Clinical and Hormonal Features of a Male Adolescent with Congenital Isolated Follicle-Stimulating Hormone Deficiency

Abstract

Aim: Our aim was to describe the clinical and genetic findings in an adolescent male with isolated follicle-stimulating hormone (FSH) deficiency and demonstrate the efficacy of recombinant human FSH (rhFSH) replacement in this case. Methods: A 14.5-year-old adolescent male was referred with normal pubertal development and small testes. Serum testosterone, FSH, and luteinising hormone (LH) were measured at baseline and after gonadotropin-releasing hormone (GnRH) stimulation. Testicular biopsy was performed, and rhFSH replacement was administered for 6 months. The patient's FSHβ gene was amplified and sequenced. Results: Basal and GnRH-stimulated FSH levels were undetectable, in contrast with increased LH levels under both conditions. Histopathological investigation of a testicular biopsy specimen revealed a reduced number of Sertoli cells, the absence of germ cells, Leydig cell hyperplasia, and a thickened basement membrane in seminiferous tubules. The testicular size changed from 1 ml at baseline to 6 ml after 6 months of rhFSH replacement. Sequencing of the FSHβ gene exon 3 revealed a new missense mutation (c.364T>C, resulting in p.Cys122Arg) in a homozygous state in the patient; both parents and a sister carried the same mutation in a heterozygous state. We also compared our case with all similar cases published previously. Conclusion: We herein described an adolescent male with isolated FSH deficiency due to a novel FSHβ gene mutation associated with a prepubertal testes size and normal virilisation.

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“…Regarding FSHB (61-66), a limited number of cases have also been described, with male or female hypogonadism. Except for a unique case with pubertal delay (62), the very rare male patients with FSHB mutations have normal puberty but are infertile with azoospermia and undetectable circulating FSH (63,64,66). Affected women have absent or partial puberty and primary amenorrhoea (61, 64,65).…”

“…Such a dissociation between the two gonadotropins is strongly evocative of this kind of diagnosis. In all the cases of hypogonadism caused by FSHB or LHB mutations so far described, the disease is transmitted in AR mode: affected patients have biallelic mutations (homozygotes or composite heterozygotes) and their parents, whether consanguineous or not, are healthy heterozygotes, and unaffected relatives are either mutation-free or heterozygous (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66).…”