Mutation of the androgen receptor (R840S) in an Egyptian patient with partial androgen insensitivity syndrome: review of the literature on the clinical expression of different R840 substitutions.

The X-linked androgen insensitivity syndrome (AIS) encompasses a heterogeneous group of defects in the androgen receptor (AR) that result in varying degrees of undermasculinization. In the current study, we characterize the R840S mutation on exon 7 of the AR ligand-binding domain. The Egyptian patient, who had been reared as female, presented ambiguous genitalia at 6.5 yr. Diagnosis of partial AIS (PAIS) was based on clinical phenotype and laboratory evidence of good testosterone response and normal testosterone/dihydrotestosterone (T/DHT) ratio. The therapeutic response to testosterone depot injections justified reassignment to male sex. To our knowledge, this mutation has been reported only once in two Brazilian brothers with PAIS. Three other mutations of this residue (R840C; R840G, nonconservative; and R840H, conservative) have been reported in patients with PAIS and, when expressed in vitro, they led to subnormal transactivation of a reporter gene. Each of these mutations was associated with a very diverse spectrum of phenotypes. These data highlight the role of the AR ligand-binding pocket (LBP) in the expression of transcriptional activity during prenatal sex differentiation.