DeCure for Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency
DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 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 moduleCongenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 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 congenital adrenal insufficiency with 46, xy sex reversal or 46,xy disorder of sex development-adrenal insufficiency due to cyp11a1 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.
Molecular view
cytochrome P450 family 11 subfamily A member 1 (CYP11A1) — CYP11A1 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…
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RCSB Protein Data Bank · entry 3N9Y · 2.1 Å · ligand PROTOPORPHYRIN IX CONTAINING FE (HEM). Experimental structure, not a prediction.
What the evidence adds up to
The condition is genetically heterogeneous. A 2009 report describes a Japanese 46,XY female with a novel heterozygous NR5A1 mutation (V41G) that failed to activate the CYP19 promoter in functional assays, yet she had no adrenal failure. The authors note that heterozygous NR5A1 mutations are more frequently found in 46,XY DSD patients without adrenal failure than in those with it. In contrast, multiple CYP11A1 mutations cause adrenal insufficiency with or without sex reversal. A 2019 case from India describes a boy with normal male external genitalia, hyperpigmentation from age 2, and a diagnosis delayed until age 11; he carried a homozygous CYP11A1 c.1351C>T (p.R451W) mutation. A 2017 report identifies compound heterozygous CYP11A1 variants (a novel splice site c.425+1G>A and the known p.E314K) in a 12-year-old male with primary adrenal insufficiency, hypospadias, and skin hyperpigmentation. A 2020 paper reports a homozygous CYP11A1 p.Thr330Met variant in a 46,XX girl diagnosed with adrenal insufficiency in the neonatal period. Another 2020 source defines inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency as a disorder with early-onset adrenal crisis, electrolyte abnormalities, vomiting, seizures, and absent or very small adrenal glands on ultrasound, but without abnormal external male genitalia.
The 2021 review of adrenal-origin DSD clarifies the pathogenic distinction: in 46,XX individuals the adrenal steroidogenic disorder directly causes genital anomalies, whereas in 46,XY patients DSD results from associated testicular dysfunction. Primary adrenal insufficiency with low cortisol and high ACTH is the rule, and aldosterone deficiency can cause life-threatening salt-wasting crises. The review lists the specific enzyme defects: 21-hydroxylase deficiency (most common) and 11β-hydroxylase deficiency cause 46,XX DSD; StAR defects (lipoid CAH), cytochrome P450scc (CYP11A1), and P450c17 deficiencies cause 46,XY DSD; SF1 mutations can cause combined adrenal and testicular failure; and 3βHSD2 or POR deficiencies can cause DSD in both karyotypes. No treatment or efficacy data are provided in any of these abstracts.
What is missing is systematic, prospective data on long-term outcomes for the various genotypes, particularly for the rarer CYP11A1 and NR5A1 mutations. No clinical trial has tested whether early genotype-directed surveillance or specific glucocorticoid/mineralocorticoid regimens improve adrenal crisis rates or quality of life. Patient stratification by mutation type (partial vs. complete loss of function) and by karyotype is not yet standardised in published cohorts, and funding for natural history studies in these ultra-rare disorders remains scarce.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Endocrine Journal · 2009 · 31 citations · open access
A Novel Heterozygous Mutation of Steroidogenic Factor-1 (SF-1/Ad4BP) Gene (NR5A1) in a 46, XY Disorders of Sex Development (DSD) Patient without Adrenal Failure
AbstractSteroidogenic factor-1 [(SF-1/Ad4BP) (MIM184757)] is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, reproduction, and other metabolic functions. Initially, mutations of SF-1/Ad4BP gene (NR5A1) in humans were identified in two 46, XY female patients with adrenal insufficiency and gonadal dysgenesis. However, recent studies have revealed that heterozygous mutations are more frequently found in 46, XY disorders of sex development (DSD) patients without adrenal failure than in 46, XY DSD patients with adrenal failure. We encountered a Japanese female patient of 46, XY DSD without adrenal failure and identified a novel mutation (V41G) of NR5A1. Functional analysis revealed that this mutant protein could not activate CYP19 promoter, indicating loss of function. In conclusion, we add a novel mutation of NR5A1 in 46, XY DSD patient without adrenal failure.
