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    92 results match your criteria Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism

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    CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism.
    J Clin Endocrinol Metab 2017 Jan 23. Epub 2017 Jan 23.
    Cukurova University, Faculty of Medicine, Division of Pediatric Endocrinology, Adana, Turkey.
    Context: GnRH neurons originate outside the central nervous system in the olfactory placode and migrate into the CNS, becoming integral components of the hypothalamic-pituitary-gonadal axis. Failure of this migration can lead to Idiopathic Hypogonadotropic Hypogonadism (IHH)/Kallmann Syndrome (KS). We have previously shown that CCDC141 knockdown leads to impaired migration of GnRH neurons but not of olfactory receptor neurons. Read More

    The mystery of puberty initiation: genetics and epigenetics of idiopathic central precocious puberty (ICPP).
    J Endocrinol Invest 2017 Mar 1. Epub 2017 Mar 1.
    Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, Faculty of Medicine, National and Kapodistrian University of Athens, Medical School, "Aghia Sofia" Children's Hospital, Athens, Greece.
    Puberty is a major developmental stage. Damaging mutations, considered as "mistakes of nature", have contributed to the unraveling of the networks implicated in the normal initiation of puberty. Genes involved in the abnormal hypothalamic-pituitary-gonadal (HPG) axis development, in the normosmic idiopathic hypogonadotropic hypogonadism (nIHH), in the X-linked or autosomal forms of Kallmann syndrome and in precocious puberty have been identified (GNRH1, GNRHR, KISS1, GPR54, FGFR1, FGF8, PROK2, PROKR2, TAC3, TACR3, KAL1, PROK2, PROKR2, CHD7, LEP, LEPR, PC1, DAX1, SF-1, HESX-1, LHX3, PROP-1). Read More

    Sexuality and quality of life in congenital hypogonadisms.
    Gynecol Endocrinol 2016 Dec 4;32(12):947-950. Epub 2016 Nov 4.
    b Clinic Institute of Gynecology, Obstetrics and Neonatology, Hospital Clinic-Institut, d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona , Barcelona , Spain.
    Turner syndrome and idiopathic congenital hypogonadism including Kallmann syndrome are conditions associated to a large number of widely known comorbidities that need a medical support forever. One of the characteristics shared by both conditions is the lack of sexual development that influencing the sexuality functioning and quality of life of the affected women. Few studies have been conducted to assess these topics, but they need to be considered in the treatment to all women with hypogonadism. Read More

    A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis.
    PLoS Genet 2016 Mar 15;12(3):e1005907. Epub 2016 Mar 15.
    Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
    Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Read More

    Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome.
    Hum Mol Genet 2016 May 29;25(10):1912-1922. Epub 2016 Feb 29.
    Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA,
    Mutations in FGFR1 have recently been associated with Hartsfield syndrome, a clinically distinct syndromic form of holoprosencephaly (HPE) with ectrodactly, which frequently includes combinations of craniofacial, limb and brain abnormalities not typical for classical HPE. Unrelated clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. FGFR1 is a principal cause for these less severe diseases as well. Read More

    Clinical characteristics and follow-up of 5 young Chinese males with gonadotropin-releasing hormone deficiency caused by mutations in the KAL1 gene.
    Meta Gene 2016 Feb 3;7:64-9. Epub 2015 Dec 3.
    Department of Endocrinology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
    Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) pertains to a group of genetic disorders consisting of anosmic hypogonadotropic hypogonadism (Kallmann syndrome, KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). KS is genetically heterogeneous. We hereby present 5 young male patients with GnRH deficiency caused by mutations in the KAL1 gene. Read More

    Snapin interacts with G-protein coupled receptor PKR2.
    Biochem Biophys Res Commun 2016 Jan 11;469(3):501-6. Epub 2015 Dec 11.
    The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, China. Electronic address:
    Mutations in Prokineticin receptor 2 (PKR2), a G-protein-coupled receptor, have been identified in patients with Kallmann syndrome and/or idiopathic hypogonadotropic hypogonadism, characterized by delayed puberty and infertility. In this study, we performed yeast two-hybrid screening by using PKR2 C-terminus (amino acids 333-384) as a bait, and identified Snapin as a novel interaction partner for PKR2. The interaction of Snapin and PKR2 was confirmed in GST pull-down and co-immunoprecipitation studies. Read More

