Homozygous mutation in the prokineticin-receptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: Case Report

Abstract

Prokineticin 2 (Prok2) or prokineticin-receptor2 (Prok-R2) gene mutations are associated with Kallmann syndrome (KS). We describe a new homozygous mutation of Prok-R2 gene in a man displaying KS with an apparent reversal of hypogonadism. The proband, offspring of consanguineous parents, presented at age 19 years with absent puberty, no sense of smell, low testosterone and gonadotrophin levels. Magnetic resonance imaging showed olfactory bulb absence. The patient achieved virilization and spermatogenesis with gonadotrophin administration. Two years after discontinuing hormonal therapy, he maintained moderate oligozoospermia and normal testosterone levels. Prok2 and Prok-R2 gene sequence analyses were performed. The proband had a homozygous mutation in Prok-R2 exon 2 that harbours the c.T820>A base substitution, causing the introduction of an aspartic acid in place of valine at position 274 (Val274Asp). His mother had the same mutation in heterozygous state. This report describes a novel homozygous mutation of Prok-R2 gene in a man with variant KS, underlying the role of Prok-R2 gene in the olfactory and reproductive system development in humans. Present findings indicate that markedly delayed activation of gonadotrophin secretion may occur in some KS cases with definite gene defects, and that oligozoospermia might result from a variant form of reversible hypogonadotrophic hypogonadism.

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…Of note, testosterone treatment will not induce gonadal maturation or fertility in these patients. 94,177 Importantly, increased testicular volume following testosterone treatment is an indicator of reversal 6,7,[179][180][181][182][183][184][185] and requires re-assessment of the HPG axis in the absence of testosterone replacement therapy. An estimated 10-20% of patients with CHH undergo spontaneous recovery of reproductive function, 6,7 and this includes patients with mutations in known CHH genes (Table 1).…”

Male infertility: Pathogenesis and clinical diagnosis

“…It is also interesting to note, that in some cases of congenital HH, long term testosterone treatment has lead to spontaneous reversibility of reproductive function. 5,6 It is therefore plausible that in the future, the identification of mutations will have not only diagnostic but also prognostic value for the treatment options and responsiveness.…”

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

“…in those with a history of cryptorchidism and/or micropenis at birth (29,49,51). Moreover, some reversal patients lack olfactory structures (44,52) pointing to the possibility that recovery of GnRH neuronal function may not always be dependent on intact olfactory structures (53). Interestingly, hypothalamic progenitor cells in rat can give rise to GnRH neurons, suggesting that postnatal genesis of GnRH neurons can occur in certain circumstances (54).…”