Genetics of male hypogonadotropic hypogonadism

Pediatric Endocrinology Reviews

Volumn 10, Issue SUPPL. 1, 2012, Pages 110-125

  Sato, Naoko ^a  

^a NATIONAL CENTER FOR CHILD HEALTH AND DEVELOPMENT   (Japan)

Author keywords

Hyposonadotropic hypogonadism; Kallmann syndrome; Oligogenicity

Indexed keywords

CHD7 PROTEIN; FIBROBLAST GROWTH FACTOR 8; FIBROBLAST GROWTH FACTOR RECEPTOR 1; FOLLITROPIN; G PROTEIN COUPLED RECEPTOR 54; GONADORELIN RECEPTOR; GONADORELIN RECEPTOR 1; HORMONE RECEPTOR; KAL1 PROTEIN; KISSPEPTIN; LUTEINIZING HORMONE; MEMBRANE PROTEIN; NELF PROTEIN; PROK2 PROTEIN; PROKR2 PROTEIN; TACHYKININ 3; TACHYKININ RECEPTOR 3; UNCLASSIFIED DRUG; WDR11 PROTEIN;

FUNCTION TEST; GENE MUTATION; GENETIC DISORDER; HUMAN; HYPOGONADOTROPIC HYPOGONADISM; HYPOPITUITARISM; HYPOTHALAMUS HYPOPHYSIS GONAD SYSTEM; KALLMANN SYNDROME; NEUROENDOCRINE SYSTEM; OLFACTORY FUNCTION TEST; PATHOGENESIS; PATHOPHYSIOLOGY; PHYSIOLOGY; REPRODUCTION; REVIEW;

CHILD; HUMANS; HYPOGONADISM; KALLMANN SYNDROME; MALE; MULTIFACTORIAL INHERITANCE;

EID: 84871249599     PISSN: 15654753     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (95)

