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46,XX testicular disorder of sex development

46,XX Testicular DSD Deep Research Fallback

⚠️ Fallback MONDO:0100249

46,XX Testicular DSD Deep Research Fallback

Provider Attempts

  • 2026-05-08T15:00Z: just research-disorder asta 46_XX_Testicular_DSD failed: ERROR - No research providers available. Please set API keys (no ASTA_API_KEY configured in this environment).
  • 2026-05-08T15:00Z: just research-disorder openai 46_XX_Testicular_DSD failed with the same provider-unavailable error (no OPENAI_API_KEY).
  • 2026-05-08T15:00Z: just research-disorder perplexity 46_XX_Testicular_DSD failed with the same provider-unavailable error (no PERPLEXITY_API_KEY).
  • 2026-05-08T15:00Z: just research-disorder falcon 46_XX_Testicular_DSD failed with the same provider-unavailable error (no provider keys at all, including Edison/Falcon).

just research-providers confirmed no providers are configured in this worktree. No provider-generated research artifact was available to integrate. Curation therefore proceeded from the PubMed-cached abstracts already referenced in kb/disorders/46_XX_Testicular_DSD.yaml, without hand-editing any references_cache/*.md files.

Evidence Scope Used For Curation

  • PMID:31336995 (Terribile et al. 2019, Medicina) — case report + systematic review of 46,XX testicular DSD. Used as the canonical clinical-presentation reference: SRY-positive vs SRY-negative classification, adult presentation with infertility, hypergonadotropic hypogonadism, gynecomastia, small testes, cryptorchidism (~15%) and anterior hypospadias (~10%), and the rationale for long-term testosterone replacement.
  • PMID:36341017 (Kouvidi et al. 2022) — two new cases plus literature review cohort. Used for SRY-translocation epidemiology (84.4% SRY-positive, 98.5% Xp), absence of AZF regions, and quantitative phenotype frequencies in the cohort: small testes (90.2%), small penis (31.8%), gynecomastia (26.8%), poor hair distribution (15.4%). The "small penis (31.8%)" figure is the source for the new Micropenis (HP:0000054) phenotype entry.
  • PMID:25077096 (Lee et al. 2014, Ann Pediatr Endocrinol Metab) — Korean boy with 46,XX testicular DSD caused by SOX9 duplication. Supports the SRY-negative SOX9 gain-of-function mechanism in which duplications upstream of SOX9 drive ectopic testis determination in 46,XX gonads.
  • PMID:34050715 (Qian et al. 2021) — whole-genome sequencing of an SRY-negative 46,XX ovotesticular DSD case identifying a cryptic SOX9 regulatory-element duplication. Reinforces the SOX9 enhancer-duplication mechanism and shows how cryptic non-coding variants can be missed by standard cytogenetics.
  • PMID:36064700 (Wei et al. 2022) — SRY-negative 46,XX male with SOX3 duplication and prostatic utricle. Supports SOX3 duplication as an alternative SRY-independent driver of testis determination, expanding the set of SRY-negative genetic etiologies beyond SOX9.
  • PMID:29575617 (Tallapaka et al. 2018, Am J Med Genet A) — novel RSPO1 mutation causing SRY-negative 46,XX testicular DSD with palmoplantar keratoderma. Defines the RSPO1-associated subtype and establishes palmoplantar hyperkeratosis as the pathognomonic extra-gonadal feature that clinically distinguishes RSPO1 cases from other SRY-negative etiologies.

Curation Conclusions

46,XX testicular disorder of sex development is a sex-reversal phenotype in which 46,XX gonads commit to the testis pathway despite the absence of a typical Y chromosome. Two broad mechanistic classes account for nearly all cases. In SRY-positive 46,XX testicular DSD (~85% of patients), aberrant paternal-meiosis recombination translocates SRY onto the X chromosome (most commonly Xp22), with rare autosomal landings; the translocated SRY drives Sertoli-cell specification and the canonical SOX9-mediated testis cascade, producing essentially complete masculinization at birth and an adult presentation dominated by hypergonadotropic hypogonadism, azoospermia, and infertility. In SRY-negative 46,XX testicular DSD, testis determination is driven by genetic perturbations that bypass SRY: gain-of-function copy-number gains around SOX9 (including cryptic enhancer duplications detectable only by whole-genome sequencing), SOX3 duplications that act as ectopic SRY-like inducers, and biallelic loss of RSPO1 that disrupts the WNT/RSPO1/CTNNB1 ovarian-determining program and permits default testis differentiation. The RSPO1 subtype is uniquely identifiable by palmoplantar keratoderma — the clinically distinguishing extra-gonadal feature.

Regardless of upstream genetic mechanism, the downstream gonadal pathology converges on dysgenetic testes lacking germ-cell development. Loss of the AZF regions on Yq and absence of normal seminiferous tubule architecture result in azoospermia in essentially all affected individuals; testicular sperm extraction is generally unsuccessful. Sertoli-cell and Leydig-cell function is partially preserved in childhood (giving rise to externally masculine genitalia and pubertal initiation), but post-pubertal Leydig-cell insufficiency manifests as low testosterone with elevated LH/FSH — hypergonadotropic hypogonadism — driving the adult clinical phenotype: small testes (~90% of patients), small penis (~32%), gynecomastia (~27%), sparse body hair (~15%), reduced bone mineral density, and infertility. SRY-negative cases more commonly show ambiguous or undermasculinized external genitalia at birth (hypospadias, cryptorchidism), reflecting attenuated fetal androgen production, and may present in childhood rather than adulthood.

Treatment is supportive and lifelong. Long-term testosterone replacement (captured here as MAXO:0000058 pharmacotherapy with CHEBI:17347 testosterone as the therapeutic agent) addresses hypogonadism, supports secondary sexual characteristics, and protects bone health. Genetic counseling addresses the rare familial recurrence risk (notably for RSPO1 biallelic families and inherited SOX3/SOX9 CNVs) and the reproductive limitations. Assisted-reproduction options are restricted to donor sperm with intrauterine insemination or IVF, since affected individuals are azoospermic. Surgical correction is appropriate for hypospadias and cryptorchidism in SRY-negative presentations.