MONDO:0043523

[PMID:40164036] [INDIRECT EVIDENCE] [SUPPORT] Exercise inhibited nuclear damage and hepatocyte apoptosis caused by Cd by increasing Bcl-2 protein expression and preventing the release of pro-apoptotic proteins such as caspase-3, Cytc, Bax, caspase-8and cleaved-caspase-3. --- Explanation: Mouse model demonstrates cadmium-induced hepatocyte apoptosis via pro-apoptotic protein release.


MONDO:0043523


MONDO:0043523

[PMID:40191670] [INDIRECT EVIDENCE] [SUPPORT] the environmental pollutant cadmium is known to increase the secretion of pro-inflammatory cytokines, including interleukin (IL)-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) by activating the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways. --- Explanation: In vitro study demonstrates cadmium activation of MAPK and NF-kB inflammatory pathways with cytokine secretion.

[PMID:40164036] [INDIRECT EVIDENCE] [SUPPORT] exercise, both before and during Cd exposure, can reduce Cd caused pathological damages in the liver and duodenum of mice, suppressing the expression levels of the IL-1beta, IL-6 and TNF-alpha genes. --- Explanation: Mouse model confirms cadmium-induced expression of pro-inflammatory cytokines IL-1beta, IL-6, and TNF-alpha.


MONDO:0043523

[PMID:41297938] [INDIRECT EVIDENCE] [SUPPORT] Cd exposure, even at a relatively low dosage (4 mg/L), significantly facilitates the progression of atherosclerosis in apolipoprotein E-deficient mice fed a high-fat diet. This pro-atherogenic effect was accompanied by comprehensive disturbances in systemic and vascular cholesterol homeostasis --- Explanation: Mouse model demonstrates cadmium promotes atherosclerosis through disruption of systemic and vascular cholesterol homeostasis, even at low doses.

[PMID:41297938] [INDIRECT EVIDENCE] [SUPPORT] we identified miR-30d-5p and miR-504-3p as novel epigenetic regulators mediating Cd-induced foam cell formation. Specifically, Cd treatment upregulated miR-30d-5p and downregulated miR-504-3p, which directly targeted NCEH1 and CD36, respectively, thereby promoting intracellular lipid accumulation. --- Explanation: Identifies the molecular mechanism: cadmium modulates specific miRNAs that regulate cholesterol handling genes, driving foam cell formation and atherosclerotic plaque development.

[PMID:41297938] [INDIRECT EVIDENCE] [SUPPORT] plasma miR-30d-5p levels were positively associated with Cd exposure and partially mediated the Cd-stroke association, accounting for 16.4% of the total effect. --- Explanation: Human case-control study (494 ischemic stroke patients vs 494 controls) validates miR-30d-5p as a mediator of cadmium-induced stroke risk.


MONDO:0043523

[PMID:16933734] [INDIRECT EVIDENCE] [SUPPORT] Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury. --- Explanation: Case report of acute lung injury from cadmium fume inhalation.

[PMID:22349354] [INDIRECT EVIDENCE] [SUPPORT] In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets --- Explanation: Fatal cadmium poisoning cases with pulmonary involvement among multi-organ damage.


MAXO:0001223

[PMID:41000307] [SUPPORT] The treatment plan includes the use of chelating agents to reduce cadmium levels in the body and antibiotics to maintain the patient's condition. --- Explanation: Systematic review confirms chelating agents as part of standard cadmium poisoning treatment.

[PMID:41453694] [PARTIAL] Conventional chelation therapy, when used long-term, can lead to renal and gastrointestinal diseases. --- Explanation: Review highlights significant limitations of conventional chelation therapy, noting long-term use can itself cause renal and gastrointestinal toxicity.


MAXO:0000058

[PMID:31974582] [SUPPORT] They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms. --- Explanation: Demonstrates effectiveness of phosphate supplementation (combined with calcitriol) for cadmium-induced osteomalacia.


MAXO:0000110

[PMID:31974582] [SUPPORT] They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms. --- Explanation: Demonstrates effectiveness of calcitriol for cadmium-induced osteomalacia.

[PMID:41000307] [SUPPORT] for patients with osteochondropathy, supplementation with calcium and vitamin D is recommended. --- Explanation: Systematic review recommends calcium and vitamin D supplementation for skeletal complications.

[PMID:7426480] [SUPPORT] typical severe osteomalacia, which responded well initially to calcium and vitamin D treatment. --- Explanation: Case report confirms initial good response to calcium and vitamin D in cadmium-induced osteomalacia.


MAXO:0000950

[PMID:41000307] [SUPPORT] For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required. --- Explanation: Systematic review confirms need for ICU-level care in severe acute cadmium poisoning.


ECTO:0001566

[PMID:18072106] [SUPPORT] Silver is mixed with cadmium and then used to make silver jewelry. During this process there is a formation of cadmium fumes, and the workers inhale the fumes. --- Explanation: Describes the mechanism of occupational cadmium exposure in the silver jewelry industry.

[PMID:31974582] [SUPPORT] We highlight the occurrence of hypophosphataemic osteomalacia due to chronic cadmium exposure in the silver industry in India. --- Explanation: Confirms the silver industry as a source of chronic cadmium exposure.

[PMID:41000307] [SUPPORT] cadmium poisoning primarily affects adult males and is often associated with occupational exposure. --- Explanation: Systematic review confirms occupational exposure as the primary route of cadmium poisoning.


ECTO:0001566

[PMID:39111871] [SUPPORT] An elderly female farmer with Cd nephropathy residing in a Cd-polluted area in the northern part of the Akita prefecture was identified through hospital-based screening --- Explanation: Documents environmental cadmium exposure in an agricultural area with contaminated soil.


ECTO:6000029

[PMID:41000307] [SUPPORT] Common risk factors include smoking and alcohol consumption. --- Explanation: Systematic review identifies smoking as a common risk factor for cadmium poisoning.


MONDO:0043523

[PMID:22349354] [SUPPORT] In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets --- Explanation: Autopsy of two fatal cadmium poisoning cases confirmed lung involvement as part of multi-organ pathological damage.

[PMID:16933734] [SUPPORT] Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury. --- Explanation: Case report of fatal cadmium inhalation with acute lung injury, the clinical manifestation of diffuse alveolar damage.


MONDO:0043523

[PMID:22349354] [SUPPORT] In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets --- Explanation: Autopsy findings confirm kidney as a major target organ in fatal cadmium poisoning.

[PMID:19106433] [SUPPORT] both entities are characterized by tubulointerstitial disease and fibrosis, but only early lead nephropathy is characterized by the presence of proximal tubule nuclear inclusion bodies, due to the combination of lead with a lead binding-protein. --- Explanation: Review confirms tubulointerstitial disease and fibrosis as the characteristic renal histopathology of cadmium nephropathy, and distinguishes it from lead nephropathy by the absence of nuclear inclusion bodies.


MONDO:0043523

[PMID:22349354] [SUPPORT] In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets --- Explanation: Autopsy confirmed liver involvement as part of multi-organ cadmium damage.

[PMID:7426480] [SUPPORT] Examination of the liver both in life and after death showed a gross excess of cadmium. This was also found in the kidneys after death. --- Explanation: Liver biopsy and postmortem analysis confirmed gross cadmium accumulation in hepatic tissue.

[PMID:41412331] [SUPPORT] Cadmium exposure affects liver health by inhibiting steatosis and promoting fibrosis, with renal and lipid metabolism factors acting as mediators, and diet influencing the outcomes. --- Explanation: NHANES cross-sectional study in adolescents demonstrates cadmium exposure promotes hepatic fibrosis, providing human epidemiological evidence for cadmium-induced hepatocellular damage.


MONDO:0043523

[PMID:41000307] [SUPPORT] Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging. --- Explanation: Systematic review confirms blood cadmium testing as a key diagnostic tool.


MONDO:0043523

[PMID:19364190] [SUPPORT] Conducting pre-flush testing is also currently the clinician's only means of identifying cadmium toxicity. --- Explanation: Identifies pre-challenge urine testing as the key diagnostic method for cadmium toxicity.


MONDO:0043523

[PMID:19106433] [SUPPORT] Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function. --- Explanation: Identifies beta-2-microglobulin excretion as a herald of cadmium nephrotoxicity.


MONDO:0043523

[PMID:31974582] [SUPPORT] Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia. --- Explanation: Confirms hypophosphataemia as a biochemical finding in cadmium-induced osteomalacia.


MONDO:0043523

[PMID:40164036] [SUPPORT] exercise significantly decreased blood ALT and AST levels, alleviating oxidative stress in the liver by reducing MDA synthesis and enhancing SOD and GSH-PX activities. --- Explanation: Mouse model confirms cadmium-induced elevation of hepatic transaminases.


MONDO:0007251

[PMID:24800790] [SUPPORT] Campomelic dysplasia is a rare hereditary congenital osteochondral dysplasia characterized by abnormal bowing of the lower limbs, sex reversal in males, and other skeletal and extraskeletal abnormalities. --- Explanation: This directly supports the hallmark campomelic limb-bowing phenotype.


MONDO:0007251

[PMID:36741086] [SUPPORT] Campomelic dysplasia (CD) is an autosomal dominant skeletal dysplasia syndrome characterized by shortness and bowing of lower extremities, and often accompanied by XY sex reversal. --- Explanation: This supports shortness as part of the core phenotypic presentation.


MONDO:0007251

[PMID:24800790] [SUPPORT] It is usually fatal in the neonatal period because of respiratory insufficiency. --- Explanation: This sentence directly supports respiratory insufficiency as a core severe phenotype.


MONDO:0007251

[PMID:17185244] [SUPPORT] Campomelic dysplasia (CD; OMIM #114290) is an autosomal dominant, frequently lethal dysplasia syndrome whose primary features include angular bowing and shortening of the limbs, and sex reversal in the majority of affected XY individuals. --- Explanation: This directly supports high prevalence of sex reversal among affected 46,XY individuals.


MONDO:0007251

[PMID:17185244] [SUPPORT] The karyotype was 46,XY despite female external genitalia. --- Explanation: This case evidence directly supports 46,XY sex reversal phenotype.


MONDO:0007251

[PMID:17185244] [SUPPORT] The presenting phenotypes included dysmorphic face with macrocephaly, prominent forehead, low nasal bridge, cleft palate and micrognathia. --- Explanation: This directly supports cleft palate as part of the CD phenotypic spectrum.


MONDO:0007251

[PMID:17185244] [SUPPORT] Skeletal deformities characteristic of CD were observed, including narrow thoracic cage, hypoplastic scapulae, scoliosis and short limbs with anterolateral femoral and tibial bowing. --- Explanation: This case description directly documents scoliosis within characteristic CD skeletal deformities.


MONDO:0007251

[PMID:39854231] [INDIRECT EVIDENCE] [SUPPORT] SOX9 is a crucial transcriptional regulator of cartilage development and homeostasis. --- Explanation: This supports a central pathogenic role for altered SOX9 function in cartilage biology.


