MONDO:0006543

[PMID:32973163] [INDIRECT EVIDENCE] [SUPPORT] mucocutaneous fragility and blister formation, inducible by often minimal trauma --- Explanation: Confirms that EB is characterized by skin fragility and blister formation from minimal trauma.

[PMID:20301481] [INDIRECT EVIDENCE] [SUPPORT] skin fragility manifested by blistering and erosions with minimal trauma --- Explanation: GeneReviews confirms skin fragility as the hallmark clinical feature.


MONDO:0006543


MONDO:0006543

[PMID:35779740] [INDIRECT EVIDENCE] [SUPPORT] severe RDEB was associated with enhanced response to TGF-beta stimulus, oxidoreductase activity, and cell contraction --- Explanation: Gene expression profiling of RDEB fibroblasts reveals enhanced TGF-beta responsiveness driving fibrosis.

[PMID:35779740] [INDIRECT EVIDENCE] [SUPPORT] The disease manifests with devastating mucocutaneous fragility leading to progressive fibrosis and metastatic squamous cell carcinomas --- Explanation: Confirms that RDEB leads to progressive fibrosis and SCC.


MONDO:0006543

[PMID:20301481] [INDIRECT EVIDENCE] [SUPPORT] Blistering of the hands and feet followed by scarring results in contractures and pseudosyndactyly --- Explanation: GeneReviews confirms that scarring from repeated blistering causes pseudosyndactyly.


MONDO:0006543

[PMID:20301481] [INDIRECT EVIDENCE] [SUPPORT] Esophageal erosions can lead to webs and strictures that can cause severe dysphagia --- Explanation: GeneReviews confirms esophageal stricture formation from mucosal blistering.

[PMID:19700011] [INDIRECT EVIDENCE] [SUPPORT] Some epidermolysis bullosa subtypes are at risk for severe injury of the bone marrow, musculoskeletal system, heart, kidney, and teeth --- Explanation: Confirms multisystem extracutaneous complications in EB including organ injury.


MONDO:0006543

[PMID:19026465] [INDIRECT EVIDENCE] [SUPPORT] Cumulative risks rose steeply in RDEB-HS, from 7.5% by age 20 to 67.8%, 80.2%, and 90.1% by ages 35, 45, and 55, respectively --- Explanation: National EB Registry data demonstrates extremely high cumulative SCC risk in severe RDEB.

[PMID:19026465] [INDIRECT EVIDENCE] [SUPPORT] By mid-adulthood, nearly all will have had at least one SCC, and nearly 80% will have died of metastatic SCC despite aggressive surgical resection --- Explanation: Confirms SCC as the leading cause of death in RDEB with high metastatic potential.

[PMID:32973163] [INDIRECT EVIDENCE] [SUPPORT] the most feared of which - and also the leading cause of mortality - is squamous cell carcinoma --- Explanation: Confirms SCC as the most feared complication and leading cause of death in EB.

[PMID:20301481] [INDIRECT EVIDENCE] [SUPPORT] The lifetime risk of aggressive squamous cell carcinoma (SCC) is greater than 90% --- Explanation: GeneReviews confirms lifetime SCC risk exceeding 90% in severe RDEB.


MAXO:0001001

[PMID:36516090] [SUPPORT] Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo --- Explanation: Phase III trial conclusions confirming B-VEC efficacy for wound healing in DEB.

[PMID:36516090] [SUPPORT] Beremagene geperpavec (B-VEC) is a topical investigational herpes simplex virus type 1 (HSV-1)-based gene therapy designed to restore C7 protein by delivering COL7A1 --- Explanation: Describes the mechanism of B-VEC gene therapy for DEB.


MAXO:0001001

[PMID:40570869] [SUPPORT] At week 24, 35 (81%) of 43 treated wounds were at least 50% healed from baseline for prademagene zamikeracel compared with seven (16%) of 43 control wounds --- Explanation: Phase III VIITAL trial demonstrates statistically significant wound healing efficacy of prademagene zamikeracel in RDEB.

[PMID:40570869] [SUPPORT] Prademagene zamikeracel is an autologous COL7A1 gene-modified cellular sheet that is sutured onto to a large, chronic RDEB wound --- Explanation: Describes the mechanism of prademagene zamikeracel as an autologous gene-modified cellular sheet for RDEB wounds.


MAXO:0000058

[PMID:34606885] [SUPPORT] Fortnightly IV injections of rC7 for 7 weeks in adult RDEB mice reduced fibrosis of skin and eye --- Explanation: Preclinical study demonstrates that systemic IV rC7 reduces fibrosis in adult RDEB animal models.

[PMID:34606885] [SUPPORT] IV rC7 in adult RDEB dogs incorporated in the dermal‒epidermal junction of skin and improved disease by promoting wound healing and reducing dermal‒epidermal separation --- Explanation: Large animal model confirms that IV rC7 incorporates at the DEJ and improves wound healing in established RDEB.


MAXO:0000058

[PMID:39539991] [SUPPORT] Losartan was well tolerated, no treatment-related severe complications leading to a serious safety concern occurred --- Explanation: REFLECT Phase 1/2 trial demonstrates safety and tolerability of losartan in children with RDEB.

[PMID:39539991] [SUPPORT] Similar to the EBDASI score, the BEBS showed a mean reduction of -3 points, 95%-CI: -0.21 to -5,79, P = 0.036) --- Explanation: REFLECT trial shows statistically significant improvement in BEBS scores with losartan treatment in RDEB children.


MAXO:0000647

[PMID:40439508] [SUPPORT] Antitumour efficacy with acceptable toxicity was seen in patients on IV or oral therapy and two patients had a complete response within 6 months of treatment --- Explanation: Phase II trial demonstrates antitumour activity and complete responses with rigosertib in RDEB-SCC patients.

[PMID:40439508] [SUPPORT] These data identify rigosertib as a promising drug therapy for patients with RDEB-SCC where there is a substantial unmet need, absence of approved therapies and where tumours arise on a background of a unique fibrotic and inflammatory environment --- Explanation: Identifies rigosertib as a promising therapeutic option for the currently untreatable RDEB-associated SCC.


MAXO:0000058

[PMID:38366625] [SUPPORT] After gentamicin treatment, skin biopsies from all three patients (age range 18-28 years) exhibited increased C7 in their DEJ --- Explanation: Open-label clinical trial demonstrates that IV gentamicin restores type VII collagen at the DEJ in RDEB patients with nonsense mutations.

[PMID:38366625] [SUPPORT] At 1 and 3 months post-treatment, 100% of the monitored wounds exhibited > 85% closure --- Explanation: Demonstrates significant wound healing improvement after IV gentamicin readthrough therapy in RDEB.


MAXO:0000950

[PMID:32973163] [SUPPORT] multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications --- Explanation: Confirms wound care as a central component of EB management.


MAXO:0000004

[PMID:20301481] [SUPPORT] dilation of esophageal strictures and webs to improve swallowing --- Explanation: GeneReviews confirms esophageal dilation as standard management.


MAXO:0000088

[PMID:20301481] [SUPPORT] nutritional support including feeding gastrostomy tube, vitamin A, zinc, selenium, and carnitine supplementation --- Explanation: GeneReviews confirms comprehensive nutritional support including supplements and gastrostomy.


MAXO:0000126

[PMID:20301481] [SUPPORT] evaluation of crusted, non-healing, and painful lesions as well as those with exuberant scar tissue at least annually beginning at age ten years; biopsies of suspicious lesions for evidence of SCC --- Explanation: GeneReviews recommends SCC surveillance starting at age 10.


MAXO:0000004

[PMID:19026465] [SUPPORT] nearly 80% will have died of metastatic SCC despite aggressive surgical resection --- Explanation: Confirms the poor prognosis of SCC in RDEB despite surgical treatment.


MAXO:0000950

[PMID:20301481] [SUPPORT] topical, oral, and psychological therapies for pain and itch --- Explanation: GeneReviews confirms multimodal pain management in DEB.


MAXO:0000011

[PMID:20301481] [SUPPORT] Occupational and physical therapy may help prevent hand and other joint contractures --- Explanation: GeneReviews confirms physical/occupational therapy for contracture prevention.


MAXO:0000747

[PMID:20818854] [SUPPORT] Increased C7 deposition and a sustained presence of donor cells were found in the skin of children with recessive dystrophic epidermolysis bullosa after allogeneic bone marrow transplantation --- Explanation: Wagner et al. demonstrated increased collagen VII after BMT in RDEB children.

[PMID:20818854] [SUPPORT] all having improved wound healing and a reduction in blister formation between 30 and 130 days after transplantation --- Explanation: Confirms clinical improvement in wound healing after BMT.


MAXO:0000079

[PMID:20301481] [SUPPORT] Once the COL7A1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible --- Explanation: GeneReviews confirms availability of prenatal and preimplantation testing.


HGNC.SYMBOL:COL7A1

[PMID:36516090] [SUPPORT] Dystrophic epidermolysis bullosa is a rare genetic blistering skin disease caused by mutations in COL7A1, which encodes type VII collagen (C7) --- Explanation: Confirms COL7A1 as the causative gene for DEB.

[PMID:20301481] [SUPPORT] biallelic COL7A1 pathogenic variants (for RDEB) or a heterozygous pathogenic variant in COL7A1 (for DDEB) --- Explanation: GeneReviews confirms both dominant and recessive inheritance patterns for COL7A1 mutations.

[PMID:20301481] [SUPPORT] Some COL7A1 pathogenic variants are associated with both DDEB and RDEB --- Explanation: Confirms that some variants can cause either dominant or recessive DEB.


MONDO:0001056


MAXO:0000004


MAXO:0000647


MAXO:0000058


HGNC.SYMBOL:PIK3CA


HGNC.SYMBOL:ARID1A


HGNC.SYMBOL:CDKN2A


NCBITaxon:10376

[PMID:41280003] [PARTIAL] Epstein-Barr virus associated gastric cancer (EBVaGC) accounts for ~9-10% of gastric cancers worldwide and is defined by a distinctive molecular profile, including extreme hypermethylation of the DNA. --- Explanation: Supports EBV association and molecular distinctness, but does not directly establish clonal infection as the initiating event.


MONDO:0001056

[PMID:40647518] [PARTIAL] with adenocarcinoma being the most  --- Explanation: Supports adenocarcinoma predominance in gastric cancer generally, but not specifically in EBV-associated cases.


MONDO:0005061


MONDO:0005061

[PMID:15118073] [INDIRECT EVIDENCE] [PARTIAL] A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. --- Explanation: This abstract links EGFR mutations in NSCLC with sensitivity to EGFR TKIs, supporting the role of activating EGFR mutations.


CHEBI:90943


CHEBI:114785


CHEBI:49668


NCIT:C124993


HGNC.SYMBOL:EGFR

[PMID:26490356] [PARTIAL] Exon 19 deletion and exon 21 L858R mutation were the most common epidermal growth factor receptor (EGFR) mutations. --- Explanation: Supports the common EGFR mutation spectrum, but does not directly establish the broader activating/resistance mutation framework.


MONDO:0005061

[PMID:32657049] [PARTIAL] Of 256 patients with NSCLC, 219 were adenocarcinoma --- Explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.


MONDO:0021116


MONDO:0021116

[PMID:22291085] [PARTIAL] defined as having 1% to 10% positivity by immunohistochemistry (IHC) --- Explanation: Supports ER IHC threshold discussion, but only partially covers the broader descriptor.


MONDO:0021116

[PMID:30054636] [SUPPORT] Late recurrence 5 or more years after diagnosis accounts for at least one-half of all cases of recurrent hormone receptor-positive breast cancer. --- Explanation: Abstract reports that late recurrences account for at least half of recurrent hormone receptor-positive cases.


