Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism

Lc, Layman; Dp, Cohen; Jin, Mei; Xie, Jiancheng; Z, Li; Rh, Reindollar; Bolbolan, S; Dp, Bick; Rr, Sherins; Lw, Duck; Lc, Musgrove; Jc, Sellers; Jd, Neill

doi:10.1038/ng0198-14

Cited by 261 publications

(180 citation statements)

References 13 publications

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“…21 Causative genes for Kallmann syndrome include: KAL1 (ANOS1) in the X-linked form; FGFR1 (encoding fibroblast growth factor receptor 1), 17,18 FGF8, 19,119 CHD7, [23][24][25][26][27] HS6ST1 (encoding heparan-sulphate 6-O-sulphotransferase 1), 20 SOX10, 28,29 SEMA3A (encoding semaphorin-3A), [36][37][38] WDR11 (encoding WD repeat-containing protein 11) 34,35 and IL17RD (encoding interleukin-17 receptor D) 21 in the autosomal dominant form; and PROKR2 and/or PROK2, [30][31][32][33] and FEZF1 39 in the autosomal recessive form, even though it should be noted that most patients carrying mutations in PROKR2 or PROK2 carry these mutations in the heterozygous state. 120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropinreleasing hormone receptor), 122,123 GNRH1 (encoding gonadotropin-releasing hormone 1), 124,125 KISS1R, 41,42 KISS1, 40,126 TACR3 and TAC3. [48][49][50] Other genes such as FGFR1 or PROKR2 can be mutated in patients with either Kallmann syndrome or CHH (Table 1).…”

Section: Genetics Of Chhmentioning

confidence: 99%

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

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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Section: Genetics Of Chhmentioning

confidence: 99%

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

et al. 2015

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“…To date, more than two dozen genetic loci have been identified to underlie CHH (6). Mutations in genes such as GNRH1, GRNHR, KISS1 or KISS1R (7, 8,9,10,11,12,13,14) can impair the action (or secretion) of GnRH, resulting in normosmic CHH. In contrast, mutations in genes impacting the migration of GnRH neurons from the olfactory placode during development (ANOS1, SEMA3A, IL17RD, SOX10 and FEZF1) (15,16,17,18,19,20,21) result in KS.…”

Section: Pathophysiology and Genetics Of Chhmentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

Dwyer

Raivio

Pitteloud

2016

European Journal of Endocrinology

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Congenital hypogonadotropic hypogonadism (CHH) is characterized by lack of puberty and infertility. Traditionally, it has been considered a life-long condition yet cases of reversibility have been described wherein patients spontaneously recover function of the reproductive axis following treatment. Reversibility occurs in both male and female CHH cases and appears to be more common (~10-15%) than previously thought. These reversal patients span a range of GnRH deficiency from mild to severe and many reversal patients harbor mutations in genes underlying CHH. However, to date there are no clear factors for predicting reversible CHH. Importantly, recovery of reproductive axis function may not be permanent. Thus, CHH is not always life-long and the incidence of reversal warrants periodic treatment withdrawal with close monitoring and follow-up. Reversible CHH highlights the importance of environmental (epigenetic) factors such as sex steroid treatment on the reproductive axis in modifying the phenotype. This review provides an overview and an update on what is known about this phenomenon.

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“…Two reports (1,2) have recently added inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) to the list. Hereditary hypogonadotropic hypogonadism (HH) is genetically heterogeneous, and so far only some forms of X-linked recessive inheritance have been explained.…”

mentioning

confidence: 99%

“…As the response to exogenous GnRH is quite variable among patients with HH, it was tempting to postulate a GnRHR defect in some patients. Layman et al (2) have screened 46 unrelated patients with HH (32 males and 14 females) without anosmia and have identified two GnRHR gene mutations in one patient. As in the family presenting with HH reported by De Roux et al (1), the affected siblings are compound heterozygotes for GnRHR gene mutation.…”

mentioning

confidence: 99%