MONDO:0007251


MONDO:0007251

[PMID:39854231] [INDIRECT EVIDENCE] [SUPPORT] We isolated a Sox9 mutant mouse with an in-frame microdeletion in the TAM domain (Sox9Asp272del), which exhibits skeletal dysplasia including kinked tails, rib cage anomalies, and scoliosis in homozygous mutants. --- Explanation: This mouse model provides organism-level mechanistic evidence linking SOX9 dysfunction to skeletal dysplasia.

[PMID:39854231] [INDIRECT EVIDENCE] [SUPPORT] both the human missense and the mouse microdeletion mutations resulted in reduced SOX9 protein stability in cell culture, while Sox9Asp272del mutant mice show decreased SOX9 expression in the growth plate and annulus fibrosus tissues of the spine. --- Explanation: This supports reduced SOX9 dosage/stability as a direct mechanism in SOX9-related skeletal pathology.


MONDO:0007251

[PMID:17185244] [INDIRECT EVIDENCE] [SUPPORT] Campomelic dysplasia (CD; OMIM #114290) is an autosomal dominant, frequently lethal dysplasia syndrome whose primary features include angular bowing and shortening of the limbs, and sex reversal in the majority of affected XY individuals. --- Explanation: This supports a direct mechanistic connection between SOX9-related CD and abnormal male sex determination.


MONDO:0007251

[PMID:24800790] [INDIRECT EVIDENCE] [SUPPORT] Campomelic dysplasia is a rare hereditary congenital osteochondral dysplasia characterized by abnormal bowing of the lower limbs, sex reversal in males, and other skeletal and extraskeletal abnormalities. It is usually fatal in the neonatal period because of respiratory insufficiency. --- Explanation: This links the developmental skeletal/cartilage disorder to life-threatening respiratory insufficiency in the neonatal period.


MAXO:0000950

[PMID:17185244] [SUPPORT] Respiratory distress and cyanosis were noted at birth, and endotracheal intubation with mechanical ventilation was performed due to respiratory failure. --- Explanation: This directly supports respiratory supportive care as a key acute management intervention in severe CD.


MAXO:0000950

[PMID:17185244] [INDIRECT EVIDENCE] [SUPPORT] Respiratory distress and cyanosis were noted at birth, and endotracheal intubation with mechanical ventilation was performed due to respiratory failure. --- Explanation: This directly supports respiratory supportive care as a key acute management intervention in severe CD.


hgnc:11204

[PMID:7485151] [SUPPORT] Campomelic dysplasia (CD) is a skeletal malformation syndrome frequently accompanied by 46,XY sex reversal. --- Explanation: This landmark SOX9 study describes the core CD disease context in which SOX9 variation causes skeletal and sex-development abnormalities.

[PMID:7485151] [SUPPORT] All mutations found affect a single allele, which is consistent with a dominant mode of inheritance. --- Explanation: This supports causative heterozygous SOX9 variants and dominant inheritance in campomelic dysplasia.


MONDO:0007250

[PMID:29397575] [SUPPORT] Camptodactyly was the first finding in 68% of patients (19 of the 28) --- Explanation: Documents camptodactyly as the most common presenting feature in CACP syndrome patients.


MONDO:0007250


MONDO:0007250

[PMID:29397575] [SUPPORT] Large joint involvement was found in all of our patients and it included symmetrical noninflammatory arthropathy resulting in swelling, limited motion, and in flexion contractures. --- Explanation: Documents joint stiffness and limited motion as universal features in CACP patients.


MONDO:0007250

[PMID:21531865] [INDIRECT EVIDENCE] [SUPPORT] A missense mutation in MYH3 (a gene coding for the heavy chain of myosin), causing an F437I amino acid substitution, was identified that segregated with distal arthrogryposis in this family. --- Explanation: Demonstrates MYH3 mutations causing distal arthrogryposis with contractures, linking sarcomeric protein dysfunction to congenital joint contractures.


MONDO:0007250

[PMID:29397575] [INDIRECT EVIDENCE] [SUPPORT] CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage. --- Explanation: Documents PRG4 as the causative gene for CACP syndrome, encoding lubricin present in synovial fluid and cartilage surfaces.


MAXO:0000011

[PMID:30897950] [PARTIAL] treatment of camptodactyly with operative or nonoperative measures reduces the degree of flexion contracture in most patients (from pretreatment averages of 20°-85° to posttreatment averages of 5°-37°) --- Explanation: Systematic review demonstrates that conservative treatment reduces flexion contracture in camptodactyly patients.


MAXO:0001351

[PMID:3693837] [SUPPORT] Most of the patients could extend the proximal interphalangeal (PIP) joints within a few months by using the dynamic splint 24 hours a day. After almost full extension of the proximal interphalangeal joint was achieved, splinting for 8 hours a day produced good final results. --- Explanation: Documents effectiveness of dynamic splinting for camptodactyly treatment.


MAXO:0000004

[PMID:30897950] [SUPPORT] There was general agreement that surgery should be reserved for contracture >30° or failure to respond to conservative management. Surgery generally led to more complications compared with conservative management. --- Explanation: Systematic review confirms surgery is reserved for severe contractures over 30 degrees or when conservative treatment fails.


MAXO:0001351


MAXO:0000079


HGNC.SYMBOL:PRG4

[PMID:29397575] [SUPPORT] The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene --- Explanation: Establishes PRG4 as the causative gene for CACP syndrome with autosomal recessive inheritance.


HGNC.SYMBOL:TNNT3

[PMID:25337069] [SUPPORT] we report a 4-generation Indian family with 18 affected members presenting variable features of camptodactyly, brachydactyly, syndactyly, decreased flexion palmar creases, ulnar deviation of the hands, sandal gaps and club feet. We undertook exome sequencing of 3 distantly related affected individuals. Bioinformatics filtering revealed a known pathogenic missense mutation c.188G>A (p.Arg63His) in TNNT3 --- Explanation: Demonstrates TNNT3 mutations causing distal arthrogryposis with camptodactyly in a large family.


HGNC.SYMBOL:TNNI2


HGNC.SYMBOL:TPM2


HGNC.SYMBOL:MYH3

[PMID:21531865] [PARTIAL] Identification of an MYH3 mutation in this family with distal arthrogryposis type 1 broadens the phenotype associated with MYH3 mutations to include distal arthrogryposis types 1, 2A (Freeman-Sheldon syndrome), and 2B (Sheldon-Hall syndrome). --- Explanation: Confirms MYH3 mutations cause multiple distal arthrogryposis subtypes including type 2A.


HGNC.SYMBOL:ACTC1


HGNC.SYMBOL:FBN2


HGNC.SYMBOL:ECEL1


MONDO:0005688

[DOI:10.3390/biom13010135] [SUPPORT] Campylobacter jejuni is likely the most common bacterial cause of gastroenteritis worldwide, responsible for millions of cases of inflammatory diarrhea characterized by severe abdominal cramps and blood in the stool. --- Explanation: Directly supports diarrhea as a cardinal phenotype.


MONDO:0005688

[DOI:10.3390/biom13010135] [SUPPORT] Campylobacter jejuni is likely the most common bacterial cause of gastroenteritis worldwide, responsible for millions of cases of inflammatory diarrhea characterized by severe abdominal cramps and blood in the stool. --- Explanation: The abstract explicitly reports blood in stool, supporting bloody diarrhea.


MONDO:0005688

[DOI:10.3390/biom13010135] [SUPPORT] Campylobacter jejuni is likely the most common bacterial cause of gastroenteritis worldwide, responsible for millions of cases of inflammatory diarrhea characterized by severe abdominal cramps and blood in the stool. --- Explanation: Severe abdominal cramps correspond to abdominal pain.


MONDO:0005688

[DOI:10.3390/microorganisms12122669] [SUPPORT] Late complications are reactive arthritis, Guillain–Barré syndrome, and Miller Fisher syndrome. --- Explanation: Supports Guillain-Barre syndrome as a recognized post-infectious complication.

[PMID:36430700] [SUPPORT] C. jejuni is responsible for about a third of GBS cases. --- Explanation: Provides quantitative support that Campylobacter jejuni is a major trigger for Guillain-Barre syndrome.


MONDO:0005688

[PMID:36635328] [SUPPORT] In summary, we found that nearly half of the patients with Campylobacter bacteremia presented with fever as a predominant manifestation without gastroenteritis symptoms. --- Explanation: Supports fever as a clinically important phenotype in systemic Campylobacter disease.


MONDO:0005688

[PMID:40395728] [SUPPORT] As a consequence, infected individuals may acquire watery and/or bloody diarrhea associated with abdominal pain, and eventually post-infection illnesses of the neural system and joints, including the Guillain-Barré, Miller Fisher and Reiter syndromes. --- Explanation: Supports reactive arthritis (Reiter syndrome) as a post-infectious complication.


MONDO:0005688

[PMID:40395728] [SUPPORT] As a consequence, infected individuals may acquire watery and/or bloody diarrhea associated with abdominal pain, and eventually post-infection illnesses of the neural system and joints, including the Guillain-Barré, Miller Fisher and Reiter syndromes. --- Explanation: Supports Miller Fisher syndrome as a recognized post-infectious neurologic sequela.


MONDO:0005688

[PMID:20856114] [SUPPORT] Also patients with infectious colitis, in particular Salmonella and Campylobacter, are at increased risk of postinfectious irritable bowel syndrome and inflammatory bowel disease on long-term follow-up. --- Explanation: Supports PI-IBS as a recognized long-term sequela after Campylobacter-associated infectious colitis.


MONDO:0005688

[DOI:10.1007/s00253-023-12456-w] [INDIRECT EVIDENCE] [SUPPORT] Chemotactically controlled motility in viscous milieu allows targeted navigation to intestinal mucus and colonization. --- Explanation: Supports mucus penetration and early colonization.


MONDO:0005688

[DOI:10.1007/s00253-023-12456-w] [INDIRECT EVIDENCE] [SUPPORT] Fibronectin at the basolateral side of polarized epithelial cells serves as binding site for adhesins CadF and FlpA, leading to intracellular signaling, which again triggers membrane ruffling and reduced host cell migration by focal adhesion. --- Explanation: Supports adhesion-linked host signaling as a discrete upstream event.


MONDO:0005688


MONDO:0005688

[DOI:10.3390/biom13010135] [INDIRECT EVIDENCE] [SUPPORT] We conclude that C. jejuni does not possess a type IV secretion system and relies on the type III and type VI secretion systems to establish a niche and potentiate disease. --- Explanation: Supports secretion-system dependence as a mechanistic step.


MONDO:0005688

[DOI:10.3390/cells13030224] [INDIRECT EVIDENCE] [SUPPORT] We recently discovered that C. jejuni serine protease HtrA disrupts intestinal epithelial barrier functions via cleavage of the tight and adherens junction components occludin, claudin-8 and E-cadherin. --- Explanation: Supports HtrA cleavage as an unbundled barrier-disruption event.


MONDO:0005688

[DOI:10.1007/s00253-023-12456-w] [INDIRECT EVIDENCE] [SUPPORT] Lesions of the epithelium result in loss of electrolytes, water, and blood, leading to diarrhea, which flushes out mucus containing C. jejuni. --- Explanation: Supports causal transition from epithelial injury to clinical gastrointestinal manifestations.