MONDO:0021116

[PMID:41549581] [INDIRECT EVIDENCE] [PARTIAL] At the heart of this subtype is the estrogen signaling pathway, especially the estrogen receptor alpha (ERα), which plays a major role in the development, growth, and response to these cancers. --- Explanation: This supports ERalpha pathway centrality, but not the full mechanistic detail in this descriptor.


MAXO:0000058

[PMID:15894097] [NO_EVIDENCE] For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3) --- Explanation: Snippet supports tamoxifen benefit in ER-positive disease, but does not directly support aromatase inhibitors.


MAXO:0000058

[PMID:15894097] [SUPPORT] For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3) --- Explanation: Landmark EBCTCG meta-analysis of 194 trials shows 5 years of tamoxifen reduces breast cancer mortality by 31%.


CHEBI:41774

[PMID:15894097] [INDIRECT EVIDENCE] [SUPPORT] For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3) --- Explanation: Landmark EBCTCG meta-analysis of 194 trials shows 5 years of tamoxifen reduces breast cancer mortality by 31%.


MAXO:0000058

[PMID:26947331] [PARTIAL] Median progression-free survival was 9·5 months (95% CI 9·2-11·0) in the fulvestrant plus palbociclib group and 4·6 months (3·5-5·6) in the fulvestrant plus placebo group (hazard ratio 0·46, 95% CI 0·36-0·59, p<0·0001). --- Explanation: Supports palbociclib efficacy in metastatic HR+/HER2- disease, but does not directly support the full CDK4/6 class-level descriptor.


MAXO:0000058

[PMID:26947331] [NO_EVIDENCE] Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo --- Explanation: PALOMA-3 confirms fulvestrant's role as backbone therapy in HR+/HER2- metastatic breast cancer, demonstrating activity when combined with CDK4/6i.


CHEBI:31638

[PMID:26947331] [INDIRECT EVIDENCE] [NO_EVIDENCE] Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo --- Explanation: PALOMA-3 confirms fulvestrant's role as backbone therapy in HR+/HER2- metastatic breast cancer, demonstrating activity when combined with CDK4/6i.


MAXO:0000058

[PMID:26947331] [SUPPORT] PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients --- Explanation: Snippet supports PIK3CA mutation prevalence only, not alpelisib efficacy or indication.


CHEBI:231324

[PMID:26947331] [INDIRECT EVIDENCE] [SUPPORT] PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients --- Explanation: Snippet supports PIK3CA mutation prevalence only, not alpelisib efficacy or indication.


MAXO:0000058

[PMID:26947331] [NO_EVIDENCE] women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy --- Explanation: Snippet describes PALOMA-3 eligibility context but does not provide direct evidence for elacestrant.


CHEBI:229213

[PMID:26947331] [INDIRECT EVIDENCE] [NO_EVIDENCE] women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy --- Explanation: Snippet describes PALOMA-3 eligibility context but does not provide direct evidence for elacestrant.


HGNC.SYMBOL:ESR1


HGNC.SYMBOL:PIK3CA


HGNC.SYMBOL:CCND1


MONDO:0021116

[PMID:39806949] [PARTIAL] Invasive ductal carcinoma (IDC) is the most common type of breast cancer, --- Explanation: Supports IDC predominance in breast cancer overall, but not specifically ER-positive cohorts.


MONDO:0005737

[PMID:32080199] [SUPPORT] EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome. --- Explanation: The literature indicates that fever is a very frequent symptom of Ebola Virus Disease (EVD).

[PMID:28457350] [NO_EVIDENCE] This review highlights the range of aspects of EVD that the authors find are relevant to laboratory medicine, including the need for robust prediagnostic and laboratory processing algorithms to inform sampling of suspect patients, the vast majority of whom, in resource-rich settings, will have another diagnosis. --- Explanation: Snippet addresses laboratory workflow context and does not directly provide fever-frequency evidence.


MONDO:0005737

[PMID:32487785] [SUPPORT] It is usually diagnosed based on several clinical symptoms such as the sudden onset of illness, high fevers for less than three weeks, and at least two hemorrhagic symptoms despite no predisposing factors. --- Explanation: The literature confirms that hemorrhagic symptoms are a key diagnostic feature of EVD.

[PMID:28484180] [SUPPORT] Ebolaviruses, members of the family Filoviridae, cause severe hemorrhagic fever in humans and nonhuman primates, with human case fatality rates of up to 90%. --- Explanation: The literature confirms severe hemorrhagic fever as a phenotype of EVD.

[PMID:30893774] [NO_EVIDENCE] Ebola Virus Disease (EVD) is one of the most lethal transmissible infections, characterized by a high fatality rate, and caused by a member of the Filoviridae family. --- Explanation: Snippet supports severity/fatality but does not directly provide hemorrhage-specific evidence.

[PMID:35657325] [SUPPORT] A group of viruses within the genus Ebolavirus causes this severe hemorrhagic disease in humans: Ebola virus (EBOV; species Zaire ebolavirus), Sudan virus (SUDV; species Sudan ebolavirus), Bundibugyo virus, and Taï Forest virus --- Explanation: The literature supports that EVD is characterized by severe systemic symptoms, including severe hemorrhagic manifestations.


MONDO:0005737

[PMID:25972150] [PARTIAL] Common gastrointestinal manifestations include...nausea and vomiting-60%...The diarrhea and nausea and vomiting frequently produce profound, life-threatening hypovolemia. --- Explanation: While vomiting is a common manifestation and can lead to severe consequences like life-threatening hypovolemia, the literature does not specifically categorize vomiting itself as "severe." The severity is associated with the complications resulting from vomiting and other symptoms.

[PMID:32080199] [PARTIAL] EVD outbreaks typically start from a single case of probable zoonotic transmission, followed by human-to-human transmission via direct contact or contact with infected bodily fluids or contaminated fomites. EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome. --- Explanation: This reference indicates the inclusion of gastrointestinal signs in EVD, which can imply vomiting, but does not specifically mention the frequency or severity of vomiting.

[PMID:27717513] [PARTIAL] The clinical spectrum of Ebola virus disease (EVD) ranges from very serious forms with organ failure and death within days to paucisymptomatic forms and perhaps even asymptomatic. --- Explanation: This suggests variability in EVD presentation, acknowledging severe forms, but it does not specify the severity or frequency of vomiting in particular.


MONDO:0005737

[PMID:32080199] [PARTIAL] EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome. --- Explanation: Supports gastrointestinal involvement broadly, but only partially supports diarrhea-specific severity/frequency.

[PMID:25972150] [SUPPORT] Common gastrointestinal manifestations include diarrhea-70 %. --- Explanation: This directly supports the statement by noting that diarrhea is a common (70% frequency) gastrointestinal manifestation.

[PMID:34986351] [SUPPORT] During the 2013-2016 West African (WA) Ebola virus (EBOV) outbreak, severe gastrointestinal symptoms were common in patients and associated with poor outcome. --- Explanation: The reference highlights that severe gastrointestinal symptoms, including diarrhea, were common and associated with poor outcomes.


MONDO:0005737

[PMID:38840082] [PARTIAL] The pooled prevalence was... fatigue 25% (95% CI: 19%-31%) --- Explanation: Fatigue is reported as a symptom in 25% of EVD survivors, which indicates it is relatively common but not 'very frequent' as the statement suggests.


MONDO:0005737

[PMID:38840082] [SUPPORT] The pooled prevalence was: arthralgia 50% (95% CI: 41%-59%); headache 44% (95% CI: 36%-52%); myalgia 32% (95% CI: 26%-38%) --- Explanation: The meta-analysis shows that myalgia has a pooled prevalence of 32% among Ebola Virus Disease (EVD) survivors, indicating it is a frequent musculoskeletal symptom.


MONDO:0005737

[PMID:31874716] [SUPPORT] The main clinical signs were asthenia (78.8%), fever (75.3%), anorexia (53.4%), headache (45.9%)... --- Explanation: This study lists headache as one of the main clinical signs in children with EVD, supporting the statement that headache is an occasional neurologic symptom of EVD.

[PMID:33493959] [NO_EVIDENCE] In patients with EVD, neurologic manifestations range from mild symptoms such as confusion to severe neurologic diseases such as meningitis and encephalitis. Altered mental status, from mild confusion to delirium with hallucinations, may also occur. --- Explanation: Snippet does not directly mention headache.

[PMID:26983037] [SUPPORT] Survivors reported musculoskeletal pain (70%), headache (48%), and ocular problems (14%). --- Explanation: This study reports that 48% of EVD survivors experienced headaches, supporting the statement that headache is an occasional neurologic symptom of EVD.


MONDO:0005737

[PMID:25972150] [SUPPORT] Common gastrointestinal manifestations include diarrhea-70 %, nausea and vomiting-60 %, and abdominal pain-45 %. --- Explanation: The literature indicates that abdominal pain occurs in 45% of EVD cases, supporting the claim that it is a frequent gastrointestinal manifestation.

[PMID:31874716] [SUPPORT] The main clinical signs were asthenia (78.8%), fever (75.3%), anorexia (53.4%), headache (45.9%), vomiting (41.8%), abdominal pain (29.5%), and diarrhea (28.8%). --- Explanation: The study shows that abdominal pain was observed in 29.5% of children with EVD, supporting the statement that it is a frequent gastrointestinal symptom.


MONDO:0005737

[PMID:32487785] [PARTIAL] Transmission of EBoV has been reported in various ways, including human to human transmission through close contact with blood and bodily fluids... It is usually diagnosed based on several clinical symptoms such as the sudden onset of illness, high fevers for less than three weeks, and at least two hemorrhagic symptoms despite no predisposing factors. --- Explanation: The literature mentions hemorrhagic symptoms but does not specifically mention thrombocytopenia or its frequency.

[PMID:25679971] [PARTIAL] Understanding bleeding in Ebola virus disease. --- Explanation: The reference discusses bleeding in Ebola virus disease but does not specifically mention thrombocytopenia or its frequency.

[PMID:35446128] [PARTIAL] Ebola virus (EBV) disease (EVD) is a highly virulent systemic disease characterized by an aggressive systemic inflammatory response and impaired vascular and coagulation systems, often leading to uncontrolled hemorrhaging and death. --- Explanation: The literature discusses impaired vascular and coagulation systems, which can be related to thrombocytopenia, but does not specifically mention its frequency.


MONDO:0005737

[PMID:2822180] [PARTIAL] Even though HAV, HBV and HNANB viruses are responsible for most of the viral hepatitis cases, many other viruses have been reported to cause hepatic injury. These viruses may involve the liver, either as part of a systemic illness (e.g. EBV, CMV, HSV) or as the primary target organ (e.g. yellow fever virus, Lassa fever virus, Ebola virus). Clinically overt hepatocellular dysfunction is rare in such viral infections. --- Explanation: The reference indicates that Ebola virus can cause hepatic injury, but clinically overt hepatocellular dysfunction is rare. This partially supports the statement as it acknowledges hepatic involvement but suggests that severe liver dysfunction is not frequent.

[PMID:25972150] [PARTIAL] The mean serum AST and ALT levels are each about 200/UL, with an unusual pattern for viral hepatitis of AST > ALT. --- Explanation: The reference indicates elevated liver enzymes (AST and ALT) in Ebola virus infection, which supports the part of the statement regarding elevated liver enzymes. However, it does not confirm frequent impaired liver function or hepatitis as a common sequela.

