46,XY Sex Reversal 11 (SRXY11): A Comprehensive Disease Characteristics Report

Disease: 46,XY Sex Reversal 11 (SRXY11) Causal gene: DHX37 (DEAH-box RNA helicase 37) OMIM (phenotype): #273250 (46,XY sex reversal 11) Category: Mendelian, autosomal dominant disorder/difference of sex development (DSD) Suggested disease ontology mapping: MONDO — 46,XY partial/complete gonadal dysgenesis spectrum; the DHX37-specific entry corresponds to OMIM #273250.

Evidence source key: [H] human clinical/genetic · [M] model organism · [V] in vitro/functional · [C] computational/in silico · [R] review.

Summary

46,XY Sex Reversal 11 (SRXY11) is a rare Mendelian disorder/difference of sex development (DSD) caused by heterozygous, mostly recurrent missense variants in DHX37, a DEAH-box RNA helicase essential for biogenesis of the small (40S) ribosomal subunit. Affected individuals have a 46,XY karyotype but fail to complete testis determination or undergo testis regression, producing a clinical spectrum that runs from phenotypic females with complete gonadal dysgenesis (Swyer syndrome), through partial gonadal dysgenesis, to testicular regression syndrome (TRS)/anorchia and, at the mildest pole, males with modest testicular underdevelopment and gynecomastia. Because a ubiquitously required housekeeping factor produces a phenotype restricted almost entirely to the developing gonad, DHX37-related DSD has been proposed as a new human ribosomopathy — a class of disease in which broadly expressed ribosome-biogenesis factors nonetheless cause tissue-specific pathology.

The molecular link between DHX37 loss and gonadal failure is coming into focus from mouse work: DHX37 safeguards nucleolar integrity and PI3K-AKT survival signaling and suppresses p53-driven apoptosis, so its deficiency triggers pro-apoptotic RNA splicing and death of the fetal supporting (Sertoli) cell lineage, aborting or reversing testis formation. In humans, DHX37 protein is expressed principally in germ cells and Leydig cells, and only rarely in Sertoli cells, so the exact cell-autonomous versus non-cell-autonomous route to Sertoli-cell failure remains partially inferred. Two recurrent variants — p.Arg308Gln and p.Arg674Trp — account for a large share of cases and are especially associated with embryonic testicular regression syndrome (ETRS).

Clinically, the disorder is diagnosed by the combination of a 46,XY karyotype discordant with gonadal/genital phenotype, hypergonadotropic hypogonadism (elevated FSH/LH, low sex steroids), imaging showing streak or absent gonads (with or without Müllerian structures), and molecular confirmation by whole-exome/genome sequencing, for which DHX37 should now be part of DSD gene panels. Management is supportive rather than curative: sex-steroid hormone replacement, prophylactic gonadectomy of dysgenetic Y-bearing gonads (which carry a ~15–23% germ-cell tumor risk), fertility and psychosocial counseling, and genetic counseling. Importantly, biallelic and de novo heterozygous DHX37 variants cause a distinct, allelic neurodevelopmental syndrome (NEDBAVC, OMIM 618731), so genotype must be interpreted with the full clinical picture.

Key Findings

Finding 1 — DHX37 heterozygous missense variants are a frequent, autosomal-dominant cause of 46,XY DSD (SRXY11) [H]

In a cohort of 145 individuals with 46,XY DSD of previously unknown etiology, 13 children carried heterozygous missense pathogenic variants in DHX37, and rare/novel DHX37 missense variants were enriched in cases versus controls with high statistical significance (P = 5.8×10⁻¹⁰). The gene encodes an RNA helicase "essential for ribosome biogenesis," and the pathogenic variants establish an autosomal dominant form of 46,XY DSD encompassing both gonadal dysgenesis and testicular regression syndrome (TRS). The authors concluded these conditions "are part of a clinical spectrum" rather than distinct entities.

"Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis." — PMID: 31337883

"DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum." — PMID: 31337883

This is the foundational human-clinical evidence identifying DHX37 as the SRXY11 gene and framing the phenotype as a spectrum. HGNC: DHX37. UniProt: Q8IY37.

