Low Incidence of Androgen Receptor Mutation Among Egyptian Children with Androgen Resistance
Introduction: In Egypt, disorders of sex development (DSD) constitute a significant entity among the birth defect list. Previous studies have reported that end organ androgen unresponsiveness, i.e. Androgen resistance, was the most prevalent underlying mechanism among Egyptian 46,XY DSD cases. Based on cytogenetic and hormonal diagnostic criteria as well as few sporadic case reports, it was proposed that androgen receptor (AR) defects [i.e. Androgen insensitivity syndrome (AIS), OMIM#300068] might constitute a major etiology within this category. However, this has never been systematically ascertained through an AR molecular diagnostic approach. Aim of the Work: The current study aimed to assess the role of AR mutations as an underlying etiology among a sample of Egyptian 46,XY DSD pediatric patients presenting with androgen end organ unresponsiveness. Patients and Method: In the current study, 21 children [age<18years] with male undermasculinization due to androgen end organ unresponsiveness were selected from 46,XY DSD cases. The selection criteria included ambiguous genital phenotype or genitalia discordant to the genotypic sex; 46,XY Karyotype and normal testicular response to HCG stimulation in prepubertal patients or normal basal testosterone (T) levels in postpubertal subjects. Molecular studies of the AR entailed PCR amplification for screening of major deletions/ insertions, single stranded conformational polymorphism (SSCP) screening for point mutations in the AR 2-8 exons followed by sequencing of these exons for all cases. Results: The results showed that none had major deletions/insertions. Five exons out of 147 (3.4%) showed abnormal SSCP migrational patterns. Out of those 5, two mutations in two Egyptian patients were detected by sequencing. The first was R840G (Arginine 840 glycine), in exon 7 (The ligand binding domain). The other was A596T (Alanine 596 Threonine) in exon 3 (The DNA binding domain). Conclusion:, This study shows that AR mutation is an uncommon underlying etiology among Egyptian paediatric 46,XY cases.
Keywords: Androgen resistance, androgen receptor, mutation, disorders of sex development, birth defects.
Egypt. J. Hum. Genet Vol. 9 (1) 2008: pp. 111-120