A homozygous R262Q mutation in the gonadotropin‐releasing hormone receptor presenting as reversal of hypogonadotropic hypogonadism and late‐onset hypogonadism

Congenital hypogonadotropic hypogonadism (HH) is caused by the lack or deficient number of hypothalamic gonadotropinreleasing hormone (GnRH) neurons, disturbed secretion or action of GnRH, or both. Up to 10% of patients with congenital HH may recover, usually in their mid 20s. Relatively little is known about the factors that lead to the recovery of endogenous gonadotropin secretion in such reversal variants, but androgen exposure seems to play a role. Similarly, the duration of reversal may be variable, and the factors affecting the function of the hypothalamic-pituitary-gonadal axis in these patients are difficult to characterize and would require long clinical and biochemical follow-up. We describe a man who initially had presented with delayed puberty at the age of 16 years and was presumed to have permanent HH. He had received a short course of human chorionic gonadotropin, followed by testosterone (T) Rx until the age of 33 years, when he participated in a study requesting cessation of exogenous T. When off Rx, however, his average serum T (18 1 nM), LH (6 0 IU/l) and FSH (3 3 IU/l) together with testis size were all normal, as was his sperm count (52–75 million/ml after approximately 18 months without Rx). In retrospect, reversal of HH had probably occurred several years earlier, as his sperm count had been repeatedly normal from the age of 27 years (Table 1). He was without T for 28 years, but, at the age of 61 years, he asked for a new appointment because of erectile dysfunction. He had biochemical signs of HH (testosterone 4 7 nM, LH 2 4 IU/l, FSH 3 7 IU/l and inhibin B 115 ng/l), haematocrit 0 39 and normal TSH (1 57 mIU/l), prolactin (90 mIU/l), IGF-I (138 ng/ml), kidney and liver function tests and cortisol response (762 nM) to ACTH. Height was 179 cm (+0 1 SD), sitting height/standing height 0 51 and BMI 30 3 kg/m. Brain MRI showed small but symmetrical anterior pituitary and normal posterior pituitary. Mutation analysis revealed a homozygous mutation, c.785G>A (p.R262Q), in exon 3 of GNRHR gene encoding the GnRH receptor. The R262Q mutation is located in the third intracellular loop of the receptor and partially impairs downstream signalling. Reinstitution of T Rx increased his haematocrit, improved bone mineral density, resolved erectile dysfunction and restored libido. This proband displayed delayed puberty, as previously described in two brothers with a homozygous R262Q mutation. Later in life, one of these brothers had frank HH, and the other one had his T in the low-normal range. We recently described a man with an R262Q mutation in a compound heterozygous state (R139H/R262Q), reversal of HH and relapse at the age of 31 years. Similarly, the proband of the current study recovered from HH at typical age and presented in his sixties with a phenotype resembling adult-onset HH (aoHH). The molecular genetics of aoHH is largely unknown. One man with aoHH and a mutation in FGF8 has been described, but the very same mutation has subsequently been described in patients with holoprosencephaly (see the references therein). However, patients with aoHH have normal onset and progression of puberty, only in adulthood present with idiopathic HH. Therefore, the current proband cannot be easily classified into any known phenotypic subcategory of HH. The mechanism of his fascinating temporal phenotypic variation remains unclear. Because human GNRHR is a biallelically expressed gene and our proband had an identical mutation in both alleles, it seems unlikely that changes in the relative expression levels of the two alleles over time would explain such changes in his phenotype. Instead, it is possible that gonadotrophs or higher centre(s) responsible for coordinated GnRH secretion are sensitive to cues such as stress, psychological factors or nutritional/hormonal changes. Indeed, rare sequence variants in genes implicated in HH have been found in women with hypothalamic amenorrhoea, and a male patient with HH and a gonadotrophic axis that is prone to shutting down has been recently described. Against this background, it is tempting to hypothesize that some community-dwelling elderly men with late-onset hypogonadism (defined as serum testosterone <11 nM and free testosterone <220 pM accompanied by three sexual symptoms), and low-normal serum LH may harbour biallelic mutations in GNRHR. In practice, this case demonstrates the need for a life-long follow-up of patients with reversal of congenital HH.