MAXO:0000058

[DOI:10.3390/microorganisms12122669] [SUPPORT] Regarding the use of specific antimicrobial therapy, international guidelines agree in recommending it for severe intestinal infections. --- Explanation: Supports severity-based use of antibiotics.


MAXO:0000058

[DOI:10.3390/antibiotics13090904] [SUPPORT] The analysis reveals a concerning trend of increasing resistance patterns, particularly to CIP and TET, across multiple regions. --- Explanation: Supports antimicrobial stewardship and local susceptibility-guided therapy.

[PMID:37910310] [SUPPORT] Quinolone resistance was high (59%), whereas only 4% of isolates exhibited macrolide resistance. --- Explanation: Supports selecting agents based on resistance patterns, with quinolone resistance substantially exceeding macrolide resistance.

[PMID:41566887] [SUPPORT] From our cohort of 331 patients over 3 years, there was 22% ciprofloxacin resistance and 100% susceptibility to erythromycin. --- Explanation: Supports preserved erythromycin susceptibility in a recent adult clinical cohort.


MAXO:0000058

[PMID:36635328] [SUPPORT] Patients with the FP type underwent intravenous antibiotic therapy more frequently (47.6% vs. 88.9%), and their treatment (median: 5 days vs. 13 days) and hospitalization (median: 7 days vs. 21 days) periods were significantly longer. --- Explanation: Supports escalation to intravenous antibiotic therapy with longer duration in fever-predominant bacteremic disease.


NCBITaxon:197

[DOI:10.3390/biom13010135] [SUPPORT] Campylobacter jejuni is likely the most common bacterial cause of gastroenteritis worldwide, responsible for millions of cases of inflammatory diarrhea characterized by severe abdominal cramps and blood in the stool. --- Explanation: Supports C. jejuni as the dominant organism associated with campylobacteriosis burden.

[DOI:10.3390/microorganisms12122669] [SUPPORT] Campylobacter infection is primarily transmitted through the consumption of contaminated food, especially uncooked meat, or untreated water; contact with infected animals or contaminated environments; poultry is the primary reservoir and source of human transmission. --- Explanation: Supports poultry meat as a major food vehicle for exposure to Campylobacter jejuni in human campylobacteriosis.


NCBITaxon:195

[DOI:10.3390/microorganisms12122669] [SUPPORT] The clinical spectrum of Campylobacter jejuni/coli infection can be classified into two distinct categories: gastrointestinal and extraintestinal manifestations. --- Explanation: Confirms C. coli as part of the clinically relevant Campylobacter infection spectrum.


MONDO:0007542

[PMID:15894597] [SUPPORT] Radiological symptoms were not fully penetrant, with 94% of the patients showing the typical long bone involvement. --- Explanation: In 100 molecularly confirmed CED patients from 24 families, 94% showed characteristic long bone diaphyseal involvement.


MONDO:0007542

[PMID:15894597] [SUPPORT] Pain in the extremities was the most common clinical symptom, present in 68% of the patients. --- Explanation: Limb pain was the most frequent symptom in a large review of 100 molecularly confirmed CED patients.

[PMID:15326622] [SUPPORT] Symptomatic relatives presented with lower limb pain and weakness. --- Explanation: Four-generation pedigree confirms lower limb pain as a presenting feature.


MONDO:0007542

[PMID:15894597] [SUPPORT] easy fatigability (44%), and muscle weakness (39%) were other important features. --- Explanation: Muscle weakness (39%) and easy fatigability (44%) were documented as prominent clinical features in 100 CED patients.


MONDO:0007542

[PMID:15894597] [SUPPORT] A waddling gait (48%), easy fatigability (44%), and muscle weakness (39%) were other important features. --- Explanation: Waddling gait was present in 48% of molecularly confirmed CED patients.


MONDO:0007542

[PMID:15326622] [SUPPORT] Cranial involvement, which occurs in 61% of patients, can be severe, entrapping cranial nerves or causing increased intracranial pressure. --- Explanation: Literature review found cranial involvement in 61% of CED patients, with potential for cranial nerve entrapment.

[PMID:15326622] [SUPPORT] The most severely affected individual had progression of mild skull hyperostosis to severe skull thickening and cranial nerve compression over 30 years. --- Explanation: Documents progressive cranial nerve compression from skull hyperostosis over decades.


MONDO:0007542

[PMID:15894597] [SUPPORT] A large percentage of the patients also showed involvement of the skull (54%) and pelvis (63%). --- Explanation: Skull involvement documented in 54% of 100 molecularly confirmed CED patients.


MONDO:0007542


MONDO:0007542

[PMID:25140400] [SUPPORT] There was also a considerable improvement in body composition with increased lean and adipose tissue. Notably, the improvement in fat deposition had not been previously observed with other treatments in CED. --- Explanation: Losartan treatment improved fat deposition, confirming that reduced subcutaneous fat is a recognized feature of CED.


MONDO:0007542

[PMID:11278244] [INDIRECT EVIDENCE] [SUPPORT] these mutations disrupt the association of beta1-LAP and TGF-beta1 and the subsequent release of the mature TGF-beta1 --- Explanation: Functional studies showed CED-causing LAP mutations (R218H, R218C, C225R) disrupt LAP-TGF-beta1 association, leading to constitutive activation of TGF-beta 1.

[PMID:11278244] [INDIRECT EVIDENCE] [SUPPORT] the proliferation of human osteoblastic MG-63 cells was accelerated by coculture with CED fibroblasts --- Explanation: Demonstrates increased osteoblast activity driven by excess TGF-beta 1 release from CED patient fibroblasts.


MONDO:0007542

[PMID:10973241] [INDIRECT EVIDENCE] [SUPPORT] Camurati-Engelmann disease (CED, MIM 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperosteosis and sclerosis of the diaphyses of long bones. --- Explanation: Landmark paper identifying TGFB1 as the CED gene and describing the characteristic diaphyseal hyperostosis and sclerosis.


HGNC.SYMBOL:TGFB1 Mutations

[PMID:10973241] [SUPPORT] As the human transforming growth factor-1 gene (TGFB1) is located within this interval, we considered it a candidate gene for CED. --- Explanation: Landmark paper identifying TGFB1 as the causative gene for CED, with mutations in the 19q13 region.

[PMID:11062463] [SUPPORT] this region contains the gene encoding transforming growth factor-beta 1 (TGFB1), an important mediator of bone remodelling, we evaluated TGFB1 as a candidate gene for causing CED. --- Explanation: Independent identification of TGFB1 LAP domain mutations as the cause of CED.

[PMID:11278244] [SUPPORT] three different missense mutations (R218H, R218C, and C225R) of beta1-LAP cause the Camurati-Engelmann disease (CED) --- Explanation: Functional characterization of the three most common LAP mutations, confirming they cause constitutive TGF-beta1 activation.

[PMID:15326622] [SUPPORT] We screened the TGFB1 gene for mutations and identified a missense mutation resulting in an R218H substitution in the affected individuals --- Explanation: Confirms R218H as a recurrent TGFB1 mutation in CED pedigrees.


MONDO:0100094

[PMID:28000146] [SUPPORT] the frequency of major characteristics was as follows: history of regular cannabis for any duration of time (100%), cyclic nausea and vomiting (100%) --- Explanation: Systematic review identifies cyclic nausea and vomiting as present in 100% of CHS cases.

[PMID:22150623] [SUPPORT] The hyperemetic phase is characterized by paroxysms of intense and persistent nausea and vomiting, commonly described as overwhelming and incapacitating. Patients vomit profusely, often without warning and can vomit and retch up to five times per hour --- Explanation: Provides detailed clinical description of the vomiting episodes characteristic of CHS.


MONDO:0100094

[PMID:28000146] [SUPPORT] compulsive hot baths with symptom relief (92.3%) --- Explanation: Systematic review reports compulsive hot bathing with symptom relief in 92.3% of cases.

[PMID:22150623] [SUPPORT] Patients often demonstrate the learned behavior of frequent hot bathing, which produces temporary cessation of nausea, vomiting, and abdominal pain. --- Explanation: Describes the compulsive hot bathing behavior and its temporary symptom-relieving effect.

[PMID:28370228] [SUPPORT] Hot showers and baths were cited in all level-4 and -5 articles as universally effective. --- Explanation: Systematic review confirms that hot water bathing is universally reported as effective for symptom relief.


MONDO:0100094

[PMID:28000146] [SUPPORT] abdominal pain (85.1%) --- Explanation: Systematic review reports abdominal pain in 85.1% of CHS cases, consistent with very frequent classification.


MONDO:0100094

[PMID:29310960] [SUPPORT] CHS patients frequently present to the emergency department and may require treatment for intractable emesis, dehydration, and electrolyte abnormalities. --- Explanation: Identifies dehydration and electrolyte abnormalities as common presentations requiring ED treatment.


MONDO:0100094

[PMID:22150623] [SUPPORT] approximately 70% of patients reported marked weight loss of at least 5 kg during their illness --- Explanation: Reports significant weight loss in a majority of CHS patients.


MONDO:0100094

[PMID:32656345] [INDIRECT EVIDENCE] [SUPPORT] prolonged high doses of the main psychotropic compound in cannabis, Δ9-tetrahydrocannabinol (THC), result in changes to the endocannabinoid system by acting on the cannabinoid 1 (CB1) receptor. These endocannabinoid system changes can dysregulate stress and anxiety responses, thermoregulation, the transient receptor potential vanilloid system, and several neurotransmitters systems, and are thus potential candidates for mediating the pathophysiology of CHS. --- Explanation: Directly describes how chronic THC exposure alters the endocannabinoid system via CB1 receptors, dysregulating multiple downstream systems.

[PMID:29310960] [INDIRECT EVIDENCE] [SUPPORT] The endocannabinoid system is a complex and important regulator of stress response and allostasis, and it is occasionally overwhelmed from excessive cannabis use. --- Explanation: Supports the role of endocannabinoid system disruption as the central mechanism in CHS.


MONDO:0100094


MONDO:0100094

[PMID:29310960] [INDIRECT EVIDENCE] [SUPPORT] Acute episodes of CHS may be precipitated by stress or fasting in chronic cannabis users who may have pre-existing abnormal hypothalamic-pituitary-adrenal axis feedback and sympathetic nervous system response. --- Explanation: Identifies HPA axis abnormalities and stress as precipitants for CHS episodes.

[PMID:22150623] [INDIRECT EVIDENCE] [SUPPORT] CB1 receptor activation in the hypothalamus and pituitary gland results in modulation of all hypothalamic-pituitary axes --- Explanation: Demonstrates that cannabinoid signaling via CB1 receptors directly modulates hypothalamic-pituitary function.

[PMID:22150623] [INDIRECT EVIDENCE] [SUPPORT] A large reservoir of stored THC in fat tissue may produce a "reintoxication effect" secondary to increased lipolysis during times of increased stress or food deprivation --- Explanation: Explains the mechanism by which THC mobilization from adipose stores creates a positive feedback loop during stress.


