Male and female hypogonadotropic hypogonadism associated with two novel non sense heterozygous mutations of Klotho beta gene (KLB)

Clinical Case 1: A 15-year-old boy, with congenital deafness of the right ear, without olfaction disorders, consults for pubertal and growth retardation (1.59m, 47kg). Bone age of 14 years, GH: 6.4 ng/ml after ITT, LHRH-stimulateable gonadotropins, testosterone-total 99ng/dl (28-1110 ng/dl). Pituitary MRI is normal. His father and sister had late puberty around the age of 16. The patient treated with GH and Sustanon, reaches 1.77m and 79 kg. At the age of 16, suffering from MS, like his father. At 18 years, the gonadic balance is re-evaluated, normal (bilateral testicular volume: 14 ml).
Clinical case 2: A 30 years old woman (1.62m, 61 kg) consults for secondary amenorrhea and infertility after clomiphene stimulation. She is normal weighted. After some left hypoesthesic symptomatology, a brain neuro inflammatory pathology was suspected on MRI (several frontal hyper intense T2 lesions) without a precise diagnosis. No pituitary lesions were identified. During follow up, a normal pregnancy was obtained. She delivered a 3.3 kg girl in 2019 .
Genetic analysis: A panel of 61 genes of hypogonadotropic hypogonadism found in case 1 an heterozygous variant KLB c.3092T>A, p.(Leu1031*). This new variant (likely pathogenic, class IV), causes the appearance of a premature stop codon in exon 5 of the KLB gene. In case 2, a novel mutation c.2230_2231insGGTT, p.(Ala744Glyfs*45) was confirmed, causing a frame shift and stop codon (since codon Ala744)..
Discussion: We describe two novel non sense KLB mutations and for the first time, a reproductive phenotype in a female affected patient. In our series of 54 consecutive patients with congenital hypogonadotropic hypogonadism sequenced with a panel of 61 candidate genes, KLB mutations represents 3.7% . This prevalence is in line with the 4% finding of Xu. et al(EMBO Mol Med 2017). In the series of XU et al, patients with missense KLB mutations had (n= 9/13) a metabolic syndrome too, unlike our patients, carrying a nonsense mutation. In mice, the loss of the klb gene leads to delayed puberty, impaired estrogenic cycle, subfertility. The association with multiple sclerosis/brain inflammatory lesions is intriguing, so other family members will be studied.