Finding 2 — DHX37 maintains supporting-cell (Sertoli) survival through nucleolar integrity and PI3K-AKT, suppressing p53 apoptosis [M][V]

Multi-omics analysis of cell-specific Dhx37 knockout mice (RIP-seq plus RNAi-RNA-seq) demonstrated that Dhx37 "safeguards nucleolar integrity and PI3K-AKT signaling, suppresses p53-driven apoptosis, and its loss triggers pro-apoptotic splicing" and Sertoli-cell death, impairing testis development. This is the strongest mechanistic account currently available and links DHX37 loss-of-function to the cellular event (supporting-cell apoptosis) that most plausibly explains failed/reversed testis determination.

"Dhx37 safeguards nucleolar integrity and PI3K-AKT signaling, suppresses p53-driven apoptosis, and its loss triggers pro-apoptotic splicing" — PMID: 41535247

Relevant GO/pathway terms: ribosome biogenesis (GO:0042254), rRNA processing (GO:0006364), nucleolus (GO:0005730), PI3K-AKT signaling, intrinsic apoptotic signaling by p53 class mediator (GO:0072332), regulation of RNA splicing (GO:0043484).

Finding 3 — Allelic heterogeneity: heterozygous → non-syndromic DSD; biallelic/de novo → syndromic NEDBAVC (OMIM 618731) [R][H]

DHX37 shows a clean genotype-driven dichotomy. Recurrent heterozygous missense variants — affecting highly conserved residues in the helicase domains and predicted deleterious — cause non-syndromic 46,XY gonadal dysgenesis, TRS, or anorchia. In contrast, compound heterozygous and de novo heterozygous DHX37 missense variants cause a complex congenital syndrome, NEDBAVC (neurodevelopmental disorder with brain anomalies and with/without vertebral or cardiac anomalies; OMIM 618731) featuring microcephaly, global developmental delay, seizures, facial dysmorphism, and kidney/cardiac anomalies.

"compound heterozygous as well as de novo heterozygous missense variants in DHX37 are also associated with a complex congenital developmental syndrome (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies; OMIM 618731), consisting of microcephaly, global developmental delay, seizures, facial dysmorphia, and kidney and cardiac anomalies" — PMID: 35835064

"All affected children have non-syndromic forms of disorders/differences of sex development (DSD)." — PMID: 35835064

This distinction is clinically critical for variant interpretation and counseling.

Finding 4 — Dysgenetic Y-bearing gonads carry a high germ-cell tumor risk, warranting gonadectomy [H]

In a series of 292 phenotypic-female DSD patients harboring Y-chromosome material, the overall germ-cell tumor (GCT) risk was 15.4%, and 46,XY pure gonadal dysgenesis carried the highest risk (~23.3%). Tumors — gonadoblastoma and dysgerminoma/seminoma — arose predominantly during adolescence (median 17–18 years). Notably, no tumor was found in five testicular-regression patients, contrasting the high dysgenesis risk with the negligible regression risk. These data support prophylactic gonadectomy of dysgenetic gonads.

"The overall GCTs risk was 15·41% and 46, XY pure gonadal dysgenesis (46, XY PGD) carried the highest risk up to 23·33%" — PMID: 27862157

"no tumour was found in five testis regression patients" — PMID: 27862157

A familial Swyer-syndrome report additionally suggests familial cases may carry higher tumor risk than sporadic ones (66.6% vs. 15–45%) (PMID: 38337479).

Finding 5 — Marked phenotypic heterogeneity from complete gonadal dysgenesis to TRS/anorchia, with variable expressivity [H]

DHX37 variants generate a phenotypic continuum: 46,XY complete gonadal dysgenesis (female external genitalia, Müllerian remnants), partial gonadal dysgenesis, testicular regression syndrome/anorchia (absent testes with variable male genitalia), and milder testicular underdevelopment with gynecomastia. Variants cluster in conserved helicase domains (e.g., RecA1); reported residues include p.Arg334Trp, p.Arg390His, p.Thr477His, and p.Gly478Arg. A striking example of variable expressivity/incomplete penetrance: a boy with TRS carried a homozygous p.T477H variant while his fertile father, carrying the same variant, had only unilateral testicular regression with otherwise typical male genital development.

"Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS)." — PMID: 34293745

"a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development." — PMID: 34293745

"manifestations ranging from complete gonadal dysgenesis to mild testicular underdevelopment with gynecomastia" — PMID: 42510869

Finding 6 — Diagnosis rests on 46,XY karyotype discordant with gonad/genitalia, hypergonadotropic hypogonadism, and molecular (WES/WGS) confirmation [H]

Complete gonadal dysgenesis (Swyer syndrome) typically presents in phenotypic females with a 46,XY karyotype, primary amenorrhea/delayed puberty, a hypoplastic uterus and streak gonads on imaging, and hypergonadotropic hypogonadism (elevated FSH/LH, low estradiol/testosterone) on hormonal assay. DHX37 is identified by whole-exome/trio sequencing once karyotype excludes sex-chromosome DSD; the gene is now recommended for inclusion in DSD gene panels and genome-wide sequencing.

"confirmed by the hormonal assay that showed hypergonadotropic-hyp[ogonadism]" — PMID: 37497464

"Genome-wide sequencing should be prioritized in VSC/DSD diagnostics, consistent with current best practices, to improve diagnostic yield" — PMID: 41466375

Finding 7 — Two recurrent variants (p.Arg308Gln, p.Arg674Trp) dominate and are enriched vs. gnomAD, with a specific ETRS association; DHX37 is expressed in germ and Leydig cells [H][V]

In 87 patients with 46,XY DSD, da Silva et al. (2019) identified pathogenic/likely-pathogenic heterozygous DHX37 missense variants in 5 families (11 patients) and 6 sporadic cases; two recurrent variants dominated — p.Arg308Gln (two families, three sporadic cases) and p.Arg674Trp (two families, two sporadic cases). Rare, predicted-deleterious DHX37 variants occurred in 14% of the cohort versus 0.4% in gnomAD (P < 0.001), and were specifically associated with embryonic testicular regression syndrome (ETRS) in 7/14 index cases (50%). Immunohistochemistry localized DHX37 mainly to germ cells (at various maturation stages) and Leydig cells, and only rarely to Sertoli cells.

"Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases)." — PMID: 31287541

"The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001)." — PMID: 31287541

"DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells" — PMID: 31287541

"The variants were specifically associated with ETRS (7/14 index cases; 50%)." — PMID: 31287541

Finding 8 — The central mechanism — how a ubiquitous ribosome-biogenesis factor produces tissue-specific gonadal failure — remains unresolved [R]

DHX37 is a housekeeping DEAH-box helicase required for 40S ribosomal subunit biogenesis in every cell, yet heterozygous missense variants produce a phenotype almost entirely restricted to gonad/testis determination — a paradox shared with other ribosomopathies. Multiple primary reports and reviews explicitly state that the pathogenic mechanism is unknown.

"Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown." — PMID: 34293745

"DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy." — PMID: 34293745

No zebrafish or invertebrate DHX37 sex-development model, and no humanized knock-in of the recurrent p.Arg308Gln/p.Arg674Trp alleles, has yet been reported; available models are a supporting-cell conditional-knockout mouse and yeast Dhr1 structural/functional studies.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

