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Table of Contents
Vol. 16, No. 2-3, 2008
Issue release date: February 2008
Section title: Paper
Neurosignals 2008;16:165–182
(DOI:10.1159/000111561)

Clinical Manifestations of Impaired GnRH Neuron Development and Function

Kim H.-G.a · Bhagavath B.b · Layman L.C.a
aSection of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Reproductive Medicine Program, Developmental Neurobiology Program, Institute of Molecular Medicine and Genetics, Neuroscience Program, Medical College of Georgia, Augusta, Ga., and bDivision of Reproductive Endocrinology and Infertility, Women and Infants’ Hospital of Rhode Island, Brown University, Providence, R.I., USA
email Corresponding Author

Lawrence C. Layman, MD

Section of Reproductive Endocrinology, Infertility, and Genetics Department of Obstetrics and Gynecology, The Medical College of Georgia

1120 15th Street, Augusta, GA 30912-3360 (USA)

Tel. +1 706 721 3832, Fax +1 706 7216830, E-Mail llayman@mcg.edu


References

  1. Wierman ME, Pawlowski JE, Allen MP, Xu M, Linseman DA, Nielsen-Preiss S: Molecular mechanisms of gonadotropin-releasing hormone neuronal migration. Trends Endocrinol Metab 2004;15:96–102.
  2. Schwarting GA, Kostek C, Bless EP, Ahmad N, Tobet SA: Deleted in colorectal cancer (DCC) regulates the migration of luteinizing hormone-releasing hormone neurons to the basal forebrain. J Neurosci 2001;21:911–919.
  3. Schwarting GA, Raitcheva D, Bless EP, Ackerman SL, Tobet S: Netrin 1-mediated chemoattraction regulates the migratory pathway of LHRH neurons. Eur J Neurosci 2004;19:11–20.
  4. Mellon PL, Windle JJ, Goldsmith PC, Padula CA, Roberts JL, Weiner RI: Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis. Neuron 1990;5:1–10.
  5. Radovick S, Wray S, Lee E, et al: Migratory arrest of gonadotropin-releasing hormone neurons in transgenic mice. Proc Natl Acad Sci USA 1991;88:3402–3406.
  6. Grumbach MM: A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metab 2005;90:3122–3127.
  7. Layman LC, Reindollar RH: The diagnosis and treatment of pubertal disorders. Adolesc Med 1994;5:37–55.
    External Resources
  8. Reindollar RH, Byrd JR, McDonough PG: Delayed sexual development: study of 252 patients. Am J Obstet Gynecol 1981;140:371–380.
  9. Crowley WF Jr, Filicori M, Spratt DI, Santoro NF: The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women. Recent Prog Horm Res 1985;41:473–531.
  10. Burris AS, Rodbard HW, Winters SJ, Sherins RJ: Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metab 1988;66:1144–1151.
  11. Layman LC: Hypogonadotropic hypogonadism. Endocrinol Metab Clin N Am 2007;36:283–296.
  12. Raivio T, Falardeau J, Dwyer A, et al: Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007;357:863–873.
  13. Waldstreicher J, Seminara SB, Jameson JL, et al: The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J Clin Endocrinol Metab 1996;81:4388–4395.
  14. Quinton R, Duke VM, Robertson A, et al: Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization. Clin Endocrinol (Oxf) 2001;55:163–174.
  15. Bhagavath B, Podolsky RH, Ozata M, et al: Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil Steril 2006;85:706–713.
  16. Bhagavath B, Layman LC: The genetics of hypogonadotropic hypogonadism. Semin Reprod Med 2007;25:272–286.
  17. Pitteloud N, Acierno JS Jr, Meysing A, et al: Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA 2006;103:6281–6286.
  18. Franco B, Guioli S, Pragliola A, et al: A gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 1991;353:529–536.
  19. Legouis R, Hardelin JP, Levilliers J, et al: The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 1991;67:423–435.
  20. Bick D, Franco B, Sherins RS, et al: Intragenic deletion of the KALIG-1 gene in Kallmann’s syndrome. N Engl J Med 1992;326:1752–1755.
  21. Hardelin JP, Levilliers J, Blanchard S, et al: Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. Hum Mol Genet 1993;2:373–377.
