DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for van Maldergem syndrome 1 — 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 moduleVan Maldergem syndrome 1 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 van maldergem syndrome 1 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
FAT atypical cadherin 4 (FAT4) — FAT4 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 cacdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8EGW · 2.3 Å · ligand CACODYLATE ION (CAC). Experimental structure, not a prediction.
What the evidence adds up to
Van Maldergem syndrome is a recessive disease affecting the face, ear, and limb extremities, caused by pathogenic variants in either DCHS1 or FAT4. A 2017 report describes a female patient with compound heterozygous variants in DCHS1, diagnosed at age 37 by whole exome sequencing. She had intellectual disability, craniofacial features, auditory malformations, and at age 15 presented with no breast development and hypogonadotropic hypogonadism. The authors note that two previously published patients may also have had hypogonadotropic hypogonadism, but endocrine abnormalities were not evaluated. A 2022 case report used expanded carrier screening of parents to identify a novel splicing variant in FAT4 (c.7018+1G>A) in two deceased infantile siblings with multiple congenital anomalies; reverse phenotyping led to a likely diagnosis of van Maldergem syndrome 2. Diagnosis is complicated by symptom overlap with Hennekam syndrome, another FAT4-related disorder.
A 1997 report describes a 4-year-old male patient with severe developmental delay, talipes equinovarus, finger camptodactyly with interphalangeal pterygium, joint laxity, bilateral microtia, and dysmorphic facies. Additional features included pharyngeal instability requiring tracheostomy, inguinal hernia, hip subluxation, small kidneys, and genital abnormalities (micropenis, bifid scrotum, cryptorchidism). Permanent tube feeding was needed for severe feeding difficulties. Metabolic tests and chromosomal analysis were normal; molecular karyotyping found two parental CNVs considered unlikely to contribute to the phenotype. A 2019 report describes a 3-year-old boy with congenital adrenal hyperplasia and suspected van Maldergem syndrome, supported by a novel likely pathogenic variant in a previously described gene. The authors note that coexisting genetic conditions are infrequent but challenging, and that advanced functional studies are needed when family segregation cannot confirm pathogenicity.
Only 13 patients had been reported as of 2017. The clinical spectrum includes intellectual disability, craniofacial features, auditory malformations, hearing loss, skeletal and limb malformations, brain abnormalities with periventricular neuronal heterotopia, and variable other anomalies. Endocrine abnormalities such as hypogonadotropic hypogonadism and breast aplasia/hypoplasia have been observed, but their molecular genetic basis remains unexplained. No treatment studies exist. What is missing is any systematic natural history study, functional work to connect DCHS1 or FAT4 variants to the endocrine and other systemic features, and a patient registry large enough to stratify by genotype.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Texas Journal of Science · 1997 · 41 citations
Trinacromerum bonneri, new species, last and fastest pliosaur of the western interior seaway
AbstractWe report on a male patient with the proposed diagnosis of the rare but very distinct entity of van Maldergem syndrome. His parents are first cousins. At the age of 4 years the boy presented with severe developmental delay, talipes equinovarus, finger camptodactyly with interphalangeal pterygium, joint laxity, bilateral microtia, and a dysmorphic facies. He showed bilateral epicanthus, telecanthus, short palpebral fissures, broad flat nasal bridge, and dental malocclusion. The combination of the specific facial features with camptodactyly, interphalangeal pterygium, joint laxity and developmental delay led to the diagnosis of van Maldergem syndrome. The medical history was further on significant for pharyngeal instability requiring the placement of a tracheostomy tube, an inguinal hernia, hip subluxation, small kidneys and genital abnormalities (micropenis, bifid scrotum, cryptorchidism). Due to severe feeding difficulties permanent tube feeding was required. Metabolic tests (newborn metabolic screening, 7-dehydrocholesterol, amino acids, organic acids in urine) and chromosomal analysis (450-500 bands; 46,XY) were normal. Molecular karyotyping revealed two parental CNVs (paternal deletion of 9q33.1; maternal duplication of 11p15.1), which are unlikely to contribute to the patient's phenotype. Taken together, the report on a further patient with van Maldergem syndrome expands the clinical spectrum of the condition by adding genital malformations, hernia, pharyngeal instability, and subluxation of the hip.
