ESPE Abstracts (2019) 92 P3-239

Normosmic Hypogonadotropic Hypogonadism: An Intrafamiliar Case

Joana Soares1,2, Filipa Briosa1,3, Rita Valsassina1,3, Marta Amorim4, Catarina Limbert1


1Paediatric Endocrinology Department, Hospital Dona Estefânia, Lisbon, Portugal. 2Paediatrics Department, Hospital de Santo André, Centro Hospitalar de Leiria, Leiria, Portugal. 3Paediatrics Department, Hospital Beatriz Ângelo, Loures, Portugal. 4Genetic Department, Hospital Dona Estefânia, Lisbon, Portugal


Background: Idiopathic hypogonadotropic hypogonadism (IHH) is due to the failure of gonadotrofin releasing hormone (GnRH) secretion which impairs the physiological initiation of puberty. About 30 to 50% of IHH is associated to hereditary causes and about 50 mutated genes have been identified.

Objective and methods: We present three intra-familial cases of normosmic IHH (nIHH) related to a new association of two heterozygotic TARC3 mutations.

Case report: The index case reports to a 16 year-old male with no pubertal development at this age. Later on, two of his three sisters also presented complete hypogonadism. All cases had a normal sense of smell. Investigation showed low sex steroid and gonadotropin levels and no evidence of a mass lesion in the cerebral MRI. The diagnosis of nIHH was supported by the identification of two heterozygous mutations on TACR3 gene: c.824G>A (p.Trp275*) and c. 689G>A (p. Arg230His) in all subjects. Although the former mutation was previously described as pathogenic by the literature, the latter was classified as of uncertain significance at date. The present family cluster supports the evidence of the pathogenicity of the second variant.

Conclusion: Congenital IHH is a very rare genetic disorder that if undiagnosed or untreated may lead to infertility associated to complete or partial absence of GnRH. TAC3/TACR3 mutations have a critical importance on sexual maturation and are an important genetic cause of nIHH that should be particularly searched in patients with high serum FSH/LH ratio. The treatment of nIHH is based on sex steroids replacement, therefore promoting the pubertal development.

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