Testicular failure and male infertility in the monogenic Mulibrey nanism disorder.

CONTEXT: Few monogenic mutations causing human male infertility have been identified to date.

OBJECTIVE

We studied pubertal development and fecundity in males with Mulibrey nanism (MUL) caused by mutations in the TRIM37 gene.

DESIGN, SETTING, AND PATIENTS: Twenty-eight male MUL patients of the Finnish national cohort aged 8.7 to 50.0 yr (median age, 28.8) at the end of observation were followed for 10 yr beginning from 2000-2001.

MAIN OUTCOME MEASURES: Clinical characteristics, reproductive hormone levels, semen quality, and testicular histology were assessed.

RESULTS

The external genital phenotype was normal. In childhood and prepuberty, serum levels of FSH, LH, testosterone (T), and inhibin B were normal. Puberty started spontaneously at a median age of 12.6 yr (range, 11.1-15.0), and FSH, LH, T, and inhibin B levels increased adequately until midpuberty. Thereafter, testicular growth and virilization proceeded slowly. Concomitantly, FSH, and to a lesser extent LH, showed a progressive increase to hypergonadotropic levels in all patients, whereas inhibin B decreased and T leveled off. Testicular size was small (median volume, 8.7 ml; range, 3.5-18.3 ml in adults). All semen samples showed severe oligoasthenozoospermia or azoospermia. None of the patients had a history of spontaneous fertility, but four men had undergone infertility treatment, which in one case was successful. All histological MUL samples showed varying degrees of degeneration.

CONCLUSIONS

All adult MUL males have a unique disorder of testicular function with small testes, elevated FSH and LH, and low inhibin B. In MUL, mutations in TRIM37 lead to disturbance of sexual maturation, and fertility is severely compromised. Thus, TRIM37 is a novel gene causing male infertility.