HLA-Compatible Paternity in Two “Fertile Eunuchs” with Congenital Hypogonadotropic Hypogonadism and Anosmia (the Kallmann Syndrome)

Rogol, Alan D.; Mittal, Kamal K.; White, Beverly J.; McGinniss, Mary H.; Lieblich, Jeffrey M.; Rosen, Saul W.

doi:10.1210/jcem-51-2-275

Cited by 30 publications

(20 citation statements)

References 24 publications

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“…This was followed by a report of reversal and proven paternity in a fertile eunuch male (36). In the subsequent two decades, additional case reports emerged documenting reversals (37) including fertility/conception (38,39,40) and two series were published demonstrating pulsatile LH secretion in a subset of CHH men following cessation of treatment (41,42).…”

Section: Chh Reversibilitymentioning

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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Section: Chh Reversibilitymentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

Dwyer

Raivio

Pitteloud

2016

European Journal of Endocrinology

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“…In four, additional features of KS were described: neurosensorial hearing loss (nZ2), facial asymmetry (nZ2), thoracic asymmetry (nZ1), and palatine cleft (nZ1). Five patients had other family members with KS and one family presented a high rate of consanguinity (26). The diagnosis of KS in these patients was established between 15 and 31 years of age.…”

Section: Review Of the Literaturementioning

confidence: 99%

“…Both KAL1 and FGFR1 genotypes have been shown to underlie this same phenotypic variability (13,14,(20)(21)(22)(23). Interestingly, a few KS patients have been reported to sustain improved gonadal function, including fertility, after testosterone withdrawal, a variant known as reversible KS (24)(25)(26)(27)(28)(29)(30)(31). The only previous molecular study of a patient with reversible KS has shown a heterozygous FGFR1 mutation (32).…”

Section: Introductionmentioning

confidence: 99%

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

2007

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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

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“…The so-called reversible forms were identified nearly 30 years ago in several case reports (35)(36)(37)(38)(39)(40)(41), mainly in male patients with Kallmann's syndrome. 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).…”

Section: Clinical Presentationmentioning

confidence: 99%

“…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).…”

Section: Clinical Presentationmentioning

confidence: 99%

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

Brioude

Bouligand

Trabado

et al. 2010

European Journal of Endocrinology

102

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Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defective GNRH release, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmann's syndrome, a disorder in which CHH is related to abnormal GNRH neuron ontogenesis and is associated with anosmia or hyposmia.In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a nonendocrine disorder, other mutations affecting GNRH and/or gonadotropin secretion have been reported.Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affecting GNRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GNRH sensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmann's syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine.This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype-phenotype relationships.

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HLA-Compatible Paternity in Two “Fertile Eunuchs” with Congenital Hypogonadotropic Hypogonadism and Anosmia (the Kallmann Syndrome)

Cited by 30 publications

References 24 publications

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

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

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

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