BMJ Case Reports · 2019 · 27 citations · open access
Normal male external genitalia do not rule out CYP11A1 deficiency
AbstractDefects in the initial steps of steroidogenesis usually present with female external genitalia in both 46,XX and 46,XY. Hence, they are not often considered in the differential diagnosis of primary adrenal insufficiency children with normal male external genitalia. Here, we report a boy with normal male external genitalia who presented with hyperpigmentation since the age of 2 years but diagnosis was delayed till 11 years of age. Evaluation revealed low-serum cortisol with elevated adrenocorticotropic hormone and direct renin level confirming primary adrenal insufficiency. Clinical exome sequencing analysis revealed a homozygous c.1351C>T (p.R451W) mutation in exon 8 of the CYP11A1 gene which was confirmed on Sanger sequencing. Both parents were heterozygous for the variation. To conclude, we report the first case of CYP11A1 deficiency from India. The report reiterates the existence of non-classic CYP11A1 deficiency characterised by primary adrenal insufficiency and normal male external genitalia in 46,XY.
Molecular Genetics & Genomic Medicine · 2017 · 16 citations · open access
A novel splice site variant in <i><scp>CYP</scp>11A1</i> in <i>trans</i> with the p.E314K variant in a male patient with congenital adrenal insufficiency
AbstractBACKGROUND: The CYP11A1 gene encodes the cytochrome P450 side-chain cleavage enzyme, which is essential for steroid formation. Recessive variants in this gene can lead to impairment of sexual differentiation caused by a complete or partial loss of steroid hormone production. The phenotypic spectrum in affected 46XY males may vary from surgically repairable defects including cryptorchidism and hypospadias to complete feminization of external gonads, accompanied by symptoms of adrenal dysfunction. METHODS: Whole-exome sequencing (WES) of a 12-year-old male proband and his parents was performed after a protracted diagnostic odyssey failed to uncover the cause of his primary adrenal insufficiency. Of note, the proband had early symptomatology and corrective surgery for hypospadias, raising suspicion for a disorder of steroidogenesis. RESULTS: WES identified compound heterozygous variants in CYP11A1 including a novel canonical splice site variant (c.425+1G>A) and a previously reported p.E314K variant, which were consistent with a diagnosis of congenital adrenal insufficiency with partial 46XY sex reversal. CONCLUSION: Congenital adrenal insufficiency with 46XY sex reversal is a rare disorder that is characterized by dysregulation of steroid hormone synthesis, leading to adrenal and gonadal dysfunction. In this report, we describe a patient with adrenal insufficiency, hypospadias, and skin hyperpigmentation who was found to have a novel c.425+1G>A variant in trans with the p.E314K variant in CYP11A1. We performed structural analyses to examine the effect of the p.E314K variant on protein function and show that it falls in the core of the protein may disrupt cholesterol binding in the active site.
Fetal and Pediatric Pathology · 2020 · 4 citations
A Novel Homozygous Mutation in <i>CYP11A1</i> Gene is Associated with Severe Adrenal Insufficiency in 46, XX Patient
AbstractBackground One of the causes of congenital adrenal insufficiency, a genetically heterogeneous disorder is a mutation in the CYP11A1 gene, which is responsible for the initiation of steriodogenesis by converting cholesterol to pregnenolone. Case: In a now 3 years and 3 months-old girl, adrenal insufficiency was diagnosed in the neonatal period. Clinical exome sequencing for primary adrenal insufficiency revealed a homozygous p.Thr330Met (c.989C>T) variant in the CYP11A1 (NM_000781) gene. Conclusion: Different types of inheritance patterns have been observed in CYP11A1-related adrenal insufficiency cases. We consider our case is an due to an autosomal recessive inheritance.
Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency
AbstractOpe n Pe e r Re v ie w on Qe ios Ope n Pe e r Re v ie w on Qe ios Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency INSERM Source INSERM.(1999).Orphanet: an online rare disease and orphan drug data base.Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency.ORPHA:289548Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency is a rare, genetic, chronic, primary adrenal insufficiency disorder, due to partial loss-of-function CYP11A1 mutations, characterized by early-onset adrenal insufficiency without associated abnormal external male genitalia.Patients present with signs of adrenal crisis, including electrolite abnormalities, severe weakness, recurrent vomiting and seizures.Ultrasound reveals absent (or very small) adrenal glands.
Greater South Information System · 2021 · 0 citations · open access
Disorders of Sex Development of Adrenal Origin
AbstractDisorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.
Greater South Information System · 2021 · 0 citations · open access
Disorders of Sex Development of Adrenal Origin
AbstractDisorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.
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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