[PMID:37170900] [PARTIAL] Results illustrate that EBOV causes macrophage phenotype alterations as well as neutrophil influx and prominent activation of interferon host responses in the liver. --- Explanation: The reference provides evidence of liver involvement and immune response alterations in Ebola virus infection, which can be associated with hepatic dysfunction. However, it does not explicitly state that hepatitis or impaired liver function is frequent.

[PMID:29020340] [NO_EVIDENCE] The role of the virus in liver damage remains unclear, but our evidence suggests that acute severe liver injury is not a typical feature of Ebola virus disease. --- Explanation: The reference suggests that acute severe liver injury is not typical in Ebola virus disease, which refutes the statement that impaired liver function is frequent.


MONDO:0005737


MAXO:0000950

[PMID:37355146] [SUPPORT] Early detection and supportive care can enhance the likelihood of survival. This includes intravenous fluids, electrolyte replacement, and treatment of secondary infections. --- Explanation: The provided literature supports that supportive care, including rehydration and symptomatic treatment, is a key component in the treatment of Ebola Virus Disease (EVD).

[PMID:28646340] [SUPPORT] Clinical management of EVD combines supportive and symptomatic care while also addressing the patient's emotional and mental health needs. --- Explanation: This literature indicates the combination of supportive and symptomatic care is part of the clinical management of EVD.

[PMID:29054555] [SUPPORT] Key recommendations include administration of oral and, as necessary, intravenous hydration; systematic monitoring of vital signs and volume status; availability of key biochemical testing; adequate staffing ratios; and availability of analgesics, including opioids, for pain relief. --- Explanation: The evidence-based guidelines for supportive care of patients with EVD include recommendations that align with rehydration and symptomatic treatments for managing fever, bleeding, and pain.


MAXO:0000168

[PMID:27337455] [SUPPORT] The armamentarium against EVD eventually included biologics such as monoclonal antibodies, convalescent plasma, and vaccines as well as small molecule therapeutics such as small interfering RNAs and nucleoside analogs. --- Explanation: The reference mentions the use of various experimental therapies including immune therapies (monoclonal antibodies), blood products (convalescent plasma), and small molecule therapeutics (antiviral drugs).

[PMID:11766882] [PARTIAL] This review describes Ebola viruses, with a particular focus on the status of research efforts to develop vaccines and therapeutics and to identify the immune mechanisms of protection. --- Explanation: Supports historical therapeutic research context, but only partially supports specific experimental therapy modalities.

[PMID:25457751] [SUPPORT] Recently, the use of convalescent blood products was proposed by the WHO as one early option for treating patients with Ebola virus disease. --- Explanation: The reference confirms the use of convalescent blood products as a treatment strategy for EVD, supporting the statement.

[PMID:32487785] [SUPPORT] Management of patients involves supportive care such as maintaining fluid along with electrolyte balance, blood pressure and oxygen saturation. This also includes treating complications arising from secondary infections. The main options include: prophylactic strategies, anti-viral therapy for EVD, immunotherapies, vaccines, and ZMapp. --- Explanation: The reference lists anti-viral therapy and immunotherapies as main treatment options, confirming the statement's reference to experimental therapies.

[PMID:30943399] [SUPPORT] We describe therapeutic monoclonal antibodies isolated from human volunteers vaccinated with recombinant adenovirus expressing Ebola virus glycoprotein (EBOV GP). --- Explanation: The reference discusses therapeutic monoclonal antibodies, which are a form of immune therapy, in line with the statement.


MAXO:0001017

[PMID:28017403] [SUPPORT] The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters. --- Explanation: The study shows that rVSV-ZEBOV vaccine offers substantial protection against Ebola virus disease, supporting the statement that it is effective in preventing Ebola infection.

[PMID:32243796] [SUPPORT] Ervebo is the first licensed vaccine for prevention of Ebola virus disease. --- Explanation: The article states that Ervebo (rVSV-ZEBOV) is licensed for the prevention of Ebola virus disease, supporting the statement that the vaccine is effective in preventing Ebola infection.

[PMID:33873076] [SUPPORT] Currently, two vaccines: Ervebo (rVSV-ZEBOV) and a two-dose combination of Zabdeno (Ad26.ZEBOV) and Mvabea (MVA-BN-Filo) have been licensed and in use. --- Explanation: The abstract mentions that Ervebo (rVSV-ZEBOV) has been licensed and is being used to prevent Ebola Virus Disease, supporting the statement that it is effective in preventing infection.

[PMID:34749265] [SUPPORT] In 2019, the FDA-approved the first anti-EBOV vaccine, rVSV-EBOV-GP (Ervebo® by Merck) --- Explanation: The article confirms that the rVSV-EBOV-GP (Ervebo) vaccine is FDA-approved and provides prophylactic protection against Ebola, supporting the statement that it is effective in preventing Ebola infection.


HGNC.SYMBOL:NPC1


HGNC.SYMBOL:HAVCR1


HGNC.SYMBOL:SLC39A9


HGNC.SYMBOL:PIK3C3


HGNC.SYMBOL:CTSB


HGNC.SYMBOL:CTSL


ECTO:3000001

[PMID:17848072] [SUPPORT] Among the various animals captured and analyzed, three species of fruit bats (suborder Megachiroptera) were found asymptomatically and naturally infected with Ebola virus: Hypsignathus monstrosus (hammer-headed fruit beats), Epomops franqueti (singing fruit bats), and Myonycteris torquata (little collared fruit bats) --- Explanation: This study confirms that certain species of fruit bats serve as Ebola virus reservoirs, supporting the notion that fruit bats are natural hosts of the virus.

[PMID:28573636] [PARTIAL] Although an ebolavirus natural reservoir has yet to be identified, the majority of disease ecologists believe the reservoir to belong to the order Chiroptera (bats). --- Explanation: While bats are strongly suspected to be the natural reservoir, the virus has not been isolated definitively from them, providing partial but not conclusive support.

[PMID:26757869] [SUPPORT] Fruits bats are its natural reservoir, the transmission to humans is across wild animals (especially primates) and the propagation in human populations is through bodily fluid contact --- Explanation: This literature indicates that fruit bats are considered the natural reservoir for Ebola, supporting the statement.

[PMID:26147380] [PARTIAL] Ebola virus disease (EVD) is a zoonotic disease that causes severe haemorrhagic fever, with high fatality rates of up to 90% in humans. --- Explanation: Supports zoonotic nature, but only partially supports specific fruit-bat reservoir assertion.


NCBITaxon:1570291

[PMID:32080199] [SUPPORT] Ebola virus disease (EVD) is a severe and frequently lethal disease caused by Ebola virus (EBOV). --- Explanation: The literature clearly states that EVD is caused by the Ebola virus.

[PMID:28643203] [SUPPORT] Ebola virus disease (EVD) in humans is associated with four ebolaviruses: Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), and Taï Forest virus --- Explanation: This reference confirms that Ebola virus (EBOV) is indeed an infectious agent of EVD.

[PMID:24040779] [SUPPORT] Since Ebola virus was discovered in 1970s, the virus has persisted in Africa and sporadic fatal outbreaks in humans and non-human primates have been reported. --- Explanation: This reference states that Ebola virus is responsible for outbreaks in humans, indicating it as the infectious agent for Ebola virus disease.

[PMID:33734027] [SUPPORT] Ebola virus (EBOV), belonging to the species Zaire ebolavirus in the genus Ebolavirus, causes a severe febrile illness in humans with case fatality rates (CFRs) up to 90%. --- Explanation: This literature directly links Ebola virus (EBOV) to the severe illness known as Ebola Virus Disease (EVD).


MONDO:0020066

[PMID:34807421] [SUPPORT] Currently, musculoskeletal manifestations related to joint hypermobility are perceived as the most prevalent determinants of the quality of life of affected individuals. --- Explanation: This reference confirms that musculoskeletal manifestations, including joint hypermobility, are highly prevalent in individuals with Ehlers-Danlos Syndrome (EDS).

[PMID:29915965] [PARTIAL] Increasing data demonstrate that pain is a major disability determinator in JH and EDS. Recent findings confirm a complex pathogenesis for pain in JH and EDS and suggest a potential role for joint instability, central sensitization and small fiber neuropathy. --- Explanation: Supports pain/instability burden in JH/EDS, but only partially supports very-frequent joint hypermobility frequency directly.

[PMID:37726791] [SUPPORT] The Ehlers-Danlos syndromes are a group of clinically and genetically heterogeneous hereditary diseases affecting the connective tissue. They are characterized by hypermobility of the joints, hyperextensible skin and friable tissue. --- Explanation: This reference supports the statement by acknowledging hypermobility of the joints as a characteristic of EDS, along with chronic pain and other musculoskeletal features.


MONDO:0020066

[PMID:19055167] [SUPPORT] Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders characterized by hyperextensibility, delayed wound healing, joint hypermobility, thin skin, easy bruising, tissue fragility, 'cigarette-paper' scarring over bony prominences, mitral valve prolapse, and other findings. --- Explanation: This reference directly mentions delayed wound healing as a characteristic of Ehlers-Danlos syndrome.

[PMID:2728341] [PARTIAL] Although delayed wound healing has been reported to be a complication of Ehlers-Danlos syndrome in humans, using clinical and histologic criteria, wound healing in dogs and cats with Ehlers-Danlos syndrome appears to be similar to nonaffected animals. --- Explanation: Primarily animal data with mixed findings; only partial support for human poor wound-healing frequency.

[PMID:20847697] [SUPPORT] Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility. --- Explanation: This reference lists delayed wound healing as a characteristic feature of classic Ehlers-Danlos syndrome.


MONDO:0020066

[PMID:36237549] [PARTIAL] In addition to these commonly recognized phenotypes, recent studies have notably highlighted variable ophthalmic features in EDS. --- Explanation: Supports variable ophthalmic involvement generally, but only partially supports keratoconus specifically.

[PMID:28757364] [NO_EVIDENCE] As the two patients reported here illustrate, patients with kEDS-PLOD1 do not always have a kyphoscoliosis present at birth or in the first year of life, neither do they necessarily develop kyphoscoliosis later in infancy. --- Explanation: This reference talks mainly about kyphoscoliotic EDS and its genetic underpinnings, without specifically mentioning ophthalmologic features or keratoconus.

[PMID:9493273] [NO_EVIDENCE] Keratoconus is most commonly an isolated disorder, although several reports describe an association with Down syndrome, Leber's congenital amaurosis, and mitral valve prolapse. --- Explanation: This reference discusses keratoconus but does not specifically link it to Ehlers-Danlos syndrome.

[PMID:14679583] [NO_EVIDENCE] The brittle cornea syndrome (BCS) is a generalized connective tissue disorder characterized by corneal rupture following only minor trauma, keratoconus or keratoglobus, blue sclerae, hyperelasticity of the skin without excessive fragility, and hypermobility of the joints. --- Explanation: Snippet is about brittle cornea syndrome and does not directly provide EDS keratoconus evidence.

[PMID:37074408] [NO_EVIDENCE] A high proportion of patients had tomographically suspect corneas when using keratoconus diagnostic indices --- Explanation: This reference discusses keratoconus in the context of osteogenesis imperfecta, not Ehlers-Danlos syndrome.


MONDO:0020066

[PMID:35000503] [SUPPORT] Mitral valve prolapse was present in 7.5% and thoracic aortic dilatation in 15.2%. --- Explanation: This study reports the presence of mitral valve prolapse in patients with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD).

[PMID:6993166] [SUPPORT] It appears to occur more frequently in females and occasionally it is familial... particularly Marfan's syndrome, rheumatic heart disease, coronary heart disease, congestive cardiomyopathy, ostium secundum atrial septal defect, Ehlers-Danlos syndrome or abnormalities of the thoracic cage. --- Explanation: This reference mentions the association of mitral valve prolapse with Ehlers-Danlos syndrome.

