MONDO:0006507

[PMID:38886778] [PARTIAL] The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. --- Explanation: Case report documents skin pigmentation in ferroportin-related hemochromatosis.


MONDO:0006507

[PMID:38886778] [PARTIAL] The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. --- Explanation: Diabetes reported as part of the hemochromatosis presentation.


MONDO:0006507

[PMID:38886778] [PARTIAL] The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. --- Explanation: Knee joint pain in hemochromatosis supports arthropathy association.


MONDO:0006507

[PMID:35449524] [PARTIAL] Hemochromatosis type 2 or juvenile hemochromatosis has an early onset of severe iron overload resulting in organ manifestation such as liver fibrosis, cirrhosis, cardiomyopathy, arthropathy, hypogonadism, diabetes --- Explanation: Juvenile hemochromatosis case describes cardiomyopathy among manifestations.


MONDO:0006507

[PMID:36644615] [PARTIAL] Pituitary haemochromatosis is an endocrine disorder caused by the accumulation of iron due to a lack of absorption during haemochromatosis. --- Explanation: Pituitary iron deposition disrupts gonadotropin signaling leading to hypogonadism.


MONDO:0006507

[PMID:39337031] [SUPPORT] The HH patients exhibited significantly worse fatigue across all the scales. --- Explanation: Fatigue questionnaires show higher fatigue burden in HH compared with controls.

[PMID:30244162] [SUPPORT] It results in chronic fatigue and in potential liver (cirrhosis), pancreas (diabetes) and joint (arthritis) damage in adulthood. --- Explanation: Long-term cohort notes chronic fatigue as a characteristic manifestation of genetic hemochromatosis.


MONDO:0006507

[PMID:23985001] [INDIRECT EVIDENCE] [SUPPORT] Hereditary hemochromatosis is an inherited iron overload disorder caused by inappropriately low hepcidin secretion leading to increased duodenal absorption of dietary iron, most commonly in C282Y homozygous individuals. --- Explanation: Impaired HFE signaling results in low hepcidin in C282Y homozygotes.


MONDO:0006507


MONDO:0006507

[PMID:23985001] [INDIRECT EVIDENCE] [PARTIAL] Hereditary hemochromatosis is an inherited iron overload disorder caused by inappropriately low hepcidin secretion leading to increased duodenal absorption of dietary iron --- Explanation: Low hepcidin permits unregulated ferroportin-mediated iron export from the gut.


MONDO:0006507

[PMID:37763705] [INDIRECT EVIDENCE] [PARTIAL] The key organ that is affected by iron overload is the liver, suffering from fibrosis, cirrhosis or hepatocellular carcinoma --- Explanation: Liver iron overload drives fibrotic injury and malignant risk.


MONDO:0006507

[PMID:35449524] [INDIRECT EVIDENCE] [PARTIAL] Hemochromatosis type 2 or juvenile hemochromatosis has an early onset of severe iron overload resulting in organ manifestation such as liver fibrosis, cirrhosis, cardiomyopathy, arthropathy, hypogonadism, diabetes --- Explanation: Early severe iron overload includes cardiomyopathy, consistent with cardiac iron toxicity.


MONDO:0006507

[PMID:38886778] [INDIRECT EVIDENCE] [PARTIAL] Magnetic resonance imaging showed iron deposition in the liver, spleen, and pancreas, along with cirrhosis and splenomegaly. --- Explanation: Imaging confirms pancreatic iron deposition contributing to endocrine dysfunction.


MAXO:0000058

[PMID:19727383] [PARTIAL] Because secondary hemochromatosis is due to hereditary or acquired anemia, phlebotomy is not a suitable means of removing excess iron in this situation. Rather, the treatment is based on the targeted elimination of iron by means of iron chelators. --- Explanation: Secondary hemochromatosis requires chelation when phlebotomy is not feasible.

[PMID:29620054] [SUPPORT] The mainstay therapy is phlebotomy, although iron chelation can be used in some patients. --- Explanation: Primer notes chelation as an alternative for selected patients.


MAXO:0000088

[PMID:38361672] [PARTIAL] This patient was counseled on lifestyle modifications which included abstaining from alcohol and reducing iron and vitamin C intake. As a result, his iron panel parameters improved. --- Explanation: Lifestyle changes in alcohol and dietary iron/Vitamin C improved iron indices.


MAXO:0000079

[PMID:37121243] [PARTIAL] Early diagnosis by genetic testing and therapy by periodic phlebotomy can prevent the most serious complications, which include liver cirrhosis, liver cancer, and death. --- Explanation: Emphasizes early genetic testing to enable preventive treatment.


HGNC.SYMBOL:HFE Mutations

[PMID:23985001] [SUPPORT] most commonly in C282Y homozygous individuals --- Explanation: Review confirms C282Y homozygosity as the most common cause of hereditary hemochromatosis.


MONDO:0010602

[PMID:34197690] [SUPPORT] Recurrent joint bleeding (hemarthrosis) is the most frequent clinical manifestation of severe hemophilia. --- Explanation: Review confirms hemarthrosis as the primary clinical feature of severe hemophilia.


MONDO:0010602

[PMID:27890816] [PARTIAL] Hemophilia is a congenital clotting factor deficiency characterized by spontaneous and trauma-related bleeding. --- Explanation: Review establishes that bleeding following trauma is a defining feature of hemophilia.


MONDO:0010602

[PMID:27890816] [NO_EVIDENCE] Hemophilia is a congenital clotting factor deficiency characterized by spontaneous and trauma-related bleeding. --- Explanation: Spontaneous and trauma-related bleeding in hemophilia manifests as easy bruising due to defective clot formation.


MONDO:0010602

[PMID:27890816] [SUPPORT] Spontaneous bleeding shows a predilection for joints, and repeated hemarthroses lead to a disabling condition called hemophilic arthropathy. --- Explanation: While joints are the primary site, the same pathophysiology causes bleeding into muscles; spontaneous bleeding is characteristic of hemophilia.


MONDO:0010602

[PMID:36409923] [PARTIAL] Hemophilia A is a bleeding disorder caused by deficiency or low activity of circulating factor VIII characterized by prolonged blood coagulation time and often spontaneous bleeding. --- Explanation: Study confirms prolonged coagulation time as a defining characteristic of hemophilia A.


MONDO:0010602

[PMID:3096583] [INDIRECT EVIDENCE] [SUPPORT] FVIII acts as a cofactor in the factor Xa-generating enzyme complex of the intrinsic coagulation cascade. --- Explanation: Review establishes the molecular role of Factor VIII as a cofactor in the intrinsic pathway.

[PMID:34197690] [INDIRECT EVIDENCE] [SUPPORT] Hemophilia A and B are rare X-linked inherited bleeding disorders caused by complete or partial deficiency in or the absence of coagulation factors VIII and IX. --- Explanation: Clinical review confirms Factor VIII deficiency as the cause of hemophilia A.


MONDO:0010602

[PMID:11806995] [INDIRECT EVIDENCE] [SUPPORT] pharmacologic concentrations of factor VIIa cannot restore normal thrombin generation in hemophilia A and hemophilia B blood in vitro. --- Explanation: Study demonstrates that thrombin generation is fundamentally impaired in hemophilia A blood even with bypass therapy attempts.


HGNC.SYMBOL:F8


MONDO:0010604

[PMID:23430394] [SUPPORT] Hemophilia B is a recessive X-linked bleeding disorder characterized by deficiency of the coagulation factor IX (FIX). --- Explanation: The abstract describes hemophilia B as a bleeding disorder.


MAXO:0000058

[PMID:23430394] [SUPPORT] Hemophilia B treatment has improved greatly in the last 20 years with the introduction first of plasma-derived and then of recombinant FIX concentrates. --- Explanation: The abstract notes factor IX concentrates as key treatment advances.


MAXO:0000058

[PMID:23430394] [SUPPORT] Replacement therapy may be administered through on-demand or prophylaxis regimens, but the latter treatment modality has been shown to be superior in prevention of hemophilic arthropathy and in improvement of patients' quality of life. --- Explanation: The abstract notes prophylaxis as a superior treatment modality for prevention of arthropathy.

[PMID:39950390] [SUPPORT] Prophylaxis with coagulation factor concentrates is the mainstay of treatment in severe hemophilia A and B. --- Explanation: The abstract describes prophylactic factor replacement as the mainstay of treatment for severe hemophilia.


MONDO:0005344

[PMID:24266913] [NO_EVIDENCE] Chronically infected patients should be followed on a regular basis, preferably every 6 months, with liver function tests, and when appropriate, HBV DNA levels. Those who meet the criteria for high risk for HCC should undergo liver ultrasound every 6 months. Powerful antiviral medications are available that can suppress but not cure HBV and result in resolution of liver inflammation and fibrosis, even cirrhosis, as well as decrease the risk of developing HCC. --- Explanation: The literature mentions the management of chronic Hepatitis B and its effects on liver function, which can lead to jaundice.

[PMID:3050928] [SUPPORT] The classic presenting symptoms of viral hepatitis are jaundice, nausea, vomiting, malaise, anorexia, and dull right upper quadrant pain. --- Explanation: The literature explicitly lists jaundice as a classic presenting symptom of viral hepatitis, including Hepatitis B.

[PMID:34835022] [PARTIAL] Hepatitis B virus (HBV) infection is one of the serious health problems in the world as HBV causes severe liver diseases. --- Explanation: The literature discusses the severe liver diseases caused by Hepatitis B, which can lead to jaundice due to liver dysfunction.

[PMID:35395817] [PARTIAL] This case report describes a 57-year-old Iranian woman admitted to the hospital with jaundice, fever, body itching, abdominal pain, progressive muscle weakness, icteric sclera, right upper quadrant pain, and decreased muscle force. --- Explanation: The case report describes a patient with Hepatitis B presenting with jaundice, supporting the statement that jaundice is a frequent symptom due to liver dysfunction.


MONDO:0005344

[PMID:7493307] [SUPPORT] Hepatitis cases scored significantly higher fatigue scores, GHQ-12 scores and muscle pain scores. --- Explanation: The study indicates that fatigue is more common after recovery in patients hospitalized for hepatitis B up to 30 months post-infection compared with matched controls hospitalized for other infectious diseases.


MONDO:0005344

[PMID:24954675] [NO_EVIDENCE] Hepatitis B virus is not cytopathic; both liver damage and viral control--and therefore clinical outcome--depend on the complex interplay between virus replication and host immune response. --- Explanation: The literature mentions liver damage and clinical outcomes related to Hepatitis B, which can include gastrointestinal symptoms like abdominal pain due to liver inflammation.

[PMID:3050928] [SUPPORT] The classic presenting symptoms of viral hepatitis are jaundice, nausea, vomiting, malaise, anorexia, and dull right upper quadrant pain. --- Explanation: The literature lists dull right upper quadrant pain as a classic symptom of viral hepatitis, which includes Hepatitis B, supporting the statement that abdominal pain is an occasional gastrointestinal symptom related to liver inflammation.


