Congenital hypothalamic hypogonadism — a Kallmann syndrome in boys. Clinical cases

Abstract

Central hypogonadism (CH) is a rare disease that occurs with a frequency of 1 : 8000 in women and 1 : 4000 in men. In 60 % of cases of CH, it is caused by Kallmann syndrome (KS) — a disease in which hypogonadotropic hypogonadism is combined with olfactory disorders (hyposmia or anosmia).Aim — to study clinical features, principles of diagnosis of CH/KS and evaluation of the effectiveness of various treatment. Materials and methods. 4 cases with CH/KS from three families had been described. Laboratory and instrumental investigations were used to confirm the KS; genetic diagnosis was performed using targeted next-generation sequencing (tNGS hypogonadotropic panel).Results. Patients with CH/KS had a wide spectrum of genital disorders (micropenia, cryptorchidism, microorchidism), which appeared at different age. Extragenital pathology was found in three of four patients: namely disorders of kidney, eye, respiratory system, hypoparathyroidism, hypothyroidism and epilepsy. It should be noted that all patients had olfactory disorders, which appeared in two of them only during a detailed survey after receiving genetic testing. In all patients, the diagnosis of CH was confirmed by the test with triptorelin 0.1. Also, all patients who underwent densitometry were found to have significant osteoporosis. In three patients, genetic testing confirmed hemizygous pathogenic variants in ANOS1 gene, while in one patient a heterozygous variant in FGFR1 gene was confirmed. After treatment with chorionic gonadotropin (HCG), two patients responded positively, with a descent of the testicles into the scrotum and an increase of testosterone level and testicular volume. However, in the other two patients there was no positive trend in treatment with HCG, therefore, the use of recombinant human FSH (r-FSH) in the form of priming and then further — in combination with HCG may be considered. Although the presence of severe microorchidism, cryptorchidism, low levels of AMH, inhibin B, and an unsatisfactory response to the previous treatment with HCG indicates extremely unfavorable prognosis. Therefore, in order to achieve the fertility in some patients with CH/KS, the most likely attempt is the use of assisted reproductive technologies.Conclusions. The leading problem in the treatment of patients with KS is their different response to hormone therapy, including different manifestations of the disease.