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 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 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 SUN-032 Digenic Inheritance of PCSK1 and CHD7 Mutations in PAX4 Homozygous Diabetic Male with Normosmic Hypogonadotropic Hypogonadism

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yun Kyung Cho ◽  
Sang-Wook Kim
Keyword(s):  
Next Generation Sequencing ◽  
Hypogonadotropic Hypogonadism ◽  
Missense Mutations ◽  
Next Generation ◽  
Wild Type ◽  
Hypogonadotrophic Hypogonadism ◽  
Digenic Inheritance ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Chd7 Gene ◽  
Generation Sequencing

Abstract Background: Normosmic congenital hypogonadotropic hypogonadism denotes Kallmann syndrome not associated with anosmia or hyposmia. Over the past few years, the availability of next-generation sequencing has started to unravel the complex molecular basis of congenital hypogonadotrophic hypogonadism including digenic or oligogenic pathogenecity in addition to classic monogenic causality (1). Clinical Case: A 22-year-old male patient was referred to the endocrine clinic in 2018 with recent -onset hyperglycemia. His weight was 82.2 kg with a height of 180 cm (BMI of 25.3 kg/m2). Physical examination revealed small testes, micropenis, and no axillary and pubic terminal hair. His smell sense was intact. His hormonal test reveals low testosterone (0.10 ng/mL) and low free testosterone (0.65 pg/mL) levels with inappropriately low gonadotrophins levels. Secretion of LH and FSH increased 2-fold after GnRH stimulation. His bone age was 13-years 6-months old, and brain magnetic resonance imaging showed the presence of olfactory bulbs, and unremarkable findings except for small size of the pituitary gland. There were no signs associated with CHARGE syndrome (coloboma ocular, heart defects, atresia or stenosis of the choanae, retardation of growth and/or development, genitourinary anomalies, and ear abnormalities). Biochemical investigation demonstrated high serum glucose level and high HbA1c (13.8%). To identify variants to cause the phenotype of the proband, we adopted trio-based whole exome sequencing (WES) and candidate gene approach. Candidate genes was listed from the orphanet (https://www.orpha.net). WES of the proband revealed the presence of heterozygote missense mutations of the CHD7 gene (c.6107C>T, p.Pro2036Leu, rs369543203) and PCSK1 gene (c.239G>A, p.Arg80Gln, rs1799904). The missense variants were predicted to have a damaging effect on the encoded protein, by SIFT and PolyPhen-2 analyses. Genetic analyses of his family revealed that his father had the same heterozygote missense mutations of the CHD7 gene, but wild type of PCSK1. Proband’s mother had the same heterozygote missense mutations of PCSK1, but wild type of CHD7. Furthermore, the proband had homozygote missense mutation of PAX4 (c.575G>A, p.Arg192His, rs2233580) known as maturity-onset diabetes of the young (MODY) 9 gene. Both parents have the same but heterozygous mutation of PAX4 p.Arg192His, and pre-diabetic range of hyperglycemia. Conclusion: This is the first case demonstrating digenic inheritance of mutations in PCSK1 and CHD7 as a potential cause of normosmic hypogonadotrophic hypogonadism, interestingly in PAX4 homozygous diabetic male. Reference: (1) Maione L, et al. Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol. 2018;178(3):R55-R80.

scholarly journals SP174, NRAS Q61R Mutant-Specific Antibody, Cross-Reacts With KRAS Q61R Mutant Protein in Colorectal Carcinoma

2017 ◽  
Vol 141 (4) ◽  
pp. 564-568 ◽  
Author(s):  
Jerzy Lasota ◽  
Artur Kowalik ◽  
Anna Felisiak-Golabek ◽  
Shingo Inaguma ◽  
Zeng-Feng Wang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Next Generation Sequencing ◽  
Sanger Sequencing ◽  
Molecular Genetic ◽  
Mutant Protein ◽  
Colorectal Carcinomas ◽  
Molecular Genetic Testing ◽  
Next Generation ◽  
Wild Type ◽  
Generation Sequencing

Context.— NRAS is a member of the RAS family oncoproteins implicated in cancer. Gain-of-function NRAS mutations were reported in a subset of colorectal cancers. These mutations occur at codons 12, 13, and 61 and are detected by molecular genetic testing. Recently, an antibody (clone SP174) became available to immunohistochemically pinpoint NRAS Q61R mutant protein. In malignant melanoma, NRAS Q61R mutant–specific immunohistochemistry was shown to be a valuable supplement to traditional genetic testing. Objective.— To evaluate the significance of NRAS Q61R mutant–specific immunohistochemistry in a cohort of colorectal carcinomas. Design.— A total of 1185 colorectal carcinomas were immunohistochemically evaluated with SP174 antibody. NRAS Q61R mutant–specific immunohistochemistry was validated by molecular genetic testing including Sanger sequencing, quantitative polymerase chain reaction (qPCR), and next-generation sequencing. Results.— Twelve tumors showed strong SP174 immunoreactivity. Sanger sequencing detected an identical c.182A>G substitution, causing NRAS Q61R mutation at the protein level, only in 8 SP174-positive cases. These results were confirmed by qPCR study. Subsequently, NRAS wild-type tumors with strong SP174 staining were evaluated by next-generation sequencing and revealed KRAS c.182A>G substitutions predicted to cause KRAS Q61R mutation. Review of colorectal carcinomas with known KRAS and NRAS genotype revealed that none of 62 wild-type tumors or 47 mutants other than Q61R were SP174 positive. Conclusion.— SP174 immunohistochemistry allows sensitive detection of NRAS and KRAS Q61R mutants. However, molecular genetic testing is necessary to determine specifically which RAS gene is mutated.

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.

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