DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for craniofacial-deafness-hand syndrome — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCraniofacial-deafness-hand syndrome maps to a 1-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 craniofacial-deafness-hand 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
paired box 3 (PAX3) — PAX3 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3CMY · 1.95 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Craniofacial-deafness-hand syndrome is an autosomal dominant disorder caused by a specific missense mutation, Asn47Lys, in the paired domain of the PAX3 gene. This was first identified in a family of three affected individuals — a mother and two children — using SSCP analysis and mutation-specific PCR. The same codon is mutated in Waardenburg syndrome type 3 (Asn47His), but the authors state that substituting a basic amino acid for asparagine at residue 47 appears to have a more drastic effect on the phenotype than the missense, frameshift and deletion mutations that cause Waardenburg syndrome type 1. A 2023 report of the first Russian patient, a 1-year-10-month-old proband, confirmed the same heterozygous c.141C>G (p.Asn47Lys) variant in PAX3 by Sanger sequencing, and noted that unlike Waardenburg syndrome types 1 and 3, this syndrome is not characterised by hair hypopigmentation or iris heterochromia, but does include congenital contractures of the wrist and interphalangeal joints.
The syndrome’s clinical features include absence or hypoplasia of the nasal bones, profound sensorineural deafness, a small short nose with slitlike nares, hypertelorism, short palpebral fissures, limited wrist movement, and ulnar deviation of the fingers. A 1987 report described a Jewish family with congenital hearing loss, facial asymmetry, temporal alopecia, frontal bossing, broad nasal root, small nasal alae, and a short frenulum of the tongue, which the authors considered a new autosomal dominant deafness syndrome with distinct craniofacial features. A 1980 case report described a child with congenital ichthyosiform eruption, neurosensory deafness, and massively elevated serum steroid disulphates — 5-androstene-3 beta,17 alpha-diol at 56 micrograms/ml, 5-androstene-3 beta,17 beta-diol at 25 micrograms/ml, and 5-pregnene-3 beta,20 alpha-diol at 26 micrograms/ml — about one hundred times the reference values at 5 days after birth, but normal by 16 months. Steroid sulfatase activity in skin biopsies was normal, and the authors hypothesised the elevations were due to neonatal hepatopathy, with no later evidence of chronic liver disease.
A 2005 study of intracranial volume in nonsyndromal craniosynostosis found that only boys older than 7 months with metopic synostosis had smaller ICVs than normal (p = 0.02), while girls with sagittal synostosis and boys with unilateral coronal synostosis had larger ICVs (p < 0.001). The authors concluded there was no evidence that ICVs are smaller than normal in most patients with nonsyndromal craniosynostosis, and that surgical intervention should focus less on ICV and more on normalising craniofacial shape. A 2009 review noted that 1% to 2% of newborns have congenital defects, 10% of which involve upper extremity malformations, and classified these by the Swanson system.
What is still missing: no therapeutic trials have been reported for craniofacial-deafness-hand syndrome; the literature consists entirely of case reports and genetic characterisation. There is no data on any drug intervention, no animal model testing, and no systematic natural history study. The condition is extremely rare — only a handful of genetically confirmed families exist — so any future work would require international collaboration, funding for a patient registry, and a trial design that accounts for the small, heterogeneous patient population.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Mutation · 1996 · 80 citations
Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome
AbstractCraniofacial-deafness-hand syndrome (MIM 122880) is inherited as an autosomal dominant mutation characterized by the absence or hypoplasia of the nasal bones, profound sensorineural deafness, a small and short nose with slitlike nares, hypertelorism, short palpebral fissures, and limited movement at the wrist and ulnar deviations of the fingers. In a family of three affected individuals with this syndrome, a mother and two children, a missense mutation (Asn47Lys) in the paired domain of PAX3 was initially detected by SSCP analysis. PCR amplification using an oligonucleotide with a terminal 3'-residue match for the C-to-G transversion in codon 47 showed the presence of this mutation in the DNA from all affected members. The DNA from unaffected members were refractory to PCR amplification with the mutation-specific oligonucleotide but did amplify a control primer pair in the same PCR reaction tube. A previously described missense mutation in this same codon (Asn47His) is associated with Waardenburg syndrome type 3 (Hoth et al., 1993). Substitution of a basic amino acid for asparagine at residue 47, conserved in all known murine Pax and human PAX genes, appears to have a more drastic effect on the phenotype than missense, frameshift and deletion mutations of PAX3 that cause Waardenburg syndrome type 1.