MONDO:0100094

[PMID:28730896] [INDIRECT EVIDENCE] [SUPPORT] Cannabinoid hyperemesis syndrome may result from a derangement in the endocannabinoid system secondary to chronic exogenous stimulation. The relief of cannabinoid hyperemesis syndrome symptoms from heat and use of transient receptor potential vanilloid 1 agonists suggests a complex interrelation between the endocannabinoid system and transient receptor potential vanilloid 1. --- Explanation: Directly links TRPV1 dysregulation to CHS pathophysiology and explains how heat and capsaicin provide relief through TRPV1 activation.

[PMID:28730896] [INDIRECT EVIDENCE] [SUPPORT] Transient receptor potential vanilloid 1 activation by heat or capsaicin results in modulation of tachykinins, somatostatin, pituitary adenylate-cyclase activating polypeptide, and calcitonin gene-related peptide as well as histaminergic, cholinergic, and serotonergic transmission. These downstream effects represent further possible explanations for transient receptor potential vanilloid 1-associated antiemesis. --- Explanation: Details the downstream neurohumoral effects of TRPV1 activation that mediate antiemetic relief in CHS.

[PMID:32656345] [INDIRECT EVIDENCE] [SUPPORT] These endocannabinoid system changes can dysregulate stress and anxiety responses, thermoregulation, the transient receptor potential vanilloid system, and several neurotransmitters systems --- Explanation: Identifies TRPV1 system dysregulation as a potential mechanism in CHS.


MONDO:0100094

[PMID:22150623] [INDIRECT EVIDENCE] [SUPPORT] CB1 receptor activation reduces gastric motility and results in delayed gastric emptying in rat models --- Explanation: Demonstrates that CB1 activation delays gastric emptying, contributing to the gastrointestinal dysfunction in CHS.

[PMID:22150623] [INDIRECT EVIDENCE] [SUPPORT] in susceptible individuals the pro-emetic effect of cannabis on the gut (e.g. delayed gastric emptying) overrides its anti-emetic CNS properties --- Explanation: Directly describes the proposed mechanism where peripheral proemetic effects of cannabis override central antiemetic effects.


MAXO:0000077

[PMID:28000146] [SUPPORT] resolution of symptoms after stopping cannabis (96.8%) --- Explanation: Systematic review reports symptom resolution in 96.8% of patients who stop cannabis.

[PMID:29310960] [SUPPORT] Discontinuation of cannabis use is the only assured cure for CHS. --- Explanation: Identifies cannabis cessation as the only definitive treatment.

[PMID:32656345] [SUPPORT] The only known way to permanently end CHS, however, is abstinence from cannabinoids. --- Explanation: Confirms that abstinence from cannabinoids is the only permanent cure.


MAXO:0000058

[PMID:28730896] [SUPPORT] Topical capsaicin binds and activates the transient receptor potential vanilloid 1 receptor, triggering influx of calcium and sodium, as well as release of inflammatory neuropeptides leading to transient burning, stinging, and itching. This elicits a novel type of desensitization analgesia. --- Explanation: Explains the pharmacologic mechanism by which topical capsaicin provides relief through TRPV1 activation.

[PMID:31104487] [SUPPORT] the limited data on alternative antiemetic therapies and capsaicin's favorable risk-benefit profile make it a reasonable adjunctive treatment option. --- Explanation: Systematic review supports capsaicin as a reasonable adjunctive treatment despite limited high-quality evidence.

[PMID:28730896] [SUPPORT] Topical capsaicin is primarily used for treatment of neuropathic pain, but it has also been used successfully in some 20 cases of cannabinoid hyperemesis syndrome. --- Explanation: Reports successful use of topical capsaicin in multiple CHS cases.


MAXO:0000058

[PMID:28370228] [SUPPORT] Benzodiazepines, followed by haloperidol and capsaicin, were most frequently reported as effective for acute treatment --- Explanation: Systematic review identifies haloperidol as one of the most frequently reported effective acute treatments.

[PMID:29310960] [SUPPORT] Benzodiazepines and antipsychotics represent logical choices for treatment of CHS because of their powerful sedating effects. --- Explanation: Supports the use of antipsychotics as mechanistically logical treatment options for CHS.


MAXO:0000458

[PMID:28730896] [SUPPORT] Hot water hydrotherapy is a mainstay of self-treatment for cannabinoid hyperemesis syndrome patients. This may be explained by heat-induced transient receptor potential vanilloid 1 activation. --- Explanation: Explains hot water hydrotherapy as a mainstay treatment with a proposed TRPV1-mediated mechanism.

[PMID:28370228] [SUPPORT] Hot showers and baths were cited in all level-4 and -5 articles as universally effective. --- Explanation: Systematic review confirms universal effectiveness of hot water bathing across published cases.


MAXO:0000950

[PMID:28000146] [SUPPORT] Supportive care with intravenous fluids, dopamine antagonists, topical capsaicin cream, and avoidance of narcotic medications has shown some benefit in the acute setting. --- Explanation: Systematic review identifies supportive care as part of acute management.

[PMID:22150623] [SUPPORT] Supportive therapy, albeit not very effective, serves as the mainstay of treatment during this phase of the syndrome --- Explanation: Confirms supportive therapy as the standard acute-phase treatment despite limited efficacy.


ECTO:0100005

[PMID:28000146] [SUPPORT] history of regular cannabis for any duration of time (100%), cyclic nausea and vomiting (100%), resolution of symptoms after stopping cannabis (96.8%) --- Explanation: Systematic review confirms that regular cannabis use is present in 100% of CHS cases.

[PMID:22150623] [SUPPORT] In nearly all cases there is a delay of several years in the onset of symptoms preceded by chronic marijuana abuse --- Explanation: Confirms the requirement for prolonged chronic cannabis use before CHS develops.


ECTO:0100005

[PMID:29310960] [SUPPORT] CHS has become more prevalent with increasing cannabis potency and use, as enabled by various states having legalized the recreational use of cannabis. --- Explanation: Links increasing cannabis potency and legalization to rising CHS prevalence.


MONDO:0009376

[PMID:39174957] [SUPPORT] Peak blood ammonia levels ranged from 160 to 1,000 µmol/L. --- Explanation: Quantifies the range of hyperammonemia severity across a CPS1D cohort.

[PMID:40218931] [SUPPORT] The median ammonia level in deceased patients was higher at 1058 µmol/L (IQR 410-1793) than in survivors at 294 µmol/L (IQR 71-494) --- Explanation: Spanish registry data showing ammonia severity correlates with mortality.


MONDO:0009376

[PMID:39469307] [SUPPORT] CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive. --- Explanation: Supports encephalopathy as a direct consequence of hyperammonemia in CPS1D.

[PMID:40125546] [SUPPORT] the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma. --- Explanation: Case report demonstrating acute encephalopathy progression in adult-onset CPS1D.


MONDO:0009376


MONDO:0009376

[PMID:39469307] [SUPPORT] One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay. --- Explanation: Directly documents global developmental delay resulting from recurrent hyperammonemia in CPS1D.

[PMID:40218931] [SUPPORT] Neurological impairment occurred in 44% of patients, with worse neurological outcomes observed in patients with argininosuccinate lyase deficiency, arginase 1 deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria, EO presentations, pre-2014 diagnosis, and patients with higher levels of ammonia at diagnosis. --- Explanation: Registry data demonstrating high rates of neurological impairment in UCDs including CPS1D.


MONDO:0009376

[PMID:39174957] [SUPPORT] The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets. --- Explanation: Directly supports intellectual disability as a presenting feature in late-onset CPS1D.


MONDO:0009376

[PMID:39469307] [SUPPORT] CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive. --- Explanation: Neonatal presentation of CPS1D includes hypotonia as part of the acute hyperammonemic crisis phenotype.


MONDO:0009376

[PMID:39469307] [SUPPORT] CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive. --- Explanation: Lethargy is part of the acute hyperammonemic presentation in neonatal CPS1D.


MONDO:0009376

[PMID:39469307] [SUPPORT] One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay. --- Explanation: Directly documents microcephaly resulting from recurrent hyperammonemia in a CPS1D patient.


MONDO:0009376

[PMID:37164630] [SUPPORT] The neurological consequences broadly reflect the ammonia level, duration and age, with paediatric patients being more susceptible. --- Explanation: Supports that severe hyperammonemia leads to neurological consequences including cerebral edema.


MONDO:0009376

[PMID:37365635] [SUPPORT] MRI of the brain showed diffuse white matter lesions. --- Explanation: Directly documents white matter lesions on MRI in a late-onset CPS1D case.


MONDO:0009376

[PMID:39174957] [SUPPORT] The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets. --- Explanation: Directly supports psychiatric/behavioral symptoms as a feature of late-onset CPS1D.


MONDO:0009376

[PMID:39469307] [INDIRECT EVIDENCE] [SUPPORT] CPS1 is an enzyme in the urea cycle that catalyzes ammonia and bicarbonate condensation. --- Explanation: Supports CPS1 catalytic dysfunction as the initiating molecular event.


MONDO:0009376

[PMID:39469307] [INDIRECT EVIDENCE] [SUPPORT] CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive. --- Explanation: Supports severe hyperammonemic consequences downstream of impaired proximal ureagenesis.

[PMID:40710547] [INDIRECT EVIDENCE] [SUPPORT] Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics. --- Explanation: Review supporting the role of hepatic mitochondria in nitrogen detoxification via the urea cycle.


MONDO:0009376

[PMID:39469307] [INDIRECT EVIDENCE] [PARTIAL] CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive. --- Explanation: Supports hyperammonemia-linked neurological injury in CPS1D; cellular astrocyte swelling details are inferred from established ammonia neurotoxicity mechanisms.


MONDO:0009376

[PMID:39469307] [INDIRECT EVIDENCE] [SUPPORT] Ammonia results from amino acid turnover and is produced by intestinal urease-positive bacteria. Ammonia must be detoxified, and the urea cycle converts ammonia into urea. --- Explanation: Supports the role of the urea cycle in ammonia disposal and the consequence of its disruption.

[PMID:40125546] [INDIRECT EVIDENCE] [SUPPORT] Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels. --- Explanation: Confirms the characteristic biochemical pattern of low citrulline and high glutamine in CPS1D.


MAXO:0000088

[PMID:38201843] [SUPPORT] The therapy should be based on a low-protein diet and nitrogen scavengers. --- Explanation: Expert consensus supporting protein-restricted diet as foundational therapy in UCDs.


MAXO:0000058

[PMID:37717413] [SUPPORT] Medications that elicit an alternate pathway for nitrogen excretion such as oral sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB) and intravenous sodium phenylacetate (NaPAA) are important for the management of urea cycle disorders (UCDs). --- Explanation: Directly supports nitrogen scavenger therapy as important in UCD management.


MAXO:0000058

[PMID:37480106] [SUPPORT] During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline. --- Explanation: Quantifies ammonia control with citrulline versus arginine supplementation in UCDs.

[PMID:37480106] [SUPPORT] At last evaluation, mean height and weight for age were normal and most patients showed normal or adapted behavior (98.7%) and normal social life (79.0%). --- Explanation: Long-term functional outcomes supporting citrulline supplementation efficacy.


