Endocrine Abstracts

Introduction: Kallmann syndrome (KS) is a genetic condition characterized by the association of anosmia or hyposmia and GnRH deficiency resulting in congenital hypogonadotropic hypogonadism (CHH). Different genes can be implicated in KS, and the most frequent allelic variant occurs in the KAL1/ANOS1 gene in the X-linked form. Differential diagnosis is often made with other rare genetic diseases as CHARGE syndrome (CS) that includes hypogonadism, hyposmia and several organ defects including eyes and heart defects. Here we report a clinical case of a patient with a clinical diagnosis of KS and in which a new genetic gene variant was found.

Methods: Patient history was collected through questionnaires and physical examination at our outpatient clinic. Blood sample for genetic evaluation of the patient was collected after obtaining informed consents. Gene variants were amplified and verified by Sanger direct sequencing after the next generation sequencing (NGS) of related genes.

Results: A 48-year-old male patient was referred to our endocrinology service for evaluation of hypogonadism. The medical history of patient started when he was 17-year-old. At that time patient was diagnosed with hypogonadism and anosmia wherefore placed on testosterone replacement therapy. No genetic tests had been conducted until our visit on suspicion of KS. Patient had no other further suspected signs or symptoms of genetic disease or CS. NGS sequencing revealed the presence of two different gene allelic variants: a heterozygous variant in the region 8 q12.2 of the CHD gene (p.L2806V: c.84716C>G) and a hemizygous X-linked variant in the Xp22.31 region of the KAL1/ANOS1 gene (p.R46H: c.137G>A). This latest is a newly identified variant and has never been described so far. Laboratory examination confirmed hypogonadotropic hypogonadism without other pituitary hormonal alterations. Magnetic resonance imaging of the olfactory bulb and of the pituitary gland and the smell test have been requested and are ongoing.

Conclusion: Both KAL1/ANOS1 and CHD7 genes are known to be important causal gene in the development of KS. Differential diagnosis between KS and CS should be considered in patients with anosmia and hypogonadism. Until now p.R46H variant in KAL1/ANOS1 gene has never been reported, while p.L2806V variant was described in the literature to be associated with benign forms of CS with CHH/KS. A possible oligogenic form of KS might be considered in this specific case.

Keywords Kallmann syndrome; KAL1/ANOS1 mutations; CHD7 mutations; CHARGE syndrome; congenital hypogonadotropic hypogonadism; anosmia.