Homozygous p.R246Q Mutation and Impaired Spermatogenesis: Long Term Follow-up of 4 Children from One Family with 5 Alpha Reductase 2 Deficiency

Excerpt

To the Editor : 5-alpha reductase 2 enzyme catalyses the conversion of Testosterone (T) to Dihydrotestosterone (DHT) in specific target tissues [1]. Children with 5 alpha reductase 2 deficiency (5αRD2) are born with malformed genitalia and about ~70 % of them opt for male gender at puberty [2]. The enzyme is encoded by SRD5A2 gene and mutations in this gene account for this disorder [3]. In this report, we describe the long term follow-up in terms of pubertal development in a family of all four children affected with 5αRD2. The eldest of the 4 siblings came to this tertiary care hospital with the complaint of primary amenorrhea at 13 y of age and later opted male genitoplasty. His two younger siblings also had genital ambiguity but were reared as boys. The 4th child had the appearance of the external genitalia, according to mother identical to that of the 1st child and she wished to raise this child as a female. All the four siblings showed 46, XY karyotype. The hormonal profile of these children suggested diagnosis of 5αRD2, as DHT was low and T/DHT was elevated (normal T/DHT < 10). Sequence analysis of SRD5A2 gene showed p.R246Q homozygous mutation (exon 5) in all the four siblings (III.17, 18, 19, 20). Mother (II.1) was heterozygous for this mutation (Fig. 1). Psychological assessment (of 3 older siblings) revealed no gender dysphoria, however they experienced certain amount of psychological distress. Semen analysis revealed low semen volume, there were no sperms in samples analysed prior to age 20 y and the counts decreased subsequently. This may suggest delay in spermatogenesis and early senescence of germ cells. Previously Marumudi et al., observed progressive reduction of sperm count in a patient with 5αRD2 and p.R246Q homozygous mutation where the count decreased from 16 million cells/ml to azoospermia [4]. In our patients, the presence of p.R246Q homozygous mutation may be responsible for the decreased sperm count.

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