  22. MacColl G, Quinton R, Bouloux PM: GnRH neuronal development: insights into hypogonadotrophic hypogonadism. Trends Endocrinol Metab 2002;13:112–118.
  23. Lutz B, Karatani S, Rugarli EI, et al: Expression of the Kallmann syndrome gene in human fetal brain and in the manipulated chick embryo. Hum Mol Genet 1994;3:1717–1723.
  24. Soussi-Yanicostas N, de Castro F, Julliard AK, Perfettini I, Chedotal A, Petit C: Anosmin-1, defective in the X-linked form of Kallmann syndrome, promotes axonal branch formation from olfactory bulb output neurons. Cell 2002;109:217–228.
  25. MacColl G, Bouloux P, Quinton R: Kallmann syndrome: adhesion, afferents, and anosmia. Neuron 2002;34:675–678.
  26. Schwanzel-Fukuda M, Crossin KL, Pfaff DW, Bouloux PM, Hardelin JP, Petit C: migration of luteinizing hormone-releasing hormone (LHRH) neurons in early human embryos. J Comp Neurol 1996;366:547–557.
  27. Cariboni A, Pimpinelli F, Colamarino S, et al: The product of X-linked Kallmann’s syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons. Hum Mol Genet 2004;13:2781–2791.
  28. Whitlock KE, Illing N, Brideau NJ, Smith KM, Twomey S: Development of GnRH cells: Setting the stage for puberty. Mol Cell Endocrinol 2006;254–255:39–50.
  29. Bhagavath B, Xu N, Ozata M, et al: KAL1 mutations are not a common cause of idiopathic hypogonadotrophic hypogonadism in humans. Mol Hum Reprod 2007;13:25–30.
    External Resources
  30. Loidi L, Castro-Feijoo L, Barreiro J, et al: Kallmann’s syndrome with a novel missense mutation in the KAL1 gene that modifies the major cell adhesion site of the anosmin-1 protein. J Pediatr Endocrinol Metab 2005;18:545–548.
    External Resources
  31. Albuisson J, Pecheux C, Carel JC, et al: Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum Mutat 2005;25:98–99.
  32. Sato N, Katsumata N, Kagami M, et al: Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. J Clin Endocrinol Metab 2004;89:1079–1088.
  33. Massin N, Pecheux C, Eloit C, et al: X chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene. J Clin Endocrinol Metab 2003;88:2003–2008.
  34. Beranova M, Oliveira LM, Bedecarrats GY, et al: Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2001;86:1580–1588.
  35. Izumi Y, Tatsumi K, Okamoto S, et al: Analysis of the KAL1 gene in 19 Japanese patients with Kallmann syndrome. Endocr J 2001;48:143–149.
  36. Jansen C, Hendriks-Stegeman BI, Jansen M: A novel nonsense mutation of the KAL gene in two brothers with Kallmann syndrome. Horm Res 2000;53:207–212.
  37. Matsuo T, Okamoto S, Izumi Y, et al: A novel mutation of the KAL1 gene in monozygotic twins with Kallmann syndrome. Eur J Endocrinol 2000;143:783–787.
  38. Hou JW, Tsai WY, Wang TR: Detection of KAL-1 gene deletion with fluorescence in situ hybridization. J Formos Med Assoc 1999;98:448–451.
  39. Izumi Y, Tatsumi K, Okamoto S, et al: A novel mutation of the KAL1 gene in Kallmann syndrome. Endocr J 1999;46:651–658.
  40. O’Neill MJ, Tridjaja B, Smith MJ, Bell KM, Warne GL, Sinclair AH: Familial Kallmann syndrome: a novel splice acceptor mutation in the KAL gene. Hum Mutat 1998;11:340–342.
  41. Gu WX, Colquhoun-Kerr JS, Kopp P, Bode HH, Jameson JL: A novel amino-terminal mutation in the KAL-1 gene in a large pedigree with X-linked Kallmann syndrome. Mol Genet Metab 1998;65:59–61.
  42. Georgopoulos NA, Pralong FP, Seidman CE, Seidman JG, Crowley WF Jr, Vallejo M: Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency. J Clin Endocrinol Metab 1997;82:213–217.
  43. Hardelin JP, Petit C: A molecular approach to the pathophysiology of the X chromosome-linked Kallmann’s syndrome. Baillières Clin Endocrinol Metab 1995;9:489–507.