[PMID:34776077] [SUPPORT] There is substantial symptoms overlap between the EDS subtypes, and they are associated with an increased incidence of cardiovascular abnormalities, such as mitral valve prolapse and aortic dissection. --- Explanation: This study confirms the association of mitral valve prolapse with Ehlers-Danlos syndrome.

[PMID:31328377] [PARTIAL] Mitral valve prolapse and bicuspid aortic valve occurred at the same incidence as the general population. --- Explanation: Indicates no excess incidence versus general population, providing only partial support for phenotype inclusion.


MONDO:0020066

[PMID:26376608] [NO_EVIDENCE] Commonest GI symptoms were: abdominal pain (56.1%), nausea (42.3%), constipation (38.6%), heartburn (37.6%), and irritable bowel syndrome-like symptoms (27.5%). --- Explanation: The literature mentions heartburn and various other gastrointestinal symptoms but does not specifically mention gastroesophageal reflux as an occasional manifestation.

[PMID:36000988] [NO_EVIDENCE] We report a significant enrichment of EDS cases in a set of patients with gastroparesis. --- Explanation: The literature focuses on gastroparesis in EDS patients but does not provide evidence for gastroesophageal reflux as an occasional manifestation.

[PMID:34811894] [PARTIAL] Functional aerodigestive manifestations such as inducible laryngeal obstruction may be misdiagnosed as asthma, with gastro-esophageal dysmotility and reflux as common contributing factors. --- Explanation: The literature mentions gastro-esophageal dysmotility and reflux as contributing factors but does not specify the frequency as 'occasional.'


MONDO:0020066

[PMID:36237549] [PARTIAL] In addition to these commonly recognized phenotypes, recent studies have notably highlighted variable ophthalmic features in EDS. --- Explanation: Supports ophthalmic variability generally, but only partially supports keratoconus specifically.

[PMID:34501218] [PARTIAL] Because many patients with HDCTs have ocular symptoms, commonly myopia, they will often present to the clinic seeking refractive surgery. Currently, corrective measures are limited, as the FDA contraindicates laser-assisted in-situ keratomileusis (LASIK) in EDS and discourages the procedure in OI and MFS due to a theoretically increased risk of post-LASIK ectasia, poor wound healing, poor refractive predictability, underlying keratoconus, and globe rupture. --- Explanation: Provides indirect refractive-surgery caution context and only partial support for keratoconus frequency claim.


MONDO:0020066


MONDO:0020066

[PMID:7086195] [INDIRECT EVIDENCE] [SUPPORT] Several abnormalities in collagen biosynthesis have been described in patients with Ehlers-Danlos syndrome. Examples of collagen structural mutations as well as post-translational enzymatic defects have been detected. --- Explanation: This reference confirms that mutations affecting collagen synthesis and enzymes responsible for collagen modification are associated with Ehlers-Danlos Syndrome.

[PMID:37187299] [INDIRECT EVIDENCE] [SUPPORT] Vascular Ehlers-Danlos Syndrome (vEDS) is a rare autosomal dominant disease caused by mutations in the COL3A1 gene. --- Explanation: This reference identifies specific gene mutations (e.g., COL3A1) responsible for defective collagen synthesis leading to Ehlers-Danlos Syndrome.

[PMID:2010058] [INDIRECT EVIDENCE] [PARTIAL] Recently, several mutations in three other collagen genes (COL2A1, COL3A1, and COL4A5) have been found in probands with genetic diseases involving tissues rich in these collagens. --- Explanation: Supports collagen-gene mutation context broadly, but only partially supports this EDS-specific mechanistic descriptor.

[PMID:30246406] [INDIRECT EVIDENCE] [PARTIAL] Human EDS may be caused by variants in several different genes including COL5A1, which encodes the collagen type V alpha 1 chain. --- Explanation: Supports COL5A1 relevance via non-human model context, providing partial support.

[PMID:30668708] [INDIRECT EVIDENCE] [PARTIAL] Bi-allelic loss-of-function mutations in the adipocyte enhancer-binding protein 1 (AEBP1) gene were reported in three families with an autosomal recessive EDS-like condition. --- Explanation: Supports an EDS-like condition and provides only partial support for generalized collagen-abnormality claim in EDS.


MONDO:0020066

[PMID:358109] [INDIRECT EVIDENCE] [SUPPORT] The cardinal features are cutaneous hyperextensibility, joint hypermobility, bleeding diathesis, and tissue fragility, and these features lead to a large variety of additional manifestations. --- Explanation: The provided snippet mentions tissue fragility as a cardinal feature of Ehlers-Danlos Syndrome (EDS), which is consistent with the statement that abnormal collagen leads to weakened connective tissues.

[PMID:36960056] [INDIRECT EVIDENCE] [PARTIAL] pEDS is caused by heterozygous missense mutations in C1R and C1S genes of the classical complement C1 complex. --- Explanation: Supports periodontal EDS molecular pathology, but only partially supports broad collagen-fragility mechanism across EDS.

[PMID:1448] [INDIRECT EVIDENCE] [PARTIAL] Any defect in the normal mechanisms responsible for the synthesis and secretion of collagen molecules or the deposition of these molecules into extracellular fibers could result in abnormal fibrillogenesis; such defects could result in a connective tissue disease. --- Explanation: Provides broad conceptual support for collagen defects and connective tissue disease, but only partially supports this specific descriptor.

[PMID:31329366] [INDIRECT EVIDENCE] [SUPPORT] Collagen, which forms the framework of vessel walls, is altered in many patients with Ehlers-Danlos syndrome (EDS) leading to weakening of the vessel wall or the supporting tissues. --- Explanation: This reference directly supports the statement by mentioning how altered collagen in EDS patients leads to weakening of vessel walls and supporting tissues.


MAXO:0000011

[PMID:38189943] [SUPPORT] Affected patients require multimodal pain management considering their individual needs, disease-specific features, and comorbidities. --- Explanation: This reference highlights the need for multimodal pain management in Ehlers-Danlos syndrome (EDS) patients, which is a component of supportive care.

[PMID:34145717] [SUPPORT] Physiotherapy benefits on proprioception and pain in patients with hEDS even if robust randomized control studies are missing. --- Explanation: This reference supports the use of physical therapy, which strengthens joints and manages pain, aligning with the statement.

[PMID:17067502] [PARTIAL] Preparticipation cardiothoracic and orthopedic screening is highly recommended for athletes with EDS, and appropriate cardiovascular, orthopedic, gastrointestinal, neurologic, and dermatologic management can often allow patients with EDS to remain active. --- Explanation: Supports multidisciplinary screening/management context, but only partially supports the full supportive-care treatment claim.

[PMID:32941194] [PARTIAL] The creation of multidisciplinary care teams and tertiary referral centers is helping improve outcomes. --- Explanation: Supports multidisciplinary care framework, but only partially supports specific supportive-care interventions listed.


MAXO:0000004

[PMID:32904109] [SUPPORT] Patients with joint hypermobility syndrome (JHS) might also present with similar symptomatology. This article will focus on the surgical management of patients with knee or shoulder abnormalities related to hEDS/JHS. --- Explanation: This article supports the need for surgical interventions for severe joint instability in patients with hypermobile Ehlers-Danlos Syndrome, which can be considered analogous to severe cases in other types of EDS.

[PMID:30999998] [NO_EVIDENCE] The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality... During the period surveyed, the authors observed a statistically significant difference in the ratio of hospitalizations for acute arterial events/hospitalizations for regular follow-up before and after 2011. --- Explanation: Snippet is pharmacologic trial context and does not directly support surgical intervention.

[PMID:33650410] [PARTIAL] The vascular subtype of EDS (type IV) is defined by characteristic facial features, translucent skin, easy bruising, and spontaneous arterial rupture and visceral perforation of such organs as the uterus and intestines, with possible life-threatening consequences. --- Explanation: Supports life-threatening complication profile, but only indirectly supports surgical treatment recommendation.


MAXO:0000088

[PMID:17067502] [PARTIAL] Preparticipation cardiothoracic and orthopedic screening is highly recommended for athletes with EDS, and appropriate cardiovascular, orthopedic, gastrointestinal, neurologic, and dermatologic management can often allow patients with EDS to remain active. --- Explanation: Supports screening/management in athletes, but only partially supports explicit avoidance recommendation.

[PMID:35756986] [PARTIAL] The results suggest that exercise and rehabilitation may be beneficial for various physical and psychological outcomes. --- Explanation: Supports exercise/rehabilitation benefit generally, but only partial support for avoiding high-impact/contact sports specifically.


MAXO:0000004

[PMID:27349123] [PARTIAL] ignorance of effective treatments such as oxygen therapy and orthotics are new concepts that should shake the prejudices derived from the history of this disease. --- Explanation: Provides limited support for orthotics; phrasing is broad and indirect.

[PMID:32709178] [SUPPORT] Occupational therapy and bracing were the most effective options with 70% of patients reporting improvement. --- Explanation: This reference supports the use of orthotic devices (e.g., bracing) as effective in the management of EDS.


HGNC.SYMBOL:COL1A1

[PMID:36896471] [SUPPORT] Pathogenic variants in COL1A1 and COL1A2 are involved in osteogenesis imperfecta (OI) and, rarely, Ehlers-Danlos syndrome (EDS) subtypes and OI-EDS overlap syndromes (OIEDS1 and OIEDS2, respectively). --- Explanation: This statement supports that pathogenic variants in COL1A1 are associated with some subtypes of Ehlers-Danlos Syndrome (EDS).


HGNC.SYMBOL:COL3A1

[PMID:34560710] [SUPPORT] vEDS patients are at risk of blood vessel rupture due to possession of pathogenic variants of the COL3A1 gene, which encodes type III collagen. --- Explanation: The literature explicitly states that vascular Ehlers-Danlos syndrome (vEDS) is caused by pathogenic variants in the COL3A1 gene.

[PMID:30837697] [SUPPORT] Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. --- Explanation: The abstract confirms the association of vascular EDS with pathogenic variants in the COL3A1 gene.

[PMID:35699227] [SUPPORT] Carriers of pathogenic or likely pathogenic COL3A1 variants were retrospectively identified through registries and specialized clinics. --- Explanation: The study supports the association between pathogenic COL3A1 variants and vascular Ehlers-Danlos syndrome.


HGNC.SYMBOL:COL5A1

[PMID:16278879] [SUPPORT] Mutations in the COL5A1 and the COL5A2 gene, encoding the alpha1 and the alpha2-chain of type V collagen respectively, are identified in approximately 50% of patients with a clinical diagnosis of classic EDS. --- Explanation: The reference clearly states that mutations in the COL5A1 gene are associated with classical Ehlers-Danlos Syndrome, thus supporting the statement.


HGNC.SYMBOL:COL5A2

[PMID:16278879] [SUPPORT] Mutations in the COL5A1 and the COL5A2 gene, encoding the alpha1 and the alpha2-chain of type V collagen respectively, are identified in approximately 50% of patients with a clinical diagnosis of classic EDS. --- Explanation: The reference confirms that mutations in the COL5A2 gene, encoding the alpha2-chain of type V collagen, are associated with classical EDS and account for approximately 50% of classic EDS cases along with COL5A1.


