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Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism (IHH) and an oligogenic etiology has been suggested. However, the associated genes may account for only approximately 50% cases. In addition, a genomic systematic pedigree analysis is still lacking. Here, we conducted whole exome sequencing (WES) on 18 unrelated men affected by IHH and their corresponding parents. Notably, one reported and 10 novel variants in eight known IHH causative genes (AXL, CCDC141, CHD7, DMXL2, FGFR1, PNPLA6, POLR3A, and PROKR2), nine variants in nine recently reported candidate genes (DCAF17, DCC, EGF, IGSF10, NOTCH1, PDE3A, RELN, SLIT2, and TRAPPC9), and four variants in four novel candidate genes for IHH (CCDC88C, CDON, GADL1, and SPRED3) were identified in 77.8% (14/18) of IHH cases. Among them, eight (8/18, 44.4%) cases carried more than one variant in IHH-related genes, supporting the oligogenic model. Interestingly, we found that those variants tended to be maternally inherited (maternal with n = 17 vs paternal with n = 7; P = 0.028). Our further retrospective investigation of published reports replicated the maternal bias (maternal with n = 46 vs paternal with n = 28; P = 0.024). Our study extended a variant spectrum for IHH and provided the first evidence that women are probably more tolerant to variants of IHH-related genes than men.
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Objective@#To compare the efficiency of the target gene panel method and whole-exome sequencing (WES) in detecting idiopathic hypogonadotropic hypogonadism (IHH), and select a more suitable gene detection method.@*METHODS@#We selected 24 genes closely related to the molecular pathogenesis of IHH to make up the gene panel, detected the mutation sites in 73 patients with IHH using the panel method, and verified the results of sequencing with the Sanger method. Using the key words "idiopathic hypogonadotropic hypogonadism", we searched databases for relevant literature, calculated the positive rate of IHH detected by WES and compared it with that detected with the panel method.@*RESULTS@#Of the 73 cases of IHH detected with the panel method, 7 were found with pathogenic mutations, including 2 cases of FGFR1, 2 cases of CHD7, 2 cases of KISS1R, and 1 case of NR5A1 mutation. Sanger sequencing showed that the positive rate of the panel method was 9.7%. Of the 1 336 articles retrieved, 5 met the inclusion criteria and were included, in which WES revealed a positive rate of about 30%.@*CONCLUSIONS@#For detection of the diseases with clear mutated genes, the panel method is relatively inexpensive and has a high sequencing depth, while for detection of the diseases with complicated genetic patterns and unclear mutated genes, WES is more efficient. Further studies are needed for choice of the two methods for different purpose of detection./.
Subject(s)
Humans , Male , Hypogonadism/genetics , Exome SequencingABSTRACT
Idiopathic hypogonadotropic hypogonadism (IHH) is often caused by hyposecretion of gonadotropin and consequently affects male fertility. The patient with IHH has a smaller penis and testes with spermatogenic dysfunction. At present, IHH is treated mainly with hCG, hMG, GnRH, and their different combinations. However, due to the lack of large-sample evidence, it is not yet clear which therapy is the best option. This article presents an overview of our experience in the treatment of IHH in the last decade and a review of relevant literature, aiming at a deeper insight into this male disease.
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[Summary] Eighteen patients with idiopathic hypogonadotropic hypogonadism( IHH) receiving aromatase-inhibitor( AI) letrozole for at least 3 months were recruited.After 3 months′treatment, LH levels were increased from (2.1 ±1.5) IU/L to (3.6 ±3.7) IU/L(P=0.029), and FSH levels from (2.6 ±1.8) IU/L to (4.3 ±3.4) IU/L (P=0.003).Total testosterol was increased from (87 ±42) ng/dl to (166 ±200) ng/dl(P=0.082), and estradiol wasdecreasedfrom(22.7±18.7) pg/ml to (13.4±10.6) pg/ml(P=0.020).The average testis volume was increased[(14.3 ±3.9 vs 11.2 ±4.9) ml, P<0.01].Sperms were detected in 8 out of 9 patients who did seminal fluid test.The result of general linear model showed that LH(60 min) was significantly related with total testosterol increment( P=0.045) .
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From Aug 2014 to July 2015, researches in the field of gonadal diseases have achieved rapid advances with image technology, the technology of biochemistry, and molecular biotechnology progressing. Considerable literatures concerning the pathogenesis, gene and clinical diagnosis, and treatment of gonadal diseases have been published. We reviewed and analyzed some more instructive literatures for clinical practice, proposed some suggestions, and the work plans for the clinicians.