  44. Parenti G, Rizzolo MG, Ghezzi M, et al: Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene. Am J Med Genet 1995;57:476–478.
  45. Hardelin JP, Levilliers J, Young J, et al: Xp22.3 deletions in isolated familial Kallmann’s syndrome. J Clin Endocrinol Metab 1993;76:827–831.
  46. Hardelin JP, Levilliers J, del Castillo I, et al: X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene. Proc Natl Acad Sci USA 1992;89:8190–8194.
  47. Dode C, Levilliers J, Dupont JM, et al: Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003;33:463–465.
  48. Pitteloud N, Acierno JS Jr, Meysing AU, Dwyer AA, Hayes FJ, Crowley WF Jr: Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab 2005;90:1317–1322.
  49. Sato N, Hasegawa T, Hori N, Fukami M, Yoshimura Y, Ogata T: Gonadotrophin therapy in Kallmann syndrome caused by heterozygous mutations of the gene for fibroblast growth factor receptor 1: report of three families. Case report. Hum Reprod 2005;20:2173–2178.
  50. Sato N, Ohyama K, Fukami M, Okada M, Ogata T: Kallmann syndrome: somatic and germline mutations of the fibroblast growth factor receptor 1 gene in a mother and the son. J Clin Endocrinol Metab 2006;91:1415–1418.
  51. Pitteloud N, Meysing A, Quinton R, et al: Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol 2006;254–255:60–69.
  52. Xu N, Qin Y, Reindollar RH, Tho SP, McDonough PG, Layman LC: A mutation in the fibroblast growth factor receptor 1 gene causes fully penetrant normosmic isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2007;92:1155–1158.
  53. Gill JC, Moenter SM, Tsai PS: Developmental regulation of gonadotropin-releasing hormone neurons by fibroblast growth factor signaling. Endocrinology 2004;145:3830–3839.
  54. Tsai PS, Moenter SM, Postigo HR, et al: Targeted expression of a dominant-negative fibroblast growth factor (FGF) receptor in gonadotropin-releasing hormone (GnRH) neurons reduces FGF responsiveness and the size of GnRH neuronal population. Mol Endocrinol 2005;19:225–236.
  55. White KE, Cabral JM, Davis SI, et al: Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 2005;76:361–367.
  56. Hurley ME, White MJ, Green AJ, Kelleher J: Antley-Bixler syndrome with radioulnar synostosis. Pediatr Radiol 2004;34:148–151.
  57. Kress W, Petersen B, Collmann H, Grimm T: An unusual FGFR1 mutation (fibroblast growth factor receptor 1 mutation) in a girl with non-syndromic trigonocephaly. Cytogenet Cell Genet 2000;91:138–140.
  58. Muenke M, Schell U, Hehr A, et al: A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet 1994;8:269–274.
  59. Bhagavath B, Ozata M, Ozdemir IC, et al: The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism. Fertil Steril 2005;84:951–957.
  60. Layman LC, Cohen DP, Jin M, et al: Mutations in the gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet 1998;18:14–15.
  61. de Roux N, Young J, Misrahi M, et al: A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med 1997;337:1597–1602.
  62. de Roux N, Young J, Brailly-Tabard S, Misrahi M, Milgrom E, Chaison G: The same molecular defects of the gonadotropin-releasing hormone determine a variable degree of hypogonadism in affected kindred. J Clin Endocrinol Metab 1999;84:567–572.
  63. Pralong FP, Gomez F, Castillo E, et al: Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab 1999;84:3811–3816.
  64. Kottler ML, Chauvin S, Lahlou N, et al: A new compound heterozygous mutation of the gonadotropin-releasing hormone receptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: chronic estrogen administration amplifies the gonadotropin defect. J Clin Endocrinol Metab 2000;85:3002–3008.
  65. Seminara SB, Beranova M, Oliveira LM, Martin KA, Crowley WF Jr, Hall JE: Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations. J Clin Endocrinol Metab 2000;85:556–562.
  66. Layman LC, McDonough PG, Cohen DP, Maddox M, Tho SP, Reindollar RH: Familial gonadotropin-releasing hormone resistance and hypogonadotropic hypogonadism in a family with multiple affected individuals. Fertil Steril 2001;75:1148–1155.