HGNC.SYMBOL:ADAMTS2

[PMID:12646579] [SUPPORT] mutations in the ADAMTS-2 gene in dermatosparaxis and Ehlers-Danlos syndrome VIIC show this enzyme to be responsible in vivo for most biosynthetic processing of procollagen I N-propeptides in skin. --- Explanation: This study demonstrates that ADAMTS2 mutations cause Ehlers-Danlos syndrome type VIIC (dermatosparaxis) by disrupting procollagen processing.


HGNC.SYMBOL:TNXB

[PMID:36108117] [SUPPORT] The diagnosis of TNXB-related clEDS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in TNXB identified by molecular genetic testing. --- Explanation: This GeneReviews entry confirms that biallelic pathogenic variants in TNXB cause classical-like EDS.


HGNC.SYMBOL:C1R

[PMID:36960056] [SUPPORT] pEDS is caused by heterozygous missense mutations in C1R and C1S genes of the classical complement C1 complex. --- Explanation: This study demonstrates that C1R mutations cause periodontal EDS by triggering intracellular activation of complement proteases.


HGNC.SYMBOL:C1S

[PMID:36960056] [SUPPORT] pEDS is caused by heterozygous missense mutations in C1R and C1S genes of the classical complement C1 complex. --- Explanation: This study demonstrates that C1S mutations cause periodontal EDS, with activated C1s degrading collagen I.


HGNC.SYMBOL:PLOD1

[PMID:32174067] [SUPPORT] Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive connective tissue disorder... The disorder results from a deficiency of the enzyme collagen lysyl hydroxylase 1 due to mutations in the gene PLOD1. --- Explanation: This source clearly states that pathogenic variants in the PLOD1 gene are responsible for kyphoscoliotic Ehlers-Danlos syndrome.

[PMID:15979919] [SUPPORT] The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) is an inheritable connective tissue disorder characterized by a deficiency of lysyl hydroxylase due to mutations in PLOD1. --- Explanation: This reference supports the association between PLOD1 mutations and kyphoscoliotic Ehlers-Danlos syndrome.

[PMID:29982180] [SUPPORT] Pathogenic variants in the lysyl-hydroxylase-1 gene (PLOD1) are responsible for the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS). --- Explanation: This source reinforces the role of PLOD1 pathogenic variants in causing kyphoscoliotic Ehlers-Danlos syndrome.

[PMID:36054293] [SUPPORT] The autosomal recessive kyphoscoliotic EDS results from deficiency of either lysyl hydroxylase 1 (encoded by PLOD1), crucial for collagen cross-linking...  --- Explanation: This study adds further confirmation of the genetic association between PLOD1 and kyphoscoliotic Ehlers-Danlos syndrome.


MONDO:0007522

[PMID:34807421] [SUPPORT] Currently, musculoskeletal manifestations related to joint hypermobility are perceived as the most prevalent determinants of the quality of life of affected individuals. --- Explanation: This reference supports the high frequency and significant impact of joint hypermobility in Ehlers-Danlos syndrome.

[PMID:19370768] [SUPPORT] Classical Ehlers-Danlos syndrome (EDS) is a heritable disorder characterized by joint hypermobility, skin hyperextensibility, and abnormal wound healing. --- Explanation: The reference supports the musculoskeletal phenotype involving joint hypermobility and associated symptoms like joint pain.

[PMID:35964930] [PARTIAL] Classical (cEDS) and vascular type (vEDS) are the most prevalent subtypes and are caused by heterozygous pathogenic variants in COL5A1, COL5A2, COL1A1 or, respectively, in COL3A1. --- Explanation: Supports COL5A1 association with cEDS, but only indirectly supports the specific joint hypermobility claim.

[PMID:10906878] [PARTIAL] Thirty patients with Type III Ehlers-Danlos syndrome reported joint pain more frequently than did patients with Types I, II, or IV. --- Explanation: Supports joint pain burden in an EDS subgroup, but only partially supports this COL5A1-specific joint hypermobility descriptor.


MONDO:0007522

[PMID:21193204] [PARTIAL] Fifteen of the 252 patients (6.0%) had mitral valve prolapse (MVP), although only one patient (0.4%) had MVP that was mild to moderate. --- Explanation: The literature shows an occasional incidence of mitral valve prolapse in Ehlers-Danlos Syndrome, and while the exact subtype related to COL5A1 is not specified, it partially supports the statement.

[PMID:34776077] [SUPPORT] The EDS are currently classified into thirteen subtypes. There is substantial symptoms overlap between the EDS subtypes, and they are associated with an increased incidence of cardiovascular abnormalities, such as mitral valve prolapse and aortic dissection. --- Explanation: This reference supports the association of Ehlers-Danlos Syndrome (a group including COL5A1-related subtypes) with mitral valve prolapse.


MONDO:0007522

[PMID:26376608] [PARTIAL] Commonest GI symptoms were: abdominal pain (56.1%), nausea (42.3%), constipation (38.6%), heartburn (37.6%), and irritable bowel syndrome-like symptoms (27.5%)... Among 37.8% of the 378 patients who underwent esophagogastroduodenoscopy, the commonest abnormalities were gastritis, hiatal hernia and reflux esophagitis. --- Explanation: The study indicates that reflux esophagitis, which is related to gastroesophageal reflux, is one of the common abnormalities observed in EDS patients. However, it does not explicitly distinguish the frequency of this phenotype for COL5A1-related EDS specifically.


MONDO:0007522

[PMID:27905128] [SUPPORT] Molluscoid pseudotumours are a characteristic finding in patients with the classic ED variant, but are rarely reported in other variants. --- Explanation: The literature confirms that molluscoid pseudotumors are characteristic of the classic variant of Ehlers-Danlos Syndrome, which can be COL5A1-related. This supports the statement that these dermatologic features can occur occasionally in such cases.


MONDO:0007522

[PMID:36237549] [PARTIAL] In addition to these commonly recognized phenotypes, recent studies have notably highlighted variable ophthalmic features in EDS. --- Explanation: The study mentions variable ophthalmic features in EDS but does not specifically mention myopia as an occasional feature related to COL5A1.

[PMID:30246406] [NO_EVIDENCE] The affected cat showed multiple recurrent skin tears, hyperextensibility of the skin and joint abnormalities. --- Explanation: The study on a cat with EDS caused by a COL5A1 mutation does not mention myopia.


MONDO:0007522

[PMID:20697718] [SUPPORT] Ehlers-Danlos Syndrome is a term that comprises a variety of inherited connective tissue disorders characterized primarily by skin hyperextensibility, joints hypermobility and excessive dislocations, easy bruisability, generalized fragility. --- Explanation: The literature supports excessive dislocations as a characteristic feature of Ehlers-Danlos Syndrome.


MONDO:0007522

[PMID:10906878] [PARTIAL] Thirty patients with Type III Ehlers-Danlos syndrome reported joint pain more frequently than did patients with Types I, II, or IV. --- Explanation: Supports joint pain in an EDS subgroup, but only partially supports this COL5A1-related phenotype frequency claim.


MONDO:0007522

[PMID:20847697] [SUPPORT] Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars. --- Explanation: Delayed wound healing is a core feature of classic EDS due to defective collagen V.


MONDO:0007522

[PMID:9042913] [INDIRECT EVIDENCE] [SUPPORT] The mutation causes the substitution of the most 5' cysteine residue by a serine within a highly conserved sequence of the pro(alpha)1(V) C-propeptide domain and causes reduction of collagen V by preventing incorporation of the mutant pro(alpha)1(V) chains in the collagen V trimers. --- Explanation: This reference describes how mutations in COL5A1 lead to defective synthesis and assembly of collagen type V, supporting the given statement.


MONDO:0007522


MONDO:0007522

[PMID:20847697] [INDIRECT EVIDENCE] [SUPPORT] In the majority of patients with molecularly characterized classic Ehlers-Danlos syndrome, the disease is caused by a mutation leading to a nonfunctional COL5A1 allele and resulting in haploinsufficiency of type V collagen. --- Explanation: The literature indicates that mutations in the COL5A1 gene lead to abnormalities in collagen type V, resulting in weakened connective tissues.

[PMID:15095409] [INDIRECT EVIDENCE] [SUPPORT] EDS cells with COL5A1 haplo-insufficiency deposited less than one-half of hydroxyproline as collagen compared to control fibroblasts. ... a reduction of type V collagen, in the EDS derived cells, was associated with the assembly of significantly fewer fibrils compared to control and OI cells. --- Explanation: This study demonstrates that reduced type V collagen results in weaker connective tissue due to a significant decrease in collagen fibril assembly.

[PMID:12836217] [INDIRECT EVIDENCE] [SUPPORT] The classical form of the syndrome, which will be principally discussed in this review, can be due to mutations on collagen V, a fibrillar collagen present in small amounts in affected tissues. --- Explanation: The literature describes the role of collagen V and its mutations in causing connective tissue fragility, therefore supporting the statement.


MONDO:0007522

[PMID:19370768] [INDIRECT EVIDENCE] [PARTIAL] Classical Ehlers-Danlos syndrome (EDS) is a heritable disorder characterized by joint hypermobility, skin hyperextensibility, and abnormal wound healing. --- Explanation: Supports core cEDS tissue fragility features, but only partially supports the full mechanistic descriptor.

[PMID:19592142] [INDIRECT EVIDENCE] [PARTIAL] The bleeding tendency is most prominent in the Ehlers-Danlos syndrome (EDS), a heterogeneous group of HDCT sharing clinical manifestations of fragility in skin, ligaments, blood vessels and internal organs. --- Explanation: Supports generalized tissue fragility in EDS, but only partially supports this COL5A1-specific mechanism statement.

[PMID:20697718] [INDIRECT EVIDENCE] [PARTIAL] Ehlers-Danlos Syndrome is a term that comprises a variety of inherited connective tissue disorders characterized primarily by skin hyperextensibility, joints hypermobility and excessive dislocations, easy bruisability, generalized fragility. --- Explanation: Supports broad EDS clinical fragility features, but not the full mechanistic details in this descriptor.

[PMID:19055167] [INDIRECT EVIDENCE] [PARTIAL] Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders characterized by hyperextensibility, delayed wound healing, joint hypermobility, thin skin, easy bruising, tissue fragility, 'cigarette-paper' scarring over bony prominences. --- Explanation: Supports core cEDS phenotype features, but only partially supports this detailed pathophysiology statement.


MAXO:0000011

[PMID:22616833] [PARTIAL] The topics addressed in this issue are Ehlers-Danlos syndrome and associated chronic pain; the information is meant to help readers understand the mechanisms for pain in this connective tissue disorder as well as general treatment principles for chronic pain management. --- Explanation: Supports chronic pain management principles in EDS, but only partially supports the full supportive-care descriptor.

[PMID:33741806] [SUPPORT] Evidence supporting physical therapy and occupational therapy is provided... Treatment should be individualized. --- Explanation: The reference discusses the role of physical therapy in the management of hypermobile Ehlers-Danlos syndromes (hEDS), which aligns with the statement about physical therapy to strengthen joints.

[PMID:9042913] [NO_EVIDENCE] These findings confirm the causal role of collagen V in at least a subgroup of EDS I. --- Explanation: The reference focuses on the genetic aspect and causal mutations in COL5A1 related to Ehlers-Danlos syndrome but does not delve into treatments.

[PMID:35162892] [NO_EVIDENCE] Treatment is currently symptomatic and focuses on increasing the quality of life of these patients, as there is no curative treatment. --- Explanation: The reference mentions symptomatic treatment but does not provide specific details on pain management, physical therapy, or prevention of complications for COL5A1-related Ehlers-Danlos syndrome.

