Expanding the Phenotype and Genotype of Female GnRH Deficiency

Shaw, Natalie D.; Seminara, Stephanie B.; Welt, Corrine K.; Au, Margaret G.; Plummer, Lacey; Hughes, Virginia; Dwyer, Andrew A.; Martin, Kathryn A.; Quinton, Richard; Mericq, Verónica; Merino, Paulina M.; Gusella, James F.; Crowley, William F.; Pitteloud, Nelly; Hall, Janet E.

doi:10.1210/jc.2010-2292

Cited by 96 publications

(66 citation statements)

References 46 publications

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“…In either sex, CHH/KS is usually diagnosed in adolescents and young adults who present with arrested or absent puberty (1)(2)(3)(4). The hormonal diagnosis is based on a concomitantly low (or inappropriately normal) serum levels of both pituitary gonadotrophins and sex steroids (1)(2)(3)(4)23,24,25).…”

Section: Clinical Diagnosis Of Chh/ksmentioning

confidence: 99%

“…The hormonal diagnosis is based on a concomitantly low (or inappropriately normal) serum levels of both pituitary gonadotrophins and sex steroids (1)(2)(3)(4)23,24,25). The rare exception concerns mutations of the genes encoding follicle stimulating hormone (FSH) and luteinizing hormone (LH) beta subunits (described later).…”

Section: Clinical Diagnosis Of Chh/ksmentioning

confidence: 99%

“…One woman with KS was found to carry a rare KAL1/ANOS1 variant in a biallelic state that was predicted to be deleterious (4). The other nine had heterozygous variants and thhese sometimes coexisted with mutations of other genes linked to CHH/KS, pointing to possible oligogenism (see below).…”

Section: Kal1/anos1mentioning

confidence: 99%

“…Congenital hypogonadotropic hypogonadism (CHH, MIM 615267) with normal olfaction (normosmic CHH, or nCHH) or with altered odor perception (anosmia or hyposmia), a form known as Kallmann syndrome (KS, MIM 147950, 244200, 308700, 610628, 612370, 612702), are rare genetic diseases that prevent pubertal development in both males and females (1)(2)(3)(4). They are also responsible for infertility in both sexes (5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Maione

Dwyer

Francou

et al. 2018

European Journal of Endocrinology

127

158

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Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women.However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation.These are genetic diseases that can be transmitted to patients' offspring. Importantly patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex, oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing, and is increasingly being used in medical practice. Thus it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission but also its role in incomplete penetrance and variable expresivity in a perspective of genetic counseling.

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Section: Clinical Diagnosis Of Chh/ksmentioning

confidence: 99%

Section: Clinical Diagnosis Of Chh/ksmentioning

confidence: 99%

Section: Kal1/anos1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Maione

Dwyer

Francou

et al. 2018

European Journal of Endocrinology

127

158

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“…However, none of these tests assesses future reproductive endocrine potential, and these tests would all produce negative results in a child with normal pubertal timing if performed well before the onset of puberty. In addition, because currently available tests assess for hormonal signs of very early pubertal development, they are unable to distinguish between constitutional delay and IHH with partial pubertal development (15,16).…”

Section: Funding Nih Eunice Kennedy Shrivermentioning

confidence: 99%

Divergent responses to kisspeptin in children with delayed puberty

et al. 2018

Self Cite

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IntroductionThe neuropeptide kisspeptin sets the reproductive endocrine cascade in motion by stimulating the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus (1). GnRH stimulates secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland, and the gonadotropins in turn stimulate the release of sex steroids and other hormones from the gonads.The ability of kisspeptin to stimulate GnRH release allows it to be used as the first available probe of human GnRH neuronal activity. Our group and others have demonstrated that administering an intravenous bolus of kisspeptin to healthy men elicits an immediate pulse of LH secretion (2-4). Healthy women in the late follicular and luteal phases of the menstrual cycle similarly respond to kisspeptin with an LH pulse, though the response is attenuated in the early follicular phase (5-8).BACKGROUND. The neuropeptide kisspeptin stimulates luteinizing hormone (LH) secretion in healthy adults but not in adults with idiopathic hypogonadotropic hypogonadism. We hypothesized that, in children presenting with delayed or stalled puberty, kisspeptin would elicit LH secretion in those children found on detailed nighttime neuroendocrine profiling to have evidence of emerging reproductive endocrine function.

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The Genetic Architecture of Neurodevelopmental Disorders

Mitchell

2015

The Genetics of Neurodevelopmental Disorders

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Expanding the Phenotype and Genotype of Female GnRH Deficiency

Cited by 96 publications

References 46 publications

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Divergent responses to kisspeptin in children with delayed puberty

The Genetic Architecture of Neurodevelopmental Disorders

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