    Study on KAL1 Gene Mutations in Idiopathic Hypogonadotropic Hypogonadism Patients with X-Linked Recessive Inheritance.
    Int J Mol Cell Med 2015 ;4(3):152-9
    Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
    Idiopathic hypogonadotropic hypogonadism (IHH) is a condition caused by low doses of hypothalamic gonadotropin-releasing hormone (GnRH) leading to absence or incomplete sexual maturation. One of the disorders leading to IHH is Kallmann syndrome which is characterized by GnRH deficiency with anosmia or hyposmia. This disorder generally occurs as a hereditary syndrome with X-linked recessive inheritance pattern. Read More

    Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform.
    Fertil Steril 2015 Nov 12;104(5):1261-7.e1. Epub 2015 Aug 12.
    CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. Electronic address:
    Objective: To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH).

    Design: Cross-sectional study.

    Setting: Multicentric. Read More

    10q26.1 Microdeletion: Redefining the critical regions for microcephaly and genital anomalies.
    Am J Med Genet A 2015 Nov 26;167A(11):2707-13. Epub 2015 Jun 26.
    Unité de Génétique Médicale et Laboratoire Associé INSERM à l'Unité UMR_S 910, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon.
    Distal 10q deletion syndrome is a well-characterized chromosomal disorder consisting of neurodevelopmental impairment, facial dysmorphism, cardiac malformations, genital and urinary tract defects, as well as digital anomalies. Patients with interstitial deletions involving band 10q26.1 present a phenotype similar to the ones with the distal 10q deletion syndrome, which led to the definition of a causal 600 kb smallest region of overlap (SRO). Read More

    Mutation analyses in pedigrees and sporadic cases of ethnic Han Chinese Kallmann syndrome patients.
    Exp Biol Med (Maywood) 2015 Nov 1;240(11):1480-9. Epub 2015 Jun 1.
    Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China
    Kallmann syndrome, a form of idiopathic hypogonadotropic hypogonadism, is characterized by developmental abnormalities of the reproductive system and abnormal olfaction. Despite association of certain genes with idiopathic hypogonadotropic hypogonadism, the genetic inheritance and expression are complex and incompletely known. In the present study, seven Kallmann syndrome pedigrees in an ethnic Han Chinese population were screened for genetic mutations. Read More

    Pulsatile GnRH Is Superior to hCG in Therapeutic Efficacy in Adolescent Boys With Hypogonadotropic Hypogonadodism.
    J Clin Endocrinol Metab 2015 Jul 15;100(7):2793-9. Epub 2015 May 15.
    Departments of Endocrinology (C.G., M.Q., D.W.) and Pharmacy (Y.L., X.W.), Capital Medical University Affiliated Beijing Children Hospital, Beijing 100045, People's Republic of China.
    Context: We investigated the efficacy and safety of two different treatments that have not been evaluated in peripuberty boys with hypogonadotropic hypogonadism (HH).

    Objective: The objective of the study was to assess the effectiveness and safety of GnRH or human chorionic gonadotropin (hCG) treatment in adolescent boys with HH.

    Design: Twelve patients received 8-10 μg of GnRH, sc injected every 90 minutes using a pump. Read More

    Clinical, endocrinological, and molecular characterization of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: a single center experience.
    Ann Pediatr Endocrinol Metab 2015 Mar 31;20(1):27-33. Epub 2015 Mar 31.
    Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
    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. Read More

    [Children with idiopathic hypogonadotropic hypogonadism: clinical data analysis and mutations analysis of KAL1 and FGFR1 gene].
    Zhonghua Er Ke Za Zhi 2014 Dec;52(12):942-7
    Email:
    Objective: To summarize the clinical features of idiopathic hypogonadotropic hypogonadism (IHH) diagnosed during childhood, and detect mutations in KAL1 and FGFR1, acting as key clues for diagnoses.