1. Mitchell AL, Dwyer A, Pitteloud N, Quinton R. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. Trends Endocrinol Metab 2011; 22:249-58
2. Sykiotis GP, Plummer L, Hughes VA, Au M, Durrani S, Nayak-Young S, Dwyer AA, Quinton R, Hall JE, Gusella JF, Seminara SB, Crowley WF Jr, Pitteloud N. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci U S A 2010;107:15140-15144
3. Raivio T, Avbelj M, McCabe MJ, Romero CJ, Dwyer AA, Tommiska J, Sykiotis GP, Gregory LC, Diaczok D, Tziaferi V, Elting MW, Padidela R, Plummer L, Martin C, Feng B, Zhang C, Zhou QY, Chen H, Mohammadi M, Quinton R, Sidis Y, Radovick S, Dattani MT, Pitteloud N. Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency and septo-optic dysplasia. J Clin Endocrinol Metab 2012;97:E694-699
4. Izumi Y, Tatsumi K, Okamoto S, Hosokawa A, Ueno S, Fukui H, Amino N. A novel mutation of the KAL1 gene in Kallmann syndrome. Endocr J 1999;46:651-658
5. Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N, Kawakita S, Minowada S,Shimotsuka A, Shishiba Y, Yokozawa M, Yasuda T, Nagasaki K, Hasegawa D, Hasegawa Y, Tachibana K, Naiki Y, Horikawa R, Tanaka T, Ogata T. 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
6. Maeda KhI, Tsukamura H, Ohkura S, Kawakami S, Nagabukuro H, Yokoyama A. The LHRH pulse generator: a mediobasal hypothalamic location. Neurosci Biobehav Rev 1995;19:427-437
7. Kotani M, Detheux M, Vandenbogaerde A, CommuniD, Vanderwinden JM, Le Pout E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G, Parmentier M. The metastasis suppressor gene KiSSh1 encodes kisspeptins, the natural ligands of the orphan G protein coupled receptor GPR54. J Biol Chem 2001; 276:34631-34636
8. Adachi S, Yamada S, Takatsu Y, Matsui H, Kinoshita M, Takase K, Sugiura H, Ohtaki T, Matsumoto H, Uenoyama Y, Tsukamura H, Inoue K, Maeda K. Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. J Reprod Dev 2007;53:367-378
9. Ohkura S, Uenoyama Y, Yamada S, Homma T, Takase K, Inoue N, Maeda KhI, Tsukamura H. Physiological role of metastin/kisspeptin in regulating gonadotropinhreleasing hormone (GnRH) secretion in female rats. Peptides 2009;30:49-56
10. 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
11. The Japanese Society for Pediatric Endocrinology. Pediatric Endocrinology 1st Ed. Tokyo: Shindan to Chiryo Sha, 2010, pp.265 (in Japanese)
12. Schwanzel-Fukuda M, Bick D, Pfaff DW. Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Brain Res Mol Brain Res 1989;6:311-326
13. Dwyer AA, Hayes FJ, Plummer L, Pitteloud N, Crowley WF Jr. The long-term clinical follow-up and natural history of men with adult-onset idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2010;95:4235-4243
14. Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007;357:863-873
15. Balasubramanian R, Dwyer A, Seminara SB, Pitteloud N, Kaiser UB, Crowley WF Jr. Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons. Neuroendocrinology. 2010;92(2):81-99.
16. Dunkel L, Perheentupa J, Virtanen M, Maenpaa J. Gonadotropin-releasing hormone test and human chorionic gonadotropin test in the diagnosis of gonadotropin deficiency in prepubertal boys. J Pediatr 1985;107:388-392
17. Jongmans MC, van Ravenswaaij-Arts CM, Pitteloud N, Ogata T, Sato N,Claahsen-van der Grinten HL, van der Donk K, Seminara S, Bergman JE, Brunner HG, Crowtey WF Jr, Hoefsloot LH. CHD7 mutations in patients initially diagnosed with Kallmann syndrome-the clinical overlap with CHARGE syndrome. Clin Genet 2009;75(1):65-71
18. Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A, Plummer L, Hughes V, Seminara S, Cheng YZ, Li WP, Maccoll G, Eliseenkova AV, Olsen SK, Ibrahimi OA, Hayes FJ, Boepple P, Hall JE, Bouloux P, Mohammadi M, Crowley W. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest 2007;117:457-463
19. Legouis R, Hardelin JP, Levilliers J, Claverie JM, Compain S, Wunderle V, Millasseau P, Le Paslier D, Cohen D, Caterina D, Bougueleret L, Delemarre-Van de Waal H, Lutfalla G, Weissenbach J, Petit C. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 1991;67:423-435
20. Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, Carrozzo R, Maestrini E, Pieretti M, Taillon-Miller P, Brown CJ, Willard HF, Lawrence C, Graziella Persico M, Camerino G, Ballabio A. A gene deleted in Kallmann'ssyndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 1991;353(6344):529-536
21. Dodé C, Levilliers J, Dupont JM, De Paepe A, Le DÛ N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pêcheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin JP. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003:33:463-465
22. Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D, Hughes VA, Dwyer AA, Raivio T, Hayes FJ, Seminara SB, Huot C, Alos N, Speiser P, Takeshita A, Van Vliet G, Pearce S, Crowley WF Jr, Zhou QY, Pitteloud N. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin- releasing hormone deficiency: molecular genetics and clinical spectrum. J Clin Endocrinol Metab 2008;93:3551-3559
23. Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y, Jacobson-Dickman EE, Eliseenkova AV, Ma J, Dwyer A, Quinton R, Na S, Hall JE, Huot C, Alois N, Pearce SH, Cole LW, Hughes V, Mohammadi M, Tsai P, Pitteloud N. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest 2008;118:2822-2831
24. Ogata T, Fujiwara I, Ogawa E, Sato N, Udaka T, Kosaki K. Kallmann syndrome phenotype ina female patient with CHARGE syndrome and CHD7 mutation. Endocr J 2006;53:741-743
25. Dodé C, Hardelin JP. Kallmann syndrome: fibroblast growth factor signaling insufficiency? J Mol Med 2004;82:725-734
26. Tsai PS, Moenter SM, Postigo HR, El Majdoubi M, Pak TR, Gill JC, Paruthiyil S, Werner S, Weiner RI. 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
27. 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
28. 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
29. Dodé C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler ML, Lespinasse J, Lienhardt-Roussie A, Mathieu M, Moerman A, Morgan G, Murat A, Toublanc JE, Wolczynski S, Delpech M, Petit C, Young J, Hardelin JP. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet 2006;2: e175
30. Pitteloud N, Zhang C, Pignatelli D, Li JD, Raivio T, Cole LW, Plummer L, Jacobson-Dickman EE, Mellon PL, Zhou QY, Crowley WF Jr. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A 2007;104:17447-17452
31. Pinto G, Abadie V, Mesnage R, Blustajn J, Cabral S, Amiet J, Hertz-Pannier L, Bertrand AM, Lyonnet S, Rappaport R, Netchine I. CHARGE syndrome includes hypogonadotropic hypogonadism and abnormal olfactory bulb development. J Clin Endocrinol Metab 2005;90:5621-5626
32. Miura K, Aderno 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
33. Kim HG, Ahn JW, Kurth I, Ullmann R, Kim HT, Kulharya A, Ha KS, Itokawa Y, Meliciani I, Wenzel W, Lee D, Rosenberger G, Ozata M, Bick DP, Sherins RJ, Nagase T, Tekin M, Kim SH, Kim CH, Ropers HH, Gusella JF, Kalscheuer V, Choi CY, Layman LC. WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 2010;87:465-479
34. de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, Milgrom E. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med 1997;337:1597-1602
35. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, BohAbbas Y, KuohungW, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'RahillyS, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med 2003;349:1614-1627
36. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E: Hypogonadotropic hypogonadism due to loss of function of the KiSS1h derived peptide receptor GPR54, Proc Natl Acad Sci USA 2003;100:10972-10976.
37. Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB,Mendonca BB, Kaiser UB, Latronico AC. A GPR54- activating mutation in a patient with central precocious puberty. N Engl J Med. 2008;358:709-15.
38. Dedes I. Kisspeptins and the control of gonadotrophin secretion. Syst Biol Reprod Med. 2012 ;58:121-128.
39. Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, Bianco SD, Kuohung W, Xu S, Gryngarten M, Escobar ME, Arnhold IJ, Mendonca BB, Kaiser UB, Latronico AC. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab 2010;95:2276-2280
40. Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, Gurbuz F, Temiz F, Millar RP, Yuksel B. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 2012;366:629-635
41. Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 2009:41:354-358
42. Chan YM, de Guillebon A, Lang-Muritano M, Plummer L, Cerrato F, Tsiaras S, Gaspert A, Lavoie HB, Wu CH, Crowley WF Jr, Amory JK, Pitteloud N, Seminara SB. GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA 2009; 106:11703-11708.
43. Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P, Lombès M, Millar RP, Guiochon-Mantel A, Young J. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med 2009;360:2742-2748
44. Weiss J, Axelrod L, Whitcomb RW, Harris PE, Crowley WF, Jameson JL. Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone. N Engl J Med 1992;326:179-183
45. Haavisto AM, Pettersson K, Bergendahl M, Virkamäki A, Huhtaniemi I. Occurrence and biological properties of a common genetic variant of luteinizing hormone. J Clin Endocrinol Metab 1995;80:1257-1263
46. Toledo SP. Leydig cell hypoplasia leading to two different phenotypes: male pseudohermaphroditism and primary hypogonadism not associated with this. Clin Endocrinol (Oxf). 1992 May;36:521-522
47. Shenker A, Laue L, Kosugi S, Merendino JJ Jr, Minegishi T, Cutler GB Jr. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993;365:652-654
48. Matthews CH, Borgato S, Beck-Peccoz P, Adams M, Tone Y, Gambino G, Casagrande S, Tedeschini G, Benedetti A, Chatterjee VK. Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nat Genet 1993;5:83-86
