ESPE Abstracts

Background: Androgen Insensitivity syndrome (AIS), the most common cause of XY DSD, is an X-linked recessive allelic disorder caused by Androgen Receptor (AR) gene mutations. The complete form (CAIS) stems from abrogation of AR activity and is characterized by an external female phenotype and scarce pubic hair, as well as lack of Mullerian structures. Postnatal gonadotropin and testosterone levels are not increased, and the classical ‘Mini-puberty’ is absent. Gender dysphoria in CAIS is rare, probably due to absence of AR activity in the brain. Herein we describe the clinical and molecular characteristics in two siblings with a novel AR mutation.

Clinical report: Two siblings presented postnatally 6 years apart with bilateral inguinal hernia and complete female external phenotype. Both had gonads in the inguinal canal, complete lack of Mullerian structures on ultrasound, and XY karyotype. On third day of life endocrine workup showed normal cortisol and unexpectedly elevated testosterone (728 ng/dl, 468 ng/dL –normal neonatal male range 75-400 ng/dL) and LH (3.83, 2.75 IU/L) levels. They were both assigned female gender. The older sibling presented at the endocrinology clinic at the age of 6 years with consistent and extreme boy-like behavior, self-professed male identity and marked gender dysphoria.

Molecular studies: Sequencing of the AR gene in both siblings revealed a novel hemizygous mutation c.1885G>A (P.Ala629Thr); The terminal nucleotide of exon 3 at the consensus splice site. The asymptomatic mother was found to be heterozygous to the mutation. The mutation was found to affect splicing; cDNA from peripheral leukocytes revealed an altered transcript, lacking entirely exon 3 (39 amino acids) without changing the reading frame in both affected siblings. The shorter transcript was also detected in maternal cDNA along with normal transcript.

Conclusion: The novel c.1885G>A (P.Ala629Thr) hemizygous mutation in the AR gene causes CAIS. This mutation alters AR transcription, skipping exon 3, which contains a D-box element crucial to AR dimerization. Interestingly, the postnatal (mini puberty) hormonal profile as well as the gender dysphoria observed in our cases are not expected in CAIS and possibly suggest that this mutant AR may have differential function in the brain vs the periphery. Further studies on the specific action of this novel mutation at different tissues are currently underway.