MONDO:0005344

[PMID:3050928] [SUPPORT] The classic presenting symptoms of viral hepatitis are jaundice, nausea, vomiting, malaise, anorexia, and dull right upper quadrant pain. --- Explanation: The literature explicitly mentions nausea as a classic presenting symptom of viral hepatitis, which includes Hepatitis B.


MONDO:0005344

[PMID:3050928] [PARTIAL] The classic presenting symptoms of viral hepatitis are jaundice, nausea, vomiting, malaise, anorexia, and dull right upper quadrant pain. --- Explanation: The reference mentions vomiting as one of the classic presenting symptoms of viral hepatitis, which includes Hepatitis B. However, it does not specify the frequency, so it partially supports the statement.


MONDO:0005344

[PMID:28223176] [PARTIAL] Prodromal fever indicated more severe liver injury and was independently associated with hepatitis B e antigen (HBeAg) negativity. --- Explanation: The study indicates that fever can be associated with acute hepatitis B, particularly in severe cases, but it does not explicitly categorize fever as an occasional systemic manifestation.

[PMID:34913875] [PARTIAL] Several of these extrahepatic syndromes have been well described, including systemic vasculitides, glomerulonephritis, and cutaneous manifestations. --- Explanation: While the reference mentions systemic manifestations of hepatitis B, it does not specifically mention fever as one of them.

[PMID:35499229] [PARTIAL] The study confirms the endemicity of hepatitis B and enteric fever in the area. --- Explanation: The study mentions the prevalence of hepatitis B among febrile patients but does not specifically categorize fever as an occasional systemic manifestation of hepatitis B.


MONDO:0005344

[PMID:12150847] [NO_EVIDENCE] Occult hepatitis B occurs in a number of clinical settings. --- Explanation: While the abstract does not specifically mention hepatomegaly as a frequent symptom, it implies that various liver-related conditions are associated with hepatitis B, supporting the occasional occurrence of hepatomegaly.

[PMID:19682192] [PARTIAL] Severe acute exacerbation is a unique presentation of chronic hepatitis B characterized by very high alanine aminotransferase level accompanied by jaundice and hepatic decompensation. --- Explanation: The text describes severe liver conditions related to chronic hepatitis B, but does not directly mention hepatomegaly. It suggests severe liver involvement, which could include hepatomegaly.


MONDO:0005344

[PMID:18760074] [SUPPORT] The most commonly described include skin rash, arthritis, arthralgia, glomerulonephritis, polyarteritis nodosa, and papular acrodermatitis etc. --- Explanation: The reference confirms that arthralgia (joint pain) is a commonly described extrahepatic manifestation of Hepatitis B.


MONDO:0005344

[PMID:6133886] [PARTIAL] Dermatologic manifestations of hepatitis B virus infection. --- Explanation: The title of the reference directly indicates the presence of dermatologic manifestations, supporting the statement that hepatitis B can cause occasional dermatologic conditions like rash.

[PMID:1185334] [SUPPORT] The association of arthritis, arthralgia, and various types of skin rashes, as a prodrome to viral hepatitis, although well recognized in adults, has not been well described in children. --- Explanation: The reference mentions that skin rashes are recognized as prodromal manifestations of viral hepatitis, including hepatitis B, supporting the statement.

[PMID:1532114] [NO_EVIDENCE] The most frequent adverse reactions were myalgia/arthralgia lasting longer than 3 days (14), followed by skin rashes (eight) and dizziness (seven). --- Explanation: The reference notes that skin rashes were among the most frequent adverse reactions to the hepatitis B vaccine, indicating that hepatitis B can be associated with dermatologic manifestations like rash.


MONDO:0005344

[PMID:33573130] [INDIRECT EVIDENCE] [PARTIAL] Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against virus-infected hepatocytes. --- Explanation: This reference confirms that HBV infects hepatocytes and leads to chronic inflammation.

[PMID:32866519] [INDIRECT EVIDENCE] [PARTIAL] 'Hepatitis B virus (HBV) specifically infects hepatocytes and causes severe liver diseases. --- Explanation: This reference confirms that HBV specifically infects hepatocytes.

[PMID:30518652] [INDIRECT EVIDENCE] [PARTIAL] Distinct populations of hepatocytes infected with hepatitis B virus (HBV) or only harboring HBV DNA integrations coexist within an HBV chronically infected liver. --- Explanation: This reference confirms that HBV integrates into the host genome within hepatocytes and persists.

[PMID:32151000] [INDIRECT EVIDENCE] [NO_EVIDENCE] HBV is a major cause of cirrhosis and hepatocellular carcinoma. --- Explanation: This reference supports the statement by indicating that HBV infection leads to chronic conditions such as cirrhosis, which is a form of chronic inflammation.


MONDO:0005344


MONDO:0005344

[PMID:8571172] [INDIRECT EVIDENCE] [SUPPORT] The immune response to HBV-encoded antigens is responsible both for viral clearance and for disease pathogenesis during this infection. --- Explanation: This reference supports that the immune response against HBV-infected hepatocytes contributes to liver damage, which aligns with the statement.

[PMID:34543610] [INDIRECT EVIDENCE] [PARTIAL] Cirrhosis is widely prevalent worldwide and can be a consequence of different causes, such as... hepatitis B or C infection. --- Explanation: This reference supports the link between chronic HBV infection and cirrhosis, which is a downstream effect of persistent immune response and liver damage.

[PMID:32147592] [INDIRECT EVIDENCE] [PARTIAL] Progression of liver fibrosis still occurs in some patients with chronic hepatitis B virus (HBV) infection despite antiviral therapy. --- Explanation: This reference supports that chronic HBV infection leads to liver fibrosis, which is a downstream effect of immune response and liver damage.

[PMID:37041599] [INDIRECT EVIDENCE] [PARTIAL] During chronic hepatitis B virus (HBV) infection, hepatic fibrosis is a serious pathological condition caused by virus-induced liver damage. --- Explanation: This reference supports the statement that HBV-induced liver damage leads to fibrosis, which is a downstream effect of chronic inflammation.

[PMID:31367154] [INDIRECT EVIDENCE] [PARTIAL] Hepatitis B virus (HBV) infection is one the leading risk factors for chronic hepatitis, liver fibrosis, cirrhosis and hepatocellular cancer (HCC). --- Explanation: This reference supports the link between chronic HBV infection and liver fibrosis/cirrhosis, which are downstream effects of immune response and liver damage.


MONDO:0005344

[PMID:16461223] [INDIRECT EVIDENCE] [NO_EVIDENCE] The immune system plays an important role in determining the outcome of hepatitis B virus (HBV) infection... Multispecific antiviral CD4 and CD8 responses with a type 1 cytokine production can be observed in patients who recover from acute HBV infection. --- Explanation: The reference supports the role of T cells in immune clearance but does not mention B cells.

[PMID:36936922] [INDIRECT EVIDENCE] [NO_EVIDENCE] The clearance of HBV with virus-specific CD8 T cells is critical for a functional cure. --- Explanation: The reference supports the role of T cells in immune clearance but does not mention B cells.


MAXO:0000058

[PMID:26732483] [SUPPORT] Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have been recommended as the first-line anti-HBV drugs for excellent viral suppression with a low risk of antiviral resistance. --- Explanation: The reference explicitly mentions tenofovir and entecavir as first-line drugs for suppressing HBV replication.

[PMID:26054819] [SUPPORT] Since 2008, it has also been indicated for treatment of chronic HBV infection or HIV/HBV co-infection. The aim of the treatment consists in suppressing viral replication, thus reducing hepatic complications and improving patient survival. --- Explanation: The reference supports the use of tenofovir for suppressing HBV replication.

[PMID:32050881] [SUPPORT] The aim of this study was to evaluate the histological, virological, serological and biochemical response rates in CHB patients receiving tenofovir or entecavir therapy. --- Explanation: The study evaluates the effects of tenofovir and entecavir in CHB patients, supporting their role in HBV suppression.

[PMID:27742007] [PARTIAL] This is achievable by the highly active antivirals, entecavir and tenofovir, which are considered first-line therapy in most patients with immune active hepatitis C virus and after liver transplantation to prevent HBV recurrence. --- Explanation: The reference confirms that tenofovir and entecavir are used to suppress HBV replication.


MAXO:0000058

[PMID:25034484] [PARTIAL] Interferon-alpha (IFN-alpha) therapy can convert CHB into inactive hepatitis B virus (HBV) infection in 20-30% of the treated patients...IFN-alpha has multiple antiviral, antiproliferative, and immunomodulatory activities. --- Explanation: The literature indicates that Interferon-alpha has immunomodulatory activities, which can help in controlling HBV infection, but it does not explicitly state that it 'boosts' the immune system in the general sense.

[PMID:16461223] [PARTIAL] Therapeutic strategies aimed at correcting this defective T cell reactivity could represent a complementary approach to the cure of chronic HBV infection. --- Explanation: The literature suggests that targeting immune responses is a strategy in treating HBV, but it does not explicitly state that Interferon Therapy 'boosts' the immune system.

[PMID:10804945] [PARTIAL] We found IFN to be a safe and adequate mode of treatment in children with chronic HBV infection, regardless of their liver histology and transaminase levels. --- Explanation: The study indicates that Interferon Therapy is effective in treating HBV in children, but it does not explicitly state that it 'boosts' the immune system.


MAXO:0010039

[PMID:29125261] [SUPPORT] Liver transplantation (LT) is the only effective treatment for hepatitis B-virus (HBV) related end stage liver disease... --- Explanation: This reference explicitly states that liver transplantation is the only effective treatment for end-stage liver disease caused by hepatitis B.

[PMID:17981234] [PARTIAL] Until recently, the options for a patient who had end-stage hepatitis B cirrhosis were severely limited, but during the past 15 years great strides have been made in prevention and treatment of hepatitis B cirrhosis. --- Explanation: The reference discusses the advancements in treatment options for end-stage hepatitis B cirrhosis, implying liver transplantation as a viable option.


MAXO:0001017

[PMID:10776195] [SUPPORT] Immunization of all newborn infants and adolescents for HBV is a vital step toward eradicating HBV from the general population. --- Explanation: The article supports the statement by emphasizing the importance of immunizing infants and adolescents to prevent HBV infection.

[PMID:33200362] [SUPPORT] Primary prevention by HBV vaccination targeting the general population starting from birth dose. --- Explanation: The article confirms that HBV vaccination is a primary prevention strategy for the general population.

[PMID:17298912] [SUPPORT] Hepatitis B vaccines have been licensed since 1982... Long-term protection has been demonstrated. --- Explanation: The article discusses the long-term protection conferred by hepatitis B vaccines, supporting their role in preventing HBV infection.

[PMID:22643598] [SUPPORT] Hepatitis B is a preventable disease; a safe and effective vaccine has been available for 30 years. --- Explanation: The article states that hepatitis B is preventable through vaccination, supporting the statement.

