F1000 Commentary: Phenotypical, biological, and molecular heterogeneity of 5alpha-reductase deficiency: an extensive international experience of 55 patients

Maimoun L, Philibert P, Cammas B, Audran F, Servant N, Lubroso S, Paris F, Sultan C. J Clin Endocrinol Metab. 2011 Feb; 96:296-307

DOI: 10.1210/jc.2010-1024


In 46,XY disorders of sex development, 5α-reductase deficiency is rare and is not usually the first-intention diagnosis in newborn ambiguous genitalia, contrary to partial androgen insensitivity syndrome. Yet the cause of ambiguous genitalia may guide sex assignment, and rapid, precise diagnosis of 5α-reductase deficiency is essential.


The aim of the study was to describe relevant data for clinical diagnosis, biological investigation, and molecular determination from 55 patients with srd5A2 mutations identified in our laboratory over 20 yr to improve early diagnosis.

The study was performed at Montpellier University Hospital.

We studied a cohort of 55 patients with srd5A2 gene mutations.

Genetic analysis of srd5A2 was conducted.

Clitoromegaly (49.1%) and microphallus with various degrees of hypospadias (32.7%) were frequent phenotypes. Female external genitalia (7.3%) and isolated micropenis (3.6%) were rare. Seventy-two percent of patients were initially assigned to female gender; five of them (12.5%) switched to male sex in peripuberty. Over 72% of patients were considered for 5α-reductase deficiency diagnosis when the testosterone/dihydrotestosterone cutoff was 10. In 55 patients (with 20 having a history of consanguinity), we identified 33 different mutations. Five have never been reported: p.G32S, p.Y91H, p.G104E, p.F223S, and c.461delT. Homozygous mutations were present in 69.1% of cases, compound heterozygous mutations in 25.5%, and compound heterozygous mutations alone with the V89L polymorphism in 5.4%. Exons 1 and 4 were most affected, with 35.8 and 21.7% mutant alleles per exon, respectively.

In the largest cohort to date, we demonstrate a wide spectrum of phenotypes and biological profiles in patients with 5α-reductase deficiency, whatever their geographical or ethnic origins._ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
This report underscores the wide variability in the genital phenotype associated with alterations in the 5alpha-reductase type 2 gene (SRD5A2) responsible for syndrome of 5alpha-reductase deficiency (5ARD), a disorder of sex development (DSD). Because of the limited sensitivity of biochemical testing, the authors strongly encourage clinicians to consider genetic testing. This study potentially also represents a major challenge to the notion that the majority of affected persons with 5ARD, assigned as girls at birth, choose to reassign themselves as boys — in this study, this transition occurred in only 12.5% of cases.Maimoun and colleagues make a substantial contribution to our understanding of genotype-phenotype relationships in 5ARD. In this international series of 55 patients with incomplete genital masculinization and alteration in the SRD5A2 gene, the investigators reported a wide variability in genotype/genital phenotype associations. The study shows that SRD5A2 alterations are occasionally observed in the presence of a normal testosterone (T)/dihydrostestosterone (DHT) ratio (i.e. <10), a common biochemical screening test for 5ARD. Accordingly, reliance on a negative biochemical test in an affected child could result in a diagnostic odyssey assuming 5ARD had been ruled out. This limitation of the biochemical diagnosis should encourage clinicians to consider genetic testing as the primary route to diagnosis in 5ARD.Although this study makes a strong case for genetic testing as the primary route to diagnosing 5ARD, it does not follow that an accurate diagnosis implies a gender assignment recommendation, as suggested in the final sentence of the paper. The observed failure to detect genotype-phenotype correlations directly challenges this expectation. Mutations of the SRD5A2 gene are associated with a genital phenotype ranging from female external genitalia with clitoromegaly to microphallus with hypospadias of varying degrees. Although rarer as outcomes, both normal female genital appearance and isolated micropenis were observed. In one salient example of this, the genital appearance of two siblings in this series with the same compound heterozygous mutation diverged substantially enough (one with a normal clitoris and the other with microphallus and hypospadias) in that one was reared as a girl and the other as a boy.

A startling finding of this study is that only five of 40 patients assigned as female (12.5%) subsequently changed their gender to male. This proportion is remarkably lower than the 63% reported in a recent systematic review {1}. Unfortunately, gaps in the details provided, in particular the age of patients at the time of recording gender assignment, make it difficult to reconcile these highly discrepant observations. Accurate diagnosis is always of value, even if it does not solve the question of optimal gender assignment. Parents, and later the affected person, will want to know even if management is unaffected. The consensus statement on the management of DSD {2} notes that gender assignment recommendations must take into account factors other than diagnosis, including genital appearance, surgical options, need for hormonal therapy, fertility and family and cultural perspectives.


1.  Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta hydroxysteroid dehydrogenase-3 deficiency. Cohen-Kettenis PT Arch Sex Behav 2005 Aug; 4(34):399-410 PMID: 16010463

2.  Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Lee PA, Houk CP, Ahmed SF, Hughes IA, International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology Pediatrics 2006 Aug; 2(118):e488-500 PMID: 16882788

Recommendation Citation:  

Sandberg D: F1000Prime Recommendation of [Maimoun L et al., J Clin Endocrinol Metab 2011, 96:296-307]. In F1000Prime, 30 Aug 2011; DOI: 10.3410/f.12909960.14201055. F1000Prime.com/12909960#eval14201055


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