiota taxa and GERD risk, identifying both protective and risk-associated bacterial groups.

[PMID:38449873] [INDIRECT EVIDENCE] [SUPPORT] For the first time, the MR analysis indicates a genetic link between gut microbiota abundance changes and GERD risk. This not only substantiates the potential of intestinal microecological therapy for GERD, but also establishes a basis for advanced research into the role of intestinal microbiota in the etiology of GERD. --- Explanation: This confirms a genetic basis for the gut microbiome's causal role in GERD development and supports microbiome-targeted therapeutic approaches.


MONDO:0007186

[PMID:17932229] [INDIRECT EVIDENCE] [SUPPORT] In SCE, Cldn-18 was the most highly expressed at the mRNA level and this finding is paralleled by marked elevation in protein expression on immunoblots. In contrast in SqE, Cldn-18 was minimally expressed at the mRNA level and undetectable at the protein level. --- Explanation: This demonstrates that Barrett's esophagus exhibits a dramatic shift in tight junction protein composition, with claudin-18 becoming the dominant protein in metaplastic epithelium.

[PMID:17932229] [INDIRECT EVIDENCE] [SUPPORT] We conclude that Cldn-18 is the dominant claudin in the TJ of SCE and propose that the change from a Cldn-18-deficient TJ in SqE to a Cldn-18-rich TJ in SCE contributes to the greater acid resistance of BE. --- Explanation: This establishes that the claudin-18-rich tight junctions in Barrett's esophagus provide enhanced acid resistance compared to normal squamous epithelium.

[PMID:17932229] [INDIRECT EVIDENCE] [SUPPORT] Barrett's esophagus (BE) is a specialized columnar epithelium (SCE) that develops as replacement for damaged squamous epithelium (SqE) in subjects with reflux disease, and as such it is apparently more acid resistant than SqE. --- Explanation: This describes Barrett's esophagus as a metaplastic adaptation that develops in response to chronic reflux-induced damage and provides greater acid resistance.


HGNC.SYMBOL:FOXF1


HGNC.SYMBOL:MHC region


MONDO:0011719


MONDO:0011719

[PMID:12181401] [INDIRECT EVIDENCE] [SUPPORT] Constitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of gastrointestinal stromal tumors. --- Explanation: This landmark NEJM study established that constitutive KIT activation is the critical driver of GIST pathogenesis.


MAXO:0000058

[PMID:12181401] [SUPPORT] Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor. Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy. --- Explanation: The Demetri et al. NEJM study demonstrated that imatinib achieves objective responses in 53.7% of advanced GIST patients by inhibiting the KIT signaling pathway.


CHEBI:45783

[PMID:12181401] [INDIRECT EVIDENCE] [SUPPORT] Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor. Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy. --- Explanation: The Demetri et al. NEJM study demonstrated that imatinib achieves objective responses in 53.7% of advanced GIST patients by inhibiting the KIT signaling pathway.


MAXO:0000058


CHEBI:38940


NCIT:C123827


MAXO:0000004


HGNC.SYMBOL:KIT


HGNC.SYMBOL:PDGFRA


MONDO:0011719

[PMID:22937603] [SUPPORT] Gastrointestinal stromal tumor, i.e., GIST is by far the most common mesenchymal --- Explanation: Abstract identifies GIST as the most common mesenchymal tumor of the GI tract.


MONDO:0018150

[PMID:28218669] [SUPPORT] The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. --- Explanation: Review confirms hepatomegaly as a major manifestation of Gaucher disease.


MONDO:0018150

[PMID:28218669] [SUPPORT] The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. --- Explanation: Review confirms splenomegaly as a major manifestation caused by Gaucher cell infiltration.


MONDO:0018150

[PMID:19047232] [SUPPORT] More than 50% of patients had platelet counts of <100000 platelets per mm3 at baseline, but >95% had platelet counts above this level after 8 years of treatment. --- Explanation: Study documents thrombocytopenia as a common baseline finding in Gaucher disease patients.


MONDO:0018150

[PMID:19047232] [SUPPORT] Anemia, although not severe, was present in >50% of patients at baseline and resolved for all patients after 8 years of treatment. --- Explanation: Study confirms anemia as a common finding in over half of Gaucher disease patients.


MONDO:0018150

[PMID:19047232] [SUPPORT] Seventeen percent of patients reported a bone crisis before treatment and in the first 2 years of treatment, but no bone crises were reported after 2 years of enzyme replacement therapy. --- Explanation: Study documents bone crises/pain as a significant manifestation that resolves with treatment.