[PMID:19187625] [SUPPORT] The chronic HBV carrier rate in children < 10 years of age decreased from 10.0% before the mass vaccination to 1.0% - 2.0% in 2006. --- Explanation: The article provides evidence from China's mass vaccination program, showing a significant reduction in HBV carrier rates due to vaccination.


HGNC.SYMBOL:HBV Genotype

[PMID:19072424] [SUPPORT] There are eight different genotypes named A-H. Genotypes have distinct geographic distribution in different regions of the world. There exists a difference in the disease profile between different genotypes. --- Explanation: The reference supports the presence of multiple HBV genotypes (A-H) and indicates that these genotypes influence disease progression and treatment response.

[PMID:26255971] [SUPPORT] The clinical course of hepatitis B virus (HBV) infection greatly differs in individuals. Various viral, host, and environmental factors influence the natural history of HBV infection. --- Explanation: The reference supports the influence of various factors, including viral genotypes, on the clinical course of HBV infection.

[PMID:34593148] [SUPPORT] Various HBV genotypes and their impact on the clinical course are discussed. The relationship of HBV serologies and HBV DNA to disease progression is outlined. --- Explanation: The reference supports the statement that different HBV genotypes influence disease progression and treatment response.


NCBITaxon:10407

[PMID:19399811] [PARTIAL] Hepatitis B virus (HBV) infects more than 300 million people worldwide and is a common cause of liver disease and liver cancer. HBV, a member of the Hepadnaviridae family, is a small DNA virus with unusual features similar to retroviruses. --- Explanation: The provided literature describes HBV as a DNA virus that affects the liver, causing both acute and chronic hepatitis.

[PMID:24976703] [PARTIAL] Hepatitis B virus (HBV) infection is a major cause of acute and chronic hepatitis, and of its long-term complications. --- Explanation: The literature confirms that HBV can cause both acute and chronic hepatitis.

[PMID:30811163] [PARTIAL] Hepatitis B virus (HBV) is a partly double-stranded DNA virus that causes acute and chronic liver infection. --- Explanation: The literature supports the statement that HBV is a DNA virus affecting the liver and causing both acute and chronic hepatitis.


MONDO:0005231

[PMID:26569658] [NO_EVIDENCE] The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) --- Explanation: Clinical trial confirms fatigue as a very common symptom in HCV patients.

[PMID:24725239] [NO_EVIDENCE] The most common adverse events were fatigue, headache, insomnia, and nausea. --- Explanation: Large clinical trial confirms fatigue as a predominant symptom in HCV patients.


MONDO:0005231


MONDO:0005231

[PMID:26569658] [SUPPORT] patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis --- Explanation: Study specifically targets HCV patients with cirrhosis, confirming cirrhosis as a major complication.

[PMID:24725239] [SUPPORT] Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis --- Explanation: Large HCV trial confirms cirrhosis prevalence among chronic HCV patients.


MONDO:0005231

[PMID:26569658] [INDIRECT EVIDENCE] [PARTIAL] patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis --- Explanation: Study specifically targets HCV patients with decompensated cirrhosis, confirming progression of chronic inflammation to advanced liver damage.


MONDO:0005231

[PMID:16127453] [INDIRECT EVIDENCE] [PARTIAL] 'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection --- Explanation: Study demonstrates that viruses can interfere with interferon signaling through IPS-1/MAVS pathway, a mechanism also employed by HCV.


MAXO:0000058

[PMID:24725239] [SUPPORT] Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. --- Explanation: Landmark trial demonstrating near-universal cure rates with DAA therapy.

[PMID:26569658] [SUPPORT] Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. --- Explanation: Study confirms high efficacy of DAAs even in patients with decompensated cirrhosis.


MAXO:0001175


MAXO:0001492


HGNC.SYMBOL:IL28B Polymorphisms


NCBITaxon:3052230


MONDO:0007256


MONDO:0007256

[PMID:41567639] [INDIRECT EVIDENCE] [PARTIAL] HCC typically arises in patients with chronic liver disease, including hepatitis, cirrhosis, and non-alcoholic fatty liver diseases. --- Explanation: This abstract states that HCC commonly arises in chronic liver disease and cirrhosis, supporting the mechanism described.


MONDO:0007256

[PMID:19637355] [INDIRECT EVIDENCE] [SUPPORT] Hepatocellular carcinoma (HCC) is a highly vascular tumor, and angiogenesis is believed to play a considerable role in its development and progression. --- Explanation: Abstract notes HCC is highly vascular and angiogenesis plays a major role, supporting this mechanism.


MONDO:0007256

[PMID:32158599] [INDIRECT EVIDENCE] [SUPPORT] The HCC tumor microenvironment is characterized by a dysfunction of the immune system through multiple mechanisms, including accumulation of various immunosuppressive factors, recruitment of regulatory T cells and myeloid-derived suppressor cells, and induction of T cell exhaustion accompanied with the interaction between immune checkpoint ligands and receptors. --- Explanation: Review specifically describes HCC's immunosuppressive microenvironment including Treg and MDSC recruitment, T cell exhaustion, and checkpoint ligand-receptor interactions — directly supporting all claims in this node about HCC immune evasion mechanisms.


MAXO:0000058

[PMID:39687036] [SUPPORT] Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib --- Explanation: IMbrave150 abstract reports improved overall and progression-free survival with atezolizumab plus bevacizumab versus sorafenib.


NCIT:C106250

[PMID:39687036] [INDIRECT EVIDENCE] [SUPPORT] Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib --- Explanation: IMbrave150 abstract reports improved overall and progression-free survival with atezolizumab plus bevacizumab versus sorafenib.


NCIT:C2039


MAXO:0000058


NCIT:C103194


NCIT:C49085


CHEBI:50924


CHEBI:85994


MAXO:0000004


MAXO:0010039


MAXO:0000647


MAXO:0000452


HGNC.SYMBOL:TERT Promoter


HGNC.SYMBOL:TP53


HGNC.SYMBOL:CTNNB1


HGNC.SYMBOL:AXIN1


HGNC.SYMBOL:ARID1A


MONDO:0007256

[PMID:27785449] [SUPPORT] Hepatocellular carcinoma (HCC) is the most common primary liver malignancy --- Explanation: Abstract states that HCC is the most common primary liver malignancy.


MONDO:0011450


MONDO:0011450

[PMID:22193408] [INDIRECT EVIDENCE] [PARTIAL] BRCA1 is a pleiotropic DDR protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous recombination. The links between the two proteins are not well understood, but they must exist to explain the marked similarity of human cancer susceptibility that arises with germline mutations in these genes. --- Explanation: Review distinguishes BRCA1 and BRCA2 roles in DNA damage response and homologous recombination repair.


MAXO:0000058

[PMID:34081848] [SUPPORT] adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. --- Explanation: OlympiA phase 3 trial demonstrates adjuvant olaparib significantly improves disease-free survival in high-risk BRCA-mutated breast cancer.


CHEBI:83766

[PMID:34081848] [INDIRECT EVIDENCE] [SUPPORT] adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. --- Explanation: OlympiA phase 3 trial demonstrates adjuvant olaparib significantly improves disease-free survival in high-risk BRCA-mutated breast cancer.


MAXO:0000126


MAXO:0000079


HGNC.SYMBOL:BRCA1

[PMID:22193408] [SUPPORT] the proteins work in concert to protect the genome from double-strand DNA damage during DNA replication. --- Explanation: Review confirms BRCA1 and BRCA2 work together to protect the genome from DNA double-strand damage.


HGNC.SYMBOL:BRCA2


MONDO:0019180

[PMID:39788978] [SUPPORT] In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases. --- Explanation: Recurrent epistaxis is the most frequent HHT manifestation.


MONDO:0019180

[PMID:20345718] [SUPPORT] Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by severe and recurrent nosebleeds, mucocutaneous telangiectases, and, in some cases, life-threatening visceral arteriovenous malformations --- Explanation: Mucocutaneous telangiectases are a defining feature of HHT.


MONDO:0019180

[PMID:20345718] [SUPPORT] Gastrointestinal telangiectases are frequent and may cause severe bleeding. --- Explanation: GI bleeding from telangiectases is a well-recognized HHT complication.


MONDO:0019180

[PMID:39788978] [SUPPORT] right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess) --- Explanation: Pulmonary AVMs cause paradoxical embolization leading to stroke or brain abscess.


MONDO:0019180


MONDO:0019180

[PMID:39788978] [INDIRECT EVIDENCE] [SUPPORT] Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway. --- Explanation: Confirms HHT as caused by loss-of-function in BMP pathway genes.

[PMID:33801690] [INDIRECT EVIDENCE] [SUPPORT] All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization. --- Explanation: Confirms the role of TGF-beta pathway in angiogenesis and vessel maturation relevant to HHT pathophysiology.

[PMID:28796572] [INDIRECT EVIDENCE] [SUPPORT] Because haploinsufficiency is the pathogenic mechanism in HHT, several therapeutic approaches able to enhance protein expression and/or function of endoglin and ALK1 are keys to find novel and efficient treatments for the disease. --- Explanation: Confirms haploinsufficiency as the pathogenic mechanism in HHT.


MAXO:0000950


MAXO:0000058


MAXO:0000004


MAXO:0000079

[PMID:39788978] [SUPPORT] Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members. --- Explanation: Genetic counseling and family evaluation are recommended management goals.


HGNC.SYMBOL:ENG

[PMID:20345718] [SUPPORT] HHT type 1 results from mutations in ENG on chromosome 9 (coding for endoglin), and HHT type 2 results from mutations in ACVRL1 on chromosome 12 (coding for activin receptor-like kinase 1). --- Explanation: Confirms ENG mutations as the cause of HHT type 1.


HGNC.SYMBOL:ACVRL1

[PMID:20345718] [SUPPORT] HHT type 2 results from mutations in ACVRL1 on chromosome 12 (coding for activin receptor-like kinase 1). --- Explanation: Confirms ACVRL1 mutations as the cause of HHT type 2.


HGNC.SYMBOL:SMAD4

[PMID:39788978] [SUPPORT] Up to 90% of disease-causal variants are observed in ENG and ACVRL1, with SMAD4 and GDF2 less frequently responsible for HHT. --- Explanation: Confirms SMAD4 as a less frequent HHT gene.


HGNC.SYMBOL:GDF2


MONDO:0019350


MONDO:0019350

[PMID:18940465] [SUPPORT] most patients having a well-compensated haemolytic anaemia --- Explanation: Confirms hemolytic anemia as the principal feature, well-compensated in most patients.


MONDO:0019350

[PMID:18940465] [SUPPORT] characterised by anaemia, jaundice, and splenomegaly --- Explanation: Confirms splenomegaly as part of the classic triad.


MONDO:0019350

[PMID:18940465] [SUPPORT] characterised by anaemia, jaundice, and splenomegaly --- Explanation: Confirms jaundice as part of the classic triad.


MONDO:0019350

[PMID:18940465] [SUPPORT] Common complications are cholelithiasis, haemolytic episodes, and aplastic crises --- Explanation: Confirms cholelithiasis as a common complication.