MAXO:0000058

[PMID:39469307] [SUPPORT] All patients except one were on Carglumic acid which could contribute to their survival and disease control. --- Explanation: Directly supports carglumic acid use and its potential contribution to survival in CPS1D.


MAXO:0000950

[PMID:39469307] [SUPPORT] One patient underwent hemodialysis, and one patient underwent peritoneal dialysis. --- Explanation: Documents use of dialysis modalities in acute CPS1D management.

[PMID:40125546] [SUPPORT] The patient responded to pharmacotherapy and continuous hemodialysis. --- Explanation: Confirms hemodialysis use in acute crisis management of adult CPS1D.


MAXO:0001175

[PMID:36937980] [SUPPORT] 16 (59%) received liver transplantationwith 100% survival, normal protein tolerance and usual need of citrulline supplementation. --- Explanation: Quantifies liver transplant outcomes in a UCD cohort including CPS1D patients.

[PMID:40218931] [SUPPORT] Among transplanted patients (20.6%), survival was 95.2%, with no significant neurological differences compared to non-transplanted patients. --- Explanation: Registry-scale transplant survival data for UCDs.


MAXO:0000079

[PMID:37365635] [SUPPORT] It also provides a preliminary understanding of the relationship between genotype and phenotype, based on a summary of previous studies, which reminds us that it may help to explore the pathogenesis of the disease and contribute to genetic counselling and prenatal diagnosis. --- Explanation: Directly supports the role of genetic counseling and prenatal diagnosis in CPS1D families.


HGNC.SYMBOL:CPS1 pathogenic variants

[PMID:39174957] [SUPPORT] No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1. --- Explanation: Supports extensive allelic heterogeneity without recurrent hotspot mutations in CPS1D.


MONDO:0015280


MONDO:0015280

[PMID:38136934] [PARTIAL] Neurological involvement in CFC is more severe than in other RASopathies. --- Explanation: Review confirming that CFC syndrome has the most severe cognitive impairment among the RASopathy spectrum disorders.


MONDO:0015280

[PMID:36308388] [SUPPORT] Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. --- Explanation: Study of 43 CFC cases documenting prenatal phenotype including polyhydramnios as a manifestation of germline RAS/MAPK dysregulation.


MONDO:0015280

[PMID:16439621] [INDIRECT EVIDENCE] [PARTIAL] heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome. The majority of cases (18 out of 23) are caused by mutations in BRAF --- Explanation: Landmark Science paper establishing that CFC syndrome is caused by de novo mutations in MAPK pathway genes, with BRAF as the predominant causative gene.


MAXO:0000004


MAXO:0000088


MAXO:0000058

[PMID:38136934] [PARTIAL] Encouraging zebrafish model system studies suggested that, in the future, MEK inhibitors could be a suitable treatment of progressive phenotypes of CFC in children. --- Explanation: Review summarizing preclinical evidence supporting MEK inhibitor therapy for CFC syndrome based on zebrafish model studies.


HGNC.SYMBOL:BRAF Mutations

[PMID:16439621] [SUPPORT] The majority of cases (18 out of 23) are caused by mutations in BRAF, a gene frequently mutated in cancer. Of the 11 mutations identified, two result in amino acid substitutions that occur in tumors, but most are unique and suggest previously unknown mechanisms of B-Raf activation. --- Explanation: Establishes BRAF as the major causative gene, with mutations distinct from common somatic cancer mutations, suggesting novel activation mechanisms.


HGNC.SYMBOL:MAP2K1/MAP2K2 Mutations

[PMID:16439621] [SUPPORT] three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf --- Explanation: Original discovery that MEK1/MEK2 mutations cause CFC syndrome in patients without BRAF mutations.


HGNC.SYMBOL:KRAS Mutations


MONDO:0008918

[PMID:35862567] [SUPPORT] Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis. --- Explanation: GeneReviews lists hypoketotic hypoglycemia as a typical clinical feature.

[PMID:25614308] [SUPPORT] the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress. --- Explanation: Literature review confirms hypoketotic hypoglycemia as among the most frequent presenting symptoms.

[PMID:33024728] [SUPPORT] A general characteristic of all mFAO disorders is hypoketotic hypoglycemia resulting from the enhanced reliance on glucose oxidation and the inability to synthesize ketone bodies from FAs. --- Explanation: Review confirms hypoketotic hypoglycemia as a general characteristic of all mitochondrial fatty acid oxidation disorders.


MONDO:0008918

[PMID:35862567] [SUPPORT] Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest. --- Explanation: GeneReviews identifies hyperammonemia as prominent in early-onset CACT deficiency.

[PMID:25614308] [SUPPORT] the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress. --- Explanation: Literature review confirms hyperammonemia as one of the most frequent presenting symptoms.


MONDO:0008918

[PMID:35862567] [SUPPORT] Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest. --- Explanation: GeneReviews identifies cardiac arrhythmia as prominent in early-onset disease.

[PMID:29502916] [SUPPORT] Fatty acid oxidation disorders (FAODs) and carnitine shuttling defects are inborn errors of energy metabolism with associated mortality and morbidity due to cardiomyopathy, exercise intolerance, rhabdomyolysis, and liver disease --- Explanation: Review confirms cardiomyopathy and cardiac morbidity in fatty acid oxidation and carnitine shuttle disorders.


MONDO:0008918

[PMID:35862567] [SUPPORT] Univentricular or biventricular hypertrophic cardiomyopathy, ranging from mild to severe, may respond to appropriate dietary and medical therapies. --- Explanation: GeneReviews describes hypertrophic cardiomyopathy as a recognized feature that may respond to treatment.

[PMID:25614308] [SUPPORT] the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress. --- Explanation: Literature review identifies cardiomyopathy as among the most frequent presenting symptoms.


MONDO:0008918

[PMID:35862567] [SUPPORT] Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis. --- Explanation: GeneReviews lists liver dysfunction with hepatomegaly as a typical clinical feature.

[PMID:25614308] [SUPPORT] the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress. --- Explanation: Literature review confirms hepatomegaly as one of the most frequent presenting symptoms.


MONDO:0008918

[PMID:35862567] [SUPPORT] Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis. --- Explanation: GeneReviews lists hypotonia as a typical clinical feature of CACT deficiency.


MONDO:0008918

[PMID:35862567] [SUPPORT] Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis. --- Explanation: GeneReviews lists rhabdomyolysis as a typical clinical feature of long-chain fatty acid oxidation disorders.

[PMID:29502916] [SUPPORT] Fatty acid oxidation disorders (FAODs) and carnitine shuttling defects are inborn errors of energy metabolism with associated mortality and morbidity due to cardiomyopathy, exercise intolerance, rhabdomyolysis, and liver disease --- Explanation: Review confirms rhabdomyolysis as a source of morbidity in FAODs and carnitine shuttle defects.


MONDO:0008918

[PMID:35862567] [SUPPORT] Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis. --- Explanation: GeneReviews lists lethargy as a typical clinical feature.


MONDO:0008918

[PMID:35862567] [SUPPORT] Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis. --- Explanation: GeneReviews lists poor feeding as a typical clinical feature.


MONDO:0008918

[PMID:35862567] [SUPPORT] Affected individuals with early-onset disease typically experience brain injury at presentation, and have recurrent hyperammonemia leading to developmental delay / intellectual disability. --- Explanation: GeneReviews directly states developmental delay as a consequence of early-onset disease.


MONDO:0008918

[PMID:25614308] [SUPPORT] the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress. --- Explanation: Literature review identifies respiratory distress among the most frequent presenting symptoms.


MONDO:0008918


MONDO:0008918

[PMID:35862567] [SUPPORT] Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis. --- Explanation: GeneReviews lists transaminitis as a typical clinical feature.


MONDO:0008918

[PMID:35862567] [INDIRECT EVIDENCE] [SUPPORT] CACT deficiency causes a defect in mitochondrial long-chain fatty acid β-oxidation, with variable clinical severity. --- Explanation: Supports SLC25A20/CACT transporter dysfunction as the initiating molecular event.


MONDO:0008918

[PMID:35862567] [INDIRECT EVIDENCE] [SUPPORT] CACT deficiency causes a defect in mitochondrial long-chain fatty acid β-oxidation, with variable clinical severity. --- Explanation: Supports impaired long-chain fatty acid oxidation downstream of CACT transporter dysfunction.


MONDO:0008918

[PMID:38628283] [INDIRECT EVIDENCE] [SUPPORT] We describe the autopsy pathology of a child with CACT deficiency dominantly in the form of microvesicular steatosis of the hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes. --- Explanation: Autopsy evidence of multi-organ lipid accumulation directly supports toxic acylcarnitine/lipid handling failure.

[PMID:35862567] [INDIRECT EVIDENCE] [SUPPORT] Characteristic elevation of long-chain acylcarnitines C16, C18, and C18:1 on acylcarnitine profile suggests a diagnosis of CACT or CPT II deficiency. --- Explanation: Elevated long-chain acylcarnitines confirm acylcarnitine accumulation as a disease hallmark.


MONDO:0008918

[PMID:35862567] [INDIRECT EVIDENCE] [SUPPORT] Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest. --- Explanation: GeneReviews confirms cardiac arrhythmia and cardiac arrest as prominent early-onset features.

[PMID:25614308] [INDIRECT EVIDENCE] [SUPPORT] The mortality rate is high (65%), most in the first year of life due to myocardiopathy or sudden death. --- Explanation: Confirms cardiomyopathy and sudden death as primary causes of mortality.

[PMID:33024728] [INDIRECT EVIDENCE] [SUPPORT] Patients with a defect in the oxidation of long-chain FAs are at risk to develop cardiac and skeletal muscle abnormalities including cardiomyopathy and arrhythmias, which may progress into early death --- Explanation: Review confirming cardiac and skeletal muscle vulnerability in long-chain fatty acid oxidation disorders.


MONDO:0008918

[PMID:35862567] [INDIRECT EVIDENCE] [SUPPORT] Hyperammonemia is difficult to treat and is an important determinant of long-term neurocognitive outcome. --- Explanation: GeneReviews directly describes hyperammonemia as a key clinical challenge and prognostic factor.

[PMID:25614308] [INDIRECT EVIDENCE] [SUPPORT] the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress. --- Explanation: Literature review confirms hyperammonemia as one of the most frequent presenting symptoms.


MAXO:0000088

[PMID:35862567] [SUPPORT] The mainstay of therapy is a high-carbohydrate diet (>60% of total caloric intake) with restriction of long-chain dietary fat (to <10% of total calories) --- Explanation: GeneReviews provides specific dietary guidelines for CACT deficiency management.

[PMID:39203843] [SUPPORT] In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% --- Explanation: Review confirms LCT restriction targets and essential fatty acid requirements for long-chain FAODs.

[PMID:25614308] [SUPPORT] Diagnosis before the occurrence of clinical symptoms by tandem MS-MS and very early therapeutic intervention together with good dietary compliance could lead to a better prognosis --- Explanation: Supports importance of early dietary intervention for improved outcomes.


