P3C309: SRY Negative Disorder of Sexual Differentiation in Two Biological Brothers

Introduction: Disorders of sexual differentiation (DSD) in phenotypic males are rare and are most commonly caused by translocation of the SRY gene from the Y to the X chromosome; however, there are rarer cases where 46 XX males have no SRY gene. This case presents brothers in which the upregulation of the SOX3 gene was believed to express a male phenotype of 46 XX by functioning as the SRY gene.

Case Description: A 17-year-old male adolescent presented for lack of phallus virilization and a history of hypospadias with webbing requiring 3 surgical repairs in infancy. Physical exam revealed a well appearing teenager with tanner 5 pubic hair, 5 cc testes, stretched penile length of 5.2 cm, and chordee present with a larger urethral opening on the ventral side of the penis. The patient was in the 46th percentile for height and the 25th percentile for weight with a normal bone age. LH was mildly elevated at 5.73 mIU/mL. Testosterone was 353 ng/dL correlating with Tanner Stage 5. Thyroid studies, IGF, FSH, Anti-Mullerian Hormone, Dihydrotestosterone and Inhibin B were normal. Karyotyping revealed 46, XX. A Disorders of Sex Development Panel resulted SRY negative with SOX 3 duplication likely causing male phenotype. The patient was referred to pediatric urology where an abdominal ultrasound revealed no ovarian or uterine tissue. Further virilization therapy via testosterone injections was offered if patient so desires in the future.

After this diagnosis, the patient’s 12-year-old brother presented for evaluation due to a similar birth history. Physical exam showed a well appearing pre-adolescent with tanner stage 2 pubic hair, testes 5cc bilaterally, and a stretched penile length of 6.5 cm. The patient was in the 70th percentile for height and the 12th percentile for weight. Labs revealed a normal FSH and LH. Testosterone was 60 ng/dL which correlated with tanner stage 2. Karyotyping showed 46, XX. The patient’s Disorders of Sex Development Panel showed a duplication of SOX3 that is likely resulting in male phenotype.

Discussion: SOX3 upregulation resulting in male phenotype in 46, XX is extremely rare. Only 5 individuals have been noted to have this SOX3 mutation, none with the exact mutation as these brothers. No identical cases in biological siblings have been documented.

Conclusion: These cases provide further evidence that SOX3 is a functional SRY substitute in sexual differentiation in individuals with DSD and demonstrates the possible hereditary component of this genetic mutation.