49. Aittomäki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila EM, Lehväslaiho H, Engel AR, Nieschlag E, Huhtaniemi I, de la Chapelle A. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 1995; 82: 959-968
50. Meyers CM, Boughman JA, Rivas M, Wilroy RS, Simpson JL. Gonadal (ovarian) dysgenesis in 46,XX individuals: frequency of the autosomal recessive form. Am J Med Genet 1996;63:518-524
51. Kuechler A, Hauffa BP, Koninger A, Kleinau G, Albrecht B, Horsthemke B, Gromoll J. An unbalanced translocation unmasks a recessive mutation in the follicle-stimulating hormone receptor (FSHR) gene and causes FSH resistance. Eur J Hum Genet 2010;18: 656-661
52. Fink, G. Gonadotropin secretion and its control. In The physiology of reproduction (Knobil, E. and N., J.D., eds), New York: Raven Press, 1988, pp.1349-1377
53. Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R, Thambundit A, Avbelj M, Dhruvakumar S, Plummer L, Hughes VA, Seminara SB, Boepple PA, Sidis Y, Crowley WF Jr, Martin KA, Hall JE, Pitteloud N. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 2011;364:215-225
54. Hameed S, Dhillo WS. Biology of kisspeptins. Front Horm Res 2010;39:25-36
55. Sarfati J, Guiochon-Mantel A, Rondard P, Arnulf I, Garcia-Piñero A, Wolczynski S, Brailly-Tabard S, Bidet M, Ramos-Arroyo M, Mathieu M, Lienhardt-Roussie A, Morgan G, Turki Z, Bremont C, Lespinasse J, Du Boullay H, Chabbert-Buffet N, Jacquemont S, Reach G, De Talence N, Tonella P, Conrad B, Despert F, Delobel B, Brue T, Bouvattier C, Cabrol S, Pugeat M, Murat A, Bouchard P, Hardelin JP, Dodé C, Young J. A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes. J Clin Endocrinol Metab 2010;95:659-669
56. Gianetti E, Tusset C, Noel SD, Au MG, Dwyer AA, Hughes VA, Abreu AP, Carroll J, Trarbach E, Silveira LF, Costa EM, de Mendonça BB, de Castro M, Lofrano A, Hall JE, Bolu E, Ozata M, Quinton R, Amory JK, Stewart SE, Arlt W, Cole TR, Crowley WF, Kaiser UB, Latronico AC, Seminara SB. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab 2010;95:2857-2867
57. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903-908
58. Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougnères P, Lebouc Y, Froguel P, Guy-Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398-401
59. Fischer-Posovszky P, von Schnurbein J, Moepps B, Lahr G, Strauss G, Barth TF, Kassubek J, Mühleder H, Möller P, Debatin KM, Gierschik P, Wabitsch M. A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness. J Clin Endocrinol Metab 2010;95:2836-2840
60. Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Ercan O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N, Ghodsi M, De Rosa V, Perna F, Fontana S, Barroso I, Undlien DE, O'Rahilly S. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007;356:237-247
61. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997;16:303-306
62. Farooqi IS, Volders K, Stanhope R, Heuschkel R, White A, Lank E, Keogh J, O'Rahilly S, Creemers JW. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J Clin Endocrinol Metab 2007;92:3369-3373
63. Presser HM, Bradley A, Caldwell MA. Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiation. Eur J Neurosci. 2007;26:3339-3344
64. Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson ML, Varro A, Dockray GJ, Holst JJ, Brubaker PL, Corvol P, Polonsky KS, Ostrega D, Becker KL, Bertagna X, Hutton JC, White A, Dattani MT, Hussain K, Middleton SJ, Nicole TM, Milla PJ, Lindley KJ, O'Rahilly S. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 2003;112:1550-1560
65. Muscatelli F, Strom TM, Walker AP, Zanaria E, Récan D, Meindl A, Bardoni B, Guioli S, Zehetner G, Rabl W, Schwarz HP, Kaplan JC, Camerino G, Meitinge T, Monaco AP. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 1994;372:672-676
66. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ER, Meitinger T, Monaco AP, Sassone-Corsi P, Camerino G. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 1994;372:635-641
67. Shaikh MG, Boyes L, Kingston H, Collins R, Besley GT, Padmakumar B, Ismayl O, Hughes I, Hall CM, Hellerud C, Achermann JC, Clayton PE. Skewed X inactivation is associated with phenotype in a female with adrenal hypoplasia congenita. J Med Genet 2008;45(9), pe1
68. Skinningsrud B, Husebye ES, Gilfillan GD, Frengen E, Erichsen A, Gervin K, Ormerod E, Egeland T, Undlien DE. X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism caused by an inversiondisrupting a conserved noncoding element upstream of the NR0B1 (DAX1) gene. J Clin Endocrinol Metab 2009;94:4086-4093
69. 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
70. Takahashi T, Shoji Y, Shoji Y, Haraguchi N, Takahashi I, Takada G. Active hypothalamic-pituitary-gonadat axis in an infant with X-linked adrenal hypoplasia congenita. J Pediatr 1997;130: 485-488
