ESPE Abstracts

Female phenotype and sex reversal are often reported in 46,XY patients with 5α-Reductase Type 2 Deficiency (5αRD2). In case of late diagnosis, at puberty, virilization occurs. Over the years, sex assignment in case of early diagnosis evolved from female to male. We report four cases of 5αRD2, managed differently over three decades. All children presented with a female phenotype (EGS 3-4), palpable gonads, absent uterus, and 46,XY karyotype. All patients were assigned female at birth. All were from consanguineous families, except for patient 1. Patient 1, of Spanish origin, was 3-months-old when referred in 1992. Six years later, the molecular diagnosis was confirmed: p.(Gly115Asp)/p.(Ala207Asp) SRD5A2 compound heterozygous mutations. At puberty, she expressed female identity, and started treatment with GnRH analogues. At 19, vaginoplasty and gonadectomy were performed. Patient 2, of Italian origin, was 9-days-old when referred in 1996. Two years later, the molecular diagnosis was confirmed: p.(Gly115Asp) SRD5A2 homozygous mutation. Parents preferred to keep the female-sex orientation. The child underwent gonadectomy at 4. Estrogen treatment started at 12. At 19, after sexual intercourses with her boyfriend, a vaginal depth of 5 cm was noted and dilatations were discussed. She currently expresses no doubts about her female identity. Patient 3, of Moroccan origin, was 2-days-old when referred in 2002. Two weeks later, the molecular diagnosis was confirmed: p.(Lys41ThrfsTer94) SRD5A2 homozygous mutation. Parents opted for female-sex orientation, bilateral gonadectomy at one year, vaginoplasty at 2, clitoro-vulvoplasty at 3. Estrogen replacement therapy began at 12. She currently seems to cope well with her situation. Patient 4, of Pakistani origin, was 1-day-old when referred in 2022. Four weeks later, the molecular diagnosis was confirmed: p.(Gly196Ser) SRD5A2 homozygous mutation. After the declaration of male sex at 3 months, topical DHT was applied from 3 to 9 months resulting in modest genital bud growth. For all patients and their families, psychological and multidisciplinary supports were provided throughout follow-up. Growing evidence suggests male sex assignment in 46,XY newborns with 5αRD2 to avoid gender dysphoria among those assigned female. This evidence is based on varying clinical management ranging from early female sex assignment with gonadectomy (surgical or pharmacological) or without gonadectomy and pubertal virilization, to early male sex assignment with DHT topical treatment. More precise long-term data, including adults’ quality of life evaluation, are required to refine the clinical approach of this condition. Psychological support along with multidisciplinary management remain pivotal.