  67. Costa EM, Bedecarrats GY, Mendonca BB, Arnhold IJ, Kaiser UB, Latronico AC: Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction. J Clin Endocrinol Metab 2001;86:2680–2686.
  68. Layman LC, Cohen DP, Xie J, Smith GD: Clinical phenotype and infertility treatment in a male with hypogonadotropic hypogonadism due to mutations Ala129Asp/Arg262Gln of the gonadotropin-releasing hormone receptor. Fertil Steril 2002;78:1317– 1320.
  69. Dewailly D, Boucher A, Decanter C, Lagarde JP, Counis R, Kottler ML: Spontaneous pregnancy in a patient who was homozygous for the Q106R mutation in the gonadotropin-releasing hormone receptor gene. Fertil Steril 2002;77:1288–1291.
  70. Maya-Nunez G, Janovick JA, Ulloa-Aguirre A, Soderlund D, Conn PM, Mendez JP: Molecular basis of hypogonadotropic hypogonadism: restoration of mutant (E(90)K) GnRH receptor function by a deletion at a distant site. J Clin Endocrinol Metab 2002;87:2144–2149.
  71. Silveira LF, Stewart PM, Thomas M, Clark DA, Bouloux PM, MacColl GS: Novel homozygous splice acceptor site GnRH receptor (GnRHR) mutation: human GnRHR ‘knockout’. J Clin Endocrinol Metab 2002;87:2973–2977.
  72. Bedecarrats GY, Linher KD, Janovick JA, et al: Four naturally occurring mutations in the human GnRH receptor affect ligand binding and receptor function. Mol Cell Endocrinol 2003;205:51–64.
  73. Wolczynski S, Laudanski P, Jarzabek K, Mittre H, Lagarde JP, Kottler ML: A case of complete hypogonadotropic hypogonadism with a mutation in the gonadotropin-releasing hormone receptor gene. Fertil Steril 2003;79:442–444.
  74. Bedecarrats GY, Linher KD, Kaiser UB: Two common naturally occurring mutations in the human gonadotropin-releasing hormone (GnRH) receptor have differential effects on gonadotropin gene expression and on GnRH-mediated signal transduction. J Clin Endocrinol Metab 2003;88:834–843.
  75. Karges B, Karges W, Mine M, et al: Mutation Ala(171)Thr stabilizes the gonadotropin-releasing hormone receptor in its inactive conformation, causing familial hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2003;88:1873–1879.
  76. Meysing AU, Kanasaki H, Bedecarrats GY, et al: GNRHR mutations in a woman with idiopathic hypogonadotropic hypogonadism highlight the differential sensitivity of luteinizing hormone and follicle-stimulating hormone to gonadotropin-releasing hormone. J Clin Endocrinol Metab 2004;89:3189–3198.
  77. Brothers SP, Cornea A, Janovick JA, Conn PM: Human loss-of-function gonadotropin-releasing hormone receptor mutants retain wild-type receptors in the endoplasmic reticulum: molecular basis of the dominant-negative effect. Mol Endocrinol 2004;18:1787–1797.
  78. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E: Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003;100:10972–10976.
  79. Seminara SB, Messager S, Chatzidaki EE, et al: The GPR54 gene as a regulator of puberty. N Engl J Med 2003;349:1614–1627.
  80. Tenenbaum-Rakover Y, Commenges-Ducos M, Iovane A, Aumas C, Admoni O, de Roux N: Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54. J Clin Endocrinol Metab 2007;92:1137–1144.
  81. Pallais JC, Bo-Abbas Y, Pitteloud N, Crowley WF Jr, Seminara SB: Neuroendocrine, gonadal, placental, and obstetric phenotypes in patients with IHH and mutations in the G-protein coupled receptor, GPR54. Mol Cell Endocrinol 2006;254–255:70–77.
  82. Lanfranco F, Gromoll J, von Eckardstein S, Herding EM, Nieschlag E, Simoni M: Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. Eur J Endocrinol 2005;153:845–852.
  83. Semple RK, Achermann JC, Ellery J, et al: Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2005;90:1849–1855.
  84. Cerrato F, Shagoury J, Kralickova M, et al: Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism. Eur J Endocrinol 2006;155(suppl 1):S3–S10.
