ESPE Abstracts

Background: Congenital hypogonadotropic hypogonadism (CHH) is a rare disease with a complex clinical picture and genetic background. In up to 50% genetic mutations are found. The goal is to be able to provide a comprehensive prognosis and genetic counseling for this family with CHH.

Case presentation: At the age of 16 years a boy with familial constitutional delay (adrenarche only with 15 years, no growth spurt, bone age 14 years) presented at our clinics with pubertal stage P2, G1 (left testis inguinal, right descended, small phallus < -2 SD), ax.1. Hypogonadotropic hypogonadism was diagnosed by LHRH and HCG testing. Within 3 years, the patient showed adequate virilization and an increase in testicular volume to 6 ml under his choice of gradually increased testosterone therapy. In addition, the patient had a cleft lip and palate and congenital deafness on the right and acquired deafness on the left from his 4th year of life, both caused by otosclerosis, necessitating a cochlear implant. Family history (our patient was son 3) was striking for many symptoms of complex CHH: Puberty was delayed in both parents and all 5 sons, cleft lip/palate was present in the father and the 4 youngest sons, oligotonia in the 3 last sons, cryptorchidism in the 3 middle sons, renal duplication in the 4th son, suspected hearing impairment in the 3rd and 5th son.

Results: Genetic tests showed a monoallelic NOS1 mutation in the father and the three middle sons, consistent with an autosomal dominant mode of inheritance. Caused by the oligogenetic mode of inheritance only our patient had CHH: He inherited the genetic background of delayed puberty of the father (NOS1 mutation) AND the mother (other unknown mutation).

Conclusion: While FGFR1 and CHD7 have been reported as the most commonly mutated genes in CHH, a NOS1 mutation has also been suggested to be pathogenic if oligogenic (Quaynor Mol Cell Endocrinol. 2016). In light of the fact that studies are underway to causally treat gonadal insufficiency with a nitric oxide synthase inhibitor in a cryptorchid mouse model (DeFoor J Urol. 2004), knowledge of this mutation found is even more important for offspring of this family.