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Objective To study the NR5A1 gene mutation in patients with idiopathic hypogonadotropic hypogonadism(IHH), and to find the new mutation point.Methods Sixty-one IHH patients and 100 normal control subjects were collected and genomic DNA was extracted from blood samples.These patients were with normal karyotype and no abnormality was discovered in magnetic resonance imaging (MRI) scan of the pituitary.Other endocrine diseases were also excluded.The 2-7 exons and splice-sites of NR5A1 gene were amplified with polymerase chain reaction.DNA of the coding sequence and splice-sites of NR5A 1 were sequenced by double deoxidizing terminal end sequencing method in 61 IHH and 100 normal control subjects.The results of sequencing were compared with their corresponding sequence data.61 IHH kindreds were investigated and the clinical data of these patients were collected.Finally, the phenotype and genotype positive cases were analyzed.Results Six patients carried NR5A1 gene mutational sites in 61 cases of IHH.Analysis of sequencing results from 100 age and ethnicity matched control subjects did not show any of these novel changes.Conclusions One mutation in NR5A1 gene may affect protein structure and function, which should be considered in male IHH patients with normal karyotype and without insufficiency of adrenal function.
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PURPOSE: Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is classified as Kallmann syndrome (KS) with anosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). This study was undertaken to investigate the clinical, endocrinological, and molecular characteristics in Korean patients with KS and nIHH. METHODS: Twenty-six patients from 25 unrelated families were included. Their clinical, endocrinological, and radiological findings were analyzed retrospectively. Mutation analysis of the GNRH1, GNRHR, KISS1, KISS1R, PROK2, PROKR2, TAC3, TACR3, FGF8, FGFR1, and KAL1 genes was performed in all patients. CHD7 and SOX10 were analyzed in patients with CHARGE (Coloboma, Heart defects, choanae Atresia, Growth retardation, Genitourinary abnormality, Ear abnormality) features or deafness. RESULTS: Of the 26 patients, 16 had KS and 10 had nIHH. At diagnosis, mean chronologic age was 18.1 years in males and 18.0 years in females; height SDS were -0.67+/-1.35 in males, -1.12+/-1.86 in females; testis volume was 2.0+/-1.3 mL; and Tanner stage was 1.5. There were associated anomalies in some of the KS patients: hearing loss (n=6) and congenital heart disease (n=4). Absence or hypoplasia of the olfactory bulb/sulci was found in 84.62% of patients with KS. Molecular defects in KAL1, SOX10, and CHD7 were identified in 5 patients from 4 families (16.0%, 4/25 pedigrees). After sex hormone replacement therapy, there were improvement in sexual characteristics and the sexual function. CONCLUSION: This study described the clinical, endocrinological, and molecular genetic features in IGD patients in Korea. Although the mutation screening was performed in 10 genes that cause IGD, molecular defects were identified in relatively small proportions of the cohort.
Subject(s)
Female , Humans , Male , Cohort Studies , Deafness , Diagnosis , Ear , Gonadotropin-Releasing Hormone , Hearing Loss , Heart , Heart Defects, Congenital , Hormone Replacement Therapy , Hypogonadism , Immunoglobulin D , Kallmann Syndrome , Korea , Mass Screening , Molecular Biology , Nasopharynx , Olfaction Disorders , Retrospective Studies , Testis , Urogenital AbnormalitiesABSTRACT
Objective To evaluate the diagnostic value of triptorelin stimulation test in disorders due to delayed puberty.Methods Triptorelin stimulation test was carried out in 128 teenagers with delayed puberty,due to idiopathic hypogonadotropic hypogonadism(IHH) in 77 cases and constitutional delayed puberty(CDP) in 51.Blood samples were obtained 15 min before and 0,30,60,and 120 min after tripotorelin administration,and the levels of LH and FSH were determined.An extended GnRH stimulation test was carried out in 3 patients with IHH.Results Peak LH,peak FSH,and LH increment were parameters with high diagnostic value.A cut-off point at 8.2 IU/L of peak LH showed a sensitivity of 87％ and a specificity of 80.4％ in the differential diagnosis of IHH and CDP.Conclusion Peak LH cut-off point at 8.2 IU/L of triptorelin stimulation test seems to be sufficient to confirm diagnosis of IHH and CDP.An extended GnRH stimulation test may distinguish hypothalamic from the pituitary hypogonadotropic hypogonadism.
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Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by delayed or absent puberty and lowered sexual function as a result of impaired pulsatile gonadotropin-realeasing hormone (GnRH) secretion.Identification of TAC3/TACR3 mutations as the culprits of IHH revealed that neurokinin B (NKB) signaling pathway was involved in the regulation of pulsatile GnRH secretion.This review focuses on the involvement of NKB signaling in pulsatile GnRH release,the discovery of TAC3/TACR3 mutations and the phenotypes,and treatment of patients who carry TAC3 or/and TACR3 mutations.
