Gonadal function in males with WFS1 spectrum disorder (Wolfram syndrome)-A European cohort perspective.

backgroundWFS1 spectrum disorder, also known as Wolfram syndrome (WS) is an ultra-rare (<1:500,000; ORPHA: 3463) monogenic (OMIM #222300) progressive neuroendocrine and neurodegenerative disorder, characterised by early-onset insulin-dependent diabetes, optic atrophy, central diabetes insipidus and sensi-neuronal deafness. It is caused predominantly by bi-allelic mutations in the WFS1 gene and exceptionally in the WFS2-gene. There is very limited published data on gonadal function in young people with WS. Expansion of the phenotype has previously included suggestions of abnormalities in puberty in adolescents with (WS) but with little detail.

methodsRetrospective case notes review of national patient cohorts comprising 21 males with WS aged 16-30 years. All patients were treated in two tertiary European health care centres: in Birmingham, UK and Münster, Germany. Hormonal parameters reflecting hypothalamic-pituitary-gonadal axis function and treatment with sex hormones were assessed. In addition, the presence or absence of erectile dysfunction was explored. In a subset of men, semen data were analysed. In one young man, testicular biopsies were examined histologically using light and electron microscopy.

resultsSeverely delayed or arrested puberty was observed in 57% of male adolescents with WS, necessitating testosterone replacement for completion of pubertal development. Subclinical (compensated) hypergonadotropic hypogonadism with still adequate testosterone serum concentration for age, but elevated LH/FSH was observed in 28.6% (n = 6). In two males, aged 19 and 16 years (9.5%), inadequately low LH/FSH and testosterone levels indicated hypogonadotropic hypogonadism. In the subset of males with normal puberty and normal endocrine testicular function (43% of male patients), the oldest, aged 30 years had normal sperm count in semen. Another young man had oligozoospermia at age 20, but azoospermia at age 25 years. Histology of his testicular tissues evidenced structural alterations of Leydig and Sertoli cells and tubular atrophy with various stages of tubular degeneration and meiotic arrest of spermatogenesis.

conclusionEndocrine testicular function and reproductive capacity are impaired in males with WS potentially due to premature degeneration of the testes, with 57% of adolescents developing hypogonadism with pubertal arrest.