  85. Seminara SB: Kisspeptin in reproduction. Semin Reprod Med 2007;25:337–343.
  86. Messager S, Chatzidaki EE, Ma D, et al: Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA 2005;102:1761–1766.
  87. Parhar IS, Ogawa S, Sakuma Y: Laser-captured single digoxigenin-labeled neurons of gonadotropin-releasing hormone types reveal a novel G protein-coupled receptor (Gpr54) during maturation in cichlid fish. Endocrinology 2004;145:3613–3618.
  88. Irwig MS, Fraley GS, Smith JT, et al: Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 2004;80:264–272.
  89. Plant TM, Ramaswamy S, Dipietro MJ: Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges. Endocrinology 2006;147:1007–1013.
  90. Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T: Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 2004;320:383–388.
  91. Dhillo WS, Chaudhri OB, Patterson M, et al: Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005;90:6609–6615.
  92. Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA: Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 2005;146:3686–3692.
  93. Smith JT, Dungan HM, Stoll EA, et al: Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 2005;146:2976–2984.
  94. Licinio J, Mantzoros C, Negrao AB, et al: Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med 1997;3:575–579.
  95. Smith JT, Acohido BV, Clifton DK, Steiner RA: KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol 2006;18:298–303.
  96. Welt CK, Chan JL, Bullen J, et al: Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351:987–997.
  97. Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM: Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 1996;14:95–97.
  98. Montague CT, Farooqi S, Whitehead FP, et al: Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903–908.
  99. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD: A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998;18:213–215.
  100. Gibson WT, Farooqi IS, Moreau M, et al: Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 2004;89:4821–4826.
  101. Farooqi IS, Matarese G, Lord GM, et al: Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002;110:1093–1103.
  102. Clement K, Vaisse C, Lahlou N, et al: A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398–401.
  103. Licinio J, Caglayan S, Ozata M, et al: Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 2004;101:4531–4536.
  104. Farooqi IS, Wangensteen T, Collins S, et al: Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007;356:237–247.
  105. Muscatelli F, Strom TM, Walker AP, et al: Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 1994;372:672–676.
  106. Zanaria E, Muscatelli F, Bardoni B, et al: An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 1994;372:635–641.
  107. Guo W, Mason JS, Stone CG, et al: Diagnosis of X-linked adrenal hypoplasia congenita by mutation analysis of the DAX1 gene. JAMA 1995;274:324–330.
  108. Zhang Y-H, Guo W, Wagner RL, et al: DAX1 mutations provide insight into structure-function relationships in steroidogenic tissue development. Am J Hum Genet 1998;62:855–864.
  109. Merke DP, Tajima T, Baron J, Cutler GB: Hypogonadotropic hypogonadism in a female caused by an X-linked recessive mutation in the DAX1 gene. N Engl J Med 1999;340:1248–1252.
  110. Seminara SB, Achermann JC, Genel M, Jameson JL, Crowley WF Jr: X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females. J Clin Endocrinol Metab 1999;84:4501–4509.
  111. Achermann JC, Gu WX, Kotlar TJ, et al: Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or pubertal delay. J Clin Endocrinol Metab 1999;84:4497–4500.
  112. Mantovani G, Ozisik G, Achermann JC, et al: Hypogonadotropic hypogonadism as a presenting feature of late-onset x-linked adrenal hypoplasia congenita. J Clin Endocrinol Metab 2002;87:44–48.
  113. Maier CC, Blalock JE: PCR-based cloning, sequencing, and exon mapping of lymphocyte derived neuroendocrine peptides. Immunomethods 1994;5:3–7.
  114. Tabarin A, Achermann JC, Recan D, et al: A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism. J Clin Invest 2000;105:321–328.
  115. Habiby RL, Boepple P, Nachtigall L, Sluss PM, Crowley WF Jr, Jameson JL: Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalmic and pituitary defects in gonadotropin production. J Clin Invest 1996;98:1055–1062.
  116. Caron P, Imbeaud S, Bennet A, Plantavid M, Camerino G, Rochiccioli P: Combined hypothalamic-pituitary-gonadal defect in a hypogonadic man with a novel mutation in the DAX-1 gene. J Clin Endocrinol Metab 1999;84:3563–3569.