[PMID:32941194] [NO_EVIDENCE] Although medical interventions to help halt the disease progression remain limited, improved awareness of vEDS by patients and practitioners have resulted in increased average life expectancy. --- Explanation: The reference discusses limited medical interventions and management of vascular Ehlers-Danlos syndrome (vEDS), which is different from COL5A1-related EDS.


MAXO:0000950

[PMID:8274350] [PARTIAL] Manifestations are highly variable, and include numerous skin abnormalities. Nurses play an important role in helping patients and their families live with this unusual disorder. --- Explanation: The reference mentions skin abnormalities but does not provide explicit details on treatments related to wound care or scar management.

[PMID:2728341] [PARTIAL] Although delayed wound healing has been reported to be a complication of Ehlers-Danlos syndrome in humans, using clinical and histologic criteria, wound healing in dogs and cats with Ehlers-Danlos syndrome appears to be similar to nonaffected animals. --- Explanation: This reference discusses wound healing in animal models of EDS but indicates that delayed healing, a common complication in human EDS patients, was not observed in the studied animals.

[PMID:28387435] [PARTIAL] Classic Ehlers-Danlos syndrome (EDS) patients suffer from connective tissue hyperelasticity, joint instability, skin hyperextensibility, tissue fragility, and poor wound healing due to heterozygous mutations in COL5a1 or COL5a2 genes. --- Explanation: Supports poor wound-healing burden in cEDS, but only indirectly supports wound-care intervention efficacy.

[PMID:37594181] [NO_EVIDENCE] The classic tragic facial expression was observed as well as chronic pruritus and mild hyperesthesia. ... Histology showed sparse, disorganized collagen and an increase in cutaneous mast cells. Electron microscopy identified ultrastructural defects commonly seen in collagen type V alpha 1 chain (COL5A1) variants including flower-like collagen fibrils in cross-section. --- Explanation: Snippet describes phenotype/histology and does not directly provide wound-care treatment evidence.


MAXO:0000267

[PMID:26376608] [NO_EVIDENCE] CONCLUSIONS & INFERENCES: EDS HM and other subtypes should be considered in patients with chronic functional GI symptoms and abdominal vascular lesions. --- Explanation: Snippet supports GI symptom burden in EDS, but does not directly provide treatment evidence for gastrointestinal management.


MAXO:0000088

[PMID:17067502] [PARTIAL] Preparticipation cardiothoracic and orthopedic screening is highly recommended for athletes with EDS, and appropriate cardiovascular, orthopedic, gastrointestinal, neurologic, and dermatologic management can often allow patients with EDS to remain active. --- Explanation: The literature emphasizes careful screening and multidisciplinary management for athletes with EDS, which implicitly supports the avoidance of high-impact activities to prevent injuries but does not explicitly mention the use of protective gear or contact sports.

[PMID:32899328] [PARTIAL] The major clinical manifestations of EDS include joint hypermobility, skin hyperextensibility, and generalized connective tissue fragility. ... These findings allow healthcare providers to know more about this disease in order to support and give advice to patients about the changes they will have to make. --- Explanation: The study highlights the importance of providing advice to patients about lifestyle changes due to EDS but does not specifically mention avoiding high-impact activities or using protective gear.


HGNC.SYMBOL:COL5A1

[PMID:30858776] [SUPPORT] Among all tested patients, nine mutations of COL5A1 gene were detected (8 missense mutations and 1 splice site). --- Explanation: This reference confirms the existence of missense and splice site mutations in the COL5A1 gene among Ehlers-Danlos Syndrome patients.

[PMID:33656776] [SUPPORT] Glycine substitution mutation of COL5A1 in classic Ehlers-Danlos syndrome: a case report and literature review. --- Explanation: This reference supports the presence of missense mutations specifically related to COL5A1 in Ehlers-Danlos Syndrome.

[PMID:35241120] [PARTIAL] This study supports that rs12722 is associated with an elevated susceptibility to ligament injury, especially in the Caucasian population. --- Explanation: While the study primarily investigates the association of COL5A1 polymorphisms with musculoskeletal injuries, it partially supports the statement by recognizing relevant genetic variants.

[PMID:2683783] [NO_EVIDENCE] Mutations in the majority of the 20 known collagen genes have not yet been identified. --- Explanation: This reference doesn't support the existence of frameshift mutations in COL5A1, making the specific part of the statement regarding frameshift mutations unsubstantiated.


MONDO:0009162

[PMID:17547743] [SUPPORT] Ellis-van Creveld syndrome (EVC) is a chondral and ectodermal dysplasia characterized by short ribs, polydactyly, growth retardation, and ectodermal and heart defects. --- Explanation: Comprehensive review identifies growth retardation as a cardinal feature of EvC.


MONDO:0009162

[PMID:10700184] [SUPPORT] an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth. --- Explanation: Postaxial polydactyly is a defining feature of EvC syndrome.


MONDO:0009162

[PMID:17547743] [SUPPORT] Prognosis is linked to the respiratory difficulties in the first months of life due to thoracic narrowness and possible heart defects. --- Explanation: Thoracic narrowness from short ribs is a major prognostic factor, causing respiratory difficulties in neonates.


MONDO:0009162

[PMID:10700184] [SUPPORT] Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. --- Explanation: Landmark paper establishing 60% frequency of cardiac defects, with common atrium as the most characteristic lesion.

[PMID:17547743] [SUPPORT] Heart defects, especially abnormalities of atrial septation, occur in about 60% of cases. --- Explanation: Comprehensive review confirms 60% cardiac defect frequency.

[PMID:21533779] [SUPPORT] Persistent left superior vena cava (LSVC) and pulmonary venous connection abnormalities were common. The incidence of persistent LSVC and pulmonary venous abnormalities were greater than previously reported for patients with EVC. --- Explanation: Large cardiac case series reveals venous connection abnormalities are more common in EvC than previously recognized.


MONDO:0009162

[PMID:17547743] [SUPPORT] cardinal features are short stature, short ribs, polydactyly, and dysplastic fingernails and teeth. --- Explanation: Dysplastic fingernails are a cardinal feature of EvC.


MONDO:0009162

[PMID:17547743] [SUPPORT] cardinal features are short stature, short ribs, polydactyly, and dysplastic fingernails and teeth. --- Explanation: Dysplastic teeth are a cardinal feature of EvC.


MONDO:0009162


MONDO:0009162

[PMID:23026747] [INDIRECT EVIDENCE] [SUPPORT] Mutations in EVC or EVC2 disrupt Hh signaling in tooth and bone development. --- Explanation: Demonstrates that EVC/EVC2 mutations specifically disrupt Hedgehog signaling in skeletal and dental tissues.

[PMID:23026747] [INDIRECT EVIDENCE] [SUPPORT] Evc and Evc2 are mutually required for localizing to primary cilia and also for maintaining their normal protein levels. --- Explanation: Shows the EVC/EVC2 complex is interdependent for ciliary localization and protein stability.

[PMID:23026747] [INDIRECT EVIDENCE] [SUPPORT] we found Smo to co-precipitate with Evc/Evc2, indicating that in some cells Hh signaling requires direct interaction of Smo with the Evc/Evc2 complex. --- Explanation: Demonstrates direct physical interaction between Smo and the Evc/Evc2 complex in Hedgehog signal transduction.


MONDO:0009162

[PMID:24582806] [INDIRECT EVIDENCE] [SUPPORT] The EFCAB7-IQCE module anchors the EVC-EVC2 complex in a signaling microdomain at the base of cilia. --- Explanation: Identifies the molecular mechanism by which EVC-EVC2 is anchored at the ciliary base for Hedgehog signal transduction.

[PMID:24582806] [INDIRECT EVIDENCE] [SUPPORT] EFCAB7 depletion mimics the Weyers cellular phenotype-the mislocalization of EVC-EVC2 within cilia and impaired activation of the transcription factor GLI2. --- Explanation: Shows that mislocalization of EVC-EVC2 within cilia impairs GLI2 activation, linking ciliary dysfunction to disease phenotype.

[PMID:23026747] [INDIRECT EVIDENCE] [SUPPORT] Gli3 recruitment to cilia tips was reduced and Sufu/Gli3 dissociation was impaired. --- Explanation: In Evc2-deficient chondrocytes, Gli3 processing at cilia tips is impaired, demonstrating the ciliary signaling defect.


MONDO:0009162

[PMID:21533779] [INDIRECT EVIDENCE] [PARTIAL] Twenty-eight (88%) had an endocardial cushion defect, with 15 of these having primary failure of atrial septation resulting in CA. --- Explanation: In 32 EvC patients with CHD, 88% had endocardial cushion defects, with common atrium being the most characteristic cardiac lesion.

[PMID:21533779] [INDIRECT EVIDENCE] [SUPPORT] The frequent association of these abnormalities is strongly reminiscent of the cardiac phenotype found in patients with heterotaxy syndromes. --- Explanation: Cardiac phenotype in EvC resembles heterotaxy, suggesting shared cilia-dependent cardiac morphogenesis mechanism.

[PMID:21533779] [INDIRECT EVIDENCE] [SUPPORT] EVC and EVC2 proteins may be important for cilia function, which is implicated in the pathogenesis of heterotaxy syndromes. --- Explanation: Suggests a cilia-related mechanism, but the statement is speculative and only partially supports the mechanistic claim.


MAXO:0000004

[PMID:21533779] [NO_EVIDENCE] Thirty-two pediatric patients with congenital heart disease (CHD) and EVC syndrome were identified in the PCCC database. --- Explanation: Snippet identifies EvC patients with CHD but does not provide direct evidence for cardiac surgery outcomes or use.


HGNC.SYMBOL:EVC Mutations

[PMID:10700184] [SUPPORT] We have identified a new gene (EVC), encoding a 992-amino-acid protein, that is mutated in individuals with EvC. --- Explanation: Landmark paper identifying EVC as a causative gene for EvC syndrome.

[PMID:10700184] [SUPPORT] We identified a splice-donor change in an Amish pedigree and six truncating mutations and a single amino acid deletion in seven pedigrees. --- Explanation: Describes the mutation spectrum in EVC including truncating and splice-site mutations.


HGNC.SYMBOL:EVC2 Mutations

[PMID:12571802] [SUPPORT] We now report that mutations in EVC2 also cause EvC. These two genes lie in a head-to-head configuration that is conserved from fish to man. --- Explanation: Identifies EVC2 as a second causative gene in a head-to-head configuration with EVC.

[PMID:12571802] [SUPPORT] Affected individuals with mutations in EVC and EVC2 have the typical spectrum of features and are phenotypically indistinguishable. --- Explanation: Confirms that EVC and EVC2 mutations produce identical clinical phenotypes.


MONDO:0009993


MONDO:0009993

[PMID:10095436] [INDIRECT EVIDENCE] [PARTIAL] Allelic losses of 11p15.5 are characteristic of embryonal RMS (eRMS), whereas an increase in the expression of the Igf2 gene located on 11p15.5 has regularly been observed in eRMS and alveolar RMS (aRMS). --- Explanation: Supports characteristic 11p15.5 LOH and IGF2 dysregulation in ERMS, but not all detailed mechanistic/frequency specifics in this descriptor.


MAXO:0000647


CHEBI:28445


CHEBI:27666


CHEBI:4026


MAXO:0000004


MAXO:0000014


HGNC.SYMBOL:Loss of Heterozygosity at 11p15


HGNC.SYMBOL:RAS Pathway Mutations


HGNC.SYMBOL:TP53 Mutations


MONDO:0009993

[PMID:10337369] [SUPPORT] Rhabdomyosarcoma (RMS) is a malignant tumor of mesenchymal origin thought to --- Explanation: Abstract describes rhabdomyosarcoma as a malignant tumor of mesenchymal origin.