Intracranial volume in patients with nonsyndromal craniosynostosis
AbstractOBJECT: In recent years, comparisons between intracranial volumes (ICVs) in patients with craniosynostosis and healthy patients have given variable results, leading to questions regarding the validity of the normal reference material and the comparability of the measurement techniques. In this study, ICVs in patients with nonsyndromal craniosynostosis without previous surgical intervention were compared with the ICVs of a normal population of European descent determined using the same method for each group. METHODS: Determination of ICV was based on measuring the area of intersection in each computerized tomography slice. For comparisons the ICV measurements for each patient were standardized with regard to age and sex by expressing them in terms of the standard deviation score. Only the group of boys with metopic synostosis had a tendency toward smaller ICV than did healthy boys (p = 0.04). Partitioning the male metopic data into age groups younger and older than 7 months of age revealed that the younger children had normal ICVs, whereas the older children had, on average, smaller ICVs (p = 0.02). Both the female sagittal synostosis and the male unilateral coronal synostosis groups had larger than normal ICVs, both with a probability value less than 0.001. CONCLUSIONS: No evidence was found that the ICVs of patients with nonsyndromal craniosynostosis are smaller than those of normal children, except for boys older than 7 months of age with metopic synostosis. This finding may have implications for the timing of surgical intervention for these patients. The indications are that interventions should be focused less on ICV and more on normalizing craniofacial shape and promoting normal development.
A congenital ichthyosiform syndrome with deafness and elevated serum steroid disulphate levels
AbstractThis is a report on a child with a syndrome characterized by an extensive congenital ichthyosiform eruption, neurosensory deafness and abnormally elevated serum steroid disulfates neonatally. When analysed by gas-liquid chromatography (glc) and gas chromatography-mass spectrometry (gc-ms) the following serum steroid disulfates were very high 5 days after birth: 5-androstene-3 beta,17 alpha-diol (56 micrograms/ml), 5-androstene-3 beta,17 beta-diol (25 micrograms/ml) and 5-pregnene-3 beta,20 alpha-diol (26 micrograms/ml). The values are about one hundred times higher than the reference values at this age. At the same time serum steroid monosulphate concentrations were normal. The patient had normal steroid sulfatase activity in skin biopsies, indicating that enzyme deficiency was not the reason for the high steroid disulfate concentrations. When serum steroid disulphatases were next analysed at 16 months of age they were normal. No hepatomegaly was observed but the other laboratory data support the hypothesis that the serum steroid disulphate concentrations were due to neonatal hepatography. Later, no indications of chronic liver disease were observed. These indications have not been described earlier in ichthyosiform erythrodermia and it is possible that the patient represents a new type of this rare disease.
Journal of Craniofacial Surgery · 2009 · 12 citations
Congenital Anomalies of the Hand
AbstractOf the 1% to 2% of newborns that are born with congenital defects, 10% of these are born with upper extremity malformations. Although many classification systems have been developed, the most widely used classification system was developed by Swanson. This system categorizes the congenital upper extremity malformations according to the embryonic process that has failed to develop. Congenital hand malformation is a broad category that is broken down into 7 subclasses. This review will focus on congenital hand defects and their associated craniofacial syndromes. The topics will include failure of formation, failure of differentiation, duplication, overgrowth, undergrowth, constriction band syndromes, and generalized skeletal abnormalities.
A new autosomal dominant craniofacial deafness syndrome
AbstractA Jewish family is reported in which the proband and her father had congenital hearing loss and unusual facies consisting of facial asymmetry, temporal alopecia with frontal bossing, a broad nasal root and small nasal alae. In addition, both were born with a short frenulum of the tongue. We believe these findings represent a new autosomal dominant deafness syndrome with distinct craniofacial features.
Neuromuscular Diseases · 2023 · 0 citations · open access
Clinical and genetic characteristics of the first Russian patient with a syndrome of craniofacial dysmorphia-deafness-anomalies of the upper limbs, caused by a mutation in the <i>PAX3</i> gene
AbstractCraniofacial dysmorphia-deafness-anomalies of the upper limbs is a rare autosomal dominant syndrome caused by variants in the PAX3 gene. In contrast to the two main nosological forms – Waardenburg syndrome types 1 and 3, caused by variants in this gene, the syndrome of craniofacial dysmorphias-deafness-anomalies of the upper limbs is not characterized by the presence of hair hypopigmentation and heterochromia of the iris, while congenital contractures of the wrist and interphalangeal joints of the hands. There is a description in the literature of three patients from the same family with a syndrome caused by the c.141CG(p.Asn47Lys) variant in the PAX3 gene. Aim of the work is to present the clinical and genetic characteristics of the first Russian patient with the syndrome of craniofacial dysmorphia-deafness-anomalies of the upper extremities.Molecular genetic analysis of a 1-year and 10-month-old proband with phenotypic signs of the syndrome of craniofacial dysmorphia-deafness-anomalies of the upper limbs was carried out by direct automatic Sanger sequencing of the entire coding sequence of the PAX3 gene. Genotyping of parents was carried out by direct automatic sequencing according to Sanger. Sequencing was carried out on an ABIPrism3500хI instrument (Applied Biosystems) in accordance with the manufacturer’s protocol; primer sequences were selected according to the reference sequence of the target regions of the PAX3 gene (NM_181459.4).In Russian proband 1 year 10 months-old, the phenotypic characteristics of the syndrome of craniofacial dysmorphia-deafness-anomalies of the upper limbs did not differ from the description of sick family members presented in the literature. A molecular genetic study revealed a heterozygous variant c.141CG(p.Asn47Lys) in the PAX3 gene in the presented patient.
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.
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