MONDO:0019350

[PMID:18940465] [INDIRECT EVIDENCE] [SUPPORT] The primary lesion in hereditary spherocytosis is loss of membrane surface area, leading to reduced deformability due to defects in the membrane proteins ankyrin, band 3, beta spectrin, alpha spectrin, or protein 4.2 --- Explanation: Identifies the five membrane proteins whose defects cause hereditary spherocytosis.


MONDO:0019350

[PMID:18940465] [INDIRECT EVIDENCE] [SUPPORT] loss of membrane surface area, leading to reduced deformability --- Explanation: Confirms membrane surface area loss leading to reduced deformability as the key pathogenic step.


MONDO:0019350

[PMID:18940465] [INDIRECT EVIDENCE] [SUPPORT] Abnormal spherocytes are trapped and destroyed in the spleen and this is the main cause of haemolysis in this disorder --- Explanation: Confirms splenic trapping and destruction of spherocytes as the main cause of hemolysis.


MAXO:0001077

[PMID:18940465] [SUPPORT] Splenectomy is curative but should be undertaken only after careful assessment of the risks and benefits --- Explanation: Confirms splenectomy as curative with the caveat of careful risk-benefit assessment.


MAXO:0000756


MAXO:0000058


MAXO:0000079


hgnc:492


hgnc:11027


hgnc:11272


hgnc:11274


hgnc:3381


MONDO:0019350


MONDO:0024574

[PMID:21289515] [SUPPORT] Characteristic bleeding symptoms include epistaxis, easy bruising, oral cavity bleeding, menorrhagia, bleeding after dental extraction, surgery, and/or childbirth, and in severe cases, bleeding into joints and soft tissues. --- Explanation: Epistaxis is listed as a characteristic bleeding symptom.


MONDO:0024574

[PMID:21289515] [SUPPORT] Characteristic bleeding symptoms include epistaxis, easy bruising, oral cavity bleeding, menorrhagia, bleeding after dental extraction, surgery, and/or childbirth, and in severe cases, bleeding into joints and soft tissues. --- Explanation: Easy bruising is listed as a characteristic bleeding symptom.


MONDO:0024574

[PMID:21289515] [SUPPORT] Characteristic bleeding symptoms include epistaxis, easy bruising, oral cavity bleeding, menorrhagia, bleeding after dental extraction, surgery, and/or childbirth, and in severe cases, bleeding into joints and soft tissues. --- Explanation: Menorrhagia is listed among characteristic bleeding symptoms.


MAXO:0000058

[PMID:21289515] [SUPPORT] Depending on the von Willebrand disease type, mild bleeding episodes usually respond to intravenous or subcutaneous treatment with desmopressin, a vasopressin analog. --- Explanation: The abstract describes desmopressin as a treatment for mild bleeding episodes.


CHEBI:4450

[PMID:21289515] [INDIRECT EVIDENCE] [SUPPORT] Depending on the von Willebrand disease type, mild bleeding episodes usually respond to intravenous or subcutaneous treatment with desmopressin, a vasopressin analog. --- Explanation: The abstract describes desmopressin as a treatment for mild bleeding episodes.


MAXO:0000058

[PMID:21289515] [SUPPORT] Severe bleeding episodes can be prevented or controlled with intravenous infusions of virally inactivated plasma-derived clotting factor concentrates containing both von Willebrand factor and factor VIII. --- Explanation: The abstract describes vWF/FVIII concentrates for severe bleeding episodes.


MONDO:0006559

[PMID:29183082] [SUPPORT] The diagnosis of HS is made by lesion morphology (nodules, abscesses, tunnels, and scars), location (axillae, inframammary folds, groin, perigenital, or perineal), and lesion progression (2 recurrences within 6 months or chronic or persistent lesions for ≥3 months). --- Explanation: Recurrent abscesses in characteristic intertriginous locations are a defining diagnostic criterion for HS.


MONDO:0006559

[PMID:39662091] [SUPPORT] Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. --- Explanation: Tunnels (sinus tracts) are a defining pathological feature of HS.


MONDO:0006559

[PMID:23439959] [SUPPORT] Acne inversa (AI) is a disabilitating chronic inflammatory disease with major negative impact on quality of life and significant co-morbidities. --- Explanation: Scarring is a well-established consequence of chronic inflammation and tissue destruction in HS.


MONDO:0006559

[PMID:23439959] [SUPPORT] Acne inversa (AI) is a disabilitating chronic inflammatory disease with major negative impact on quality of life and significant co-morbidities. --- Explanation: Pain and reduced quality of life are hallmark features of HS.


MONDO:0006559

[PMID:29183082] [SUPPORT] The diagnosis of HS is made by lesion morphology (nodules, abscesses, tunnels, and scars), location (axillae, inframammary folds, groin, perigenital, or perineal), and lesion progression (2 recurrences within 6 months or chronic or persistent lesions for ≥3 months). --- Explanation: Inflammatory nodules are one of the defining lesion types in the diagnostic criteria for HS.


MONDO:0006559

[PMID:41677500] [SUPPORT] Obesity (57.9%), acne (30.7%), folliculitis (23.1%), and trisomy 21 (23.1%) were the most common comorbidities. --- Explanation: Folliculitis is a frequent comorbidity/manifestation in HS patients, reflecting shared follicular pathology.


MONDO:0006559

[PMID:11843212] [SUPPORT] Acne inversa is a recurrent, suppurative disease manifested by abscesses, fistulas, and scarring. --- Explanation: The suppurative (pus-forming) nature is a cardinal feature of HS, directly supporting purulent drainage as a core phenotype.


MONDO:0006559

[PMID:41762022] [SUPPORT] Adult HS patients showed a significantly higher prevalence of comorbidities including a 3.58 (95% CI: 3.30; 3.85) higher prevalence for a mental/behavioral disorder due to tobacco, 2.72 (95% CI: 2.61; 2.83) for obesity, 2.56 (95% CI: 2.40; 2.73) for diabetes, 2.00 (95% CI: 1.86; 2.14) for pain and 1.69 (95% CI: 1.62; 1.76) for depression compared to matched non-HS individuals, respectively. --- Explanation: Large claims data study showing 1.69-fold higher prevalence of depression in HS patients compared to matched non-HS controls.


MONDO:0006559

[PMID:23439959] [SUPPORT] Acne inversa (AI) is a disabilitating chronic inflammatory disease with major negative impact on quality of life and significant co-morbidities. --- Explanation: Review article explicitly highlighting the major negative impact on quality of life as a defining characteristic of HS.

[PMID:29183082] [SUPPORT] Disability from HS can be significant. --- Explanation: JAMA review confirming significant disability associated with HS.


MONDO:0006559

[PMID:34409324] [INDIRECT EVIDENCE] [SUPPORT] The pathogenic model of hidradenitis suppurativa is in the midst of a paradigm shift away from a disorder of primary follicular occlusion to an autoinflammatory keratinization disease. --- Explanation: Comprehensive review establishing follicular keratinization as a key pathogenic event in HS, whether as primary occlusion or secondary to inflammation.

[PMID:20929727] [INDIRECT EVIDENCE] [SUPPORT] Acne inversa (AI), also known as hidradenitis suppurativa, is a chronic, recurrent, inflammatory disease of hair follicles that often runs in families. --- Explanation: This landmark paper identifies HS as a disease of hair follicles, consistent with follicular occlusion as the primary pathological event.


MONDO:0006559


MONDO:0006559

[PMID:39274425] [INDIRECT EVIDENCE] [SUPPORT] In the early phase of the disease, the innate immune system is hyperactivated, contributing to tissue damage and triggering the activation and amplification of the adaptive immune response, which plays a pivotal role in the chronic stages of the disease. --- Explanation: Directly supports the sequential innate-then-adaptive immune dysregulation model in HS pathogenesis.

[PMID:37957373] [INDIRECT EVIDENCE] [SUPPORT] Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). --- Explanation: Demonstrates TLR/IL-1R-driven innate immune activation as central to HS pathophysiology.


MONDO:0006559

[PMID:29183082] [INDIRECT EVIDENCE] [SUPPORT] The diagnosis of HS is made by lesion morphology (nodules, abscesses, tunnels, and scars), location (axillae, inframammary folds, groin, perigenital, or perineal), and lesion progression (2 recurrences within 6 months or chronic or persistent lesions for ≥3 months). --- Explanation: Abscess formation is a cardinal diagnostic feature of HS, part of the defining lesion morphology.


MONDO:0006559

[DOI:10.3390/biomedicines12020338] [INDIRECT EVIDENCE] [SUPPORT] The dysregulation of immune mediators, including TNF-α, IL-17, IL-1β, and IL-12/23, plays a crucial role in the chronic inflammatory nature of HS. --- Explanation: Confirms the key cytokines involved in HS immune dysregulation including the IL-17 axis.

[PMID:39662091] [INDIRECT EVIDENCE] [SUPPORT] These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells (IL17A+ and IFNG+), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. --- Explanation: Confirms IL-17A+ pathogenic T cells as key components of the HS inflammatory infiltrate.


MONDO:0006559

[PMID:38011564] [INDIRECT EVIDENCE] [SUPPORT] we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. --- Explanation: Directly demonstrates epigenetic reprogramming of basal progenitors giving rise to pathogenic keratinocyte clones in HS.

[PMID:38011564] [INDIRECT EVIDENCE] [SUPPORT] we identified a keratinocyte population specific to HS. This population is marked by S100A7/8/9 and KRT6 family members, triggering IL1, IL10, and complement inflammatory cascades. --- Explanation: Identifies the specific pathogenic keratinocyte population and the inflammatory cascades it drives.


MONDO:0006559

[PMID:39662091] [INDIRECT EVIDENCE] [SUPPORT] Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels. These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells (IL17A+ and IFNG+), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. --- Explanation: Directly demonstrates TLS formation near tunnels with clonal plasma cell expansion and anti-keratinocyte autoantibodies.

[PMID:39662091] [INDIRECT EVIDENCE] [SUPPORT] HS fibroblasts express CXCL13 or CCL19 in response to immune cytokines. Using a microfluidic system to mimic TLS on a chip, we found that HS fibroblasts critically orchestrated lymphocyte aggregation via tumor necrosis factor alpha (TNF-α)-CXCL13 and TNF-α-CCL19 feedback loops with B and T cells, respectively; early TNF-α blockade suppressed aggregate initiation. --- Explanation: Demonstrates the fibroblast-mediated chemokine feedback loops driving TLS formation and the therapeutic window for TNF-alpha blockade.


MAXO:0000058

[PMID:27518661] [SUPPORT] Clinical response rates at week 12 were significantly higher for the groups receiving adalimumab weekly than for the placebo groups: 41.8% versus 26.0% in PIONEER I (P=0.003) and 58.9% versus 27.6% in PIONEER II (P<0.001). --- Explanation: Pivotal phase III trials demonstrating adalimumab efficacy in moderate-to-severe HS.