71. Achermann JC, Gu WX, Kotlar TJ, Meeks JJ, Sabacan LP, Seminara SB, Habiby RL, Hindmarsh PC, Bick DP, Sherins RJ, Crowley WF Jr, Layman LC, Jameson JL. Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or pubertal delay. J Clin Endocrinol Metab 1999;84:4497-4500
72. Xu N, Bhagavath B, Kim HG, Halvorson L, Podolsky RS, Chorich LP, Prasad P, Xiong WC, Cameron RS, Layman LC. NELF is a nuclear protein involved in hypothalamic GnRH neuronal migration. Mol Cell Endocrinol 2009;319:47-55
73. Xu N, Kim HG, Bhagavath B, Cho SG, Lee JH, Ha K, Meliciani I, Wenzel W, Podolsky RH, Chorich LP, Stackhouse KA, Grove AM, Odom LN, Ozata M, Bick DP, Sherins RJ, Kim SH, Cameron RS, Layman LC. Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Fertil Steril 2011;95:1613-1620.e7
74. Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W, Eom SH, Kang GB, Rosenberger G, Tekin M, Ozata M, Bick DP, Sherins RJ, Walker SL, Shi Y, Gusella JF, Layman LC. Mutations in CHD7, encoding a chromatinremodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 2008;83:511-519
75. Hardelin JP, Levilliers J, del Castillo I, Cohen-Salmon M, Legouis R, Blanchard S, Compain S, Bouloux P, Kirk J, Moraine C, Chaussain JL, Weissenbach J, Petit C. X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene. Proc Natl Acad Sci U S A 1992;89:8190-8194
76. Rugarli El, Ghezzi C, Valsecchi V, Ballabio A. The Kallmann syndrome gene product expressed in COS cells is cleaved on the cell surface to yield a diffusible component. Hum Mol Genet 1996;5:1109-1115
77. Cariboni A, Pimpinelli F, Colamarino S, Zaninetti R, Piccolella M, Rumio C, Piva F, Rugarli El, Maggi R. 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
78. Hu Y, Guimond SE, Travers P, Cadman S, Hohenester E, Turnbull JE, Kim SH, Bouloux PM. Novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1. J Biol Chem 2009;284:29905-29920
79. Quinton R, Duke VM, Robertson A, Kirk JM, Matfin G, de Zoysa PA, Azcona C, MacColl GS, Jacobs HS, Conway GS, Besser M, Stanhope RG, Bouloux PM. Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization. Clin Endocrinol (Oxf.) 2001;55:163-174
80. Massin N, Pêcheux C, Eloit C, Bensimon JL, Galey J, Kuttenn F, Hardelin JP, Dodé C, Touraine P. 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
81. Ribeiro RS, Vieira TC, Abucham J. Reversible Kallmann syndrome: report of the first case with a KAL1 mutation and literature review. Eur J Endocrinol. 2007;156:285-290
82. Parenti G, Rizzolo MG, Ghezzi M, Di Maio S, Sperandeo MP, Incerti B, Franco B, Ballabio A, Andria G. 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
83. Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol 2009;5:569-576
84. Chung WC, Moyle SS, Tsai PS. Fibroblast growth factor 8 signaling through fibroblast growth factor receptor 1 is required for the emergence of gonadotropin-releasing hormone neurons. Endocrinology 2008;149:4997-5003
85. Canto P, Munguía P, Söderlund D, Castro JJ, Méndez JP. Genetic analysis in patients with Kallmann syndrome: coexistence of mutations in prokineticin receptor 2 and KAL1. J Androl 2009;30:41-45
86. 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
87. Pitteloud N, Meysing A, Quinton R, Acierno JS Jr, Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, Hughes VA, Ma J, Bouloux P, Mohammadi M, Crowley WF Jr. 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
88. Lin DC, Bullock CM, Ehlert FJ, Chen JL, Tian H, Zhou QY. Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor. J Biol Chem 2002;277:19276-19280
89. Cheng MY, Bullock CM, Li C, Lee AG, Bermak JC, Belluzzi J, Weaver DR, Leslie FM, Zhou QY. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 2002;23:405-410
90. Maldonado-Pérez D, Evans J, Denison F, Millar RP, Jabbour HN. Potential roles of the prokineticins in reproduction. Trends Endocrinol Metab 2007;18:66-72
91. Sinisi AA, Asci R, Bellastella G, Maione L, Esposito D, Elefante A, De Bellis A, Bellastella A, Iolascon A. Homozygous mutation in the prokineticinreceptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: case report. Hum Reprod 2008;23:2380-2384
92. Pitteloud N, Acierno JS Jr, Meysing A, Eliseenkova AV, Ma J, Ibrahimi OA, Metzger DL, Hayes FJ, Dwyer AA, Hughes VA, Yialamas M, Hall JE, Grant E, Mohammadi M, Crowley WF Jr. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A 2006;103:6281-6286
93. Matsumoto S, Yamazaki C, Masumoto KH, Nagano M, Naito M, Soga T, Hiyama H, Matsumoto M, Takasaki J, Kamohara M, Matsuo A, Ishii H, Kobori M, Katoh M, Matsushime H, Furuichi K, Shigeyoshi Y. Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc Natl Acad Sci U S A 2006;103:4140-4145
94. Rugarli EI, Ballabio A. Kallmann syndrome: from genetics to neurobiology. JAMA 1993;270:2713-2715
95. Fujieda K, Mukai T. Clinical Molecular Endocrinology 4. Reproductive Endocrinology. Kallmann syndrome. Nippon Rinsho 2006;64(Suppl 4):47-53 (in Japanese)