  117. Achermann JC, Silverman BL, Habiby RL, Jameson JL: Presymptomatic diagnosis of X-linked adrenal hypoplasia congenita by analysis of DAX1. J Pediatr 2000;137:878–881.
  118. Wiltshire E, Couper J, Rodda C, Jameson JL, Achermann JC: Variable presentation of X-linked adrenal hypoplasia congenita. J Pediatr Endocrinol Metab 2001;14:1093–1096.
  119. Achermann JC, Ito M, Silverman BL, et al: Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression. J Clin Endocrinol Metab 2001;86:3171–3175.
  120. Salvi R, Gomez F, Fiaux M, et al: Progressive onset of adrenal insufficiency and hypogonadism of pituitary origin caused by a complex genetic rearrangement within DAX-1. J Clin Endocrinol Metab 2002;87:4094–4100.
  121. Ozisik G, Mantovani G, Achermann JC, et al: An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita. J Clin Endocrinol Metab 2003;88:417–423.
  122. Lin L, Gu WX, Ozisik G, et al: Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years’ experience. J Clin Endocrinol Metab 2006;91:3048–3054.
  123. Achermann JC: The role of SF1/DAX1 in adrenal and reproductive function. Ann Endocrinol (Paris) 2005;66:233–239.
  124. Yu RN, Ito M, Saunders TL, Camper SA, Jameson JL: Role of Ahch in gonadal development and gametogenesis. Nat Genet 1998;20:353–357.
  125. Jackson RS, Creemers JW, Ohagi S, et al: Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997;16:303–306.
  126. O’Rahilly S, Gray H, Humphreys PJ, et al: Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N Engl J Med 1995;333:1386–1390.
  127. Jackson RS, Creemers JW, Farooqi IS, et al: Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 2003;112:1550–1560.
  128. Dattani MT, Martinez-Barbera J-P, Thomas PQ, et al: Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 1998;19:125–133.
  129. Thomas PQ, Dattani MT, Brickman JM, et al: Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 2001;10:39–45.
  130. Brickman JM, Clements M, Tyrell R, et al: Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders. Development 2001;128:5189–5199.
  131. Quirk J, Brown P: Hesx1 homeodomain protein represses transcription as a monomer and antagonises transactivation of specific sites as a homodimer. J Mol Endocrinol 2002;28:193–205.
  132. Kim SS, Kim Y, Shin YL, Kim GH, Kim TU, Yoo HW: Clinical characteristics and molecular analysis of PIT1, PROP1,LHX3, and HESX1 in combined pituitary hormone deficiency patients with abnormal pituitary MR imaging. Horm Res 2003;60:277–283.
  133. Carvalho LR, Woods KS, Mendonca BB, et al: A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. J Clin Invest 2003;112:1192–1201.
  134. Cohen RN, Cohen LE, Botero D, et al: Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia. J Clin Endocrinol Metab 2003;88:4832–4839.
  135. Reynaud R, Gueydan M, Saveanu A, et al: Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. J Clin Endocrinol Metab 2006;91:3329–3336.
  136. Fluck C, Deladoey J, Rutishauser K, et al: Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg to Cys at codon 120 (R120C). J Clin Endocrinol Metab 1998;83:3727–3734.
  137. Cogan JD, Wu W, Phillips JAI, et al: The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency. J Clin Endocrinol Metab 1998;83:3346–3349.
  138. Wu W, Cogan JD, Pfaffle RW, et al: Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 1998;18:147–149.
  139. Arroyo A, Pernasetti F, Vasilyev VV, Amato P, Yen SS, Mellon PL: A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty. Clin Endocrinol (Oxf) 2002;57:283–291.
  140. Park JK, Ozata M, Chorich LP, et al: Analysis of the PROP1 gene in a large cohort of patients with idiopathic hypogonadotropic hypogonadism. Clin Endocrinol (Oxf) 2004;60:147–149.
  141. Andersen B, Pearse RV 2nd, Jenne K, et al: The Ames dwarf gene is required for Pit-1 gene activation. Dev Biol 1995;172:495–503.
  142. Kelberman D, Rizzoti K, Avilion A, et al: Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 2006;116:2442–2455.
  143. Laumonnier F, Ronce N, Hamel BC, et al: Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am J Hum Genet 2002;71:1450–1455.