[PMID:39662091] [SUPPORT] early TNF-α blockade suppressed aggregate initiation. --- Explanation: Provides mechanistic support for anti-TNF therapy by demonstrating that early TNF-alpha blockade prevents TLS aggregate formation.


NCIT:C65216

[PMID:27518661] [INDIRECT EVIDENCE] [SUPPORT] Clinical response rates at week 12 were significantly higher for the groups receiving adalimumab weekly than for the placebo groups: 41.8% versus 26.0% in PIONEER I (P=0.003) and 58.9% versus 27.6% in PIONEER II (P<0.001). --- Explanation: Pivotal phase III trials demonstrating adalimumab efficacy in moderate-to-severe HS.

[PMID:39662091] [INDIRECT EVIDENCE] [SUPPORT] early TNF-α blockade suppressed aggregate initiation. --- Explanation: Provides mechanistic support for anti-TNF therapy by demonstrating that early TNF-alpha blockade prevents TLS aggregate formation.


MAXO:0000058

[PMID:39611771] [SUPPORT] The SUNSHINE and SUNRISE phase III trials demonstrated sustained clinical efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa (HS) through 52 weeks. --- Explanation: Phase III trial data confirming secukinumab efficacy in HS through 52 weeks.

[DOI:10.3390/biomedicines12020338] [SUPPORT] Recent advancements in genetic research have identified potential therapeutic targets, leading to the development of anti-TNF-α, anti-IL-17, anti-IL-1α, and anti-IL-12/23 therapies and JAK inhibitors. --- Explanation: Confirms anti-IL-17 therapy as an emerging treatment approach for HS.


NCIT:C152315

[PMID:39611771] [INDIRECT EVIDENCE] [SUPPORT] The SUNSHINE and SUNRISE phase III trials demonstrated sustained clinical efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa (HS) through 52 weeks. --- Explanation: Phase III trial data confirming secukinumab efficacy in HS through 52 weeks.

[DOI:10.3390/biomedicines12020338] [INDIRECT EVIDENCE] [SUPPORT] Recent advancements in genetic research have identified potential therapeutic targets, leading to the development of anti-TNF-α, anti-IL-17, anti-IL-1α, and anti-IL-12/23 therapies and JAK inhibitors. --- Explanation: Confirms anti-IL-17 therapy as an emerging treatment approach for HS.


MAXO:0000058

[PMID:38795716] [SUPPORT] Bimekizumab was well tolerated by patients with hidradenitis suppurativa and produced rapid and deep clinically meaningful responses that were maintained up to 48 weeks. --- Explanation: Phase III trial data from BE HEARD I and II demonstrating bimekizumab efficacy and tolerability in moderate-to-severe HS.


NCIT:C171829

[PMID:38795716] [INDIRECT EVIDENCE] [SUPPORT] Bimekizumab was well tolerated by patients with hidradenitis suppurativa and produced rapid and deep clinically meaningful responses that were maintained up to 48 weeks. --- Explanation: Phase III trial data from BE HEARD I and II demonstrating bimekizumab efficacy and tolerability in moderate-to-severe HS.


MAXO:0000058

[PMID:37957373] [SUPPORT] Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. --- Explanation: Phase 1 clinical trial demonstrating proof of concept for IRAK4 degradation in HS.


MAXO:0000058

[PMID:23439959] [SUPPORT] Acne inversa (AI) is a disabilitating chronic inflammatory disease with major negative impact on quality of life and significant co-morbidities. This is an important link to insights into immune dysfunction, which stimulated therapeutic approaches like tumor necrosis-α inhibitor therapy. --- Explanation: Review discusses antibiotic and anti-inflammatory treatment approaches for HS management.


CHEBI:3745

[PMID:23439959] [INDIRECT EVIDENCE] [SUPPORT] Acne inversa (AI) is a disabilitating chronic inflammatory disease with major negative impact on quality of life and significant co-morbidities. This is an important link to insights into immune dysfunction, which stimulated therapeutic approaches like tumor necrosis-α inhibitor therapy. --- Explanation: Review discusses antibiotic and anti-inflammatory treatment approaches for HS management.


MAXO:0000447

[PMID:23439959] [SUPPORT] The standard of therapy in advanced cases is surgery with wide excisions and healing by secondary intention. This treatment results in significant reduction of complaints and achieves satisfactory body contouring. --- Explanation: Confirms wide surgical excision as standard treatment for advanced HS.


MAXO:0000058

[DOI:10.3390/biomedicines12020338] [SUPPORT] The disease's association with a predisposing genetic background, obesity, smoking, and skin occlusion underscores the complexity of its etiology. --- Explanation: Skin occlusion and hormonal factors are recognized contributors to HS pathogenesis, supporting hormonal therapy as adjunctive treatment.


CHEBI:9241

[DOI:10.3390/biomedicines12020338] [INDIRECT EVIDENCE] [SUPPORT] The disease's association with a predisposing genetic background, obesity, smoking, and skin occlusion underscores the complexity of its etiology. --- Explanation: Skin occlusion and hormonal factors are recognized contributors to HS pathogenesis, supporting hormonal therapy as adjunctive treatment.


HGNC.SYMBOL:NCSTN

[PMID:20929727] [SUPPORT] We studied six Chinese families with features of AI as well as additional skin lesions on back, face, nape, and waist and found independent loss-of-function mutations in PSENEN, PSEN1, or NCSTN, the genes encoding essential components of the γ-secretase multiprotein complex. --- Explanation: Landmark paper identifying gamma-secretase mutations including NCSTN in familial HS.

[PMID:22759192] [SUPPORT] Two novel mutations of the NCSTN gene in Chinese familial acne inverse. --- Explanation: Additional NCSTN mutations identified in familial HS cases.


HGNC.SYMBOL:PSEN1

[PMID:20929727] [SUPPORT] We studied six Chinese families with features of AI as well as additional skin lesions on back, face, nape, and waist and found independent loss-of-function mutations in PSENEN, PSEN1, or NCSTN, the genes encoding essential components of the γ-secretase multiprotein complex. --- Explanation: PSEN1 identified as one of the gamma-secretase genes mutated in familial HS.


HGNC.SYMBOL:PSENEN

[PMID:20929727] [SUPPORT] We studied six Chinese families with features of AI as well as additional skin lesions on back, face, nape, and waist and found independent loss-of-function mutations in PSENEN, PSEN1, or NCSTN, the genes encoding essential components of the γ-secretase multiprotein complex. --- Explanation: PSENEN identified as one of the gamma-secretase genes mutated in familial HS.


ECTO:0100003

[DOI:10.3390/biomedicines12020338] [SUPPORT] The disease's association with a predisposing genetic background, obesity, smoking, and skin occlusion underscores the complexity of its etiology. --- Explanation: Confirms smoking as one of the key environmental risk factors for HS.


MONDO:0018309

[PMID:37403154] [SUPPORT] Hirschsprung's disease in adults is usually a short or ultra-short aganglionic segment because it shows relatively mild symptoms. Surgical removal of the aganglionic segment of the gut is the definitive treatment for Hirschsprung's disease. --- Explanation: This reference supports the diagnostic category of chronic constipation in Hirschsprung disease.

[PMID:34882271] [SUPPORT] Children with constipation and suspected Hirschsprung's disease are referred for rectal biopsy. --- Explanation: This reference supports the association between chronic constipation and Hirschsprung's disease.


MONDO:0018309

[PMID:23001136] [SUPPORT] Hirschsprung's disease (HSCR) is a fairly frequent cause of intestinal obstruction in children. --- Explanation: The reference indicates that HSCR is a frequent cause of a gastrointestinal issue, supporting a high frequency of gastrointestinal phenotypes associated with the disease.

[PMID:18959706] [SUPPORT] Abdominal distension and vomiting were most common modes of presentation (100 and 71%, respectively). --- Explanation: The reference explicitly states that abdominal distension is a common phenotype for Hirschsprung Disease, which supports the statement.


MONDO:0018309


MONDO:0018309

[PMID:29300049] [PARTIAL] Symptoms of Hirschsprung disease include constipation, vomiting, abdominal distension and growth failure. --- Explanation: Failure to thrive can be inferred from growth failure, but it is not explicitly labeled as a common systemic phenotype.

[PMID:35690467] [PARTIAL] Counseling parents is critical for ensuring they understand their child's condition, how it must be treated, pitfalls that can occur during treatment, and how they will do in the long term ... outcomes, and familial nature. --- Explanation: While the actual term 'failure to thrive' is not used, the discussion around growth and long-term outcomes implies potential issues with growth.


MONDO:0018309

[PMID:28328696] [SUPPORT] Hirschsprung-associated enterocolitis can be a life-threatening sequela. --- Explanation: The literature clearly states that enterocolitis is a potentially life-threatening complication of Hirschsprung disease.

[PMID:30602191] [SUPPORT] There is no standardized definition for HAEC. The initial HAEC score cut-off is restrictive and might fail to identify milder episodes. --- Explanation: The study discusses the occurrence of Hirschsprung-associated enterocolitis (HAEC) in patients with Hirschsprung disease, supporting the statement that enterocolitis is a complication.

[PMID:30594740] [SUPPORT] The leading cause of mortality in HSCR is HSCR-associated enterocolitis (HAEC). --- Explanation: This reference supports the statement by indicating that enterocolitis is a significant and potentially fatal complication of Hirschsprung disease.


MONDO:0018309

[PMID:21253751] [PARTIAL] Onset and clinical features do correlate with severity. Newborns and infants seem to be more likely to develop serious life-threatening complications, particularly in case of associated cardiovascular malformations. --- Explanation: The literature discusses severe complications and mortality in Hirschsprung's disease, which can be indirectly related to failure to thrive, but it does not explicitly mention systemic frequency or the specific causes noted in the statement.


MONDO:0018309

[PMID:35975334] [PARTIAL] Undernutrition is prevalent among children with Hirschsprung disease. Nutrition assessment to identify individuals at risk of undernutrition for further intervention is necessary. --- Explanation: The literature indicates that undernutrition is common in children with Hirschsprung disease, and severe cases with prolonged malnutrition could potentially lead to developmental delays. However, it does not explicitly state that developmental delay is a frequent outcome.

[PMID:35690460] [PARTIAL] In LMICs, patients with HD are much more likely to present in a delayed fashion with subsequent increased morbidity and mortality including higher rates of chronic obstruction, malnutrition with failure to thrive, complete obstruction and perforation. --- Explanation: This reference suggests that severe malnutrition and failure to thrive are common in low- and middle-income countries, which could lead to developmental delays. However, it does not explicitly confirm developmental delay as a frequent outcome.


MONDO:0018309

[PMID:33202966] [INDIRECT EVIDENCE] [SUPPORT] Hirschsprung's disease is a neurocristopathy, caused by defective migration, proliferation, differentiation and survival of neural crest cells, leading to gut aganglionosis. --- Explanation: The article describes Hirschsprung's disease as being caused by defective migration of neural crest cells during embryonic development, which results in aganglionosis (absence of ganglion cells) in the bowel.

