DeCure for Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleJuvenile polyposis/hereditary hemorrhagic telangiectasia syndrome maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
SMAD family member 4 (SMAD4) — SMAD4 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet pgedrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9HZA · 2.03 Å · ligand TRIETHYLENE GLYCOL (PGE). Experimental structure, not a prediction.
What the evidence adds up to
In a cohort of 41 juvenile polyposis families, SMAD4 mutations were found in 21 relatives across 9 families. Among those SMAD4 patients, 81% met diagnostic criteria for hereditary hemorrhagic telangiectasia and a further 14% were suspected of having it. Epistaxis and asthma were the most common symptoms, and arteriovenous malformations, both symptomatic and subclinical, were noted near universally. A separate study of 33 SMAD4 variant carriers drawn from an HHT reference centre found that 88% had a definite clinical HHT diagnosis by Curaçao criteria, 81% met criteria for juvenile polyposis syndrome, 61% had at least one connective tissue symptom, and 15% of those who had echocardiography showed aortic dilation. Digestive complications were frequent, early, and diffuse: 21% of patients had undergone prophylactic gastrectomy for extensive gastric polyposis, and 13% had developed a digestive cancer.
A case report from Korea described a 15-year-old boy previously diagnosed with juvenile polyposis at age 7, who was found to have a novel de novo deletion in SMAD4 (c.1146_1163del; p.His382_Val387del). He had numerous polyps throughout the gastrointestinal tract, mucocutaneous telangiectases on the lips, tongue, and jejunum, and arteriovenous malformations in both lungs. Another case report described a 32-year-old man with no family history of either condition who presented with a large fungating gastric mass, polyposis in both upper and lower GI tract, and iron deficiency anaemia, and was found to carry a SMAD4 mutation. In the 2011 study, 14 of 21 affected relatives from 6 families underwent systematic HHT screening: 79% had three or more HHT manifestations, and 14% had at least two. Greater than 90% of juvenile polyposis patients with SMAD4 mutations in that series had clinically diagnosed or suspected HHT.
The 2024 observational study reported complication frequencies among SMAD4 carriers: epistaxis in 82%, cutaneous telangiectases in 58%, pulmonary arteriovenous malformations in 53%, hepatic arteriovenous malformations in 39%, and digestive angiodysplasia in 59%. No cerebral arteriovenous malformations were diagnosed. The authors recommended upper and lower GI endoscopy every two years, systematic screening for pulmonary and hepatic AVMs, and cardiac ultrasound and skeletal screening for connective tissue involvement. What remains missing is prospective data on whether such screening reduces mortality or prevents complications, and whether any medical therapy alters the natural history of the overlap syndrome. No drug treatment was tested or recommended in any of these studies.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Diseases of the Colon & Rectum · 2012 · 81 citations
The Prevalence of Hereditary Hemorrhagic Telangiectasia in Juvenile Polyposis Syndrome
AbstractBACKGROUND: Juvenile polyposis syndrome is a dominant GI polyposis syndrome defined by ≥ 5 GI juvenile polyps or ≥ 1 juvenile polyps with a family history of juvenile polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of individuals. Hereditary hemorrhagic telangiectasia is a dominant disorder characterized by epistaxis, visceral arteriovenous malformations, and telangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when ≥ 3 criteria including clinical manifestations or a family history, are present. A juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome has previously been reported in 22% of patients with juvenile polyposis due to a SMAD4 mutation. OBJECTIVE: Our objective was to determine the prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in our juvenile polyposis SMAD4 patients. DESIGN, PATIENTS, AND SETTING: This was a cohort study of juvenile polyposis patients in our inherited colon cancer registries. Hereditary hemorrhagic telangiectasia manifestations were obtained from medical records, patient contact, and/or prospective hereditary hemorrhagic telangiectasia screening. The Curacao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia (≥ 3 criteria diagnostic; 2 criteria suspect of). MAIN OUTCOME MEASURES: Prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia in juvenile polyposis SMAD4 patients. RESULTS: Forty-one juvenile polyposis families were identified. Genetic testing was available for individuals within 18 families. SMAD4 mutations were found in 21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary hemorrhagic telangiectasia and 14% were suspected of having hereditary hemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in our overlap patients. Symptomatic and subclinical arteriovenous malformations were noted near universally. LIMITATIONS: There was a single, tertiary referral center. CONCLUSIONS: Nearly all juvenile polyposis SMAD4 patients have the overlap syndrome. The clinical implications and need for hereditary hemorrhagic telangiectasia screening are important factors for genetic testing in juvenile polyposis. Health care providers must be cognizant of the juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome and the implications for management of these patients.