  144. Woods KS, Cundall M, Turton J, et al: Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet 2005;76:833–849.
  145. Rizzoti K, Brunelli S, Carmignac D, Thomas PQ, Robinson IC, Lovell-Badge R: SOX3 is required during the formation of the hypothalamo-pituitary axis. Nat Genet 2004;36:247–255.
  146. Netchine I, Sobrier ML, Krude H, et al: Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 2000;25:182–186.
  147. Sloop KW, Parker GE, Hanna KR, Wright HA, Rhodes SJ: LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes. Gene 2001;265:61–69.
  148. Machinis K, Pantel J, Netchine I, et al: Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet 2001;69:961–968.
  149. Tajima T, Hattori T, Nakajima T, Okuhara K, Tsubaki J, Fujieda K: A novel missense mutation (P366T) of the LHX4 gene causes severe combined pituitary hormone deficiency with pituitary hypoplasia, ectopic posterior lobe and a poorly developed sella turcica. Endocr J 2007;54:637–641.
  150. Layman LC, Edwards JL, Osborne WE, et al: Human chorionic gonadotropin-b sequences in women with disorders of HCG production. Mol Hum Reprod 1997;3:315–320.
  151. Weiss J, Adams E, Whitcomb RW, Crowley WF Jr, Jameson JL: Normal sequence of the gonadotropin-releasing hormone gene in patients with idiopathic hypgonadotropic hypogonadism. Biol Reprod 1991;45:743–747.
  152. Valdes-Socin H, Salvi R, Daly AF, et al: Hypogonadism in a patient with a mutation in the luteinizing hormone beta-subunit gene. N Engl J Med 2004;351:2619–2625.
  153. Lofrano-Porto A, Barra GB, Giacomini LA, et al: Luteinizing hormone beta mutation and hypogonadism in men and women. N Engl J Med 2007;357:897–904.
  154. Layman LC, Lee EJ, Peak DB, et al: Delayed puberty and hypogonadism caused by a mutation in the follicle stimulating hormone β-subunit gene. N Engl J Med 1997;337:607–611.
  155. Layman LC, Porto AL, Xie J, et al: FSH beta gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia. J Clin Endocrinol Metab 2002;87:3702–3707.
  156. Matthews CH, Borgato S, Beck-Peccoz P, et al: Primary amenorrhea and infertility due to a mutation in the β-subunit of follicle-stimulating hormone. Nat Genet 1993;5:83–86.
  157. Clark AD, Layman LC: Analysis of the Cys82Arg mutation in follicle-stimulating hormone beta (FSHbeta) using a novel FSH expression vector. Fertil Steril 2003;79:379–385.
  158. Lindstedt G, Nystrom E, Matthews C, Ernest I, Janson PO, Chatterjee K: Follitropin (FSH) deficiency in an infertile male due to FSHbeta gene mutation: a syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations. Clin Chem Lab Med 1998;36:663–665.
  159. Phillip M, Arbelle JE, Segev Y, Parvari R: Male hypogonadism due to a mutation in the gene for the b-subunit of follicle stimulating hormone. N Engl J Med 1998;338:1729–1732.
  160. Barnes RB, Namnoum A, Rosenfield RL, Layman LC: Effects of follicle-stimulating hormone on ovarian androgen production in a woman with isolated follicle-stimulating hormone deficiency. N Engl J Med 2000;343:1197–1198.
  161. Barnes RB, Namnoum A, Rosenfield RL, Layman LC: The role of LH and FSH in ovarian androgen secretion and ovarian follicular development: Clinical studies in a patient with isolated FSH deficiency and multicystic ovaries. Hum Reprod 2002;17:88–91.
  162. Vissers LE, van Ravenswaaij CM, Admiraal R, et al: Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004;36:955–957.
  163. Hurst JA, Meinecke P, Baraitser M: Balanced t(6;8)(6p8p;6q8q) and the CHARGE association. J Med Genet 1991;28:54–55.
  164. Lalani SR, Safiullah AM, Fernbach SD, et al: Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. Am J Hum Genet 2006;78:303–314.
  165. Sanlaville D, Etchevers HC, Gonzales M, et al: Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development. J Med Genet 2006;43:211–217.
  166. Jongmans MC, Admiraal RJ, van der Donk KP, et al: CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet 2006;43:306–314.
