Reversible Kallmann syndrome: report of the first case with a KAL1 mutation and literature review

Abstract

Kallmann syndrome (KS) describes the association of isolated hypogonadotropic hypogonadism with hypo/anosmia. A few KS patients may reverse hypogonadism after testosterone withdrawal, a variant known as reversible KS. Herein, we describe the first mutation in KAL1 in a patient with reversible KS and review the literature. The proband was first seen at 22 years complaining of anosmia and lack of puberty. His brother had puberty at 30 years and a maternal granduncle had anosmia and delayed puberty. On physical examination, he was P 2 G 1 , testes were 3 ml and bone age was 14 years. During 20 years of irregular testosterone replacement, he developed secondary sexual characteristics and testicular enlargement. At the age of 41 years, after stopping testosterone replacement for 5 months, his testes were 15 ml, serum testosterone, LH, and FSH responses to GnRH were normal, and his wife was pregnant. The molecular study revealed a cytosine insertion in exon 2 of KAL1, generating a frameshift at codon 75 and a premature stop at codon 85. The expected gene product is a truncated peptide with 85 of the 610 amino acids present in the wild-type protein. Fourteen cases of reversible KS have been described but the genotype was only studied in a single case showing a heterozygous fibroblast growth factor receptor type 1 (FGFR1) mutation. Considering the low prevalence of mutations in KAL1 or FGFR1 in KS, it is possible that these genotypes are more prevalent in reversible KS than in other KS patients, but additional studies are necessary to confirm this hypothesis.European Journal of Endocrinology 156 285-290

Kallmann syndrome

“…7,10,13,14,17 In addition, apparent reversal of the hypogonadism after discontinuation of hormonal treatment has been reported in a few KS patients. 9,18,19 Finally, a variety of non-reproductive non-olfactory additional anomalies are present in only a fraction of KS patients. These disorders include involuntary upper limb mirror movements (bimanual synkinesis), 17,20 -22 abnormal eye movements, 21,23 congenital ptosis, 24,25 abnormal visual spatial attention, 26 hearing impairment, 5,6,8,27 -29 agenesis of the corpus callosum, 7,13 unilateral (occasionally bilateral) renal agenesis, 30 -32 cleft lip or palate, [5][6][7]33 agenesis of one or several teeth (hypodontia), 7,24,33,34 obesity 6,10 and other less documented anomalies (see reference 35 for review).…”

Factors affecting spermatogenesis upon gonadotropin‐replacement therapy: a meta‐analytic study

“…When considering also those studies which excluded patients with previous TRT, the outcome after gonadotropins was not improved with respect to the rest of the studies; however, the number of the available investigations was small, and data of studies excluding TRT were largely derived from one single survey, with relatively low baseline gonadotropin levels (Warne et al, 2009). It must also be underlined that genetic forms of HHG after treatment with either TRT or gonadotropins or GnRH, in a variable percentage of cases, revert the condition (Quinton et al, 1999;Pitteloud et al, 2005;Raivio et al, 2007a;Ribeiro et al, 2007). In particular, it has been recently reported, in a retrospective analysis of more than 300 HHG subjects, that reversal is achieved in 20% of cases after the discontinuation of therapy lasted for a mean time of 4.4 years (Sidhoum et al, 2014).…”

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

“…They were initially identified on clinical grounds, and were later characterized in detail, both clinically and hormonally, in a UK series published by Quinton et al in 1999 (42) and, more recently, by Raivio et al (43). Their existence was demonstrated in patients with mutations in KAL1, FGFR1, the GNRH receptor (GNRHR) gene, and PROKR2 (43)(44)(45)(46). These reversible forms are associated with very late activation of pulsatile gonadotropin secretion (42,43), pointing to late activation of the GNRH pulse generator and/or gonadotropic cells, allowing gonadotropin secretion to improve with time.…”

“…These reversible forms are associated with very late activation of pulsatile gonadotropin secretion (42,43), pointing to late activation of the GNRH pulse generator and/or gonadotropic cells, allowing gonadotropin secretion to improve with time. This clinical variant should be suspected if testicular volume increases in the absence of endocrine therapy or during testosterone administration (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46).…”