Endocrine Abstracts

Introduction: Congenital hypogonadotropic hypogonadism (CHH) is a rare disease. Mutations in various genes have been implicated in its pathophysiology, the most frequent being ANOS1, FGFR1 and GNRHR genes. FGFR1 is essential for cell proliferation, differentiation and migration during embryonic development and is involved in GnRH neuron development and maintenance. Klotho-beta protein (KLB) is expressed in the postnatal hypothalamus and is the co-receptor for FGF21 binding to his receptor FGFR1. Recent evidence suggests that FGF21/KLB/FGFR1 pathway is implicated in approximately 17% of CHH cases.

Case report: Male, 19 years old, diagnosed with hypogonadism at the age of 16 because of pubertal delay and anosmia. He had no history of testicular/head trauma. No family history of hypogonadism or congenital malformations. He was treated with testosterone with complete pubertal development and stopped for no apparent reason. He had normal libido and no erectile dysfunction. Physical examination: no congenital abnormalities, weight 69.9 Kg, height 180.5 cm, BMI 21.45 kg/m², arm-span 178 cm, waist-circumference 98 cm. Testicular volume: 12 ml(left) and 10 ml(right). He had secondary sexual characteristics and gynecomastia. No synkinesis. His total testosterone without treatment was <0.1 ng/ml, FSH 1.5 mUI/ml, LH 0.6 mUI/ml, TSH 1.33 uUI/ml, free T4 0.84 ng/dl, 8h 00 cortisol 10.01 ug/dl, prolactin 10.2ng/ml, IGF-1 357ng/ml, total cholesterol 201mg/dl, HDL-cholesterol 47 mg/dl, LDL-cholesterol 123mg/dl, triglycerides 150 mg/dl, insulin 23.4 µUI/ml, glucose 87 mg/dl, HbA1c 5.0%. Pituitary MRI: normal-sized gland, no sellar/parasellar masses and olfactory bulbs and tracts were present. Normal renal ultrasound. Karyotype: 46,X,inv (Y) (p11.2 q11.2). Genetic next-generation sequencing identified the variant NM_175737,3:c,2443A>G p.(Lys815Glu) in KLB gene and the variant NM_000406.2:c,937_947del p.(Phe313Metfs*3) in GNRHR gene, both in heterozygosity. He was diagnosed with congenital hypogonadotropic hypogonadism due to heterozygous mutations in KLB and GNHRHR genes and started on testosterone treatment.

Discussion: The mechanism involved in CHH caused by loss-of-function KLB mutations is not well understood, however it appears to be related to the inability of GnRH neurons to release GnRH in response to FGF21. The phenotypic spectrum is wide. Most patients have metabolic defects consistent with the metabolic role of the FGF21/KLB/FGFR1 pathway. This was present in our patient, who had hypercholesterolemia, insulin resistance and increased waist circumference. The KLB gene variant presented was described only once in literature, however, this is the first case ever associated with a GNRHR gene mutation. The GNRHR gene normally cause autosomal recessive CHH but the presence of a heterozygous GNRHR mutations in a patient with a KLB mutations might have act synergically in the pathogenesis and phenotype of this disease.