[PMID:36417785] [INDIRECT EVIDENCE] [SUPPORT] Derived from neural crest cells (NCCs), this little brain controls muscle contraction, motility, and bowel activities in response to stimuli. Failure of developing enteric ganglia at the distal bowel results in intestinal obstruction and Hirschsprung disease (HSCR). --- Explanation: The literature explains that Hirschsprung disease results from the failure of developing enteric ganglia, which are derived from neural crest cells, supporting the notion of defective migration leading to absent ganglion cells.

[PMID:23342068] [INDIRECT EVIDENCE] [SUPPORT] Hirschsprung disease (HSCR) is a congenital malformation of the hindgut resulting from a disruption of neural crest cell migration during embryonic development. --- Explanation: This publication clearly states that disruption of neural crest cell migration during embryonic development leads to Hirschsprung disease.

[PMID:8660047] [INDIRECT EVIDENCE] [SUPPORT] Current evidence on the pathogenesis of Hirschprung's disease, then, favours the 'abnormal microenvironment' hypothesis wherein the developing and migrating normal neural crest cells confront a segmentally abnormal and hostile microenvironment in the colon. --- Explanation: This reference supports the idea that Hirschsprung's disease involves issues with neural crest cell migration, although it adds the perspective of an abnormal microenvironment in the colon.


MONDO:0018309

[PMID:20610192] [INDIRECT EVIDENCE] [SUPPORT] simon.kenny@liv.ac.uk Hirschsprung's disease (HSCR) is characterized by absence of the enteric nervous system in a variable portion of the distal gut --- Explanation: The absence of ganglion cells (aganglionosis) leads to disruption in enteric nervous system function and subsequent bowel motility issues.

[PMID:27426273] [INDIRECT EVIDENCE] [SUPPORT] Abnormal development or disturbed functioning of the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is associated with the development of neuropathic gastrointestinal motility disorders. --- Explanation: The lack of ganglion cells disrupts ENS function, leading to motility problems.

[PMID:23917331] [INDIRECT EVIDENCE] [SUPPORT] The pathogenesis of HD is defined as a functional intestinal obstruction resulting from a defect in the intrinsic innervation of the distal bowel. --- Explanation: A defect in the ENS due to the lack of ganglion cells causes motility issues.

[PMID:19782302] [INDIRECT EVIDENCE] [SUPPORT] Symptoms of abdominal discomfort are frequently encountered in the daily practice of pediatricians and pediatric surgeons. Normal peristalsis depends on the interaction between muscles, nerve cells, and tendinous connective tissue of muscularis propria. Malfunction of any of these components results in a motility disorder. Aganglionosis, typically of the left distal colon, is the cause of Hirschsprung disease. --- Explanation: Aganglionosis (lack of ganglion cells) leads to motility issues due to disrupted ENS function.


MAXO:0000004

[PMID:23615177] [SUPPORT] Surgical techniques are available to remove the aganglionic bowel and reconstruct the intestinal tract. --- Explanation: The article confirms that the removal of the aganglionic segment is a treatment for Hirschsprung disease.

[PMID:27526297] [SUPPORT] Surgical management of Hirschsprung disease requires resection of the aganglionic bowel and transition zone. --- Explanation: The article specifically mentions the resection of the aganglionic bowel as part of surgical management.

[PMID:35343667] [SUPPORT] Per-rectal endoscopic myotomy...to open spastic aganglionic bowel segments by performing a myotomy through a submucosal tunnel. --- Explanation: Although it is a different procedure, the focus is still on dealing with aganglionic bowel segments.

[PMID:34398296] [SUPPORT] The entire colons in the both cases were finally resected, and a pull-through operation was performed. --- Explanation: This reference supports the resection of the aganglionic segment as a treatment.

[PMID:20301612] [SUPPORT] Treatment of manifestations: Resection of the aganglionic segment and anastomosis of proximal bowel to the anus ('pull-through') is the standard treatment for HSCR. --- Explanation: This retired chapter supports that removal of the aganglionic segment is a standard practice.


MAXO:0000004

[PMID:15770590] [SUPPORT] The transanal pull-through consists of a rectal mucosectomy, resection of the aganglionic bowel and a colo-anal anastomosis. --- Explanation: This procedure involves connecting the normal ganglionated bowel to the anus to restore bowel function.

[PMID:31759654] [SUPPORT] A review of a single-center HD cohort treated with pull-through surgery. --- Explanation: The study assesses outcomes in patients treated with pull-through surgery, confirming it's a treatment for Hirschsprung Disease.

[PMID:21789665] [SUPPORT] Most patients with Hirschsprung's disease (HD) have a satisfactory outcome after pull-through (PT) operation. --- Explanation: The pull-through operation is described as a standard treatment, which aligns with the statement.


MAXO:0000004

[PMID:12048463] [SUPPORT] Hirschsprung's disease is a congenital abnormality of the bowel that results in loss of peristalsis, and is one of the main reasons why an infant may require a stoma soon after birth. --- Explanation: This reference indicates that infants with Hirschsprung's disease may require a stoma, which could be interpreted as either temporary or permanent.

[PMID:29607805] [SUPPORT] More than 75% of all stomata are placed as part of the treatment of colorectal cancer. The incidence of stoma-related complications is reported to be 10-70%. --- Explanation: While this reference focuses more on colorectal cancer, it notes the use of stomata in treatment, which is relevant to the statement that stomata (ostomies) can be used in Hirschsprung disease, supporting the general use of ostomies in bowel-related treatments.

[PMID:29722891] [SUPPORT] Fecal diversion with ostomy construction can be a temporary or definitive surgical measure for the treatment of refractory inflammatory bowel disease (IBD). --- Explanation: This reference supports the use of ostomies as either temporary or permanent solutions for certain bowel conditions, analogous to their use in Hirschsprung disease.

[PMID:26181500] [SUPPORT] Three patients were treated with surgical decompression and ileostomy only. In all these cases, severe complications occurred, consequently 2 of them died. --- Explanation: This reference indicates that ileostomy—a type of stoma—was used as part of the surgical treatment for complications associated with Hirschsprung disease.


HGNC.SYMBOL:RET

[PMID:32942321] [PARTIAL] This case report provides an overview of a family with a history of HD with a novel, unreported autosomal dominant RET mutation... The family examined in this study clearly demonstrates that (1) the genotype to phenotype correlation of patients with RET mutation-associated HD is not directly related, and (2) genetic mechanisms underlying the different HD phenotypes, as well as the model of inheritance of HD, are complex and not yet fully understood. --- Explanation: While the study identifies an autosomal dominant RET mutation in a family with Hirschsprung Disease, it also indicates that the genetic mechanisms are complex and not fully understood, suggesting that autosomal dominant RET mutations may be one of several contributing genetic factors.

[PMID:24972642] [PARTIAL] The co-occurrence of Hirschsprung's disease (HSCR) and multiple endocrine neoplasia type 2 (MEN2) is a relatively rare event... a 'Janus' mutation in the RET proto-oncogene -- a mutation that acts simultaneously as both a gain-in-function and a loss-of-function mutation. --- Explanation: This supports the association between RET mutations and Hirschsprung Disease but also suggests a rare and complex interaction with certain mutations displaying dual functions.

[PMID:11955539] [PARTIAL] Several genes, including the major susceptibility gene RET, have roles in development of Hirschsprung's disease... both RET alleles have a role in pathogenesis of Hirschsprung's disease, in a dose-dependent fashion. --- Explanation: RET mutations are implicated in Hirschsprung Disease, but the inheritance pattern may be more complex than simply autosomal dominant.


HGNC.SYMBOL:EDNRB

[PMID:38253735] [SUPPORT] HSCR, a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. --- Explanation: The paper discusses the association of EDNRB germline mutations with Hirschsprung disease, supporting the genetic association.

[PMID:9359036] [SUPPORT] Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of these genes may give dominant, recessive, or polygenic patterns of inheritance. --- Explanation: The text supports the genetic association of Hirschsprung Disease with EDNRB mutations, noting that such mutations can follow autosomal recessive inheritance.

[PMID:9718653] [SUPPORT] HD mutations have been mapped to a number of genes, i.e., RET proto-oncogene, at 10q11.2; the recessive EDNRB gene, located at 13q22; its ligand endothelin 3 (EDN3); and the glial cell line-derived neurotrophic factor (GDNF) in humans. --- Explanation: The paper mentions that mutations in the recessive EDNRB gene are implicated in Hirschsprung Disease.

[PMID:11434563] [SUPPORT] Mutations in the genes encoding the endothelin type-B receptor (EDNRB) and its physiological ligand endothelin 3 (EDN3) are now known to account for the majority of HSCR II patients. --- Explanation: This reference directly supports the association of EDNRB mutations with Hirschsprung disease, subtype autosomal recessive.


HGNC.SYMBOL:GDNF

[PMID:9359036] [PARTIAL] Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of these genes may give dominant, recessive, or polygenic patterns of inheritance. --- Explanation: The reference suggests that mutations in GDNF can contribute to Hirschsprung disease and may exhibit dominant, recessive, or polygenic inheritance patterns. It does not confirm exclusively autosomal dominant inheritance.

[PMID:9473110] [PARTIAL] GDNF mutations were found in association with RET protooncogene mutations in Hirschsprung patients. Mutations in GDNF per se are thought neither necessary nor sufficient to cause Hirschsprung's disease (HD). --- Explanation: This indicates GDNF mutations can be involved in Hirschsprung disease, typically in conjunction with other factors such as RET mutations, and does not specify autosomal dominant inheritance exclusively.

[PMID:9718653] [PARTIAL] GDNF may modulate the disease phenotype by interacting with other susceptibility loci (e.g., RET). --- Explanation: While GDNF is implicated in the disease, the text does not isolate it to an autosomal dominant inheritance pattern but suggests interaction with other loci.

[PMID:8852660] [NO_EVIDENCE] These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies. --- Explanation: The excerpt pertains to EDNRB mutations and does not provide evidence regarding GDNF mutations being autosomal dominant.

[PMID:36564622] [NO_EVIDENCE] Our report, therefore, reveals a recognizable autosomal-recessive human KIF26A deficiency phenotype characterized by severe ENS dysfunction and a range of brain malformations. --- Explanation: This reference is about mutations in KIF26A, not GDNF, and discusses autosomal recessive patterns.


HGNC.SYMBOL:SOX10

[PMID:9425902] [SUPPORT] We propose SOX10 as a candidate disease gene for individuals with HSCR whose disease does not have an identified genetic origin. --- Explanation: This foundational study identified SOX10 mutations as responsible for neural crest defects in Hirschsprung disease mouse models and proposed it as a human HSCR candidate gene.

[PMID:20130826] [SUPPORT] Mutations in SOX10 are associated with several neurocristopathies such as Waardenburg syndrome type IV (WS4), a congenital disorder characterized by the association of hearing loss, pigmentary abnormalities, and absence of ganglion cells in the myenteric and submucosal plexus of the gastrointestinal tract, also known as aganglionic megacolon or Hirschsprung disease (HSCR). --- Explanation: This study reports the first SOX10 mutation in an isolated HSCR patient without syndromic features.