    Method: We collected and analyzed clinical data of 21 cases (including demographic data, chief complaint, history of present illness, family history, physical examination, laboratory tests and imaging studies, etc.) diagnosed with IHH from December 2008 to February 2013. Read More

    A female patient with normosmic idiopathic hypogonadotropic hypogonadism carrying a novel mutation in FGFR1.
    Genet Mol Res 2014 Nov 11;13(4):9472-6. Epub 2014 Nov 11.
    Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China.
    Mutations in the fibroblast growth factor receptor 1 gene (FGFR1) have been reported in patients with Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). Here, we report an nIHH patient with a novel mutation in FGFR1. The patient was a 19-year-old female who presented the nIHH phenotype with primary amenorrhea, cleft lip and palate, mixed hearing disorders, and skeletal malformations. Read More

    Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes.
    Front Endocrinol (Lausanne) 2014 9;5:109. Epub 2014 Jul 9.
    Service of Endocrinology, CHU Liège, University of Liège , Liège , Belgium.
    The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. Read More

    Genetic diagnosis of idiopathic hypogonadotrophic hypogonadism: a new point mutation in the KAL2 gene.
    Hormones (Athens) 2014 Apr-Jun;13(2):280-5
    UGC Endocrinologίa y Nutriciόn, Complejo Hospitalario de Jan, Spain.
    Kallmann Syndrome (KS) is a genetic disease of embryonic development which is characterized by the association of hypogonadotropic hypogonadism (HH) due to a deficit of the gonadotropin-releasing hormone (GnRH) and a hypo/anosmia (including a hypoplasia of the nasal sulcus and agenesis of the olfactory bulbs). Even though it is a genotypically and phenotypically heterogeneous clinical disease, there are some key genes related to KS (KAL1, FGFR1 (KAL2), GNRHR, KISSR1 (GPR54), GNRH1, NELF and PROK2). The aim of this study was to present a case report of a genetic diagnosis of KS linked to the presence of mutations in the FGFR1 (fibroblast growth factor receptor 1, also known as KAL2) gene. Read More

    Functional rescue of Kallmann syndrome-associated prokineticin receptor 2 (PKR2) mutants deficient in trafficking.
    J Biol Chem 2014 May 21;289(22):15518-26. Epub 2014 Apr 21.
    From the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China, the Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, China, and
    Mutations in the G protein-coupled prokineticin receptor 2 (PKR2) are known to cause Kallmann syndrome and idiopathic hypogonadotropic hypogonadism manifesting with delayed puberty and infertility. Some of the mutant receptors are not routed to the cell surface; instead, they are trapped in the cellular secretory pathway. The cell-permeant agonists/antagonists have been used to rescue some membrane receptors that are not targeted onto the cell membrane. Read More

    Functional consequences of AXL sequence variants in hypogonadotropic hypogonadism.
    J Clin Endocrinol Metab 2014 Apr 29;99(4):1452-60. Epub 2014 Jan 29.
    Division of Endocrinology, Metabolism, and Diabetes (S.S.-M., M.X., A.J.K., M.E.W.), Division of Cardiology (D.S., M.T.), and Department of Biochemistry and Molecular Genetics (S.B., R.S.H.), University of Colorado School of Medicine, Aurora, Colorado 80045; Veterans Affairs Research Service (M.E.W.), Veterans Affairs Medical Center, Denver, Colorado 80220; and Harvard Reproductive Endocrine Science Center and the Reproductive Endocrine Unit (L.P., W.F.C.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.
    Context: Prior studies showed that Axl /Tyro3 null mice have delayed first estrus and abnormal cyclicity due to developmental defects in GnRH neuron migration and survival.

    Objective: The objective of the study was to test whether the absence of Axl would alter reproductive function in mice and that mutations in AXL are present in patients with Kallmann syndrome (KS) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).

    Design And Setting: The sexual maturation of Axl null mice was examined. Read More

    Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system.
    J Clin Endocrinol Metab 2014 Mar 1;99(3):861-70. Epub 2013 Jan 1.
    Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit (V.F.S., Y.-M.C., M.F.L., R.B., L.P., A.D., N.P., F.J.H., J.E.H., K.A.M., P.A.B., S.B.S.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology (Y.-M.C.), Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115; and Department of Endocrinology (R.Q.), Institute for Human Genetics, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne NE1 3BZ, United Kingdom.
    Context: A subset of patients diagnosed with idiopathic hypogonadotropic hypogonadism (IHH) later achieves activation of their hypothalamic-pituitary-gonadal axis with normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal.

    Objective: The objective of this study was to determine the natural history of reversal and to identify associated phenotypes and genotypes.