1. A heterozygous missense variant in DHX37 (most often at recurrent hotspots p.Arg308Gln or p.Arg674Trp, in conserved helicase RecA domains) leads to a partial loss of DHX37 RNA-helicase activity. (Demonstrated genetically; the loss-of-function nature at the protein level is partly inferred from conservation, in silico prediction, and yeast Dhr1 structural work — [PMID: 31188444].)
2. Impaired DHX37 helicase function results in defective displacement of the U3 snoRNA from pre-rRNA and impaired 40S small ribosomal subunit biogenesis / nucleolar homeostasis. (Mechanism established for yeast Dhr1; extrapolated to human DHX37.)
3. Disturbed nucleolar integrity leads to nucleolar stress, which results in stabilization/activation of p53 and reduced PI3K-AKT survival signaling. (Demonstrated in Dhx37-knockout mouse multi-omics — [PMID: 41535247].)
4. p53 activation plus loss of AKT survival signaling triggers pro-apoptotic RNA splicing and apoptosis of the fetal supporting (Sertoli) cell lineage. (Demonstrated in mouse; human Sertoli involvement is partly inferred because human DHX37 protein is expressed mainly in germ and Leydig cells and only rarely in Sertoli cells — [PMID: 31287541].)
5. Loss/failure of Sertoli-supporting cells during the narrow window of fetal sex determination results in failed testis determination (gonadal dysgenesis) or, if determination initially succeeds, testis regression (TRS/anorchia). (Branch point — see below.)
6. Absent or dysgenetic testis leads to deficient anti-Müllerian hormone and androgen output, which results in incomplete/absent virilization, persistence of Müllerian structures (in dysgenesis), and hypergonadotropic hypogonadism at expected puberty. (Human clinical — [PMID: 37497464].)
7. Retained dysgenetic Y-bearing gonadal tissue creates a germ-cell tumor predisposition (gonadoblastoma → dysgerminoma/seminoma). (Human clinical — [PMID: 27862157].)

Branch point

 DHX37 helicase-domain missense (heterozygous)
                    |
        nucleolar stress / p53↑ / PI3K-AKT↓
                    |
        supporting-cell (Sertoli) apoptosis
             /                        \
   determination never completes    determination completes, then fails
             |                                |
   Complete/partial gonadal dysgenesis   Testicular regression syndrome /
   (Swyer; streak gonads; Müllerian      anorchia (absent testes; variable
   remnants; female genitalia)           male genital development)
             \                        /
              High GCT risk        Low/negligible GCT risk
              (~15–23%)            (0/5 in one series)

Genotype–phenotype and dose logic

The recurrence of specific residues and their autosomal-dominant behavior suggest the DSD-causing alleles act through a specific (possibly dominant-negative or hypomorphic gain-of-toxicity) mechanism rather than simple haploinsufficiency — consistent with the observation that a different mutational configuration (biallelic/de novo) produces an entirely different, neurodevelopmental disease. This remains a hypothesis; direct allele-specific functional proof is lacking.

Why a housekeeping factor hits the gonad selectively (open question)

The defining unresolved question (Finding 8) is the tissue-specificity paradox. Proposed but unproven explanations, by analogy to other ribosomopathies, include: (i) heightened dependence of the rapidly proliferating fetal gonadal-somatic lineage on ribosome flux during the brief sex-determination window; (ii) a low p53 threshold in supporting cells; and (iii) selective translational requirements for pro-testis regulators (e.g., the SRY/SOX9 pathway). None has been experimentally demonstrated for DHX37.

Section-by-Section Details

1. Disease Information

• Overview: SRXY11 is a monogenic 46,XY DSD in which testis determination fails or reverses despite a Y chromosome, spanning Swyer syndrome (complete gonadal dysgenesis) to testicular regression/anorchia to mild male undervirilization.
• Identifiers: OMIM #273250 (46,XY sex reversal 11); allelic OMIM 618731 (NEDBAVC). Gene: DHX37 (HGNC:16192; NCBI Gene 57647; UniProt Q8IY37). Orphanet/ICD map to broader "46,XY complete/partial gonadal dysgenesis" and "swyer syndrome" categories; MeSH: Gonadal Dysgenesis, 46,XY; Disorders of Sex Development. MONDO: 46,XY gonadal dysgenesis spectrum.
• Synonyms/alternatives: DHX37-related 46,XY DSD; 46,XY gonadal dysgenesis with DHX37; 46,XY testicular regression syndrome (DHX37); "new ribosomopathy of sex development."
• Data source type: Predominantly aggregated case-series/cohort literature and gene-level resources (OMIM), not EHR-derived.

2. Etiology

• Causal factor: Monogenic — heterozygous missense variants in DHX37 (Findings 1, 7). No environmental or infectious cause.
• Genetic risk: The DHX37 variant itself is causal (autosomal dominant); rare deleterious DHX37 variants enriched ~35-fold vs gnomAD (14% vs 0.4%; [PMID: 31287541]). Modifier genes are implied by incomplete penetrance but unidentified.
• Protective factors: None established (no known protective alleles or exposures).
• Gene–environment interactions: None documented; considered a purely genetic condition.

