Congenital hypogonadotropic hypogonadism and Kallmann syndrome as models for studying hormonal regulation of human testicular endocrine functions

2014 ◽  
Vol 75 (2) ◽  
pp. 79-87 ◽  
Author(s):  
Séverine Trabado ◽  
Sophie Lamothe ◽  
Luigi Maione ◽  
Claire Bouvattier ◽  
Julie Sarfati ◽  
...  
Keyword(s):  
Hormonal Regulation ◽  
Hypogonadotropic Hypogonadism ◽  
Kallmann Syndrome ◽  
Congenital Hypogonadotropic Hypogonadism

scholarly journals Sex Steroids, Precursors, and Metabolite Deficiencies in Men With Isolated Hypogonadotropic Hypogonadism and Panhypopituitarism: A GCMS-Based Comparative Study

2015 ◽  
Vol 100 (2) ◽  
pp. E292-E296 ◽  
Author(s):  
Frank Giton ◽  
Séverine Trabado ◽  
Luigi Maione ◽  
Julie Sarfati ◽  
Yves Le Bouc ◽  
...  
Keyword(s):  
Sex Steroids ◽  
Hypogonadotropic Hypogonadism ◽  
Serum Levels ◽  
Dehydroepiandrosterone Sulfate ◽  
Kallmann Syndrome ◽  
Gas Chromatography Mass Spectrometry ◽  
Adrenal Steroid ◽  
Estrone Sulfate ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
17 Hydroxyprogesterone

Abstract Context: Both testicular and adrenal steroid secretions are impaired in men with panhypopituitarism (Hypo-Pit), whereas only testicular steroid secretion is impaired in men with isolated gonadotropin deficiency (IHH) caused by normosmic congenital hypogonadotropic hypogonadism or Kallmann syndrome. Objective: The objective of the study was to compare the serum levels of sex steroids, precursors, and metabolites between men with complete IHH and those with Hypo-Pit. Patients: We studied 42 healthy men, 16 untreated men with IHH (normosmic congenital hypogonadotropic hypogonadism/Kallmann syndrome) and 23 men with Hypo-Pit (14 with craniopharyngioma, 9 with congenital hypopituitarism) receiving hydrocortisone, thyroxine, and GH replacement therapy but not T. Methods: Gas chromatography/mass spectrometry (GCMS) was used to measure the serum levels of sex steroids [T, dihydrotestosterone (DHT), and estradiol (E2)], their precursors (pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, androstenediol, progesterone, 17-hydroxyprogesterone, and androstenedione), and their metabolites (androsterone, estrone, and estrone sulfate) as well as pregnenolone and dehydroepiandrosterone sulfate esters. Results: All the above-mentioned steroids, and notably T, DHT, and E2, were significantly lower in IHH patients than in controls but remained well above the detection limit of the relevant assays. In Hypo-Pit men, all these steroids were dramatically and significantly lower than in IHH. Interestingly, T, DHT, and E2, as well as pregnenolone and dehydroepiandrosterone sulfate esters, were undetectable or barely detectable in the Hypo-Pit men. Conclusions: Steroid deficiencies are marked but partial in men with complete IHH. In contrast, men with Hypo-Pit have a very severe overall steroid deficiency. These deficiencies could affect health and quality of life.

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

2018 ◽  
Vol 178 (3) ◽  
pp. R55-R80 ◽  
Author(s):  
Luigi Maione ◽  
Andrew A Dwyer ◽  
Bruno Francou ◽  
Anne Guiochon-Mantel ◽  
Nadine Binart ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Next Generation Sequencing ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Kallmann Syndrome ◽  
Incomplete Penetrance ◽  
Next Generation ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Main Challenge ◽  
Generation Sequencing

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 and also its role in incomplete penetrance and variable expressivity in a perspective of genetic counseling.

scholarly journals Congenital hypogonadotropic hypogonadism/Kallmann syndrome is associated with statural gain in both men and women: a monocentric study

2020 ◽  
Vol 182 (2) ◽  
pp. 185 ◽  
Author(s):  
Luigi Maione ◽  
Giovanna Pala ◽  
Claire Bouvattier ◽  
Séverine Trabado ◽  
Georgios Papadakis ◽  
...  
Keyword(s):  
General Population ◽  
Hypogonadotropic Hypogonadism ◽  
Genetic Defect ◽  
Hormonal Treatment ◽  
Rare Condition ◽  
Kallmann Syndrome ◽  
Age At Diagnosis ◽  
Individual Growth ◽  
Men And Women ◽  
Congenital Hypogonadotropic Hypogonadism