MONDO:1060148

[PMID:34630863] [SUPPORT] The main feature of ENS is paradoxical nasal obstruction feeling despite objectively wide nasal airway. --- Explanation: Directly describes paradoxical nasal obstruction as the main feature of ENS.

[PMID:34665687] [PARTIAL] ENS patients demonstrated high symptom severity. --- Explanation: Supports high overall symptom burden, but does not specifically quantify paradoxical obstruction.


MONDO:1060148

[PMID:25430954] [SUPPORT] The most common clinical symptoms are paradoxical nasal obstruction, nasal dryness and crusting, and a persistent feeling of dyspnea. --- Explanation: Review identifying nasal dryness and crusting as among the most common clinical symptoms of ENS.

[PMID:34630863] [SUPPORT] This leads to the development of ENS symptomatology such as dyspnea, nasal dryness, nasal burning, nasal obstruction, feeling of suffocation and even comorbid psychiatric disorders that significantly impairs life quality. --- Explanation: Confirms nasal dryness as a core ENS symptom arising from the multifactorial pathogenesis.


MONDO:1060148

[PMID:25430954] [SUPPORT] The most common clinical symptoms are paradoxical nasal obstruction, nasal dryness and crusting, and a persistent feeling of dyspnea. --- Explanation: Identifies persistent dyspnea as one of the most common clinical symptoms of ENS.

[PMID:34630863] [SUPPORT] This leads to the development of ENS symptomatology such as dyspnea, nasal dryness, nasal burning, nasal obstruction, feeling of suffocation and even comorbid psychiatric disorders that significantly impairs life quality. --- Explanation: Lists dyspnea and suffocation among the core ENS symptoms.


MONDO:1060148

[PMID:32125703] [SUPPORT] The nasal mucosa of ENS experienced some airway remodeling and thermoreceptors downregulation, which contribute to clinical symptoms. --- Explanation: Demonstrates distinct histopathological changes in ENS nasal mucosa including airway remodeling.

[PMID:32125703] [SUPPORT] The respiratory epitheliums of ENS were mostly intact with preservation of ciliated cells and goblet cells. --- Explanation: Characterizes the unique histological pattern where respiratory epithelium is partially preserved despite other mucosal remodeling.

[PMID:34665687] [SUPPORT] Turbinate histopathology in ENS showed a tissue-remodeling pattern. --- Explanation: Systematic review confirming tissue remodeling as a pathophysiologic theme in ENS.


MONDO:1060148

[PMID:26692010] [SUPPORT] Facial pain was significantly correlated with smaller anterior ITV (P = 0.011). --- Explanation: SNOT-25 data showing facial pain/pressure significantly correlates with reduced anterior inferior turbinate volume in ENS patients.


MONDO:1060148

[PMID:34665687] [PARTIAL] Subjective impairment was reported in ENS, but quantitative measures were similar to non-ENS patients. --- Explanation: Systematic review finding that subjective olfactory impairment is reported but objective quantitative measures show no significant difference from controls.


MONDO:1060148

[PMID:40617870] [SUPPORT] Depression and anxiety are common among patients with ENS, with a possible increased prevalence of depression in patients with ENS compared to those with CRS. --- Explanation: Meta-analysis confirming high prevalence of depression in ENS patients, with prevalence significantly exceeding that in chronic rhinosinusitis.

[PMID:34665687] [SUPPORT] Anxiety and depression including hyperventilation were reported in >50% of ENS patients and correlated with ENS symptom severity. --- Explanation: Systematic review confirming depression in over 50% of ENS patients with correlation to symptom severity.

[PMID:35155779] [PARTIAL] Suicidal thoughts are frequently identified in patients with ENS. --- Explanation: Supports severe psychological burden in ENS, but only indirectly supports depression prevalence.


MONDO:1060148

[PMID:40617870] [SUPPORT] Depression and anxiety are common among patients with ENS, with a possible increased prevalence of depression in patients with ENS compared to those with CRS. --- Explanation: Meta-analysis confirming high prevalence of anxiety in ENS patients.

[PMID:34665687] [PARTIAL] There is evidence of high comorbid mental health disorders in ENS patients. --- Explanation: Supports psychiatric comorbidity broadly, but only partially supports anxiety specifically.


MONDO:1060148

[PMID:34665687] [SUPPORT] Anxiety and depression including hyperventilation were reported in >50% of ENS patients and correlated with ENS symptom severity. --- Explanation: Identifies hyperventilation as occurring in association with anxiety and depression in ENS patients.


MONDO:1060148

[PMID:36306524] [SUPPORT] Patients with ENS experienced significantly impaired sleep quality and sleepiness. --- Explanation: Prospective study demonstrating significantly impaired sleep quality and daytime sleepiness in ENS patients compared to controls.

[PMID:36306524] [SUPPORT] The severity of sleep dysfunction is associated with the severity of ENS symptoms. --- Explanation: Demonstrates that sleep dysfunction severity correlates with overall ENS symptom severity.


MONDO:1060148

[PMID:35155779] [SUPPORT] Suicidal thoughts were identified in 23 ENS patients preoperatively and in four patients postoperatively. --- Explanation: Prospective study demonstrating high prevalence of suicidal thoughts in ENS patients, with improvement after surgical reconstruction.

[PMID:35155779] [SUPPORT] ENS patients with suicidal thoughts experienced significantly more severe symptoms, impaired quality of life, and psychological burden than those without suicidal thoughts. --- Explanation: Suicidal ideation correlates with more severe ENS symptoms and greater psychological burden.


MONDO:1060148

[PMID:25430954] [INDIRECT EVIDENCE] [SUPPORT] Empty nose syndrome (ENS) is a rare, late complication of turbinate surgery. --- Explanation: Confirms ENS develops as a complication of turbinate surgery, establishing the iatrogenic surgical origin.

[PMID:40461852] [INDIRECT EVIDENCE] [SUPPORT] Empty nose syndrome (ENS) is a complex iatrogenic condition resulting from excessive inferior turbinate resection, leading to paradoxical nasal obstruction despite an objectively patent airway. --- Explanation: Confirms ENS as an iatrogenic condition specifically resulting from excessive inferior turbinate resection.


MONDO:1060148


MONDO:1060148

[DOI:10.1002/alr.22350] [INDIRECT EVIDENCE] [PARTIAL] symptomatic ENS patients have paradoxical significantly less airflow in the inferior meatus --- Explanation: CFD analysis demonstrates paradoxical redistribution of airflow away from the inferior meatus in ENS patients despite surgical enlargement of the nasal passages.

[PMID:34630863] [INDIRECT EVIDENCE] [SUPPORT] ENS pathogenesis is multifactorial and includes changes in laminar physiological airflow, disruption of mucosa functions and deficient neural sensation. --- Explanation: Confirms that altered laminar airflow is a key component of ENS pathogenesis alongside mucosal and neural factors.


MONDO:1060148

[PMID:32125703] [INDIRECT EVIDENCE] [SUPPORT] Additionally, a unique histological change called goblet cell metaplasia was found in the ENS group. --- Explanation: Identifies goblet cell metaplasia as a distinct histological feature of ENS, reflecting mucosal remodeling that disrupts normal goblet cell secretory function and mucociliary clearance.


MONDO:1060148

[PMID:32125703] [INDIRECT EVIDENCE] [SUPPORT] Patients with ENS presented significantly more squamous metaplasia, a higher rate of submucosal fibrosis, and a lower submucosal gland number grading. --- Explanation: Histopathological evidence directly demonstrating reduced submucosal glands and mucosal remodeling that impairs the capacity to warm and humidify inspired air.


MONDO:1060148

[PMID:32125703] [INDIRECT EVIDENCE] [SUPPORT] The ENS group had a significantly lower expression level of TRPM8. --- Explanation: Direct immunohistochemical evidence of TRPM8 downregulation in ENS nasal mucosa, confirming peripheral neurosensory dysfunction.

[DOI:10.1002/alr.22350] [INDIRECT EVIDENCE] [SUPPORT] a combination of distorted nasal aerodynamics and loss of mucosal sensory function may potentially lead to ENS symptomology. --- Explanation: Supports combined aerodynamic and sensory mechanisms as a plausible contributor, but wording in the source remains tentative.

[PMID:31116142] [INDIRECT EVIDENCE] [PARTIAL] new data suggest that impaired trigeminal nerve function may also play a role in the pathophysiology of the disease. --- Explanation: Review notes impaired trigeminal function as a possible mechanism, providing partial support.

[PMID:24978195] [INDIRECT EVIDENCE] [PARTIAL] Aberrations in neurosensory systems from improper healing may play a major role in the abnormal sensations ENS patients experience. --- Explanation: Hypothesis-level review statement provides partial support for neurosensory contribution.

[PMID:34665687] [INDIRECT EVIDENCE] [PARTIAL] An abnormal trigeminal-thermoreceptor response may be present in some patients. --- Explanation: Systematic review indicates abnormal trigeminal-thermoreceptor response in some patients, partially supporting this claim.


MONDO:1060148

[PMID:34630863] [INDIRECT EVIDENCE] [SUPPORT] The main feature of ENS is paradoxical nasal obstruction feeling despite objectively wide nasal airway. --- Explanation: Directly describes the paradoxical nature of ENS where patients experience obstruction despite patent airways.

[PMID:25430954] [INDIRECT EVIDENCE] [SUPPORT] The most common clinical symptoms are paradoxical nasal obstruction, nasal dryness and crusting, and a persistent feeling of dyspnea. --- Explanation: Review confirming paradoxical nasal obstruction and dyspnea as the most common clinical symptoms of ENS.

[PMID:19328896] [INDIRECT EVIDENCE] [SUPPORT] The problem with empty nose syndrome is probably not that it does not exist, it is that we cannot adequately explain its existence by what we currently understand about the nose. --- Explanation: Editorial acknowledging the reality of ENS as a clinical entity while highlighting the difficulty of explaining the paradoxical symptoms.


MAXO:0000004

[PMID:40461852] [SUPPORT] While surgical interventions demonstrate sustained improvements in patient quality of life, substantial heterogeneity across meta-analyses and overlapping primary data highlight the need for standardized protocols --- Explanation: Meta-analysis of meta-analyses covering over 1500 cases confirms sustained quality of life improvements from surgical interventions, though evidence heterogeneity is noted.

[PMID:37750541] [SUPPORT] These data and analysis suggest that performing inferior turbinate/meatus augmentation on ENS patients may improve not only nasal symptom scores but also accompanying psychological problems such as anxiety and depression. --- Explanation: Meta-analysis showing that turbinate augmentation improves both nasal symptoms and psychological comorbidities.

[PMID:25430954] [SUPPORT] Surgical therapy should be reserved for refractory cases and may involve turbinate reconstruction, most commonly using implantable biomaterials. --- Explanation: Review recommending surgical reconstruction with implantable biomaterials for refractory ENS cases.

[PMID:31116142] [PARTIAL] there has been a marked increase in surgical treatment strategies to reconstitute turbinate volume with various implant materials. --- Explanation: Documents increased use of implant strategies, but does not directly establish treatment efficacy.


MAXO:0000950

[PMID:31116142] [SUPPORT] Nasal humidification, patient education, and treatment of possible concomitant medical conditions (e.g., depression) constitute first lines of treatment. --- Explanation: Identifies nasal humidification as a first-line treatment along with patient education and management of psychological comorbidities.

[PMID:25430954] [NO_EVIDENCE] Medical therapies include mucosal humidification, irrigations, and emollients. --- Explanation: Review listing mucosal humidification, irrigations, and emollients as medical therapy options for ENS.


