ESPE Abstracts

Hypogonadotropic hypogonadism is characterized by low levels of gonadotropins and delayed or absent sexual development. Most of the patients reach the diagnosis in late adolescence or in adulthood. A timely, appropriate diagnosis implicates a better clinical outcome and treatment timing. We describe the clinical case of a 15-year-old girl with primary amenorrhea. Stature and weight were in accordance with mid parental height; Tanner stage: PH2 B1. FSH, LH, oestradiol showed prebubertal levels; IGF-1, TSH, fT4, prolactin, ACTH, cortisol were in the normal range. Organic diseases (Crohn disease, Celiac disease, etc) were excluded. Pelvic ultrasound showed ovaries and uterine prepubertal morphology and diameters. Encephalic, hypothalamic and hypophyseal MRI was normal. NGS analysis for the study of genes associated with hypogonadism, showed that our patient had two heterozygous GnRHR mutations: c.159T>G (P.Asn53Lys) in exon 1, Chr4 and c.317A>G (P.Gln106Arg) in exon 1, Chr4. These mutations were studied by Sanger sequencing in the parents, confirming that they were inherited from the father (c.317A>G (P.Gln106Arg) in exon 1, Chr4) and the mother (c.159T>G (P.Asn53Lys) in exon 1) and were in trans, confirming their pathogenetic role in the clinical phenotype. The variant c.317A>G (P.Gln106Arg) is a rare mutation associated with hypogonadotropic hypogonadism; the variant c.159T>G (P.Asn53Lys) is a new mutation defined as VUS. According to the diagnosis, timely estrogenic treatment, with a slow dosage increase and a a further association with progesterone, can be given for the patients to induce puberty with beneficial effects for metabolic, bone, sexual and psychological health. NGS is a valid support to the genetic study of patients with hypogonadism, contributing to recognize also rare genetic mutations and to support the clinician in the management of rare diseases.

References:

1. Bonomi M, et al. Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH). Eur J Endocrinol. 2018;178(1):23-32.