3. Phenotypes

Severity is highly variable (Finding 5); the primary gonadal defect is stable/non-progressive but its consequences (pubertal failure, tumor risk) evolve. Quality-of-life impacts include infertility, need for lifelong hormone therapy, psychosocial burden of atypical sex development, and cancer surveillance/gonadectomy; disease-specific QOL instruments have not been reported for this ultra-rare condition.

4. Genetic/Molecular Information

• Causal gene: DHX37 (DEAH-box helicase 37); encodes an ATP-dependent RNA helicase required for 40S biogenesis.
• Variant class: Missense predominates, in conserved helicase (RecA) domains. Recurrent hotspots: p.Arg308Gln, p.Arg674Trp ([PMID: 31287541]). Other reported residues: p.Arg334Trp, p.Arg390His, p.Thr477His, p.Gly478Arg ([PMID: 34293745]).
• Classification: Pathogenic/likely-pathogenic per ACMG for hotspots; some variants remain VUS requiring functional/segregation support ([PMID: 42057034]).
• Allele frequency: Rare/near-absent in gnomAD (aggregate deleterious ~0.4%).
• Origin: Germline; both inherited (dominant) and de novo reported.
• Functional consequence: Loss/alteration of helicase function; a dominant-negative or hypomorphic mechanism is hypothesized but unproven.
• Modifier genes/epigenetics/chromosomal: Modifiers unidentified; no epigenetic mechanism established; the causal lesion is a point mutation, not a large chromosomal rearrangement (distinguishing it from 45,X/46,XY mosaicism).

5. Environmental Information

Not applicable — no environmental, lifestyle, or infectious contributors are known; SRXY11 is monogenic.

6. Mechanism / Pathophysiology

See the ordered causal chain and branch diagram above. Molecular pathway: ribosome biogenesis (40S/SSU maturation, U3 snoRNA displacement) → nucleolar stress → p53 activation + reduced PI3K-AKT → pro-apoptotic splicing → supporting-cell apoptosis. GO terms: GO:0042254, GO:0030490, GO:0005730, GO:0072332, GO:0006915, GO:0007530, GO:0008584. CL terms: Sertoli/supporting cell (CL:0000216), Leydig cell (CL:0000178), male germ cell (CL:0000015).

7. Anatomical Structures Affected

• Organ/system: Gonad/testis (primary); endocrine and reproductive systems; internal (uterus/Müllerian remnants) and external genitalia (secondary). UBERON: gonad (UBERON:0000991), testis (UBERON:0000473), uterus (UBERON:0000995).
• Tissue/cell: Gonadal somatic supporting lineage (Sertoli), Leydig cells, germ cells.
• Subcellular: Nucleolus (GO:0005730), cytosolic small ribosomal subunit (GO:0022627).
• Lateralization: Usually bilateral (dysgenesis); unilateral regression documented (variable, [PMID: 34293745]).

8. Temporal Development

• Onset: Congenital/fetal at the level of gonadal determination; clinically silent until puberty in complete dysgenesis (primary amenorrhea), or noted at birth when genitalia are atypical or testes absent.
• Course: Underlying defect fixed/non-progressive; consequences evolve; germ-cell tumors cluster in adolescence (median 17–18 y; [PMID: 27862157]).
• Critical period: Fetal sex-determination window (the window of intervention for any future mechanistic therapy is developmental and effectively closed postnatally).

9. Inheritance and Population

• Inheritance: Autosomal dominant (SRXY11) with incomplete penetrance and variable expressivity ([PMID: 31337883], [PMID: 34293745]); allelic recessive/de novo → NEDBAVC ([PMID: 35835064]).
• Epidemiology: DHX37-specific prevalence/incidence not quantified; identified in enriched DSD cohorts (e.g., 14% of one 87-patient cohort; 13/145 in another). Reported across French, Brazilian, Japanese, Iranian, Chinese, and Polish cohorts.
• Sex ratio: Affects 46,XY individuals; presentation ranges phenotypic female → male.
• Founder/consanguinity: No founder effect established; homozygous cases reported in consanguineous contexts ([PMID: 34293745]).