    Design, Setting, And Subjects: This was a retrospective review of clinical, biochemical, and genetic features of patients with IHH evaluated at an academic medical center. Read More

    [Multiplex ligation dependent probe amplification analysis of KAL1, GNRH1, GNRHR, PROK2 and PROKR2 in male patients with idiopathic hypogonadotropic hypogonadism].
    Endokrynol Pol 2013 ;64(4):285-92
    Departments of Endocrinology and Metabolism, Gulhane School of Medicine, Ankara, Turkey.
    Introduction: The purpose of this study was to determine the prevalence of KAL1, GNRH1, GNRHR, PROK2, and PROKR2 copy numbervariations in patients with idiopathic hypogonadotropic hypogonadism (IHH).

    Material And Methods: 86 hypogonadal males (76 diagnosed with normosmic idiopathic hypogonadotropic hypogonadism [nIHH] andten with Kallmann syndrome [KS]) and 95 healthy control individuals were studied for the presence of aforementioned genomic rearrangements,using multiplex ligation dependent probe amplification (MLPA).

    Results: We detected that of the 86 patients, three with KS had a deletion of the KAL1 gene in exon 9, one of whom also carried a duplicationin exon 11; and three with nIHH had a duplication of the PROK2 gene in exon 3; a deletion of the GNRHR gene in exon 1; anda duplication of the same gene in exon 2, respectively. Read More

    Functional analysis of the distal region of the third intracellular loop of PROKR2.
    Biochem Biophys Res Commun 2013 Sep 19;439(1):12-7. Epub 2013 Aug 19.
    Xiangya Hospital, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan Province 410078, PR China; Department of Immunology, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830054, PR China.
    Mutations in the G-protein-coupled receptor PROKR2 have been identified in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) manifesting with delayed puberty and infertility. Recently, the homozygous mutation V274D was identified in a man displaying KS with an apparent reversal of hypogonadism. The affected amino acid, valine 274, is located at the junction region of the third intracellular loop (IL3) and the sixth transmembrane domain (TM6). Read More

    Hypogonadotropic hypogonadism associated with hereditary hemorrhagic telangiectasia [corrected].
    Case Rep Endocrinol 2013 4;2013:465376. Epub 2013 Apr 4.
    Neurology Unit, "S. Maria del Pozzo" Hospital, Somma Vesuviana, 80049 Naples, Italy.
    A 65-year-old man was referred to our clinic for the rehabilitation of right hemiparesis caused by ischaemic stroke. Hypertension, postphlebitic syndrome of lower limbs, frequent nose bleeding, and anemia were present in his history; in his adolescence, he was treated for idiopathic hypogonadotropic hypogonadism. Further investigations have revealed also microsomia, suggesting a clinical diagnosis of Kallmann syndrome, that is, an association, possible in males and females, of hypogonadotropic hypogonadism with olfactory deficits. Read More

    Normosmic idiopathic hypogonadotropic hypogonadism: update on the genetic background and future challenges.
    J Pediatr Endocrinol Metab 2013 ;26(5-6):405-15
    Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
    Purpose Of Review: What controls puberty remains largely unknown, and current gene mutations account for only about one-third of the apparently genetic cases of idiopathic hypogonadotropic hypogonadism. Lately, important developments have occurred in this field.

    Recent Findings: The neuroendocrine control of reproduction in all mammals is governed by a hypothalamic neural network of approximately 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that control the activity of the reproductive axis across life. Read More

    Hypogonadotropic hypogonadism revisited.
    Clinics (Sao Paulo) 2013 ;68 Suppl 1:81-8
    Division of Urology, Department of Surgery, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
    Impaired testicular function, i.e., hypogonadism, can result from a primary testicular disorder (hypergonadotropic) or occur secondary to hypothalamic-pituitary dysfunction (hypogonadotropic). Read More

    An objective olfactory evaluation and its correlation with magnetic resonance imaging findings in Asian Indian patients with idiopathic hypogonadotropic hypogonadism.
    Endocr Pract 2013 Jul-Aug;19(4):669-74
    Department of Endocrinology, Seth GS Medical College, Maharashtra, India.
    Objective: Idiopathic hypogonadotropic hypogonadism (IHH) can be associated with subnormal sense of smell. The objective of our study was to determine if there is a correlation between the olfactory phenotype (clinical smell test) of IHH patients and structural abnormalities in the olfactory apparatus on magnetic resonance imaging (MRI).

