Endocrine Abstracts

Introduction

Hypogonadotropic hypogonadism (HH) is a rare disease. When associated with anosmia/hyposmia, it is called Kallmann syndrome (KS). Several mutations in different genes have been implicated in its pathophysiology, the most frequent being ANOS1/KAL1, FGFR1 and GNRHR genes. This heterogenicity can be explained by the increasing detection of more than one pathogenic variant in the genes responsible for causing the disease (oligogenism). The prevalence of this phenomenon is estimated to be 2.5–11.3%. Therefore, the classical paradigm of monogenic transmission of the disease has been challenged over the past years.

Case report

Male patient, 32 years old, referred to our endocrinology clinic because of decreased libido and erectile dysfunction. He had been diagnosed with hypogonadism at the age of 13 due to pubertal delay and anosmia. No history of testicular or head trauma. He was temporarily supplemented with testosterone. Past medical history included diabetes mellitus type 2, obesity and gastroesophageal reflux disease. Family history: hypogonadism in his brother and maternal cousin. In the physical examination: weight 98 kg, height 172 cm, arm-span 170 cm and body mass index 33 kg/m². Testicular volume of 10 ml with no masses or lesions. He had normal secondary sexual characteristics and no gynecomastia nor synkinesis. Blood results: total testosterone 0.5 ng/ml, free testosterone 0.84 pg/ml, LH 0.2mU/ml, FSH 0.6mU/ml, prolactin 3.5 ng/ml, TSH 1.56 µUI/ml, IGF-1 79.2 ng/ml, 60-minute cortisol (tetracosactide stimulation test) 34.7 µg/dl, HbA1c 7.8% and C-peptide 5.24 ng/ml. Renal ultrasound showed no genitourinary abnormalities. Pituitary MRI evidenced a small-sized gland, no sellar/parasellar masses and absence of olfactory bulbs and tracts. Bone densitometry showed no signs of osteoporosis. Genetic next generation sequencing identified the variant (Arg457Ter) in ANOS1 gene in hemizygosity and the variant (Gin106Arg) in GNRHR gene in heterozygosity. He was diagnosed with KS due to the mutation of ANOS1 gene and was treated with testosterone, showing clinical and analytical improvement.

Discussion

This is the first case described of HH due to a hemizygotic mutation in ANOS1 gene and the additional presence of a mutation in GNRHR gene, which is usually associated with an autosomal recessive form of non-anosmic HH. It has been proposed that the presence of more than one heterozygous mutation of genes normally associated with an autosomal recessive disease can act synergically to the pathogeny. In this case, however, we cannot affirm that the GNRHR mutation contributed to the disease, since the ANOS1 mutation is usually sufficient to cause the disease in males.