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Molecular Characterization of 6 Unrelated Italian Patients With 5-Reductase Type 2 Deficiency

S. MAJORE

G. MARROCCO

S. TUMINI

B. BOSCHERINI

S. SCOMMEGNA

R. RINALDI

P. GRAMMATICO

From the ^* Cytogenetic and Molecular Genetic Unit, S. Chiara Hospital, Pisa, Italy; the Centre for the Disorders of Sexual Development, Medical Genetics, University "La Sapienza," S. Camillo-Forlanini Hospital, Rome, Italy; the Department of Pediatrics, University of Chieti, Ospedale Policlinico, Chieti, Italy; the Pediatric Unit, Policlinico Tor Vergata, Rome, Italy; and the ^|| Medical School of Endocrinology, Garibaldi Hospital, Catania, Italy.

Correspondence to: Dr Fulvia Baldinotti, Unitû Operativa Cito-genetica e Genetica Molecolare, Dipartimento di Ginecologia e Ostetricia, Ospedale S.Chiara: via Roma, 67, 56100 Pisa, Italy (e-mail: f.baldinotti{at}ao-pisa.toscana.it).

Steroid 5-reductase (5R) deficiency (OMIM number #264600) is a rare 46,XY disorder of sex differentiation caused by mutations in the 5R type 2 gene (SRD5A2) resulting in dihydrotestosterone deficiency during fetal development. We report on the analysis of the SRD5A2 gene in 6 unrelated 46,XY Italian patients with external genitalia morphology ranging from predominantly female to nearly completely male. Three subjects were seen and assessed at birth, 1 patient was referred to us before puberty, and 2 at postpubertal age. Six different causative mutations (5 missense and 1 nonsense) and a rare polymorphism were identified. Four patients presented homozygous single-base substitutions. These SRD5A2 mutations were located in exon 2 (variant Cys133Gly), exon 4 (Gly196Ser and Ala207Asp) and exon 5 (Tyr235Phe). A fifth subject was a compound heterozygote who carried a nonsense mutation in exon 1 (Trp53X) and a second SRD5A2 alteration in exon 5 (Tyr235Phe). The final patient presented a mutation in only 1 allele (Gly34Trp) together with the Ala49Thr variant. The molecular characterization of these patients made it possible to identify novel mutations and to confirm, before gender assignment or any surgical approach, the suspected 5R deficiency in 2 newborns, 1 of whom had inconclusive hormonal data. 5R deficiency in subjects without parental consanguinity and the presence of compound heterozygotic patients suggest that SRD5A2 mutations carrier frequency may be higher than previously thought.

     Key words: 5-reductase deficiency, SRD5A2 gene, hypospadias