10. Diagnostics

• Cytogenetics: Karyotype/FISH confirming 46,XY (exclude 45,X/46,XY mosaicism — [PMID: 31883875], [PMID: 32057790]).
• Endocrine: Hypergonadotropic hypogonadism (↑FSH/LH, ↓estradiol/testosterone); AMH/inhibin B to gauge functional gonadal tissue.
• Imaging: Pelvic ultrasound/MRI for uterus/Müllerian structures and streak vs absent gonads.
• Molecular: WES/WGS or trio sequencing; DHX37 on DSD panels ([PMID: 41466375], [PMID: 42365275]); ACMG classification with functional support for VUS ([PMID: 42057034]).
• Histopathology: Streak gonads; surveillance for gonadoblastoma/dysgerminoma.
• Differential diagnosis: NR5A1, SRY, SOX9, MAP3K1, WT1, GATA4, AR (androgen insensitivity), HSD17B3, and 45,X/46,XY mosaicism ([PMID: 42365275], [PMID: 42057034]).

11. Outcome / Prognosis

• Survival: Life expectancy is essentially normal with appropriate management; the major life-threatening risk is malignant transformation of retained dysgenetic gonads.
• Morbidity: Infertility, need for lifelong hormone replacement, and cancer risk (~15–23% in dysgenesis; [PMID: 27862157]).
• Prognostic factors: Degree of gonadal dysgenesis (dysgenesis > regression for tumor risk); familial cases may carry higher tumor risk ([PMID: 38337479]).

12. Treatment

• Hormone replacement therapy (estrogen ± progestin, or testosterone as appropriate) — NCIT: Hormone Replacement Therapy.
• Prophylactic/therapeutic gonadectomy of dysgenetic Y-bearing gonads — NCIT: Gonadectomy/Orchiectomy.
• Fertility counseling (typically infertile; assisted reproduction/oocyte donation for uterus-bearing individuals).
• Psychosocial and gender-affirming care, individualized.
• Genetic counseling (AD recurrence, variable expressivity/penetrance, distinct NEDBAVC risk).
• No gene/RNA/cell therapy, disease-specific drug, or pharmacogenomic guidance exists.

13. Prevention

• Primary: Not applicable (congenital genetic condition).
• Secondary: Cascade genetic testing of at-risk relatives; early identification enabling timely tumor surveillance and gonadal management.
• Tertiary: Prophylactic gonadectomy to prevent malignancy; hormone replacement to prevent osteoporosis and secondary-sex-characteristic deficits.
• Reproductive options: Genetic counseling, prenatal/preimplantation genetic testing for known familial variants.

14. Other Species / Natural Disease

• Orthologs: Mouse Dhx37 (used in the conditional-knockout model — [PMID: 41535247]); yeast ortholog DHR1 (structural/functional studies — [PMID: 31188444]). NCBI Gene (human) 57647.
• Natural disease: No naturally occurring companion-animal or wildlife DHX37 sex-reversal disease is documented in OMIA to date.
• Conservation: The ribosome-biogenesis function of DHX37/Dhr1 is deeply conserved from yeast to human; the sex-determination consequence is a vertebrate/mammalian-specific downstream effect.

15. Model Organisms

• Mouse: Cell-specific (supporting-cell) conditional Dhx37 knockout recapitulates impaired testis development via nucleolar stress/p53 apoptosis ([PMID: 41535247]) — the best available model; limitation: it is a knockout, not a patient-allele knock-in, so dominant/hotspot-allele effects are not directly modeled.
• Yeast: Dhr1 structural/functional studies define the helicase mechanism (U3 snoRNA displacement, C-terminal domain) and the biogenesis consequences of DHX37 mutations ([PMID: 31188444]); limitation: no sex-development readout.
• Gaps: No zebrafish/invertebrate DHX37 sex-development model; no humanized R308Q/R674W knock-in. Resources: MGI (mouse), SGD (yeast).

