Endocrine Abstracts

Introduction: Steroid 5-α reductase type 2 deficiency causes 46,XY disorder of sex development (DSD) and is an autosomal recessive disorder resulting from mutations in the SRD5A2 gene. SRD5A2 facilitates the conversion of testosterone to dihydrotestosterone (DHT), crucially required for masculinisation of external genitalia. Thus 46,XY individuals with SRD5A2 mutations present with varying severity of undermasculinisation.

We describe the clinical presentation, investigations and management of two infants with novel SRD5A2 mutations.

Cases: Two children presented in the neonatal period with ambiguous genitalia. Patient 1, born to non-consanguineous Indian parents presented with micropenis, bifid scrotum and penoscrotal hypospadias. Patient 2, born to consanguineous Pakistani parents presented with micropenis. In both patients, scrotal testes were palpated, karyotype was 46,XY and pelvic ultrasound did not reveal Müllerian structures.

Following three injections of chorionic gonadotrophin, plasma testosterone:DHT ratio was equivocal in both patients (15 and 14 respectively). Rapid molecular genetic analysis, performed within 3 days by direct DNA sequencing of the SRD5A2 gene revealed novel mutations in both patients: patient 1 was compound heterozygous for the g.237_250 dup and g.264C>G genetic variants in the SRD5A2 gene that results in a premature stop codon 150 bp downstream and predicted to result in an aberrant protein. Patient 2 had a homozygous mutation, c.598G>A in exon 4 of the SRD5A2 gene that is also predicted to result in an abnormal protein, p.(Glu200Lys).

Topical Andractim gel (DHT 2.5%) applied once daily resulted in good phallic growth in both boys and surgical correction is planned at an older age.

Conclusion: Establishing the diagnosis of SRD5A2 deficiency is vital for personalised treatment and counselling. Rapid genetic analysis of the SRD5A2 gene is recommended in suspected patients. Development of comprehensive rapid DSD assays will support such a diagnostic strategy, enabling timely diagnosis and institution of appropriate personalised treatment.