Gynecomastia and Partial Androgen Insensitivity Syndrome (PAIS)

Purpose: Partial androgen insensitivity syndrome (PAIS) is a rare genetic disorder, with a prevalence of 1:130,000. Caused by a loss-of-function mutation in the androgen receptor (AR) gene located on the X-chromosome, PAIS is clinically characterized by hypospadias, gynecomastia, and infertility due to azoospermia.Phenotypic manifestations often overlap with other genetic disorders. Therefore, genetic screening can not only help provide a definitive diagnosis, but can also assure accurate genetic counseling – especially for female carriers. Case Presentation: A 13-year-old male Caucasian was referred for gynecomastia. His past medical history was unremarkable, except for attention deficit hyperactivity disorder. Family history included cancer, cardiovascular disease, and obesity. On physical exam, his penis was underdeveloped while his pubic hair was Tanner 3. He had large well-formed breasts similar to Tanner 4 in females. His testicles were 6 mls. Laboratory testing revealed elevated serum testosterone of 1610 ng/dL, LH 4.75 mIU/mL, FSH 0.57 mIU/mL and estradiol 17 pg/mL. His initial lab results were consistent with (partial) androgen insensitivity syndrome. Following 10 mg/d of tamoxifen, his breast tissue dissappeared completely and the drug was discontinued. Within a year, significant breast hypertrophy was again noted and tamoxifen was resumed. With further treatment, his gynecomastia once again resolved. F-up lab results showed continued elevation of serum testosterone of 1678 ng/dL with LH levels of 20.24 mIU/mL, and estradiol of 73 pg/m. FSH levels remained normal (2.66 mIU/mL). Genetic testing confirmed a known mutation for PAIS. The patient was advised to continue tamoxifen. Whole exome sequencing was completed (illumina HiSeq 2000, McDermott Center Sequencing Core at UT Southwestern Medical Center, Dallas, TX) from DNA isolated from peripheral blood. The patient harbored a missense mutation (A700D) in the AR gene. Sanger sequencing was completed to confirm the mutation. His mother was heterozygous for the mutation while his father and unaffected brother lacked the mutation. Summary: Gynecomastia, the proliferation of male breast tissue, may occur as a consequence of physiologic or pathologic causes. Although physiologic gynecomastia commonly associated with male puberty resolves spontaneously, pathologic causes often result in persistent breast enlargement, accompanied by tenderness and, in some, galactorrhea. Further diagnostic testing is recommended in those with persistent, unexplained gynecomastia. Current treatment options for PAIS are limited to symptomatic management. Genetic and psychological counseling, and hormone replacement therapy should be proved.4,5 Affected males with hypospadias may benefit from assistance with sex assignment, genitoplasty and gonadectomy. Conclusions: Overall, PAIS is often overlooked due its rarity and may be confused with other genetic disorders with similar clinical presentations. As such, PAIS should be included in differential diagnosis of children who present with abnormal secondary sexual organ development or ambiguous genitalia. Individuals with PAIS should be managed by a multidisciplinary team to assure the best outcomes.