Context Congenital hypogonadotropic hypogonadism/Kallmann syndrome (CHH/KS) is a rare condition characterized by gonadotropin deficiency and pubertal failure. Adult height (AH) in patients with CHH/KS has not been well studied. Objective To assess AH in a large cohort of patients with CHH/KS. Patients A total of 219 patients (165 males, 54 females). Parents and siblings were included. Methods AH was assessed in patients and family members. AH was compared to the general French population, mid parental target height (TH) and between patients and same-sex siblings. Delta height (∆H) was considered as the difference between AH and parental TH. ∆H was compared between patients and siblings, normosmic CHH and KS (CHH with anosmia/hyposmia), and according to underlying genetic defect. We examined the correlations between ∆H and age at diagnosis and therapeutically induced individual statural gain. Results Mean AH in men and women with CHH/KS was greater than that in the French general population. Patients of both sexes had AH > TH. Males with CHH/KS were significantly, albeit moderately, taller than their brothers. ∆H was higher in CHH/KS compared to unaffected siblings (+6.2 ± 7.2 cm vs +3.4 ± 5.2 cm, P < 0.0001). ∆H was positively correlated with age at diagnosis. Neither olfactory function (normosmic CHH vs KS) nor specific genetic cause impacted ∆H. Individual growth during replacement therapy inversely correlated with the age at initiation of hormonal treatment (P < 0.0001). Conclusions CHH/KS is associated with higher AH compared to the general population and mid-parental TH. Greater height in CHH/KS than siblings indicates that those differences are in part independent of an intergenerational effect.

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

1980 ◽  
Vol 51 (2) ◽  
pp. 275-279 ◽  
Author(s):  
ALAN D. ROGOL ◽  
KAMAL K. MITTAL ◽  
BEVERLY J. WHITE ◽  
MARY H. McGINNISS ◽  
JEFFREY M. LIEBLICH ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Kallmann Syndrome ◽  
Congenital Hypogonadotropic Hypogonadism

Molecular genetic and clinical delineation of 22 patients with congenital hypogonadotropic hypogonadism

2017 ◽  
Vol 30 (10) ◽  
Author(s):  
Kohei Aoyama ◽  
Haruo Mizuno ◽  
Tatsushi Tanaka ◽  
Takao Togawa ◽  
Yutaka Negishi ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Hypogonadotropic Hypogonadism ◽  
Molecular Genetic ◽  
Japanese Patients ◽  
Kallmann Syndrome ◽  
Next Generation ◽  
Genetic Causes ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Pathogenic Mutations

AbstractBackground:Congenital hypogonadotropic hypogonadism (CHH) is classified as Kallmann syndrome (KS) with anosmia/hyposmia or normosmic (n)CHH. Here, we investigated the genetic causes and phenotype-genotype correlations in Japanese patients with CHH.Methods:We enrolled 22 Japanese patients with CHH from 21 families (18 patients with KS and 4 with nCHH) and analyzed 27 genes implicated in CHH by next-generation and Sanger sequencing.Results:We detected 12 potentially pathogenic mutations in 11 families, with three having a mutation inConclusions:The frequency of CHH genes in the Japanese was compatible with previous reports, except that

scholarly journals Advances in Genetic Diagnosis of Kallmann Syndrome and Genetic Interruption

2021 ◽  
Author(s):  
Yujun Liu ◽  
Xu Zhi
Keyword(s):  
Prenatal Diagnosis ◽  
Genetic Testing ◽  
Early Stage ◽  
Hypogonadotropic Hypogonadism ◽  
Genetic Diagnosis ◽  
Kallmann Syndrome ◽  
Hereditary Diseases ◽  
Congenital Defects ◽  
Unilateral Renal Agenesis ◽  
Congenital Hypogonadotropic Hypogonadism

AbstractKallmann syndrome (KS) is a rare hereditary disease with high phenotypic and genetic heterogeneity. Congenital hypogonadotropic hypogonadism and hyposmia/anosmia are the two major characterized phenotypes of KS. Besides, mirror movements, dental agenesis, digital bone abnormalities, unilateral renal agenesis, midline facial defects, hearing loss, and eye movement abnormalities can also be observed in KS patients. Because of the phenotypic heterogeneity, genetic diagnosis become increasingly valuable to distinguish KS from other disorders including normosmic congenital hypogonadotropic hypogonadism, constitutional delay of growth and puberty, CHARGE syndrome, and functional hypogonadotropic hypogonadism. Application of next-generation sequencing has promoted the discovery of novel pathogenic genes in KS pedigrees. Prenatal diagnosis is an effective method in clinical settings to decrease birth defects and block transmission of genetic disorders. However, pregnant women may suffer from physical and psychological distress when fetuses are diagnosed with congenital defects. Preimplantation genetic testing (PGT) is a prospective approach during the in vitro fertilization process that helps to interrupt transmission of hereditary diseases to offspring at an early stage. Thus, genetic testing and counseling are recommended to KS patients with family histories, prenatal diagnosis and PGT are considered to be useful options.

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

2020 ◽  
Vol 111 (1-2) ◽  
pp. 99-114 ◽  
Author(s):  
Sara Barraud ◽  
Brigitte Delemer ◽  
Céline Poirsier-Violle ◽  
Jérôme Bouligand ◽  
Jean-Claude Mérol ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Messenger Rna ◽  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Family Members ◽  
Clinical Signs ◽  
Dominant Mode ◽  
Kallmann Syndrome ◽  
Heterozygous Mutation ◽  
Congenital Hypogonadotropic Hypogonadism

<b><i>Background:</i></b> Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. <b><i>Study Design, Size, Duration:</i></b> We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. <b><i>Participants/Materials, Methods:</i></b> Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. <b><i>Results:</i></b> The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G&#x3e; T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. <b><i>Conclusion:</i></b> This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

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