Hypogonadotropic hypogonadism-25 with anosmia (HH25) is characterized by delayed or absent puberty with low gonadotropic hormones in the setting of low testoster...
Hypogonadotropic hypogonadism-25 with anosmia (HH25) is characterized by delayed or absent puberty with low gonadotropic hormones in the setting of low testosterone or estradiol. Affected individuals also exhibit hyposmia or anosmia, with hypoplastic olfactory bulbs on MRI. Intrafamilial variable expressivity and incomplete penetrance has been observed (Messina et al., 2020).
For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia, see 147950.
▼ Clinical Features
Messina et al. (2020) described 4 unrelated patients with congenital HH and mutations in the NDNF gene. All 4 had severe GnRH (152760) deficiency and anosmia, resulting in a diagnosis of Kallmann syndrome. The 3 male probands had cryptorchidism and micropenis at birth, and prepubertal testes in their teenage years. The female proband presented with primary amenorrhea at age 17 years; pelvic ultrasound showed small ovaries and a small unestrogenized uterus. MRI was performed in 2 patients, both of whom had hypoplastic or rudimentary olfactory bulbs with normal pituitary glands. Endocrine analysis showed low gonadotropic hormone levels with low testosterone or estradiol levels, respectively. Family members of 3 probands exhibited partial phenotypes, such as anosmia and/or delayed puberty.
The transmission pattern of hypogonadotropic hypogonadism and anosmia in the families reported by Messina et al. (2020) was consistent with autosomal dominant inheritance.
▼ Molecular Genetics
Messina et al. (2020) screened whole-exome sequencing data from a cohort of 240 probands with congenital hypogonadotropic hypogonadism for rare variants in FN3 domain-containing proteins, and identified 4 probands who were heterozygous for mutations in the NDNF gene, including 3 nonsense or frameshift mutations (616506.0001-616506.0003) and 1 missense mutation. None of the patients had mutations in any known HH-associated genes. None of the mutant proteins exhibited the chemorepellent effect on migratory GnRH cells observed with wildtype NDNF.