Sudanese Journal of Paediatrics · 2019 · 4 citations
Coexistence of genetic conditions: Exploring a possible relationship
AbstractWe report on a 3-year-old boy who has congenital adrenal hyperplasia and a suspected Van Maldergem syndrome, another genetic condition, with the classic phenotype seen in our patient. The latter diagnosis was supported by a genetic test that showed a novel and likely pathogenic variant in a previously described gene of the syndrome. Paediatricians do encounter such a challenge of coexisting genetic conditions albeit infrequently, and advanced genetic analysis, example whole exome sequencing, increasingly report variants of unknown significance with a variable degree of potential pathogenicity. The treating physician needs to follow a systematic approach and entertain thorough literature search and brainstorming in order to prove or disprove any possible relationship between coexisting genetic conditions. The first step should be confirming the existence of the two conditions in the first place. In addition, when family segregation is unable to confidently make a sensible conclusion in such cases, a clinician should proceed to advanced functional studies to confirm pathogenicity. Then, one can explore further any hidden relationship between coexisting and possibly clinically-related genetic conditions.
Asian Biomedicine · 2022 · 2 citations · open access
Use of expanded carrier screening for retrospective diagnosis of two deceased siblings with Van Maldergem syndrome 2: case report
AbstractVan Maldergem syndrome (VMLDS) is a recessive disease which affects multiple organs including the face, ear, and limb extremities. It can be caused by pathogenic variants in either the gene DCHS1 or FAT4. Diagnosis of VMLDS is complicated, especially regarding its similarity of symptoms to Hennekam syndrome, another disorder caused by FAT4 variants. Reported patients are two infantile siblings with multiple congenital anomalies, who deceased without clinical diagnosis. Whole exome sequencing was exploited for expanded carrier screening (ECS) of their parents, which revealed a novel splicing variant in the gene FAT4, NM_024582.6: c.7018+1G>A. In silico analysis of the variant indicates loss of canonical donor splice site of intron 6. This variant is classified as pathogenic based on ACMG criteria. Reverse phenotyping of patients resulted in likely diagnosis of VMLDS2. This study reaffirms the possibility of using ECS, leading to the genetic diagnosis of a rare disease with complicated clinical features.
A patient with van Maldergem syndrome with endocrine abnormalities, hypogonadotropic hypogonadism, and breast aplasia/hypoplasia
AbstractAbstract Background We report a female patient with endocrine abnormalities, hypogonadotropic hypogonadism and amazia (breasts aplasia/hypoplasia but normal nipples and areolas) in a rare syndrome: Van Maldergem syndrome (VMS). Case presentation Our patient was first evaluated at age 4 for intellectual disability, craniofacial features, and auditory malformations. At age 15, she presented with no breast development and other findings consistent with hypogonadotropic hypogonadism. At age 37, she underwent whole exome sequencing (WES) to identify pathogenic variants. WES revealed compound heterozygous variants in DCHS1 (rs145099391:G > A, p.P197L & rs753548138:G > A, p.T2334 M) [RefSeq NM_003737.3], diagnostic of Van Maldergem syndrome (VMS-1). VMS is a rare autosomal disorder reported in only 13 patients, characterized by intellectual disability, typical craniofacial features, auditory malformations, hearing loss, skeletal and limb malformations, brain abnormalities with periventricular neuronal heterotopia and other variable anomalies. Our patient had similar phenotypic abnormalities. She also had hypogonadotropic hypogonadism and amazia. Based on the clinical findings reported, two previously published patients with VMS may also have been affected by hypogonadotropic hypogonadism, but endocrine abnormalities were not evaluated or mentioned. Conclusion This case highlights an individual with VMS, characterized by compound heterozygous variants in DCHS1. Our observations may provide additional information on the phenotypic spectrum of VMS, including hypogonadotropic hypogonadism and amazia. However, the molecular genetic basis for endocrine anomalies observed in some VMS patients, including ours, remains unexplained.
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.