    Methods: This was a single-center prospective case control study. Read More

    Identification of HESX1 mutations in Kallmann syndrome.
    Fertil Steril 2013 Jun 1;99(7):1831-7. Epub 2013 Mar 1.
    Department of Obstetrics and Gynecology, Section of Reproductive Endocrinology, Infertility, and Genetics, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
    Objective: To determine whether HESX1 mutations are present in patients with idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS).

    Design: Polymerase chain reaction-based DNA sequencing was performed on 217 well-characterized IHH/KS patients. Putative missense mutations were analyzed by sorting intolerant from tolerant (SIFT) and Clustal Ω. Read More

    Clinical features and testicular morphology in patients with Kallmann syndrome.
    Urology 2012 Mar 14;79(3):684-6. Epub 2011 Dec 14.
    Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
    Kallmann syndrome (KS) is a genetic disorder characterized by the simultaneous occurrence of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. Here, we present 3 cases of KS with detailed description. In Case 1, testicular morphology was examined by testicular biopsy, and Leydig cells were examined by immunohistochemistry using antibodies against Ad4BP/SF1. Read More

    New understandings of the genetic basis of isolated idiopathic central hypogonadism.
    Asian J Androl 2012 Jan 5;14(1):49-56. Epub 2011 Dec 5.
    Division of Endocrinology and Metabolism, Istituto Auxologico Italiano IRCCS, Milan, Italy.
    Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Read More

    Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications.
    J Clin Endocrinol Metab 2012 Jan 9;97(1):E136-44. Epub 2011 Nov 9.
    Harvard Reproductive Endocrine Sciences Center, Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Bartlett Hall Extension, 5th Floor, 55 Fruit Street, Boston, Massachusetts 02114, USA.
    Context: The olfactory phenotype in patients with idiopathic hypogonadotropic hypogonadism (IHH) ranges from complete anosmia (Kallmann syndrome) to normosmia (normosmic IHH). However, the true prevalence of intermediary olfactory phenotypes (hyposmia) in IHH patients has not yet been assessed, and systematic correlations with anatomical and genetic abnormalities have not been reported.

    Objective: The objective of this study was to evaluate olfactory function in a large IHH cohort and correlate these findings with olfactory magnetic resonance imaging (MRI) and underlying genetic etiology. Read More

    The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome.
    Fertil Steril 2011 Dec 28;96(6):1424-1430.e6. Epub 2011 Oct 28.
    Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Institute of Molecular Medicine and Genetics, Neuroscience Program, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
    Objective: To determine the prevalence of digenic mutations in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS).

    Design: Molecular analysis of DNA in IHH/KS patients.

    Setting: Academic medical center. Read More

    Application of hormonal treatment in hypogonadotropic hypogonadism: more than ten years experience.
    Int Urol Nephrol 2012 Apr 12;44(2):393-9. Epub 2011 Oct 12.
    Department of Urology, West China Hospital of Sichuan University, 37#Guoxuexiang street, Chengdu 610041, Sichuan, China.
    Objective: To demonstrate the efficacy of hormone treatment on the patients with hypogonadotropic hypogonadism (HH), we summarized our more than 10 years experience.

    Materials And Methods: A total of 242 male patients (age range 15-52 years old) with HH including two Kallmann syndrome treated at the andrology outpatient clinics of university hospital in the past 10 years were reviewed retrospectively. The patients were divided into three groups based on the different treatment strategy. Read More

    The role of CHD7 and the newly identified WDR11 gene in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.
    Mol Cell Endocrinol 2011 Oct 2;346(1-2):74-83. Epub 2011 Aug 2.
    Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Georgia Health Sciences University, Augusta, GA 30912, United States.
    Mutations in the chromodomain helicase DNA binding protein-7 (CHD7) cause CHARGE syndrome, which includes eye coloboma, heart malformations, atresia of the choanae, retardation of growth/development, genital anomalies, and ear abnormalities. CHARGE syndrome is usually sporadic, but is also autosomal dominant. CHD7 encodes a large protein that participates in chromatin remodeling and transcription. Read More

    G protein-coupled receptors involved in GnRH regulation: molecular insights from human disease.
    Mol Cell Endocrinol 2011 Oct 29;346(1-2):91-101. Epub 2011 Jun 29.
    Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
    In the past two decades, an increasing body of evidence has demonstrated that several G protein-coupled receptor (GPCR)-ligand pairs are critical for normal human reproductive development and function. Patients harboring genetic insults in either the receptors or their cognate ligands have presented with reproductive disorders characterized by varying degrees of GnRH deficiency. These disorders include idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann Syndrome (KS). Read More

    Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.
    Proc Natl Acad Sci U S A 2011 Jul 23;108(28):11524-9. Epub 2011 Jun 23.
    Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
    Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. Read More

    Role of fibroblast growth factor (FGF) signaling in the neuroendocrine control of human reproduction.
    Mol Cell Endocrinol 2011 Oct 1;346(1-2):37-43. Epub 2011 Jun 1.
    Centre Hospitalier Universitaire Vaudois, Endocrine, Diabetes, & Metabolism Service, BH 19-701, Rue du Bugnon 46, 1011 Lausanne, Switzerland.
    Fibroblast growth factor (FGF) signaling is critical for a broad range of developmental processes. In 2003, Fibroblast growth factor receptor 1 (FGFR1) was discovered as a novel locus causing both forms of isolate GnRH Deficiency, Kallmann syndrome [KS with anosmia] and normosmic idiopathic hypogonadotropic hypogonadism [nIHH] eventually accounting for approximately 10% of gonadotropin-releasing hormone (GnRH) deficiency cases. Such cases are characterized by a broad spectrum of reproductive phenotypes from severe congenital forms of GnRH deficiency to reversal of HH. Read More

    Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory.
    Trends Endocrinol Metab 2011 Jul 20;22(7):249-58. Epub 2011 Apr 20.
    Endocrine Research Group, Institute for Genetic Medicine, University of Newcastle-upon-Tyne, UK.
    Idiopathic hypogonadotropic hypogonadism (IHH) is defined by absent or incomplete puberty and characterised biochemically by low levels of sex steroids, with low or inappropriately normal gonadotropin hormones. IHH is frequently accompanied by non-reproductive abnormalities, most commonly anosmia, which is present in 50-60% of cases and defines Kallmann syndrome. The understanding of IHH has undergone rapid evolution, both in respect of genetics and breadth of phenotype. Read More

    Disease-causing mutation in PKR2 receptor reveals a critical role of positive charges in the second intracellular loop for G-protein coupling and receptor trafficking.
    J Biol Chem 2011 May 16;286(19):16615-22. Epub 2011 Mar 16.
    State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.
    Prokineticins are a pair of signal factors involved in many physiological processes by binding to two closely related G-protein-coupled receptors, PKR1 and PKR2. Recently, mutations in prokineticin 2 (PK2) and PKR2 are found to be associated with Kallmann syndrome and/or idiopathic hypogonadotropic hypogonadism, disorders characterized by delayed puberty and infertility. However, little is known how PKRs interact and activate G-proteins to elicit signal transduction. Read More

    [Mutation of the KAL1 gene in 30 male patients with idiopathic hypogonadotropic hypogonadism].
    Zhonghua Nan Ke Xue 2011 Jan;17(1):32-7
    Center of Reproductive Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
    Objective: To analyze the mutation of the KAL1 gene in male patients with idiopathic hypogonadotropic hypogonadism (IHH).

    Methods: We analyzed the exon mutation of the KAL1 gene in 30 IHH patients using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) combined with the PCR product direct sequencing technique.

    Results: Three cases of the KAL1 gene mutation were found among the total number of patients, including 1 case of nonsense mutation (c. Read More

    Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome.
    Fertil Steril 2011 Apr 15;95(5):1613-20.e1-7. Epub 2011 Feb 15.
    Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia 30912, USA.
    Objective: To determine if mutations in NELF, a gene isolated from migratory GnRH neurons, cause normosmic idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS).

    Design: Molecular analysis correlated with phenotype.