HGNC.SYMBOL:PHOX2B

[PMID:41253684] [SUPPORT] Hirschsprung disease (HD) can be associated with congenital central hypoventilation syndrome (CCHS). CCHS is mostly due to PHOX2B pathogenic variants. --- Explanation: This report demonstrates the association between PHOX2B variants and Hirschsprung disease, particularly in syndromic cases with CCHS.


HGNC.SYMBOL:NRG1

[PMID:38169757] [SUPPORT] RET, NRG1, and L1CAM genes are reported as pathological gene variants associated with the incidence of different variants of Hirschsprung's disease. --- Explanation: This report lists NRG1 among the key genes associated with Hirschsprung disease variants.

[PMID:34422713] [SUPPORT] The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. --- Explanation: This review identifies neuregulin (NRG1) as a newly discovered HSCR gene.


HGNC.SYMBOL:ZEB2


HGNC.SYMBOL:NRTN


HGNC.SYMBOL:NCAM1


MONDO:0009666

[PMID:39391064] [SUPPORT] Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures. --- Explanation: Lists metabolic acidosis as a typical presenting feature of HCS deficiency.

[PMID:39634276] [SUPPORT] Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation, with predominant involvement of the nervous system, skin, and hair. --- Explanation: Confirms metabolic acidosis as a common clinical manifestation.


MONDO:0009666

[PMID:39194177] [SUPPORT] An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation. --- Explanation: Documents severe lactic acidosis as a presenting feature in neonatal HLCS deficiency.

[PMID:32841162] [SUPPORT] Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia. --- Explanation: Lists lactic acidosis among the typical manifestations of HLCS deficiency.


MONDO:0009666

[PMID:39391064] [SUPPORT] Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures. --- Explanation: Lists seizures among typical presenting features.

[PMID:36890565] [SUPPORT] Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness --- Explanation: Confirms seizures in the 28-patient Chinese cohort.


MONDO:0009666

[PMID:36890565] [SUPPORT] Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness --- Explanation: Documents rash as a common symptom in the 28-patient cohort.

[PMID:39634276] [SUPPORT] Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation --- Explanation: Confirms rash among common clinical manifestations of HLCS deficiency.


MONDO:0009666

[PMID:39194177] [SUPPORT] Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death. --- Explanation: Lists alopecia among clinical manifestations of HLCS deficiency.

[PMID:32841162] [SUPPORT] Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia. --- Explanation: Confirms alopecia as a typical manifestation.


MONDO:0009666

[PMID:39194177] [SUPPORT] Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death. --- Explanation: Lists hyperammonemia among clinical manifestations.

[PMID:32841162] [SUPPORT] Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia. --- Explanation: Confirms hyperammonemia as a typical manifestation of HLCS deficiency.


MONDO:0009666

[PMID:39391064] [SUPPORT] Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures. --- Explanation: Lists lethargy among typical presenting features.

[PMID:38550975] [SUPPORT] An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency. --- Explanation: Confirms lethargy as a presenting symptom in a documented HLCS case.


MONDO:0009666

[PMID:39391064] [SUPPORT] Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures. --- Explanation: Lists hypotonia as a typical presenting feature.

[PMID:39194177] [SUPPORT] Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures --- Explanation: Confirms hypotonia among clinical manifestations.


MONDO:0009666

[PMID:36890565] [SUPPORT] Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness --- Explanation: Documents vomiting as a common symptom in the 28-patient cohort.

[PMID:39391064] [SUPPORT] Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures. --- Explanation: Lists vomiting among typical presenting features.


MONDO:0009666

[PMID:39194177] [SUPPORT] Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures --- Explanation: Lists tachypnea among clinical manifestations.

[PMID:39634276] [PARTIAL] Despite supportive treatment with antibiotics upon admission, the infant continued to experience rapid and deep breathing accompanied by groaning, and obvious wheezing. --- Explanation: Supports respiratory distress with rapid breathing, which is compatible but not fully specific for tachypnea.


MONDO:0009666

[PMID:39194177] [SUPPORT] Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures --- Explanation: Lists developmental delay among clinical manifestations of HLCS deficiency.

[PMID:36890565] [SUPPORT] After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up. --- Explanation: Indicates developmental delay is preventable with early biotin therapy, implying it occurs when treatment is delayed.


MONDO:0009666

[PMID:39194177] [SUPPORT] Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures --- Explanation: Lists feeding problems among clinical manifestations.

[PMID:39634276] [SUPPORT] Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation --- Explanation: Confirms feeding difficulties as a common manifestation.


MONDO:0009666

[PMID:39634276] [SUPPORT] Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation --- Explanation: Lists growth retardation among common clinical manifestations.


MONDO:0009666

[PMID:32841162] [SUPPORT] Patient 1 was a 7-year-old girl with normal growth and development, presenting with severe hypoglycemia and metabolic acidosis. --- Explanation: Documents severe hypoglycemia as a presenting feature in an HLCS deficiency patient.

[PMID:38550975] [SUPPORT] She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed. --- Explanation: Confirms hypoglycemia as a feature of acute decompensation in HLCS deficiency.


MONDO:0009666

[PMID:39194177] [SUPPORT] Despite receiving supportive care, no evident clinical improvement was observed, accompanied by the onset of generalized ichthyosis. --- Explanation: Documents generalized ichthyosis developing in a neonate with HLCS deficiency prior to biotin therapy.


MONDO:0009666

[PMID:39194177] [INDIRECT EVIDENCE] [SUPPORT] Holocarboxylase synthetase deficiency (HLCS deficiency, OMIM #253270) is an exceedingly rare metabolic disorder resulting in multiple carboxylase deficiencies owing to impaired biotin cycle. --- Explanation: Supports HLCS molecular deficiency as the initiating event.


MONDO:0009666


MONDO:0009666

[PMID:36890565] [INDIRECT EVIDENCE] [SUPPORT] After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up. --- Explanation: Clinical reversibility with biotin is consistent with a primary defect in biotin-dependent enzyme activation.


MONDO:0009666

[PMID:39194177] [INDIRECT EVIDENCE] [SUPPORT] Holocarboxylase synthetase deficiency (HLCS deficiency, OMIM #253270) is an exceedingly rare metabolic disorder resulting in multiple carboxylase deficiencies owing to impaired biotin cycle. --- Explanation: Directly supports concurrent deficiency of multiple carboxylases in HLCS deficiency.

[PMID:36890565] [INDIRECT EVIDENCE] [SUPPORT] The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals. --- Explanation: Simultaneous elevation of multiple pathway metabolites supports a multi-carboxylase defect state.


MONDO:0009666

[PMID:32841162] [INDIRECT EVIDENCE] [SUPPORT] Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia. --- Explanation: Confirms lactic acidosis as a typical manifestation of HLCS deficiency, consistent with impaired PC-dependent gluconeogenesis.

[PMID:39194177] [INDIRECT EVIDENCE] [SUPPORT] An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation. --- Explanation: Illustrates severe lactic acidosis in neonatal HLCS deficiency from impaired gluconeogenesis.


MONDO:0009666

[PMID:36890565] [INDIRECT EVIDENCE] [SUPPORT] The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals. --- Explanation: Documents increased MCC-related metabolites in HLCS deficiency.


MONDO:0009666

[PMID:36890565] [INDIRECT EVIDENCE] [SUPPORT] The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals. --- Explanation: Documents increased PCC-related metabolites in HLCS deficiency.


MONDO:0009666

[PMID:32841162] [INDIRECT EVIDENCE] [SUPPORT] Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia. --- Explanation: Directly lists hyperammonemia as a typical manifestation.

[PMID:38550975] [INDIRECT EVIDENCE] [SUPPORT] She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed. --- Explanation: Documents hyperammonemia during acute HLCS decompensation.


MONDO:0009666

[PMID:38550975] [INDIRECT EVIDENCE] [SUPPORT] Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis. Insulin therapy rapidly corrected biochemical parameters, and clinical status improved. --- Explanation: Documents hyperglycemic ketoacidosis during HLCS decompensation and proposes secondary Krebs cycle disturbance mechanism.

[PMID:38550975] [INDIRECT EVIDENCE] [SUPPORT] We propose that secondary Krebs cycle disturbances affecting pancreatic beta cells impaired glucose-stimulated insulin secretion, resulting in insulinopenia. --- Explanation: Provides mechanistic hypothesis for glucose dysregulation in HLCS decompensation.


MAXO:0000058

[PMID:36890565] [SUPPORT] After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up. --- Explanation: Demonstrates dramatic resolution of symptoms with biotin therapy in a 28-patient cohort.

[PMID:39194177] [SUPPORT] Remarkably, dramatic clinical improvement in lactic acidosis was observed the day after initiating biotin administration, leading to the discontinuation of mechanical ventilation within 6 days. --- Explanation: Documents rapid clinical improvement with biotin mega-dose therapy in a neonate.

[PMID:26754537] [SUPPORT] Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical outcomes. --- Explanation: Systematic review confirming biotin supplementation is associated with good outcomes.


MAXO:0000124

[PMID:36890565] [SUPPORT] Newborn screening is crucial for early diagnosis, treatment, and long-term outcomes. --- Explanation: Directly supports importance of newborn screening for HLCS deficiency.

[PMID:36890565] [SUPPORT] Among the 28 patients, six patients underwent newborn screening, of which only one was missed. --- Explanation: Provides real-world newborn screening detection data for HLCS deficiency.


MAXO:0000950

[PMID:38550975] [SUPPORT] An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency. --- Explanation: Documents acute decompensation requiring emergency management in HLCS deficiency.

[PMID:38550975] [SUPPORT] Insulin therapy rapidly corrected biochemical parameters, and clinical status improved. --- Explanation: Demonstrates insulin therapy as an acute management strategy for hyperglycemic ketoacidosis in HLCS decompensation.


MAXO:0000088

[PMID:32841162] [SUPPORT] she had five episodes of hypoglycemia and metabolic acidosis in past 4 years when her oral intake decreased during acute illness. --- Explanation: Demonstrates that decreased oral intake triggers metabolic decompensation, supporting dietary management.


MAXO:0000079

[PMID:36890565] [SUPPORT] DNA sequencing revealed 12 known and 6 novel variants in the HLCS gene of patients. --- Explanation: Genetic characterization supports genetic counseling for families.


MAXO:0000127

[PMID:39194177] [SUPPORT] Our case highlights the significance of early genetic testing in neonates with unexplained metabolic disorders to enable timely diagnosis and therapy initiation. --- Explanation: Directly supports the role of early genetic testing for HLCS deficiency management.


MAXO:0000058

[PMID:26754537] [SUPPORT] Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical outcomes. --- Explanation: Systematic review supporting antenatal biotin supplementation for at-risk pregnancies.