Translational Pediatrics · 2021 · 9 citations · open access
Case report of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome: first report in Korea with a novel mutation in the SMAD4 gene
AbstractAbstract: Juvenile polyposis/hereditary hemorrhagic telangiectasia (JPS/HHT) syndrome is a rare, autosomal dominant disorder caused by mutations in the SMAD4 gene, presenting with features of both juvenile polyposis syndrome (JPS) and HHT. Reports and studies of JPS/HHT syndrome are mostly from Western countries, while there are scarce reports from East Asian countries. We report a case of a Korean boy who had been previously diagnosed with JPS at 7 years and had first visited to our center at 15 years of age. Genetic studies of the patient and parents revealed a novel variant in the SMAD4 gene, SMAD4 c.1146_1163del; p.His382_Val387del (NM_005359.5), which had developed de novo. Numerous pedunculated and sessile polyps were observed throughout the gastrointestinal (GI) tract. Mucocutaneous telangiectases were observed on the lips, tongue, and jejunum, and arteriovenous malformations (AVMs) were observed in both lungs. This is the first case report of JPS/HHT syndrome in Korea, with a novel deletion variant in the SMAD4 gene. Patients with JPS should undergo genetic evaluation of associated genes including SMAD4, and those with genetically confirmed SMAD4 variants should undergo further evaluation for coexisting asymptomatic AVMs in order to prevent life-threatening complications of thrombotic emboli and pulmonary hemorrhage.
Journal of Medical Genetics · 2024 · 7 citations · open access
Phenotypic characterisation of <i>SMAD4</i> variant carriers
AbstractBackground Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by SMAD4 pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of SMAD4 variants followed in an HHT reference centre to further delineate the phenotype. Methods Observational study based on data collected from the Clinical Investigation for the Rendu-Osler Cohort database. Results Thirty-three participants from 15 families, out of 1114 patients with HHT, had an SMAD4 variant (3%). Regarding HHT, 26 out of 33 participants (88%) had a definite clinical diagnosis based on Curaçao criteria. Complication frequencies were as follows: epistaxis (n=27/33, 82%), cutaneous telangiectases (n=19/33, 58%), pulmonary arteriovenous malformations (n=17/32, 53%), hepatic arteriovenous malformations (AVMs) (n=7/18, 39%), digestive angiodysplasia (n=13/22, 59%). No cerebral AVMs were diagnosed. Regarding juvenile polyposis, 25 out of 31 participants (81%) met the criteria defined by Jass et al for juvenile polyposis syndrome. Seven patients (21%) had a prophylactic gastrectomy due to an extensive gastric polyposis incompatible with endoscopic follow-up, and four patients (13%) developed a digestive cancer. Regarding connective tissue disorders, 20 (61%) had at least one symptom, and 4 (15%) participants who underwent echocardiography had an aortic dilation. Conclusion We describe a large cohort of SMAD4 variant carriers in the context of HHT. Digestive complications are frequent, early and diffuse, justifying endoscopy every 2 years. The HHT phenotype, associating pulmonary and hepatic AVMs, warrants systematic screening. Connective tissue disorders broaden the phenotype associated with SMAD4 gene variants and justify systematic cardiac ultrasound and skeletal complications screening.
BMJ Case Reports · 2020 · 3 citations · open access
SMAD4 juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia presenting in a middle-aged man as a large fungating gastric mass, polyposis in both upper and lower GI tract and iron deficiency anaemia, with no known family history
AbstractJuvenile polyposis syndrome (JPS) and hereditary haemorrhagic telangiectasia (HHT) are rare autosomal dominant diseases, where symptoms manifest at childhood. A 32-year-old man with no family history of JPS or HHT with SMAD4 gene mutation who developed signs and symptoms only at the age of 32, when he was an adult. In this article, we highlight the steps taken to diagnose this rare pathology, explain its pathophysiology and management.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
