One enzyme decides how the body is built before birth: 5α-reductase type 2 converts testosterone into dihydrotestosterone (DHT), the signal that sculpts the external genitalia during gestation. When the gene that makes it, SRD5A2, carries a mutation, that signal never arrives and a newborn may present with ambiguous or even apparently female genitalia despite normal testes and normal testosterone. This is 5α-reductase type 2 deficiency (5α-RD2), an autosomal recessive difference of sex development (DSD). A review published in Frontiers in Endocrinology now pools 279 genetically confirmed cases from 36 countries and adds a finding that unsettles anyone who believes genotype explains everything: neither the type of mutation predicts what the body will look like, nor does it predict gender identity.
How the work was done
The authors searched PubMed, Embase, CNKI, Wanfang and Chinese Medical Journals up to December 2025 and gathered every patient whose diagnosis had been confirmed by mutational analysis of SRD5A2: 279 people from 36 countries, 64.77% of them in Asia, with individual genetic, clinical and hormonal data. Age at diagnosis ranged from 4 days to 57 years: 35.16% were detected in infancy, 26.48% in childhood and 38.36% in adolescence or adulthood. Four patients had initially been misdiagnosed with androgen insensitivity syndrome.
What the genes say
- Seventy-eight pathogenic mutations, mostly (64.10%) missense. The most frequent was p.R246Q (12.79%). Exons 1 and 4 are the gene’s hotspots.
- 70% of patients were homozygous (two identical mutated copies) and 30% compound heterozygous (two different mutations). Homozygotes showed significantly more severe undermasculinisation of the external genitalia than compound heterozygotes (p=0.011) and were diagnosed later (p=0.029).
- Parental consanguinity, documented in 40.57% of the cases with that data available, was strongly associated with homozygosity (p<0.001).
- The mutation spectrum is geographic: p.R246Q, p.G203S and p.R227Q predominate in Asian populations; p.G34R is Africa-specific (OR 61.75); p.H231R characterises Europe and p.R246W the Americas. The most feminised phenotypes cluster in West Asia, the Middle East and North Africa, and the most masculinised in East Asia.
- Frameshift mutations were associated with poorer pubertal development (p=0.013).
The marker that does measure severity
Follicle-stimulating hormone (FSH) was the only hormonal parameter linked to phenotypic severity: the higher the FSH, the more severe the presentation (rs=0.290; p=0.021). Neither baseline testosterone, nor DHT, nor the T/DHT ratio could stratify severity: they are useful for diagnosis, not for predicting the course. The authors propose three warning signals — homozygosity, elevated FSH and frameshift mutations — to guide long-term follow-up.
The part that speaks about identity
Here lies the core of this work for our blog. Among the 241 patients with data on upbringing, 68.05% had been reared as girls and 31.54% as boys, with one case of gender fluidity. Forty-four social gender changes from female to male were documented. The clinical records include 18 cases of gender dysphoria and 10 of gender identity disorder: among nine patients reared as girls, five identified as male, five underwent social transition, two had gender dysphoria and two an undifferentiated gender identity.
The key finding is a non-finding: mutation type was not associated with sex assigned at birth (p=0.985) or with the incidence of dysphoria (p=0.211). Genetics describes the body; it does not dictate identity. The authors themselves conclude that clinical decisions on gender assignment should not rest on genotype alone, nor even on genital appearance alone, but must integrate psychological assessment and sociocultural context. It is an explicit correction of the idea of deciding from a genetic test.
It is no accident that many of these cases reach the clinic at puberty. 5α-RD2 has a distinctive feature: in adolescence, alternative enzymatic pathways produce enough DHT for voice deepening and penile growth to appear spontaneously. For many of these boys and men, pubertal virilisation precedes or accompanies social transition, and has historically been the gateway to diagnosis.
Decisions, surgery and fertility
- Seventy-eight surgical interventions were recorded. Among 27 patients reared as boys, hypospadias repair was the most common (14 cases). Among 49 reared as girls, all underwent gonadectomy — 13 in infancy, 11 in childhood and 3 in adulthood — and 18 also had reconstructive surgery.
- Thirty-nine patients received drug treatment: androgens in 25 of those reared as boys, with stretched penile length increasing by 0.5 to 3 centimetres, and oestrogens in 15 of those reared as girls.
- Reproductive data exist for only 16 patients: 11 had fathered children (6 through assisted reproduction and 3 by natural conception) and semen analysis showed oligozoospermia in 10 of the 13 tested.
Limits that demand caution
This is not a new study of its own patients but a pooled analysis of published, highly heterogeneous series. Virilisation scores were rarely reported in the original papers, so the reviewers had to recalculate them retrospectively from narrative descriptions; hCG stimulation protocols differed between centres, which is why stimulated hormone data are presented descriptively only. Long-term follow-up (identity, fertility, quality of life) exists for a minority of cases, and the authors warn that the 44 gender changes and 18 cases of dysphoria are too few for statistical inference. The message holds nonetheless: in a condition where sex of rearing was decided for decades by looking at genitalia and karyotypes, pooled evidence from 279 people says that neither gene nor phenotype is enough. Identity is not written in SRD5A2.
Source: Clinical characteristics and genotype–phenotype correlation analysis in 279 patients with 5α-reductase type 2 deficiency. Wang K, Shi B, Huang L, Qiao L, Liao L, Tang T, Bai J. Frontiers in Endocrinology 2026;17:1919643. DOI: 10.3389/fendo.2026.1919643.
Article published on dosier.es. Image generated with artificial intelligence (marta ai → marta.syf.es).
