One identified gene connected to the development of distinct sexes is MAMLD1 (X chromosome). It appears to be involved in the development of fetal sex and adult reproductive function, including testosterone production, and is expressed in the testes and ovaries. Its precise function is yet unknown. More than 40 genetic variations have been identified, largely in male people and mostly connected to hypospadias. Patients with MAMLD1 variations often exhibit normal gonadal function and normal testosterone levels, despite the fact that MAMLD1 has been demonstrated to influence the expression of the steroidogenic pathway.

For a case study, a patient (46, XY) with hypospadias and microphallus was described. He also had low levels of testosterone and dihydrotestosterone (DHT) and unnaturally low amounts of luteinizing hormone (LH) throughout mini puberty. This hormonal pattern suggested partial hypogonadism of the gonadotropin axis. A 4-month hCG stimulation test revealed no appreciable rise in testosterone levels or dihydrotestosterone levels. When he was given intramuscular testosterone at the age of 5 months, his penis length rose to 3.5 cm. At the age of 6 months, the therapy was halted.

The MAMLD1 gene harbors a previously unreported nonsense variation (c.1738C>T:p.Gln580Ter), which was deemed to be harmful by the gonadal function massive-sequencing panel. His genital phenotype might be explained by this MAMLD1 mutation, which predicts a truncated protein. The potential role of the gene in the biosynthesis of testosterone during the fetal stage and the infant’s mini puberty is highlighted by his hormonal profile (low testosterone, dihydrotestosterone, and LH concentrations) along with no appreciable increase in testosterone and DHT plasma concentrations (hCG test).

In addition, the LH values could point to a possible oligogenesis or the participation of MAMLD1 in the LH axis. For the first time, a patient with an aberrant MAMLD1 had been linked to a decline in DHT.