  167. Sanlaville D, Verloes A: CHARGE syndrome: an update. Eur J Hum Genet 2007;15:389–399.
  168. Bosman EA, Penn AC, Ambrose JC, Kettleborough R, Stemple DL, Steel KP: Multiple mutations in mouse Chd7 provide models for CHARGE syndrome. Hum Mol Genet 2005;14:3463–3476.
  169. Hurd EA, Capers PL, Blauwkamp MN, et al: Loss of Chd7 function in gene-trapped reporter mice is embryonic lethal and associated with severe defects in multiple developing tissues. Mamm Genome 2007;18:94–104.
  170. Chalouhi C, Faulcon P, Le Bihan C, Hertz-Pannier L, Bonfils P, Abadie V: Olfactory evaluation in children: application to the CHARGE syndrome. Pediatrics 2005;116:e81–e88.
  171. Pinto G, Abadie V, Mesnage R, et al: CHARGE syndrome includes hypogonadotropic hypogonadism and abnormal olfactory bulb development. J Clin Endocrinol Metab 2005;90:5621–5626.
  172. Ogata T, Fujiwara I, Ogawa E, Sato N, Udaka T, Kosaki K: Kallmann syndrome phenotype in a female patient with CHARGE syndrome and CHD7 mutation. Endocr J 2006;53:741–743.
  173. Kramer PR, Wray S: Novel gene expressed in nasal region influences outgrowth of olfactory axons and migration of luteinizing hormone-releasing hormone (LHRH) neurons. Genes Dev 2000;14:1824–1834.
  174. Miura K, Acierno JS Jr, Seminara SB: Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). J Hum Genet 2004;49:265–268.
  175. Pitteloud N, Quinton R, Pearce S, et al: Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest 2007;117:457–463.
  176. Matsumoto S, Yamazaki C, Masumoto KH, et al: Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc Natl Acad Sci USA 2006;103:4140–4145.
  177. Dode C, Teixeira L, Levilliers J, et al: Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet 2006;2:e175.
  178. Best LG, Wasdahl WA, Larson LM, Sturlaugson J: Chromosome abnormality in Kallmann syndrome. Am J Med Genet 1990;35:306–309.
  179. Guioli S, Incerti B, Zanaria E, et al: Kallmann syndrome due to a translocation resulting in an X/Y fusion gene. Nat Genet 1992;1:337–340.
  180. Casamassima AC, Wilmot PL, Vibert BK, Shapiro LR: Kallmann syndrome associated with complex chromosome rearrangement. Am J Med Genet 1993;45:539–541.
  181. Kikuchi I, Nagamine M, Ueda A, Mihara K, Seita M, Minoda M: Chromosomal translocation t(13;16) in a patient with idiopathic hypogonadotropic hypogonadism. Intern Med 1993;32:465–467.
  182. Elbistan M, Aydin M, Bagci H, Kara N: A case of hypogonadism with a translocation: t(4; 12) (q25; q24.2). Indian J Pediatr 1994;61:421–426.
  183. Schinzel A, Lorda-Sanchez I, Binkert F, et al: Kallmann syndrome in a boy with a t(1;10) translocation detected by reverse chromosome painting. J Med Genet 1995;32:957–961.
  184. Kroisel PM, Petek E, Wagner K, Kurnik P: Complex chromosomal translocation in a patient with Kallmann syndrome. Am J Med Genet 2000;91:240.
  185. Vermeulen S, Messiaen L, Scheir P, De Bie S, Speleman F, De Paepe A: Kallmann syndrome in a patient with congenital spherocytosis and an interstitial 8p11.2 deletion. Am J Med Genet 2002;108:315–318.
  186. Helszer Z, Lach J, Nowacka J, Constantinou M, Kaluzewski B: Inv(10) in a patient with hypogonadotropic hypogonadism. J Appl Genet 2003;44:225–229.
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  187. Talaban R, Sellick GS, Spendlove HE, et al: Inherited pericentric inversion (X)(p11. 4q11.2) associated with delayed puberty and obesity in two brothers. Cytogenet Genome Res 2005;109:480–484.
  188. Kim HG, Herrick SR, Lemyre E, Kishikawa S, Salisz JA, Seminara S, MacDonald ME, Bruns GA, Morton CC, Quade BJ, Gusella JF: Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1. J Med Genet 2005;42: 666–672.