MAXO:0000058

[PMID:39375714] [SUPPORT] The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014) --- Explanation: Italian cohort study showing significant reduction in catabolic episodes and hospitalizations with triheptanoin versus MCT oil in LC-FAOD patients.


MAXO:0000088

[PMID:35862567] [SUPPORT] If triheptanoin is not available, medium-chain triglyceride (MCT) oil (10%-30% of total calories) could be used as a substitute. --- Explanation: GeneReviews recommends MCT oil as an alternative when triheptanoin is unavailable.


MAXO:0000058

[PMID:29502916] [SUPPORT] Carnitine supplementation may be helpful. --- Explanation: Review supports carnitine supplementation in long-chain fatty acid oxidation disorders.


MAXO:0000950

[PMID:35862567] [SUPPORT] Hyperammonemia is most sensitive to high rates of dextrose infusion (12-15 g/kg/day glucose for infants and 10-12 g/kg/day for children age 1-6 years), while ammonia scavenging medications (sodium benzoate, sodium phenylbutyrate) are of limited efficacy. --- Explanation: GeneReviews provides specific emergency management guidelines including dextrose infusion rates.


MAXO:0000124

[PMID:37305732] [SUPPORT] Newborn screening via tandem mass spectrometry (MS/MS) technology enables early diagnosis. --- Explanation: Confirms the role of MS/MS-based newborn screening for early CACT deficiency diagnosis.

[PMID:37305732] [SUPPORT] The ratios of the primary markers (C16 + C18:1)/C2, C16/C2, C16:1/C3, and C16:1-OH/C3 can facilitate the diagnosis of CACT deficiency, thereby increasing sensitivity and reducing false-positivity. --- Explanation: Demonstrates improved newborn screening performance with ratio-based markers.


MAXO:0000079

[PMID:35862567] [SUPPORT] Once the SLC25A20 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible. --- Explanation: GeneReviews confirms availability of carrier, prenatal, and preimplantation genetic testing.


MAXO:0000950

[PMID:35862567] [SUPPORT] A home emergency plan for prompt illness management should be provided to parents, primary care providers, teachers, and school staff. --- Explanation: GeneReviews emphasizes the importance of emergency planning and fasting avoidance.

[PMID:39203843] [SUPPORT] Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis --- Explanation: Review confirms the central importance of preventing lipolysis and managing catabolic states.


HGNC.SYMBOL:SLC25A20 pathogenic variants

[PMID:35862567] [SUPPORT] The diagnosis of CACT deficiency is confirmed by identification of biallelic pathogenic variants in SLC25A20 --- Explanation: GeneReviews confirms SLC25A20 as the causal gene with biallelic variants required for diagnosis.

[PMID:36835358] [SUPPORT] The Carnitine-Acylcarnitine Carrier is a member of the mitochondrial Solute Carrier Family 25 (SLC25), known as SLC25A20, involved in the electroneutral exchange of acylcarnitine and carnitine across the inner mitochondrial membrane. --- Explanation: Structural biology study confirming SLC25A20 function in acylcarnitine-carnitine exchange.


MONDO:0015515

[PMID:28054946] [SUPPORT] Clinical features are attacks of muscle weakness, myalgia, pain and rhabdomyolysis with or without renal failure. --- Explanation: Directly lists rhabdomyolysis as a clinical feature of muscle CPT II deficiency.

[PMID:28054946] [SUPPORT] Following the main clinical symptoms were myoglobinuria (86%) and muscle weakness (76%) --- Explanation: Quantifies myoglobinuria at 86% in a cohort of 50 patients.


MONDO:0015515

[PMID:28054946] [SUPPORT] Almost all patients (94%) described attacks of myalgia. --- Explanation: Quantifies myalgia at 94% in cohort study of 50 patients.

[PMID:37933340] [SUPPORT] We report an otherwise healthy 38-year-old patient who presented with severe myalgia, cramps, fatigue, low-grade fever, and transient myoglobinuria, after intense physical training. --- Explanation: Case report illustrating typical exercise-triggered myalgia presentation.


MONDO:0015515

[PMID:28054946] [SUPPORT] Following the main clinical symptoms were myoglobinuria (86%) and muscle weakness (76%) --- Explanation: Quantifies muscle weakness at 76% in myopathic CPT II cohort.


MONDO:0015515

[PMID:28054946] [SUPPORT] Following the main clinical symptoms were myoglobinuria (86%) and muscle weakness (76%) --- Explanation: Quantifies myoglobinuria at 86% in myopathic CPT II deficiency cohort.

[PMID:37933340] [SUPPORT] We report an otherwise healthy 38-year-old patient who presented with severe myalgia, cramps, fatigue, low-grade fever, and transient myoglobinuria, after intense physical training. --- Explanation: Case presentation showing transient myoglobinuria as a presenting feature.


MONDO:0015515

[PMID:28054946] [SUPPORT] Clinical features are attacks of muscle weakness, myalgia, pain and rhabdomyolysis with or without renal failure. --- Explanation: Lists renal failure as a complication of rhabdomyolysis in CPT II deficiency.

[PMID:37933340] [SUPPORT] One of the most common complications is acute kidney injury (AKI) following massive rhabdomyolysis, which is managed with aggressive fluid therapy --- Explanation: Directly identifies AKI as a common rhabdomyolysis complication in CPT II deficiency.


MONDO:0015515

[PMID:37933340] [SUPPORT] The first two are early-onset severe disorders presenting with marked hypoketotic hypoglycemia, cardiomyopathy, and liver dysfunction. --- Explanation: Confirms hypoketotic hypoglycemia as a hallmark of severe early-onset CPT II forms.


MONDO:0015515

[PMID:37933340] [SUPPORT] Echocardiogram showed a left ventricle ejection fraction (LVEF) of 40%. --- Explanation: Documents cardiomyopathy with reduced ejection fraction in a myopathic CPT II patient.

[PMID:37933340] [SUPPORT] The first two are early-onset severe disorders presenting with marked hypoketotic hypoglycemia, cardiomyopathy, and liver dysfunction. --- Explanation: Identifies cardiomyopathy as a feature of severe early-onset CPT II deficiency.


MONDO:0015515

[PMID:37933340] [SUPPORT] The first two are early-onset severe disorders presenting with marked hypoketotic hypoglycemia, cardiomyopathy, and liver dysfunction. --- Explanation: Liver dysfunction in early-onset forms is consistent with hepatomegaly.


MONDO:0015515

[PMID:38650450] [SUPPORT] 3 cases presented with clinical manifestations of fever, muscle weakness, and increased muscle enzymes. --- Explanation: Documents increased muscle enzymes (including CK) as a clinical manifestation in CPT2-deficient children.


MONDO:0015515

[PMID:37933340] [SUPPORT] The latter is characterized by muscle pain and weakness and stiffness, typically triggered by exercise or febrile illnesses --- Explanation: Directly describes muscle stiffness as a characteristic feature of myopathic CPT II deficiency.


MONDO:0015515

[PMID:28054946] [INDIRECT EVIDENCE] [SUPPORT] CPT (carnitine palmitoyltransferase) II muscle deficiency is the most common form of muscle fatty acid metabolism disorders. --- Explanation: Directly supports impaired fatty acid oxidation as the core defect in CPT II deficiency.


MONDO:0015515


MONDO:0015515

[PMID:28054946] [INDIRECT EVIDENCE] [SUPPORT] the wild-type and the S113L variants showed the same enzymatic activity. However, the mutated enzyme showed an abnormal thermal destabilization at 40 and 45 °C and an abnormal sensitivity to inhibition by malony-CoA. --- Explanation: Demonstrates thermolability of S113L variant and abnormal malonyl-CoA sensitivity using recombinant enzymes.

[PMID:28054946] [INDIRECT EVIDENCE] [SUPPORT] The thermolability of the mutant enzyme might explain why symptoms in muscle CPT II deficiency mainly occur during prolonged exercise, infections and exposure to cold. --- Explanation: Links thermolability mechanism to clinical trigger factors.


MONDO:0015515

[PMID:39182841] [INDIRECT EVIDENCE] [SUPPORT] Exposing isolated sarcoplasmic reticulum to long-chain acylcarnitines (LCACs) inhibited calcium uptake. --- Explanation: Directly demonstrates LCAC-mediated inhibition of SR calcium uptake in CPT2-deficient muscle model.


MONDO:0015515

[PMID:28054946] [INDIRECT EVIDENCE] [SUPPORT] The carnitine palmitoyltransferase (CPT) system consists of two enzymes, CPT I and CPT II, and is involved in the transport of long-chain fatty acids into the mitochondrial compartment. The enzymes are located in the outer (CPT I) and inner mitochondrial membrane (CPT II). --- Explanation: Describes the carnitine shuttle system and localization of CPT-I and CPT-II.


MAXO:0000950

[PMID:37933340] [SUPPORT] The patient was discharged upon the improvement of renal function with lifestyle modification recommendations. --- Explanation: Supports lifestyle modification as a key management strategy.

[PMID:28054946] [SUPPORT] Trigger factors are prolonged exercise, fasting, fever and exposure to cold --- Explanation: Identification of trigger factors directly supports avoidance strategy.


MAXO:0000088


MAXO:0000950

[PMID:37933340] [SUPPORT] One of the most common complications is acute kidney injury (AKI) following massive rhabdomyolysis, which is managed with aggressive fluid therapy; crystalloid solutions are preferred. --- Explanation: Directly recommends aggressive fluid resuscitation with crystalloids for rhabdomyolysis-associated AKI.

[PMID:37933340] [SUPPORT] Fluid resuscitation was started. Acute kidney injury was diagnosed and managed with plasmapheresis and five sessions of hemodialysis. --- Explanation: Documents clinical management of AKI with fluid resuscitation and renal replacement therapy.


MAXO:0000058

[PMID:38650450] [SUPPORT] Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines. --- Explanation: Decreased free carnitine provides rationale for supplementation.


MAXO:0000058

[clinicaltrials:NCT00983788] [SUPPORT] The investigators propose to evaluate the effect of bezafibrate on metabolism during exercise in 22 adult patients affected with carnitine palmitoyltransferase II (CPTII) or very-long chain acyl-CoA-dehydrogenase (VLCAD) deficiencies. --- Explanation: Directly supports bezafibrate as a studied intervention in adults with CPT II deficiency.


MAXO:0000058

[clinicaltrials:NCT01379625] [SUPPORT] This study will determine if a new experimental oil called Triheptanoin can decrease the muscle pain and increase the heart function and the amount of energy in patients with long-chain fatty acid oxidation disorders. --- Explanation: Supports triheptanoin as a clinical trial intervention for LC-FAOD populations that include CPT II deficiency.


MAXO:0000124

[PMID:38650450] [SUPPORT] Three cases were diagnosed at neonatal screening --- Explanation: Documents successful neonatal screening diagnosis in CPT2 deficiency.

[PMID:38650450] [SUPPORT] An early diagnosis can be facilitated by neonatal blood tandem mass spectrometry screening and genetic testing, and most patients have good prognosis after a timely diagnosis and treatment. --- Explanation: Supports the value of newborn screening for early diagnosis and improved outcomes.