MAXO:0000004

[PMID:36630732] [SUPPORT] We present two cases of ENS treated by injection of PRP as a simple and less invasive method, and describe its efficacy with nasal endoscopy and subjective questionnaires. --- Explanation: Case report demonstrating PRP injection as a less invasive treatment option for ENS with documented symptomatic improvement.


MONDO:1060148

[PMID:32125703] [SUPPORT] Patients with ENS presented significantly more squamous metaplasia, a higher rate of submucosal fibrosis, and a lower submucosal gland number grading. --- Explanation: Prospective case-control study demonstrating significantly increased squamous metaplasia in ENS nasal mucosa compared to controls.


MONDO:1060148

[PMID:32125703] [SUPPORT] Patients with ENS presented significantly more squamous metaplasia, a higher rate of submucosal fibrosis, and a lower submucosal gland number grading. --- Explanation: Histopathological evidence of increased submucosal fibrosis and reduced submucosal gland density in ENS tissue.


MONDO:0013074

[PMID:34547955] [SUPPORT] Key clinical features include hairless fatty tissue nevus of the scalp, choristoma of the eye and intraspinal and intracerebral lipomas. --- Explanation: Intracerebral and intraspinal lipomas are listed as key clinical features.


MONDO:0013074

[PMID:34547955] [SUPPORT] It is characterized by unilateral ocular, cutaneous and central nervous system anomalies. --- Explanation: Unilateral cutaneous anomalies are a defining feature of ECCL.


MONDO:0013074

[PMID:34547955] [SUPPORT] Key clinical features include hairless fatty tissue nevus of the scalp, choristoma of the eye and intraspinal and intracerebral lipomas. --- Explanation: Choristoma of the eye is listed as a key clinical feature of ECCL.


MONDO:0013074

[PMID:34547955] [SUPPORT] Prenatal ultrasound and MRI of the third trimester showed multifocal spinal lesions and left lateral cerebral ventriculomegaly with cerebral atrophy. --- Explanation: Ventriculomegaly demonstrated on prenatal imaging in an ECCL case.


MONDO:0013074

[PMID:37486073] [INDIRECT EVIDENCE] [SUPPORT] Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder caused by somatic FGFR1 and KRAS variants. --- Explanation: Confirms somatic FGFR1 variants as a cause of ECCL.


MAXO:0000004


MAXO:0000950

[PMID:37486073] [SUPPORT] Patients with FGFR1-associated ECCL carry a risk of developing malignant brain tumors; thus, genetic testing of patients with suspected ECCL has important management implications. --- Explanation: Establishes the need for brain tumor surveillance in FGFR1-associated ECCL.


hgnc:3688

[PMID:37486073] [SUPPORT] next-generation sequencing of affected tissue identified a pathologic FGFR1 p.K656E variant, thereby establishing a molecular diagnosis. --- Explanation: Identifies p.K656E as a pathogenic FGFR1 variant in ECCL.


MONDO:0013074

[PMID:34547955] [SUPPORT] ECCL was confirmed by the identification of a postzygotic FGFR1 mutation. --- Explanation: Confirms postzygotic (somatic mosaic) origin of the FGFR1 mutation in ECCL.


MONDO:0005133


MONDO:0005133

[PMID:30074218] [SUPPORT] The expression of all three proteins in both serum and endometrial tissues increased significantly with the R-AFS stage (P<0.05) and with dysmenorrheal severity (P<0.05). --- Explanation: VEGF and HIF-1alpha expression correlates with dysmenorrhea severity, linking hypoxia and angiogenesis to pain


MONDO:0005133

[PMID:16166933] [SUPPORT] Increased levels of several cytokines and growth factors which are secreted by either immune and endometrial cells seem to promote implantation and growth of ectopic endometrium by inducing proliferation and angiogenesis. --- Explanation: Snippet supports inflammatory lesion growth mechanisms but does not directly support infertility frequency.


MONDO:0005133

[PMID:16166933] [INDIRECT EVIDENCE] [PARTIAL] Endometriosis is classically described as the presence of both endometrial glandular and stromal cells outside the uterine cavity, mainly in the pelvis. --- Explanation: Defines endometriosis as ectopic presence of endometrial glandular and stromal cells outside the uterus


MONDO:0005133

[PMID:16166933] [INDIRECT EVIDENCE] [SUPPORT] Increased levels of several cytokines and growth factors which are secreted by either immune and endometrial cells seem to promote implantation and growth of ectopic endometrium by inducing proliferation and angiogenesis. --- Explanation: Supports inflammatory cytokine/growth-factor milieu, but not the full downstream pain and adhesion statement.


MONDO:0005133

[PMID:10731122] [INDIRECT EVIDENCE] [SUPPORT] Estrogen is the most important known factor that stimulates the growth of endometriosis. Estrogen delivery to endometriotic implants was classically viewed to be only via the circulating blood in an endocrine fashion. We recently uncovered an autocrine positive feedback mechanism, which favored the continuous production of estrogen and prostaglandin (PG)E2 in the endometriotic stromal cells. --- Explanation: Estrogen drives endometriosis growth through both systemic delivery and local autocrine production

[PMID:10731122] [INDIRECT EVIDENCE] [SUPPORT] The enzyme, aromatase, is aberrantly expressed in endometriotic stromal cells and catalyzes the conversion of C19 steroids to estrogens, which then stimulate cyclooxygenase-2 to increase the levels of PGE2. PGE2, in turn, is a potent inducer of aromatase activity in endometriotic stromal cells. Aromatase is not expressed in the eutopic endometrium. --- Explanation: Aromatase expression in endometriotic stromal cells creates a positive feedback loop with PGE2 for local estrogen production

[PMID:10731122] [INDIRECT EVIDENCE] [SUPPORT] In addition, we find that endometriotic tissue is deficient in 17beta-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrial glandular cells and inactivates estradiol-17beta to estrone. This deficiency is another aberration that favors higher levels of estradiol-17beta in endometriotic tissues in comparison with the eutopic endometrium. --- Explanation: Deficiency of 17beta-HSD type 2 prevents estradiol inactivation, contributing to local estrogen dominance


MONDO:0005133

[PMID:16166933] [INDIRECT EVIDENCE] [NO_EVIDENCE] Increased number and activation of peritoneal macrophages, decreased T cell and natural killer (NK) cell cytotoxicities are the alterations in cellular immunity and result in inadequate removal of ectopic endometrial cells from the peritoneal cavity. --- Explanation: Immune cell dysfunction leads to impaired clearance of ectopic endometrial cells

[PMID:28971893] [INDIRECT EVIDENCE] [SUPPORT] The dysfunction of NK cells in women with endometriosis (EMS) contributes to the immune escape of menstrual endometrial fragments refluxed into the peritoneal cavity. --- Explanation: NK cell dysfunction is a key mechanism enabling immune escape of refluxed endometrial fragments

[PMID:28971893] [INDIRECT EVIDENCE] [SUPPORT] After incubation with ESCs and macrophages, the expression of CD16, NKG2D, perforin and IFN-γ, viability and cytotoxicity of NK cells were significantly downregulated. The secretion of interleukin (IL)-1β, IL-10 and transforming growth factor (TGF)-β in the co-culture system of ESCs and macrophages was increased. --- Explanation: Interaction between endometrial stromal cells and macrophages suppresses NK cell cytotoxicity through IL-10 and TGF-beta


MONDO:0005133

[PMID:26408396] [INDIRECT EVIDENCE] [SUPPORT] Endometriosis is associated with local angiogenic and hypoxic mechanisms. Indeed, peritoneal fluid of women with endometriosis generates a specific microenvironment to support the growth and development of ectopic endometrial tissues. --- Explanation: Angiogenic and hypoxic mechanisms create a supportive microenvironment for ectopic lesion growth

[PMID:26408396] [INDIRECT EVIDENCE] [SUPPORT] Ovarian endometrioma expresses high levels of HIF-1/2α, PAR-1/4, and VEGF-A, while DIE did not show significantly different gene expression compared to endometrium from unaffected women. A positive correlation between the expression of HIF-1/2α and VEGF-A mRNA was observed in OMA. --- Explanation: Ovarian endometriomas specifically show elevated hypoxia-inducible factors and VEGF with correlated expression

[PMID:30074218] [INDIRECT EVIDENCE] [SUPPORT] The results showed that serum concentrations of MMIF, HIF-1α, and VEGF were significantly higher in EM patients than in controls (P<0.05). The expression of all three proteins in both serum and endometrial tissues increased significantly with the R-AFS stage (P<0.05) and with dysmenorrheal severity (P<0.05). --- Explanation: HIF-1alpha and VEGF expression correlates with disease stage and dysmenorrhea severity


HGNC.SYMBOL:WNT4


HGNC.SYMBOL:VEZT


HGNC.SYMBOL:GREB1


HGNC.SYMBOL:ID4


MONDO:0006541

[PMID:32973163] [SUPPORT] mucocutaneous fragility and blister formation, inducible by often minimal trauma --- Explanation: Confirms skin fragility and blister formation as the defining feature of EB.

[PMID:20507631] [SUPPORT] a number of disorders characterized by recurrent blister formation as the result of structural fragility within the skin and selected other tissues --- Explanation: Confirms recurrent blistering due to structural skin fragility across all EB types.


MONDO:0006541

[PMID:20507631] [SUPPORT] generalized blistering of the skin and oral cavity, and injury to many internal organs --- Explanation: Confirms oral cavity involvement as part of the generalized disease spectrum.

[PMID:34036913] [SUPPORT] Severe complications may arise in some EB types and subtypes within the eye, ear, nose, upper airway, gastrointestinal and genitourinary tracts --- Explanation: Confirms extracutaneous mucosal involvement across multiple organ systems.


MONDO:0006541

[PMID:20301304] [SUPPORT] Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia --- Explanation: JEB GeneReviews confirms nail dystrophy as a shared feature across all major forms of EB.


MONDO:0006541

[PMID:20301481] [SUPPORT] skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring --- Explanation: Supports milia as a characteristic healing outcome in dystrophic epidermolysis bullosa.


MONDO:0006541

[PMID:20301481] [SUPPORT] skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring --- Explanation: GeneReviews confirms that blisters in DEB heal with scarring, a key distinguishing feature of dystrophic forms.


MONDO:0006541

[PMID:20507631] [SUPPORT] Optimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct whenever possible the extracutaneous complications --- Explanation: The need for aggressive nutritional support as a core management pillar implies significant growth and nutritional challenges in severe EB.

[PMID:34036913] [SUPPORT] involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications --- Explanation: Nutritional support as a core management pillar confirms failure to thrive as a significant clinical issue.


MONDO:0006541

[PMID:20301481] [SUPPORT] Anemia is treated with iron supplements and transfusions as needed --- Explanation: GeneReviews confirms anemia as a recognized complication of DEB requiring treatment with iron supplementation and transfusions.


MONDO:0006541

[PMID:34036913] [SUPPORT] painful blistering of the skin and mucous membranes --- Explanation: Confirms pain as a cardinal symptom associated with blistering in EB.

[PMID:25279494] [SUPPORT] management of itching and pain --- Explanation: Confirms pain management as a major component of EB care.


MONDO:0006541

[PMID:32973163] [INDIRECT EVIDENCE] [SUPPORT] pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion --- Explanation: Confirms that mutations in at least 16 genes encoding structural and adhesion proteins underlie all forms of EB.

[PMID:32017015] [INDIRECT EVIDENCE] [SUPPORT] we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype --- Explanation: Confirms that EB is the prototypical genetic disorder with skin fragility resulting from structural protein defects.


MONDO:0006541