Introduction: Androgen insensitivity syndrome (AIS) is a heterogeneous condition. At the milder end of the clinical spectrum, patients with mild AIS (MAIS) are phenotypically male, and may present with infertility, either isolated or associated with gynaecomastia or signs of mild undervirilization. Most cases of complete and approximately 25% of partial AIS patients harbour mutations in the androgen receptor (AR) gene. Over 1,000 pathogenic variants have been described, but only approximately 40 of these are reported to cause MAIS.
Case report: A 30 year-old male with a history of infertility was referred to us following the finding of severe oligozoospermia and a raised testosterone. He had scant facial and body hair and gynaecomastia since puberty. His brother (who was also found to have oligozoospermia), and a male cousin from his mothers side had similar physical appearance. On examination, testicles were of normal volume (15 ml) and penile length was normal. Biochemistry showed raised testosterone (43 nmol/l, normal 8.629), raised LH (12 U/l, normal 1.78.6) and normal FSH (6 U/l, normal 4.612.5), with an increased androgen sensitivity index (516 U*nmol/l2, normal 14.6249.4). In view of these results and the putative family history, MAIS due to an AR mutation was suspected. Sequencing of the AR gene showed a novel hemizygous six base pair duplication resulting in the duplication of two amino acids (p.Leu56_Leu57dup). The same variant was identified in his brother and cousin. While this variant has not been previously reported, duplication of Leu57 was described in a subject with MAIS, further supporting the pathogenic role of the p.Leu56_Leu57dup variant.
Conclusion: We report a case of familial MAIS due to a novel, likely pathogenic variant in the AR gene. Considering its clinical presentation, MAIS is an underdiagnosed condition. Evidence of raised testosterone and a positive family history may guide the diagnosis and help identifying the causative genetic abnormality.