Genetic profiles and three-year follow-up study of Chinese males with
congenital hypogonadotropic hypogonadism
Abstract
Genotypes-phenotypes correlation and treatment outcomes for 73 Chinese
CHH male patients was performed in this study. Patients self-selected
one of the four treatments: pulsatile Gonadorelin® pump, cyclical
gonadotropins therapy, human menopausal gonadotropin monotherapy, or
testosterone replacement treatment. Clinical assessments were performed
every 3 months for 3 years. Baseline clinical features, spermatogenesis
and secondary sexual development outcomes were analyzed. Whole exome
sequencing identified 63 variants in 52 patients (70%), 18 of which
were novel. Variants on FGFR1, PROKR2, CHD7, ANOS1 and NSMF gene were 10
(15.87%), 10 (15.87%), 7(11.11%), 5(7.93%) and 5(7.93%)
respectively. Some null variants could lead to severe clinical
manifestations than missense variants on FGFR1 and CHD7. The Lasso
regression model for spermatogenic failure risk showed that
cryptorchidism history, abnormal epididymis or prostate, lower basal LH
and peak-LH post Triptorelin® stimulation were significant predictors.
Approximately, 30% normosmic patients defined by simple olfactory
assessment showed olfactory nerve center maldevelopment with nasal sinus
MRI. The severity of reproductive system was attributed to
spermatogenesis that could be predicted by nomogram model. No direct
correlation was observed between candidate genes and spermatogenic
outcome, however, the clinical severity is partially related with
specific variants, and clinical features might in turn affect the
treatment efficacy.