Long-term clinical course in three patients with MAMLD1 mutations

Although MAMLD1 on chromosome Xq28 is known as a causative gene for 46,XY disorders of sex development, clinical information is virtually limited in patients of infancy to early childhood. Here, we report long-term genital and hormonal findings in three previously described Japanese patients with MAMLD1 mutations, i.e., patients 1 and 2 with p.E197X and patient 3 with p.R726X. As previously reported, patients 1-3 exhibited penoscrotal hypospadias with chordee, microphallus, bifid/hypoplastic scrotum, and/or bilateral cryptorchidism/retractile testes, in the presence of sufficiently high serum basal or hCG-stimulated testosterone values in the mini-pubertal period to early childhood. Subsequently, patient 1 had low serum hCG-stimulated testosterone value (126 ng/dL) at 13 11/12 years of age, and manifested microphallus (4.5 cm), relatively small testes (left 8 mL and right 10 mL), Tanner stage 3 genitalia and pubic hair development at 18 3/12 years of age. Similarly, patients 2 and 3 showed mild hypergonadotropic hypogonadism at 7 0/12 and 9 9/12 years of age, respectively, with serum GnRH-stimulated LH values of 5.5 and 7.2 mIU/mL and FSH values of 10.3 and 19.8 mIU/mL and hCG-stimulated testosterone values of 70 and 80 ng/dL, respectively. Testis ultrasound studies delineated microlithiasis in patients 1 and 3. These results imply for the first time deterioration of testicular function with age in patients with pathologic MAMLD1 mutations.