DeCure for 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency — 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 module46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency 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 46,xy disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency 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.
What the evidence adds up to
In two newborns with 46,XY disorder of sex development due to 17β-hydroxysteroid dehydrogenase type 3 deficiency, low testosterone/androstenedione ratios of 0.22 and 0.24 (normal >0.8) after hCG stimulation confirmed the diagnosis. One had low basal and GnRH-stimulated gonadotropins; the other had borderline basal but normal stimulated gonadotropins. Sequencing found a novel homozygous HSD17B3 mutation (c.464A>C, p.H155P) in one case and a known homozygous mutation (c.239G>A, p.R80Q) in the other.
Among 20 Iranian phenotypic females with 46,XY DSD, one had a homozygous HSD17B3 missense mutation Ser65Leu (c.194C>T). Three other individuals had 17β-HSD3 deficiencies without identified mutations. Overall, SRD5A2 and HSD17B3 mutations were found in 10% of this cohort.
Three cases diagnosed at a single US paediatric centre had T:A ratios of 0.29, 0.29, and 0.32. One had a confirmed pathogenic splice site variant in HSD17B3; two others had clinical diagnoses based on the ratio and deferred genetic testing. All three were initially misdiagnosed as androgen insensitivity syndrome. Two requested gonadectomy to stop unwanted virilisation, then began oestrogen. The authors note that only 12 cases had been reported in the US before this series, suggesting the condition is under-recognised and often misdiagnosed.
No treatment trials, no survival data, and no response rates are reported in these abstracts. What is missing is prospective natural history data, standardised diagnostic criteria across centres, and any study of long-term outcomes such as gender identity stability, bone health, or malignancy risk in retained gonads. No drug repurposing evidence appears in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Pediatric Endocrinology and Metabolism · 2015 · 4 citations
Two different patterns of mini-puberty in two 46,XY newborns with 17β-hydroxysteroid dehydrogenase type 3 deficiency
AbstractWe report two newborns with female external genitalia and bilateral inguinal swelling who were diagnosed with 17β-hydroxysteroid dehydrogenase type 3 deficiency, a rare cause of 46,XY disorder of sexual development. The first case had normal clitoral size and vaginal and urethral openings, palpable gonads in the inguinal region, low testosterone, and low levels of basal and GNRH-stimulated gonadotropin. The second case had similar external genitalia, low testosterone but borderline basal and normal stimulated gonadotropin levels. Low testosterone/androstenedione ratios (0.22 and 0.24, respectively; normal, >0.8) after human chorionic gonadotropin stimulation indicated 17β-hydroxysteroid dehydrogenase type 3 deficiency. HSD17B3 sequencing revealed a homozygous novel mutation (c.464A>C, p.H155P) in exon 6 in the first case and homozygous c.239G>A (p.R80Q) in exon 3 in the second.
Fetal and Pediatric Pathology · 2020 · 3 citations
Novel Deleterious Mutation in Steroid-5α-Reductase-2 in 46, XY Disorders of Sex Development: Case Report Study
AbstractBackground: Steroid-5α-reductase-2 (SRD5A2) and 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) enzyme deficiencies are frequent causes of 46, XY disorder of sex development (46, XY DSD), where an infant with 46, XY has a female phenotype. We assessed the hydroxy-steroid-17β-dehydrogenase-3 (HSD17B3)and SRD5A2 genes in twenty Iranian phenotypic females with 46,XY DSD. Materials and methods: All exons in HSD17B3 and SRD5A2 genes were subjected to PCR amplification followed by sequencing. Results: Of 20 identified 46, XY DSD patients, one had a homozygous missense 17β-HSD3 mutation Ser65Leu (c.194C > T). We found 1 SRD5A2 novel homozygous missense mutation of Tyr242Asp (c.891T > G) in exon 5, which in-silico analyses revealed that this mutation may have deleterious impact on ligand binding site of SRD5A2 protein. Three other individuals harbored 17β-HSD3 deficiencies without identified mutations. Conclusions: SRD5A2 and 17β-HSD3 mutations are found in 10% of 46, XY DSD Iranian patients.
Journal of the Endocrine Society · 2020 · 0 citations · open access
MON-066 17B-hydroxysteroid dehydrogenase Type 3 Deficiency: An Under-Recognized Cause of 46,XY DSD in the United States?
AbstractAbstract Title: 17β-hydroxysteroid dehydrogenase type 3 deficiency: An under-recognized cause of 46,XY DSD in the United States? Introduction: The 17β-hydroxysteroid dehydrogenase type 3 (17BHSD3) enzyme, expressed in the testes, converts androstenedione (A) to testosterone (T). 17BHSD3 deficiency causes a 46,XY difference of sex development (DSD), or intersex condition, characterized by lack of prenatal virilization followed by marked virilization at puberty due to peripheral conversation of A to T by other 17BHSD isoenzymes. Diagnosis is suspected with an abnormal T:A ratio of <0.8 and confirmed by HSD17B3 sequencing and deletion/duplication analysis. 17BHSD3 deficiency may present similarly to complete or partial androgen insensitivity syndrome (CAIS, PAIS) due to undervirilization in infancy, and to 5α-reductase deficiency due to virilization during puberty. Previously, only 12 cases of this autosomal recessive disorder have been reported in the US. We report 3 cases of 17BHSD3 deficiency diagnosed at a single pediatric center in the US. Clinical Cases: Patient A had atypical genitalia at birth and a presumed diagnosis of PAIS though sequencing of AR was normal. He underwent multiple genital surgeries throughout childhood, had significant psychiatric and behavioral concerns, and was referred to our multidisciplinary clinic at age 16 years. Additional diagnostic testing revealed a T:A ratio of 0.29 consistent with 17BHSD3 deficiency; confirmatory genetic testing was deferred per family preference. Patient B was noted to have testicular tissue present at age 3 years during an inguinal hernia repair and was diagnosed with CAIS. She presented to our institution at age 14 years with clitoromegaly. T:A ratio was 0.29 and genetic testing revealed a pathogenic splice site variant in HSD17B3. She requested gonadectomy due to unwanted virilization inconsistent with her female gender identity. Following gonadectomy at age 16 years, she began estrogen treatment and vaginal dilations. Patient C presented to our institution at age 18 years with pubertal delay and primary amenorrhea. She was noted to have palpable gonads and clitoromegaly. Evaluation revealed a 46,XY karyotype and a T:A ratio of 0.32. She was raised as a girl and identified as female. She requested gonadectomy to avoid further virilization, after which she began estrogen for pubertal induction. She deferred confirmatory genetic testing. Conclusions: Previous studies noted 17BHSD3 deficiency to be rare in the US, but the presence of 2 suspected and 1 confirmed diagnoses at a single US institution suggests it is likely more common and may be misdiagnosed as other types of DSD. Differentiating 17BHSD3 deficiency from other causes of 46,XY DSD is essential to inform accurate counseling about sex designation, gender identity, gonadal function, malignancy risk, potential fertility and heritability.
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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