MAXO:0000079

[PMID:28054946] [SUPPORT] The disease follows an autosomal recessive mode of inheritance. --- Explanation: Autosomal recessive inheritance directly supports the role of genetic counseling for carrier and recurrence risk assessment.


HGNC.SYMBOL:CPT2 gene variants

[PMID:28054946] [SUPPORT] Three phenotypes of CPT II deficiency are known: a lethal neonatal form, a severe infantile hepatocardiomuscular form, and a mild myopathic form --- Explanation: Describes the three clinical phenotypes of CPT II deficiency.

[PMID:39429887] [SUPPORT] The review detailed 245 cases across various forms, including lethal neonatal, severe infantile hepatocardiomuscular, and myopathic forms. --- Explanation: Quantifies case distribution across the three clinical subtypes.


MONDO:0011581

[PMID:11063735] [SUPPORT] a dilated left ventricular cardiomyopathy. A number of the patients with this syndromic disorder suffer heart failure in their teenage years, resulting in early morbidity. --- Explanation: Documents dilated cardiomyopathy with early heart failure.

[PMID:37799505] [SUPPORT] We diagnosed a 7-year-old female patient with Carvajal syndrome characterized by dilated cardiomyopathy, palmoplantar keratoderma, woolly hair, and dental dysplasia --- Explanation: Confirms childhood presentation with DCM.


MONDO:0011581

[PMID:11063735] [SUPPORT] a generalized striate keratoderma particularly affecting the palmoplantar epidermis --- Explanation: PPK is a defining feature of Carvajal syndrome.


MONDO:0011581

[PMID:11063735] [SUPPORT] woolly hair --- Explanation: Woolly hair is part of the Carvajal triad.


MONDO:0011581

[PMID:37799505] [SUPPORT] dilated cardiomyopathy, palmoplantar keratoderma, woolly hair, and dental dysplasia --- Explanation: Dental dysplasia documented as part of Carvajal phenotype.


MONDO:0011581

[PMID:11063735] [INDIRECT EVIDENCE] [SUPPORT] we describe the first recessive human mutation, 7901delG, in the desmoplakin gene which causes a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair and a dilated left ventricular cardiomyopathy --- Explanation: Landmark paper identifying the DSP mutation causing Carvajal syndrome and defining its cardiocutaneous phenotype.


MONDO:0011581


MONDO:0011581

[PMID:11063735] [INDIRECT EVIDENCE] [SUPPORT] Histology of the skin revealed large intercellular spaces and clustering of desmosomes at the infrequent sites of keratinocyte adhesion. Immunohistochemistry of skin from the patients showed a perinuclear localization of keratin in suprabasal keratinocytes, suggesting a collapsed intermediate filament network. --- Explanation: Demonstrates the desmosome-IF disruption mechanism at the cellular level in keratinocytes.


MONDO:0011581

[PMID:11063735] [INDIRECT EVIDENCE] [SUPPORT] a dilated left ventricular cardiomyopathy. A number of the patients with this syndromic disorder suffer heart failure in their teenage years, resulting in early morbidity. --- Explanation: Documents cardiomyocyte-level disease leading to DCM and early heart failure.


MAXO:0000058


MAXO:0000079


hgnc:3052

[PMID:11063735] [SUPPORT] All tested affected members of three families from Ecuador were homozygous for this mutation which produces a premature stop codon leading to a truncated desmoplakin protein missing the C domain of the tail region. --- Explanation: Defines the homozygous truncation as the cause of Carvajal syndrome.

[PMID:25516398] [SUPPORT] Genetic testing revealed a novel combination of two heterozygous mutations in the DSP gene encoding desmoplakin: R1400X and R2284X. --- Explanation: Compound heterozygosity as alternative mechanism for Carvajal-like phenotype.


MONDO:0005130

[PMID:39273359] [PARTIAL] CD induces an altered immune response that leads to chronic inflammation and duodenal mucosal damage. --- Explanation: Chronic inflammation and mucosal damage from immune response to gluten leads to malabsorption and chronic diarrhea as a cardinal symptom.


MONDO:0005130

[PMID:28722929] [SUPPORT] Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation. --- Explanation: Abdominal pain/discomfort is a typical gastrointestinal symptom of celiac disease.


MONDO:0005130

[PMID:28722929] [SUPPORT] Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation. --- Explanation: Bloating is a typical gastrointestinal symptom of celiac disease.


MONDO:0005130

[PMID:38914866] [PARTIAL] ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. --- Explanation: Weight loss results from impaired nutrient absorption due to villous atrophy and loss of epithelial cell differentiation and absorptive capacity.


MONDO:0005130

[PMID:38914866] [PARTIAL] ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. --- Explanation: Anemia results from malabsorption of iron and other nutrients due to villous atrophy and impaired epithelial absorptive function in damaged small intestine.


MONDO:0005130

[PMID:28722929] [SUPPORT] celiac disease can also present with extraintestinal manifestations such as fatigue, weight loss, skin rashes, anemia, and osteoporosis. --- Explanation: Fatigue is a common extraintestinal manifestation of celiac disease.


MONDO:0005130

[PMID:29757210] [SUPPORT] Dermatitis herpetiformis (DH) is a common extraintestinal manifestation of coeliac disease presenting with itchy papules and vesicles on the elbows, knees, and buttocks. --- Explanation: Dermatitis herpetiformis is the specific cutaneous manifestation of celiac disease.


MONDO:0005130

[PMID:10071918] [SUPPORT] 26% of all celiac patients, but only 5% of control subjects, were classified as having osteoporosis --- Explanation: Osteoporosis is significantly more prevalent in celiac disease patients due to calcium and vitamin D malabsorption.


MONDO:0005130

[PMID:10684852] [INDIRECT EVIDENCE] [SUPPORT] tissue transglutaminase (tTG)-mediated deamidation of gliadin plays an important role in recognition of this food antigen by intestinal T cells --- Explanation: Demonstrates the critical role of tTG deamidation in converting gluten peptides into immunogenic epitopes recognized by T cells in celiac disease.

[PMID:10684852] [INDIRECT EVIDENCE] [SUPPORT] the deamidated peptides displayed an increased affinity for DQ2, a molecule known to preferentially bind peptides containing negatively charged residues --- Explanation: Shows how tTG deamidation increases HLA-DQ2 binding affinity by introducing negatively charged glutamate residues, enhancing antigen presentation.

[PMID:38914866] [INDIRECT EVIDENCE] [SUPPORT] Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. --- Explanation: Confirms TG2 deamidation as the pivotal mechanism enabling gluten peptide presentation and T cell activation in celiac disease pathogenesis.


MONDO:0005130


MONDO:0005130

[PMID:38914866] [INDIRECT EVIDENCE] [SUPPORT] Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. --- Explanation: Demonstrates that IFN-gamma signaling drives a major portion of the transcriptional changes underlying epithelial damage in celiac disease.

[PMID:15357947] [INDIRECT EVIDENCE] [SUPPORT] under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells --- Explanation: Shows how IL-15 converts intraepithelial CD8+ T cells into cytotoxic lymphokine-activated killer cells via NKG2D signaling, mediating epithelial damage.

[PMID:24942692] [INDIRECT EVIDENCE] [SUPPORT] the upregulation of IL-15 expression in the intestinal mucosa has become a hallmark of the disease --- Explanation: Identifies IL-15 upregulation as a defining feature of celiac disease that drives intraepithelial lymphocyte expansion and epithelial injury.

[PMID:38914866] [INDIRECT EVIDENCE] [SUPPORT] ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. --- Explanation: Provides interventional evidence that blocking TG2-mediated T cell activation prevents the downstream epithelial damage, villous atrophy, and malabsorption.


MONDO:0005130

[PMID:39273359] [INDIRECT EVIDENCE] [NO_EVIDENCE] Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of proline- and glutamine-rich proteins, widely termed "gluten", in genetically susceptible individuals. CD induces an altered immune response that leads to chronic inflammation and duodenal mucosal damage. --- Explanation: Describes the immune-mediated nature of celiac disease, which includes both cellular and humoral (antibody) responses to gluten antigens.


MAXO:0000088

[PMID:39273359] [SUPPORT] The only available treatment strategy is lifelong adherence to a gluten-free diet. --- Explanation: Gluten-free diet is established as the only effective treatment for celiac disease.


MAXO:0000088


MAXO:0000058


HGNC.SYMBOL:HLA-DQ2


HGNC.SYMBOL:HLA-DQ8


HGNC.SYMBOL:IL2


HGNC.SYMBOL:IL21


HGNC.SYMBOL:BACH2


HGNC.SYMBOL:TNFAIP3


HGNC.SYMBOL:CD28


HGNC.SYMBOL:EGR2


HGNC.SYMBOL:ETS1


HGNC.SYMBOL:IRF4


HGNC.SYMBOL:SMAD3


HGNC.SYMBOL:PTPN22


MONDO:0007294

[PMID:17504518] [SUPPORT] CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness pronounced in the hip girdle
 --- Explanation: Comprehensive review establishing proximal weakness pronounced in the hip girdle as a characteristic feature of CCD.

[PMID:29391587] [PARTIAL] Pronounced weakness in axial and proximal muscle groups is a common feature
 --- Explanation: Major Nature Reviews Neurology review confirming axial and proximal weakness as common in congenital myopathies including CCD.


MONDO:0007294

[PMID:17504518] [SUPPORT] CCD typically presents in infancy with hypotonia and motor developmental delay
 --- Explanation: Establishes infantile hypotonia as a typical presenting feature of CCD.


MONDO:0007294

[PMID:17504518] [SUPPORT] CCD typically presents in infancy with hypotonia and motor developmental delay
 --- Explanation: Motor developmental delay is identified as a typical presenting feature.


MONDO:0007294

[PMID:17504518] [PARTIAL] orthopaedic complications are common
 --- Explanation: Orthopaedic complications including scoliosis are identified as common in CCD.


MONDO:0007294

[PMID:17504518] [PARTIAL] orthopaedic complications are common
 --- Explanation: Congenital hip dislocation is one of the common orthopaedic complications in CCD.


MONDO:0007294

[PMID:17504518] [SUPPORT] malignant hyperthermia susceptibility (MHS) is a frequent complication
 --- Explanation: Establishes MHS as a frequent complication of CCD.

[PMID:8220423] [SUPPORT] Central core disease (CCD) of muscle is an inherited myopathy which is closely associated with malignant hyperthermia (MH) in humans.
 --- Explanation: Confirms the close association between CCD and MH.


MONDO:0007294

[PMID:22473935] [SUPPORT] Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group.
 --- Explanation: Demonstrates that facial and bulbar involvement is characteristic of recessive RYR1-related myopathies.


MONDO:0007294

[PMID:22473935] [SUPPORT] Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group.
 --- Explanation: Extraocular involvement (ophthalmoplegia) is almost exclusively seen in recessive RYR1-related myopathies.


MONDO:0007294

[PMID:29391587] [PARTIAL] involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects
 --- Explanation: Cardiorespiratory involvement is noted as a feature that can occur in congenital myopathies.