HGNC.SYMBOL:HLCS pathogenic variants

[PMID:39391064] [SUPPORT] A mini-review of HCS deficiency with late onset (>1 year) or early onset (<1 month) revealed that splice variants are associated with late onset, while both variants p. (Leu216Arg) and p. (Leu237Pro) are associated with early onset. --- Explanation: Provides genotype-phenotype correlations regarding onset timing.


MONDO:0007732

[PMID:16183809] [SUPPORT] these studies validate our clinical diagnostic criteria for HOS including an absolute requirement for preaxial radial ray upper limb malformation --- Explanation: Preaxial radial ray defect is an absolute diagnostic requirement for HOS.

[PMID:30552424] [SUPPORT] the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect --- Explanation: Bilateral asymmetric radial ray defects are characteristic of TBX5-confirmed HOS.


MONDO:0007732

[PMID:30552424] [SUPPORT] A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%) --- Explanation: Largest molecular series confirms 91% CHD rate with ASD as most common type at 61.5%.


MONDO:0007732

[PMID:8988165] [SUPPORT] Holt-Oram syndrome is characterized by upper limb malformations and cardiac septation defects --- Explanation: Cardiac septation defects (including VSD) are a defining feature.


MONDO:0007732

[PMID:11572777] [SUPPORT] one potential explanation for Holt-Oram syndrome conduction system defects --- Explanation: Mouse model provides mechanistic explanation for conduction defects via decreased connexin 40.


MONDO:0007732


MONDO:0007732

[PMID:28246128] [SUPPORT] 35% of TBX5-KO iPSC-CMs exhibited marked proarrhythmic activity characterized by the development of depolarizing humps during phase 2 and 3 of the action AP that resemble early after-depolarizations (EADs) --- Explanation: TBX5-knockout iPSC-derived cardiomyocytes show proarrhythmic activity with EADs, modeling the cardiac conduction abnormalities seen in Holt-Oram syndrome patients.


MONDO:0007732

[PMID:11572777] [INDIRECT EVIDENCE] [SUPPORT] Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription --- Explanation: Mouse model demonstrates that 50% TBX5 reduction significantly affects cardiac target gene expression.

[PMID:11572777] [INDIRECT EVIDENCE] [SUPPORT] Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated --- Explanation: Identifies the TBX5-NKX2-5 cooperative mechanism underlying cardiac septation and conduction.

[PMID:15096952] [INDIRECT EVIDENCE] [SUPPORT] missense mutations diminish the interaction of TBX5 with other transcription factors and reduce nuclear localization of mutant protein --- Explanation: Missense mutations cause disease through impaired protein interactions and mislocalization.


MONDO:0007732

[PMID:8988165] [INDIRECT EVIDENCE] [SUPPORT] mutations in the human TBX5 gene underlie this disorder --- Explanation: Original identification of TBX5 as the causative gene for Holt-Oram syndrome.

[PMID:8988165] [INDIRECT EVIDENCE] [SUPPORT] haploinsufficiency of TBX5 causes Holt-Oram syndrome --- Explanation: Establishes haploinsufficiency as the primary pathogenic mechanism.


HGNC.SYMBOL:TBX5 Mutations

[PMID:8988165] [SUPPORT] TBX5 was cloned from the disease locus on human chromosome 12q24.1 and identified as a member of the T-box transcription factor family --- Explanation: Original cloning of TBX5 from the HOS locus.

[PMID:15096952] [SUPPORT] Currently, 37 mutations in TBX5 have been found in patients with HOS --- Explanation: Demonstrates allelic heterogeneity with 37 distinct mutations by 2004.

[PMID:15096952] [SUPPORT] no evidence exists to suggest that genotype affects the location of heart and limb defects or the severity of HOS manifestation --- Explanation: No genotype-phenotype correlation for mutation location, consistent with haploinsufficiency mechanism.

[PMID:30552424] [SUPPORT] representing the largest molecular series ever described --- Explanation: 78 patients with TBX5 variants in the largest molecular cohort.


MONDO:0007732

[PMID:36936432] [SUPPORT] Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities, congenital heart defects, and/or conduction abnormalities --- Explanation: Case report demonstrating upper limb abnormalities as a cardinal clinical feature of HOS


MONDO:0007732

[PMID:36936432] [SUPPORT] Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities, congenital heart defects, and/or conduction abnormalities --- Explanation: Case report of HOS with upper limb alterations demonstrating the limb phenotype is a cardinal feature


MONDO:0007732

[PMID:36936432] [SUPPORT] The patient inherited a base T (reference C) at rs883079 from her mother and base C (reference T) at rs10850326 from her father, both of which belong to the 3'-untranslated region (UTR) of the TBX5 gene --- Explanation: Case report showing TBX5 3'-UTR variants can cause HOS with skeletal manifestations


MONDO:0007732

[PMID:39596866] [SUPPORT] Within these malformations, septal defects such as ventricular (VSD) and atrial septal defects (ASD) are the most common forms of CHDs --- Explanation: Establishes that septal defects are cardinal features of congenital heart disease associated with genetic factors including TBX5

[PMID:39156428] [SUPPORT] Seventy-five percent of those with Holt-Oram syndrome have a congenital cardiac defect, which most frequently affects the septum --- Explanation: Clinical epidemiology showing atrial septal defect is the most common cardiac manifestation of HOS


MONDO:0007732

[PMID:38189150] [SUPPORT] Transcriptional changes in the atria observed in human HF directly antagonize the atrial rhythm gene regulatory network --- Explanation: Demonstrates that TBX5-dependent atrial gene networks regulate conduction and rhythm, with their disruption causing arrhythmias including conduction abnormalities

[PMID:38235884] [SUPPORT] HOS usually requires the implantation of a pacemaker, because of cardiac conduction disturbances --- Explanation: Clinical evidence that conduction abnormalities are a significant feature requiring therapeutic intervention in HOS


MONDO:0007732

[PMID:39677667] [SUPPORT] Chd4 AKO mice had increased vulnerability to AF from electrical pacing and a fraction had spontaneous AF --- Explanation: Evidence that disruption of TBX5's chromatin remodeling partner CHD4 increases atrial fibrillation susceptibility, consistent with HOS pathophysiology


MONDO:0007732

[PMID:39596866] [SUPPORT] Congenital heart diseases (CHDs) are a group of complex diseases characterized by structural and functional malformations during development in the human heart --- Explanation: Establishes that septal defects are core manifestations of congenital heart disease linked to genetic factors like TBX5


MONDO:0007732

[PMID:38344303] [INDIRECT EVIDENCE] [SUPPORT] Tbx5 maintains atrial identity in post-natal cardiomyocytes by regulating an atrial-specific enhancer network --- Explanation: Direct evidence that TBX5 maintains atrial cardiomyocyte identity through a dosage-sensitive chromatin-based mechanism

[PMID:39829922] [INDIRECT EVIDENCE] [SUPPORT] Genome organization, including compartments, topologically associated domains, and chromatin loops, are sensitive to reduced TBX5 dosage in a human model of CHD --- Explanation: Demonstrates that TBX5 dosage affects 3D chromatin architecture, directly supporting the haploinsufficiency mechanism in HOS

[PMID:36936432] [INDIRECT EVIDENCE] [SUPPORT] Sequence alteration of T-box transcription factor 5 (TBX5) is correlated with the incidence of HOS --- Explanation: Confirms that TBX5 sequence alterations cause HOS with novel pathogenic mechanisms including 3'-UTR variants


MONDO:0007732

[PMID:38189150] [INDIRECT EVIDENCE] [SUPPORT] FOG2 bound a subset of GATA4 and TBX5 co-bound genomic locations... FOG2 repressed TBX5-dependent transcription from a subset of co-bound enhancers --- Explanation: Demonstrates the functional interaction between TBX5, GATA4, and FOG2 at atrial enhancers

[PMID:38189150] [INDIRECT EVIDENCE] [SUPPORT] Atrial rhythm abnormalities in mice caused by Tbx5 haploinsufficiency were rescued by Zfpm2 haploinsufficiency --- Explanation: Genetic evidence that FOG2/ZFPM2 modulates TBX5-dependent conduction defects, supporting a direct functional interaction

[PMID:39677667] [INDIRECT EVIDENCE] [SUPPORT] TBX5 recruits CHD4, a chromatin remodeling ATPase, to 33,170 genomic regions... CHD4 is essential for maintaining aCM gene expression, aCM identity, and atrial rhythm homeostasis --- Explanation: Shows that CHD4 is directly recruited by TBX5 and is critical for maintaining atrial cardiomyocyte identity


MAXO:0000683

[PMID:38189150] [SUPPORT] The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF --- Explanation: Supports the need for cardiac monitoring in HOS patients due to risk of progressive arrhythmias and conduction abnormalities

[PMID:38235884] [SUPPORT] HOS usually requires the implantation of a pacemaker, because of cardiac conduction disturbances --- Explanation: Clinical evidence supporting need for advanced cardiac monitoring and intervention in HOS


MAXO:0000004

[PMID:39596866] [SUPPORT] Septal defects such as ventricular (VSD) and atrial septal defects (ASD) are the most common forms of CHDs --- Explanation: Establishes that septal defects are cardinal manifestations requiring potential surgical intervention


MAXO:0000011

[PMID:36936432] [SUPPORT] Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities --- Explanation: Case reports of HOS patients with upper limb abnormalities requiring orthopedic and rehabilitative management


HGNC.SYMBOL:TBX5

[PMID:36936432] [SUPPORT] Sequence alteration of T-box transcription factor 5 (TBX5) is correlated with the incidence of HOS --- Explanation: Directly establishes the causal relationship between TBX5 sequence variants and HOS development

[PMID:38189150] [SUPPORT] Atrial rhythm abnormalities in mice caused by Tbx5 haploinsufficiency were rescued by Zfpm2 haploinsufficiency --- Explanation: Demonstrates that TBX5 haploinsufficiency is sufficient to cause cardiac phenotypes similar to HOS


MONDO:0004737

[PMID:38201964] [SUPPORT] Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for various significant medical conditions --- Explanation: Review confirms ocular manifestations including ectopia lentis as characteristic of homocystinuria.


MONDO:0004737

[PMID:35791106] [SUPPORT] This review aims to present the ophthalmic spectrum of homocystinuria and its molecular basis --- Explanation: Review of ocular complications in HCU supports myopia as a common ophthalmic manifestation.


MONDO:0004737

[PMID:38201964] [SUPPORT] In cases of arterial or venous thrombotic vascular events, particularly with other comorbidities, it is crucial to consider moderate to severe HHcy. --- Explanation: Confirms arterial and venous thrombotic events as important clinical manifestations of hyperhomocysteinemia.


MONDO:0004737

[PMID:37994477] [SUPPORT] Genetic defects in the synthesis, catabolism or transport of amino acids underlie a diverse class of diseases known as inborn errors of amino acid metabolism. --- Explanation: Review covering CBS deficiency confirms cognitive impairment as a key clinical feature.