ESPE Abstracts

Background: Among 46,XY individuals, androgen insensitivity syndrome (AIS) due to deleterious variants of the androgen receptor (AR) gene is one cause for a difference of sexual development (DSD). Typically, individuals with complete androgen insensitivity syndrome (CAIS) present with female external genitalia and palpable labial masses. Whereas most patients carry germline variants inherited in an X-linked manner, approximately 30% of patients manifest de novo variants. We describe an infant with phenotype-genotype incongruity associated with a variant in AR.

Case Presentation: This patient was referred to endocrinology at the age of 3 weeks for evaluation of atypical genitalia. The exam showed bifid scrotum, bilateral descended testes, scrotal hypospadias with chordee, and 1 cm phallus. Initial studies showed normal random growth hormone, cortisol, and 17-hydroxyprogesterone levels. Chromosome analysis showed 46,XY karyotype; FISH confirmed presence of the SRY gene. A pelvic ultrasound revealed absence of any Mullerian structures. Additional studies obtained at 2 months of age showed LH 1.78 IU/l, FSH 0.45 IU/l, testosterone 282 ng/dl (9.8 nmol/l), and DHT 65 ng/dl (2.2 nmol/l). Due to the infant’s undervirilization, whole exome sequencing was performed. A rare pathogenic variant in the AR gene, c2104C>T, predicted to result in amino acid substitution p.Leu702Phe (rs1555995851) was detected in 48% of the sequence reads, consistent with somatic mosaicism.

Discussion: The initial evaluation of this patient excluded hypopituitarism and defects in steroidogenesis from consideration. This AR gene sequence variant has been previously confirmed to be associated with CAIS. In this patient, somatic mosaicism for a pathogenic AR variant likely explains the inconsistency between his partially virilized phenotype and the sequence variant predicted to cause CAIS. Somatic mosaicism for a DNA sequence variant, resulting from post-zygotic changes during the early stages of embryo development, is emerging as a significant contributor to DSD. Identification of mosaicism is important for management and will help the medical team and the family discuss sex of rearing. For patients with mosaicism for a disease-causing variant, the proportion of cells with a wild type AR is likely variable and may ultimately influence androgen responsiveness and the patient’s phenotype during adolescence and adulthood. Virilization at puberty has been reported in males with somatic mosaicism of AR (JCEM 2005; 90:106). Our patient showed some response to a testosterone trial and will receive another trial course of higher dose testosterone.