MONDO:0007294

[PMID:17504518] [INDIRECT EVIDENCE] [SUPPORT] Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes of the RyR protein are considered the main pathogenetic mechanism(s).
 --- Explanation: Comprehensive Orphanet review of CCD establishing that mutation-induced conformational changes in RyR1 leading to altered calcium homeostasis are the main pathogenetic mechanism.

[PMID:16917943] [INDIRECT EVIDENCE] [SUPPORT] The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation-contraction coupling and skeletal muscle calcium homeostasis.
 --- Explanation: Review of RYR1 mutations in MH and CCD confirming the role of RYR1 in excitation-contraction coupling and calcium homeostasis.

[PMID:16917943] [INDIRECT EVIDENCE] [SUPPORT] In vitro analysis has confirmed that alteration of normal calcium homeostasis is a functional consequence of some of these changes.
 --- Explanation: Confirms functional evidence that RYR1 mutations alter calcium homeostasis through in vitro studies.


MONDO:0007294


MONDO:0007294

[PMID:17504518] [INDIRECT EVIDENCE] [PARTIAL] Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy.
 --- Explanation: Establishes the defining histopathological feature of CCD as central cores on muscle biopsy.


MONDO:0007294

[PMID:17504518] [INDIRECT EVIDENCE] [SUPPORT] CCD and MHS are allelic conditions both due to (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1).
 --- Explanation: Establishes that CCD and MHS are allelic conditions caused by mutations in the same RYR1 gene.

[PMID:8220423] [INDIRECT EVIDENCE] [SUPPORT] One of these mutations was also detected in an unrelated MH pedigree whose members are asymptomatic of CCD. The data suggest a model to explain how a single mutation may result in two apparently distinct clinical phenotypes.
 --- Explanation: Demonstrates that the same RYR1 mutation can cause CCD in one family and isolated MH susceptibility in another, establishing the allelic relationship.


MAXO:0000058

[PMID:17504518] [SUPPORT] Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia.
 --- Explanation: Establishes the critical importance of anesthetic precautions in CCD management.


MAXO:0000058


CHEBI:4317


MAXO:0000011


MAXO:0000004


MAXO:0000079

[PMID:17504518] [PARTIAL] Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis.
 --- Explanation: Supports the role of genetic testing and counseling in CCD diagnosis and family management.


hgnc:10483

[PMID:8220422] [SUPPORT] The only amino acid substitution found was an Arg2434His mutation, resulting from the substitution of A for G7301. This mutation was linked to CCD with a lod score of 4.8 at a recombinant fraction of 0.0 in 16 informative meioses in a 130 member family, suggesting a causal relationship to CCD.
 --- Explanation: Landmark 1993 Nature Genetics paper that first identified a specific RYR1 mutation (Arg2434His) as causative of central core disease through linkage analysis in a large family.

[PMID:16917943] [SUPPORT] Mapping to chromosome 19q13.2, the gene comprises 106 exons and encodes a protein of 5,038 amino acids. Mutations in the gene have been found in association with several diseases: the pharmacogenetic disorder, malignant hyperthermia (MH); and three congenital myopathies, including central core disease (CCD), multiminicore disease (MmD), and in an isolated case of a congenital myopathy characterized on histology by cores and rods.
 --- Explanation: Comprehensive review of RYR1 mutations establishing the gene structure and its association with CCD, MH, and other congenital myopathies.

[PMID:22473935] [SUPPORT] Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital myopathies associated with both dominant and recessive inheritance.
 --- Explanation: Large cohort study confirming RYR1 mutations as a common cause of congenital myopathies with both inheritance patterns.

[PMID:29391587] [SUPPORT] RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups.
 --- Explanation: Nature Reviews Neurology review confirming RYR1 as the most frequent genetic cause of congenital myopathies.


MONDO:0007294

[PMID:22473935] [SUPPORT] Dominant mutations, typically missense, were frequently located in recognized mutational hotspot regions, while recessive mutations were distributed throughout the entire coding sequence.
 --- Explanation: Large cohort study of 71 families confirms that dominant RYR1 mutations are typically missense and cluster in hotspot regions.

[PMID:8220422] [SUPPORT] Central core disease (CCD) is a morphologically distinct, autosomal dominant myopathy with variable clinical features.
 --- Explanation: The landmark 1993 Nature Genetics paper establishing the RYR1 link describes CCD as autosomal dominant with variable features.


MONDO:0007294

[PMID:22473935] [SUPPORT] As a group, dominant mutations were associated with milder phenotypes; patients with recessive inheritance had earlier onset, more weakness, and functional limitations. Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group.
 --- Explanation: This large cohort study of 71 families (35 dominant, 36 recessive) demonstrates the clinical distinction between dominant and recessive RYR1-related myopathies.


MONDO:0002974


MAXO:0001017


MAXO:0000014


NCIT:C376


NCIT:C106432


HGNC.SYMBOL:TP53


HGNC.SYMBOL:PIK3CA


NCBITaxon:333760

[PMID:41503346] [SUPPORT] Persistent infection with high-risk human papillomavirus (HR HPV) is the necessary cause of cervical cancer. --- Explanation: Supports HPV as the necessary causal agent for cervical cancer.


MONDO:0002974

[PMID:14690308] [SUPPORT] Squamous cell carcinoma is the most common malignant cervical tumor --- Explanation: Abstract reports squamous cell carcinoma as the most common malignant cervical tumor.


MONDO:0001444

[PMID:28284779] [SUPPORT] Chagas cardiomyopathy (CC) is one of the chronic manifestations of Trypanosoma cruzi (T. cruzi) infection --- Explanation: The abstract identifies cardiomyopathy as a chronic manifestation of Chagas disease.


MONDO:0001444

[PMID:28284779] [SUPPORT] Chagas etiology of heart failure has become the third most common indication for HT in South America. --- Explanation: The abstract links Chagas disease to heart failure requiring transplantation.


MAXO:0000058

[PMID:30111183] [SUPPORT] Currently, only benznidazole (BZN) and nifurtimox are recognized by the World Health Organization as effective drugs for treatment of CD. --- Explanation: The review lists benznidazole and nifurtimox as WHO-recognized therapies.


NCBITaxon:5693

[PMID:34207491] [SUPPORT] Chagas disease is caused by the kinetoplastid parasite Trypanosoma cruzi --- Explanation: The review identifies Trypanosoma cruzi as the causative agent.


MONDO:0001673

[PMID:25186048] [SUPPORT] Diarrhoea induced by chemotherapy in cancer patients is common, causes notable morbidity and mortality, and is managed inconsistently. --- Explanation: This guideline review directly establishes diarrhea as the central treatment-related phenotype.


MONDO:0001673

[PMID:34017262] [INDIRECT EVIDENCE] [SUPPORT] The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. --- Explanation: Review evidence directly links chemotherapy-associated mucositis to stem-cell apoptosis and failed epithelial renewal.


MONDO:0001673


MONDO:0001673

[PMID:24316664] [INDIRECT EVIDENCE] [SUPPORT] Findings strongly suggest irinotecan causes tight junction defects which lead to mucosal barrier dysfunction and the development of diarrhea. --- Explanation: Preclinical irinotecan data support chemotherapy-associated tight-junction disruption as a proximal step in diarrhea pathogenesis.

[PMID:32028590] [INDIRECT EVIDENCE] [SUPPORT] In many cases, this barrier loss reflects increased permeability of the paracellular tight junction as a consequence of myosin light chain kinase (MLCK) activation and myosin II regulatory light chain (MLC) phosphorylation. --- Explanation: General intestinal barrier evidence provides the MLCK/MLC mechanism that connects tight-junction remodeling to paracellular leak.


MONDO:0001673

[PMID:37231829] [INDIRECT EVIDENCE] [SUPPORT] Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. --- Explanation: Prospective human study explicitly ties fluoropyrimidine exposure to barrier dysfunction and downstream diarrhea.

[PMID:30739515] [INDIRECT EVIDENCE] [SUPPORT] Many patients with diarrhea caused by chemotherapy including fluoropyrimidine had small intestinal mucosal breaks. --- Explanation: Human capsule-endoscopy data show that chemotherapy-related diarrhea is commonly accompanied by structural mucosal injury.


MONDO:0001673

[PMID:37231829] [INDIRECT EVIDENCE] [SUPPORT] Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs. --- Explanation: Supports a microbiome-associated amplification step in chemotherapy-linked diarrhea.

[PMID:32170007] [INDIRECT EVIDENCE] [SUPPORT] These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage. --- Explanation: Mouse irinotecan models implicate microbiome-dependent amplification of epithelial damage and dysbiosis in chemotherapy toxicity.


MONDO:0001673

[PMID:34017262] [INDIRECT EVIDENCE] [SUPPORT] The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. --- Explanation: Review evidence links chemotherapy mucositis to epithelial apoptosis and failed renewal.

[PMID:23072534] [INDIRECT EVIDENCE] [SUPPORT] Continuous administration of 5-FU to mice caused severe intestinal mucositis, which was histologically characterized by the shortening of villi and destruction of intestinal crypts, accompanied by body weight loss and diarrhoea. --- Explanation: Mouse mucositis data show villus shortening and crypt destruction downstream of chemotherapy injury.


MONDO:0001673

[PMID:35170355] [INDIRECT EVIDENCE] [SUPPORT] However, in conditions of secretory diarrhea, this balance becomes dysregulated, so that fluid secretion, driven primarily by Cl- secretion, overwhelms absorptive capacity, leading to increased loss of water in the stool. --- Explanation: General intestinal transport physiology shows that diarrhea emerges when fluid secretion overwhelms absorptive capacity.

[PMID:30739515] [INDIRECT EVIDENCE] [SUPPORT] The diarrhea grade (per the Common Terminology Criteria for Adverse Events, version 4.0) was significantly correlated with the percentage of patients with a small intestinal mucosal break --- Explanation: Human data tie worsening diarrhea severity to more extensive small-bowel mucosal injury, consistent with absorptive failure.


MAXO:0000058

[PMID:25186048] [SUPPORT] Adequate--and, if necessary, repeated--assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step. --- Explanation: The guideline review identifies loperamide as a standard component of CID management.


MAXO:0000950

[PMID:25186048] [SUPPORT] Adequate--and, if necessary, repeated--assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step. --- Explanation: Supports hydration-focused supportive care as a core management step.


MAXO:0000058

[PMID:25186048] [SUPPORT] Use of octreotide and seeking specialist advice early for patients who do not respond to treatment will reduce morbidity and mortality. --- Explanation: The guideline review supports octreotide as escalation management for refractory chemotherapy-induced diarrhea.


MONDO:0005700

[PMID:37632006] [SUPPORT] Varicella-Zoster virus (VZV) is a pathogenic human alpha herpes virus that causes varicella (chicken pox) as a primary infection --- Explanation: Review confirming vesicular exanthem as the defining clinical feature of primary VZV infection (chickenpox).

[PMID:25453570] [SUPPORT] Varicella-zoster virus (VZV) can be detected in the blood from approximately 5 days before to 4 days after varicella. --- Explanation: Study establishing temporal relationship between viremia and the characteristic varicella rash.