Clinical, biochemical, and genetic findings in a large pedigree of male and female patients with 5 alpha-reductase 2 deficiency.

Abstract

The present report describes a cluster of eight patients with male pseudohermaphroditism from a large pedigree with steroid 5 alpha-reductase 2 deficiency (5 alpha RD), who reside in Southern Lebanon. They were born with unambiguous female external genitalia and reared as girls until puberty, when masculinization occurred, followed by a change of gender role. Semen analysis and testicular histology revealed maturation arrest of spermatogenesis, with low sperm count and motility. Determination of urinary 5 alpha- and 5 beta-reduced adrenal steroids enabled us to diagnose the disease in a male patient with the full-blown clinical syndrome, in another male patient who had undergone bilateral orchidectomy, and in three female individuals with the biochemical derangement. The female patients were unique in this family with respect to their low degree of virilization, but had normal menstrual cycles. Molecular genetic studies were performed on DNA extracted from peripheral leukocytes and from cultured genital skin fibroblasts. The coding sequence of the 5 alpha R2 gene (SRD5A2) was studied by exon-specific PCR, single strand conformation polymorphism, and direct sequencing. A homozygous point mutation was identified in exon 1, leading to a thymidine for adenine substitution, predicting amino acid substitution of leucine for glutamine at position 55.

Gender Change in 46,XY Persons with 5α-Reductase-2 Deficiency and 17β-Hydroxysteroid Dehydrogenase-3 Deficiency

“…Our review does not support this explanation. About half of the persons with female appearing external genitalia developed a male gender identity (see also Hochberg et al, 1996;Mendonca et al, 2003) and about half of the persons with genital ambiguity developed a female gender identity, suggesting that genital appearance at birth does not determine psychosexual outcome in a consistent way. Our clinical impression is that the general appearance of the child, in combination with masculine behavior, is probably more important than the genital appearance for developing a male gender identity.…”

Disorders of sex development (DSDs), their presentation and management in different cultures

“…5α-Reductase deficiency was first reported on one island in the Dominican Republic [22]. It is also prevalent in southern Lebanon [23], the Eastern Highlands Province of PapuaNew Guinea [24] but is relatively rare in the Caucasian race. Steroid 17β-Hydroxysteroid dehydrogenase deficiency is very common in the Gaza Strip [25].…”

Primary amenorrhea in four adolescents revealed 5α-reductase deficiency confirmed by molecular analysis

“…The homozygous substitution of leucine by glutamine at position 55 (p.L55Q), which was identified in patient 1, was originally reported in the context of a compound heterozygous mutation (6), but this mutation is most often identified in homozygous forms (18)(19)(20). Female phenotypes have been reported mainly for patients with p.L55Q, although a patient with male phenotype with micropenis and hypospadias, similar to patient 1 in this study, was reported (6,18,20).…”

“…A female-tomale gender switch has been reported only twice before, once by Mendonca et al (17) in four of four patients with compound heterozygous mutations (N193S/Q126R) and once by Hochberg et al (18) in a 17-year-old patient with an L55Q homozygous mutation. In our experience in the clinical, biological, and genetic analysis of 55 children (L. Maïmoun et al), only five of these 55 patients raised as girls chose a sex reorientation.…”