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Idiopathic hypogonadotropic hypogonadism(IHH) is a complex oligogenic disease.About 60％ of patients are associated with anosmia or hyposmia,also known as Kallmann syndrome. Based on genetic and molecular biological research,about more than ten IHH responsible genes have been discovered.
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ObjectiveTo analyze the clinical features,diagnosis and treatment of male idiopathic hypogonadotropic hypogonadism (IHH).MethodsClinical data of 92 male IHH cases were analyzed retrospectively.ResultsThe mean age at evaluation was 21.0 ± 3.2 yrs,and 52 patients were diagnosed with Kallman syndrome (KS; IHH with anosmia/hyposmia) while the remainder were normosmic IHH (nIHH).All had normal radiological imaging of the hypothalamic and pituitary areas.The level of serum LH,FSH and T was low,and the clinical parameters (development of secondary sexual characteristics,sexual function,and serum testosterone levels.) were significantly improved after hormone replacement therapy.ConclusionsDiagnosis and differential diagnosis of IHH can be clearly defined based on clinical features and laboratory results.Hormone replacement therapy is an effective treatment option.
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Clinical characteristics,including primary and secondary sexual characteristics,basal endocrine profiles,and imaging results were reviewed.Follow-up data were recorded.16 patients had normal karyotypes,manifest amastia,infantile genitalia,amenorrhea,and delayed epiphyseal fusion at the knee and wrist joints.Serum gonadotropic hormone levels were significantly below normal values.15 patients underwent a gonadotropin-releasing hormone (GnRH) stimulation test and 6 patients had a prolonged GnRH stimulation test.16 patients underwent pituitary or brain magnetic resonance imaging (MRI),which showed small pituitaries in three patients,wing tips of suspicious nodules in 2 patients,an empty sella turcica in 1 patient,and a missing right olfactory bulb and tract in 1 patient.1 patient had no detectable uterus or accessory organs,while the other patients had primordial uteri.1 patient was diagnosed as a case of severe osteoporosis.1 patient suffered from pituitary stalk interruption syndrome.An artificial menstrual cycle due to hormone replacement therapy was not sustained after discontinuation of hormone therapy.As disease severity and the date of initiating hormone replacement varied,the results of treatment were quite different.For patients of reproductive age,it was rare to see a reversal of idiopathic hypogonadotropic hypogonadism after discontinuation of hormone therapy.
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Puberty is an important developmental stage that leads to sexual maturation and reproductive capability. Genetic factors play a significant role in regulating the variation of pubertal timing. Recent genetic analysis are increasingly elucidating the genetic basis of disorders of pubertal timing such as hypogonadotropic hypogonadism and Kallmann syndrome. Ongoing studies are also investigating the genetic control of puberty in the general population, although no genetic loci have been reproducibly associated with pubertal timing thus far. This review summarizes an update of the genes implicated in disorders of puberty,discusses genes that may be involved in the timing of normal puberty.
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Isolated gonadotropin deficiency can be idiopathic or a part of X-linked Kallmann syndrome associated with anosmia. There have been several trials to reveal the genetic mutations that affect gonadotropin secretion, and approximately 10% of sporadic patients have mutations in either gonadotropin releasing hormone receptor (GnRHR) or KAL1 gene. Here we report one familial cases of idiopathic hypogonadotropic hypogonadism occurred in a boy and his elder sister. They presented with delayed puberty and hypoplastic gonads, but normal sense of smell. We performed GnRHR and KAL1 mutation analysis, but could not find any mutation.
Subject(s)
Humans , Male , Gonadotropins , Gonads , Hypogonadism , Kallmann Syndrome , Olfaction Disorders , Puberty, Delayed , Receptors, LHRH , Siblings , SmellABSTRACT
Objective To analyse the clinical characteristics of male hypogonadotropic hypogonadism.Methods Clinical data of 87 cases of male hypogonadotropic hypogonadism were retrospectively analyzed.Results Mean age was(18.8?4)years old,and 25 patients were diagnosed as Kallman syndrome.The level of serum LH,FSH,and T was low,and LH responded poorly to GnRH stimulation.Most patients' bone age was delayed,and all patients' CT or MRI of pituitary was normal.Conclusion According to the above clinical features,and testosterone replacement or hCG and/or plus hMG are the choice of treatment.
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Female sexual dysfunction is now of great concern and have a relatively high prevalence. It is related with psychosocial disorder, organic disease and iatrogenic cause. But until recently, basic science and clinical study on it is limited and medical therapy stays in early experimental steps except conventional hormone replacement therapy. Hormonal based female sexual dysfunction can be caused by dysfunction of the hypothalamic-pituitary axis, surgical or medical castration, menopause and premature ovarian failure. We report two cases of female sexual dysfunction derived from hormonal deficiency. One case is about premature menopause induced and the other is about rare form of adult onset idiopathic hypogonadotropic hypogonadism.