    Setting: Academic medical center. Read More

    A genetic basis for functional hypothalamic amenorrhea.
    N Engl J Med 2011 Jan;364(3):215-25
    Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit and the Department of Medicine, Massachusetts General Hospital, Boston, USA.
    Background: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. Read More

    Clinical assessment and genomic landscape of a consanguineous family with three Kallmann syndrome descendants.
    Asian J Androl 2011 Jan 1;13(1):166-71. Epub 2010 Nov 1.
    Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
    Although some genes that cause Kallmann syndrome (KS) have been identified by traditional linkage analysis and candidate gene techniques, the syndrome's molecular etiology in the majority of patients remains poorly understood. In this paper, we present the clinical assessments of a consanguineous Han Chinese family with three KS descendants. To understand the molecular etiology of KS from a genome-wide perspective, we investigated the genome-wide profile of structural variation in this family using the Affymetrix Genome-Wide Human SNP Array 6. Read More

    Clues to an early diagnosis of Kallmann syndrome.
    Am J Med Genet A 2010 Nov;152A(11):2796-801
    Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
    Kallmann syndrome (KS) is defined by the association of idiopathic hypogonadotropic hypogonadism and anosmia/hyposmia. Diagnosis is frequently delayed, however, because hypogonadotropic hypogonadism is usually not apparent until puberty and individuals with anosmia/hyposmia are often unaware of this sensory deficit. Mutations in at least six genes have been associated with KS; however, the sensitivity of molecular testing is only about 30% and, therefore, the diagnosis is largely based on clinical findings. Read More

    WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.
    Am J Hum Genet 2010 Oct;87(4):465-79
    Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia, 1120 15th Street, Augusta, Georgia 30912, USA.
    By defining the chromosomal breakpoint of a balanced t(10;12) translocation from a subject with Kallmann syndrome and scanning genes in its vicinity in unrelated hypogonadal subjects, we have identified WDR11 as a gene involved in human puberty. We found six patients with a total of five different heterozygous WDR11 missense mutations, including three alterations (A435T, R448Q, and H690Q) in WD domains important for β propeller formation and protein-protein interaction. In addition, we discovered that WDR11 interacts with EMX1, a homeodomain transcription factor involved in the development of olfactory neurons, and that missense alterations reduce or abolish this interaction. Read More

    Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons.
    Neuroendocrinology 2010 7;92(2):81-99. Epub 2010 Jul 7.
    Harvard Reproductive Endocrine Sciences Center of Excellence, Reproductive Endocrine Unit of the Department of Medicine of the Massachusetts General Hospital and Endocrine Division of the Brigham and Women's Hospital, Boston, MA 02114, USA.
    Evolutionary survival of a species is largely a function of its reproductive fitness. In mammals, a sparsely populated and widely dispersed network of hypothalamic neurons, the gonadotropin-releasing hormone (GnRH) neurons, serve as the pilot light of reproduction via coordinated secretion of GnRH. Since it first description, human GnRH deficiency has been recognized both clinically and genetically as a heterogeneous disease. Read More

    Compound deficiencies in multiple fibroblast growth factor signalling components differentially impact the murine gonadotrophin-releasing hormone system.
    J Neuroendocrinol 2010 Aug 9;22(8):944-50. Epub 2010 Jun 9.
    Department of Integrative Physiology and Center for Neuroscience, University of Colorado, Boulder, CO 80309-0354, USA.
    Gonadotrophin-releasing hormone (GnRH) neurones control the onset and maintenance of fertility. Aberrant development of the GnRH system underlies infertility in Kallmann syndrome [KS; idiopathic hypogonadotropic hypogonadism (IHH) and anosmia]. Some KS patients harbour mutations in the fibroblast growth factor receptor 1 (Fgfr1) and Fgf8 genes. Read More

    Molecular causes of hypogonadotropic hypogonadism.
    Curr Opin Obstet Gynecol 2010 Aug;22(4):264-70
    Department of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, Balcali, Adana 01330, Turkey.
    Purpose Of Review: What controls puberty remains largely unknown and current gene mutations account for only about one-third of the apparently genetic cases of idiopathic hypogonadotropic hypogonadism. Lately important developments have occurred in this field.

    Recent Findings: Substantial variation in clinical expression, from complete anosmia and hypogonadotropic hypogonadism to delayed puberty and normosmia, of the same Kallmann syndrome gene defects including in newer ones (FGF8 and CHD7) continues to be repeatedly observed. Read More

    Complex genetics in idiopathic hypogonadotropic hypogonadism.
    Front Horm Res 2010 8;39:142-53. Epub 2010 Apr 8.
    Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Mass. 02114, USA.
    Idiopathic hypogonadotropic hypogonadism (IHH) is an important human disease model. Investigations of the genetics of IHH have facilitated insights into critical pathways regulating sexual maturation and fertility. IHH has been traditionally considered a monogenic disorder. Read More

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