Evidence Base

Where the evidence converges: Independent human cohorts ([31337883], [31287541]) establish DHX37 causation, hotspot recurrence, and statistical enrichment; the mouse multi-omics study ([41535247]) supplies the cell-and-pathway mechanism (Sertoli apoptosis via nucleolar stress/p53/PI3K-AKT); tumor-risk data ([27862157]) drive the management recommendation.

Where the evidence is in tension / incomplete: Human IHC localizes DHX37 mainly to germ and Leydig cells, "rarely" to Sertoli cells ([31287541]), whereas the mechanistic mouse model centers on Sertoli-cell apoptosis ([41535247]) — leaving open whether the human phenotype arises cell-autonomously in supporting cells, non-cell-autonomously from germ/Leydig-cell dysfunction, or both. Reviews explicitly state the mechanism of tissue specificity is unknown ([34293745]).

Limitations and Knowledge Gaps

1. Unresolved tissue-specificity paradox (central gap). No experimental demonstration explains why a ubiquitous 40S-biogenesis factor selectively disables gonadal determination ([PMID: 34293745]).
2. Allele-specific functional data are sparse. The dominant-negative vs hypomorphic nature of hotspot alleles (R308Q, R674W) is inferred, not proven; some clinically encountered variants remain VUS ([PMID: 42057034]).
3. Cell-of-origin ambiguity. Human expression (germ/Leydig-dominant) versus mouse phenotype (Sertoli apoptosis) are not fully reconciled.
4. No humanized/knock-in model of the recurrent DSD alleles, and no zebrafish/invertebrate sex-development model exists; the mouse model is a conditional knockout.
5. Incomplete penetrance/variable expressivity (e.g., fertile carrier fathers) implies unidentified genetic/environmental modifiers; none are established.
6. Epidemiology is imprecise — DHX37-specific prevalence/incidence are unquantified; data come from enriched DSD cohorts, not population registries.
7. No environmental/infectious contributors are known; environmental sections are largely not applicable.

Proposed Follow-up Experiments / Actions

1. Generate patient-allele knock-in mice (Dhx37^R308Q/+, R674W/+) to test dominant-negative behavior and recapitulate the graded dysgenesis→regression phenotype in vivo.
2. Cell-type-resolved fetal gonad profiling (single-cell/spatial transcriptomics of human and mouse fetal gonad) to determine whether the primary lesion is in Sertoli, germ, or Leydig cells and to map ribosome-flux dependence during the determination window. (Search: Human Cell Atlas, GEO, CELLxGENE.)
3. Allele-specific functional assays — 40S maturation, U3 snoRNA displacement, nucleolar-stress and p53 readouts — for each recurrent and VUS allele to move variants from VUS toward pathogenic/benign per ACMG.
4. Zebrafish dhx37 sex-development model to exploit tractable gonad genetics and test conservation of the mechanism.
5. Prospective natural-history/registry study capturing penetrance, tumor incidence and timing, and modifier genotypes across DHX37 carriers, to refine gonadectomy timing and counseling.
6. Test the tissue-specificity hypotheses directly — e.g., titrate p53 activity (Trp53 co-deletion) in the Dhx37 model to establish whether p53-driven apoptosis is necessary and sufficient for the gonadal phenotype.

Conclusion

46,XY Sex Reversal 11 (SRXY11; OMIM #273250) is an autosomal-dominant disorder of sex development caused by heterozygous, largely recurrent missense variants in the ribosome-biogenesis helicase DHX37. It presents as a phenotypic spectrum from complete gonadal dysgenesis (Swyer) to testicular regression/anorchia and mild male undervirilization, and is best understood as a putative ribosomopathy in which nucleolar stress, p53-driven apoptosis, and reduced PI3K-AKT survival signaling cause failure/regression of the fetal testis-supporting lineage. Diagnosis combines a discordant 46,XY karyotype, hypergonadotropic hypogonadism, and molecular sequencing; management is supportive — hormone replacement, prophylactic gonadectomy of Y-bearing dysgenetic gonads (~15–23% tumor risk), and genetic counseling. The defining open question is how a housekeeping ribosome factor produces a gonad-restricted phenotype.