Abstract
AbstractAndrogen insensitivity syndrome (AIS) is caused by mutations in the gene encoding the androgen receptor (AR). The incidence of AIS is estimated to be 1 in 99,000. Complete androgen insensitivity syndrome (CAIS) is characterized by a 46,XY karyotype with external genitalia that appear typically female and results from mutations that render the androgen receptor non-functional. Partial androgen insensitivity syndrome (PAIS) results from partial loss of function mutations in AR. Rarely, PAIS results from somatic mosaicism for an AR mutation and not from a hypomorphic variant. We present two cases of PAIS due to somatic mosaicism, one caused by a novel nonsense mutation and one caused by a missense mutation previously reported in CAIS. Two patients with atypical genitalia presented to our multidisciplinary clinic for disorders of sex development and sequencing of AR was performed as part of the diagnostic evaluation. In case one, AR sequencing revealed mosaicism for a nonsense mutation, c.1331T > A; p.Leu444Ter. This mutation has not previously been reported, but is presumed to be pathogenic. In case two, AR sequencing revealed a mosaic missense mutation, c.2279 C > A; p.Ser760Tyr, which has previously been reported in CAIS but not in PAIS. Similar phenotypes may result from AR mutations that are present in a mosaic state with full loss of function or hypomorphic mutations that partially impair the function of the protein in either all tissues or in a mosaic state.
Highlights
Androgen insensitivity syndrome (OMIM #300068) is an X-linked condition in which 46,XY individuals have varying degrees of undervirilization secondary to defects in androgen action due to mutations in the androgen receptor (AR) gene (OMIM#313700) [1]
We present two males with partial androgen insensitivity syndrome (PAIS) due to somatic mosaicism, one caused by a novel nonsense mutation that has not previously been reported and another caused by a missense mutation that has been reported to cause complete androgen insensitivity syndrome (CAIS) [9], but not PAIS
We reviewed the records of two individuals with known somatic mosaicism for an AR mutation
Summary
Androgen insensitivity syndrome (OMIM #300068) is an X-linked condition in which 46,XY individuals have varying degrees of undervirilization secondary to defects in androgen action due to mutations in the androgen receptor (AR) gene (OMIM#313700) [1]. There are three main types of androgen insensitivity syndrome (AIS): complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS) and mild androgen insensitivity syndrome [1]. Individuals with CAIS have a 46,XY karyotype and due to the complete inaction of androgens in utero, infants are born with phenotypically normal female external genitalia. The phenotypes associated with PAIS are wide-ranging due to varying degrees of androgen resistance [2]. Those with mild androgen insensitivity can have impaired spermatogenesis, impaired pubertal virilization or gynecomastia in puberty [1]. AIS due to somatic mosaicism has been reported as a rare cause of PAIS [4,5,6,7,8]
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