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Open Access 01-12-2011 | Research

Incidence, Phenotypic Features and Molecular Genetics of Kallmann Syndrome in Finland

Authors: Eeva-Maria Laitinen, Kirsi Vaaralahti, Johanna Tommiska, Elina Eklund, Mari Tervaniemi, Leena Valanne, Taneli Raivio

Published in: Orphanet Journal of Rare Diseases | Issue 1/2011

Abstract

Background

Kallmann syndrome (KS), comprised of congenital hypogonadotropic hypogonadism (HH) and anosmia, is a clinically and genetically heterogeneous disorder. Its exact incidence is currently unknown, and a mutation in one of the identified KS genes has only been found in ~30% of the patients.

Methods

Herein, we investigated epidemiological, clinical, and genetic features of KS in Finland.

Results

The minimal incidence estimate of KS in Finland was 1:48 000, with clear difference between males (1:30 000) and females (1:125 000) (p = 0.02). The reproductive phenotype of 30 probands (25 men; 5 women) ranged from severe HH to partial puberty. Comprehensive mutation analysis of all 7 known KS genes (KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, and WDR11) in these 30 well-phenotyped probands revealed mutations in KAL1 (3 men) and FGFR1 (all 5 women vs. 4/25 men), but not in other genes.

Conclusions

Our results suggest that Finnish KS men harbor mutations in gene(s) yet-to-be discovered with sex-dependent penetrance of the disease phenotype. In addition, some KS patients without CHD7 mutations display CHARGE-syndrome associated phenotypic features (e.g. ear or eye anomalies), possibly implying that, in addition to CHD7, there may be other genes associated with phenotypes ranging from KS to CHARGE.

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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.CrossRefPubMed

Cariboni A, Maggi R: Kallmann's syndrome, a neuronal migration defect. Cell Mol Life Sci. 2006, 63: 2512-2526. 10.1007/s00018-005-5604-3.CrossRefPubMed

Teixeira L, Guimiot F, Dode C, Fallet-Bianco C, Millar RP, Delezoide AL, Hardelin JP: Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions. J Clin Invest. 2010, 120: 3668-3672. 10.1172/JCI43699.PubMedCentralCrossRefPubMed

Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF, Pitteloud N: Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007, 357: 863-873. 10.1056/NEJMoa066494.CrossRefPubMed

Raivio T, Sidis Y, Plummer L, Chen H, Ma J, Mukherjee A, Jacobson-Dickman E, Quinton R, Van Vliet G, Lavoie H, Hughes VA, Dwyer A, Hayes FJ, Xu S, Sparks S, Kaiser UB, Mohammadi M, Pitteloud N: Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2009, 94: 4380-4390. 10.1210/jc.2009-0179.PubMedCentralCrossRefPubMed

Seminara SB, Hayes FJ, Crowley WF: Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations. Endocr Rev. 1998, 19: 521-539. 10.1210/er.19.5.521.PubMed

Jones JR, Kemmann E: Olfacto-genital dysplasia in the female. Obstet Gynecol Annu. 1976, 5: 443-466.PubMed

Sedlmeyer IL, Palmert MR: Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab. 2002, 87: 1613-1620. 10.1210/jc.87.4.1613.CrossRefPubMed

Oliveira LM, Seminara SB, Beranova M, Hayes FJ, Valkenburgh SB, Schipani E, Costa EM, Latronico AC, Crowley WF, Vallejo M: The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab. 2001, 86: 1532-1538. 10.1210/jc.86.4.1532.PubMed

10.

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. 10.1172/JCI29884.PubMedCentralCrossRefPubMed

11.

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. 10.1172/JCI34538.PubMedCentralCrossRefPubMed

12.

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, Pitteloud N: Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci USA. 2010, 107: 15140-15144. 10.1073/pnas.1009622107.PubMedCentralCrossRefPubMed

13.

Dode 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. 10.1371/journal.pgen.0020175.PubMedCentralCrossRefPubMed

14.

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, Persico MG, Camerino G, Ballabio A: A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature. 1991, 353: 529-536. 10.1038/353529a0.CrossRefPubMed

15.

Legouis R, Hardelin JP, Levilliers J, Claverie JM, Compain S, Wunderle V, Millasseau P, Le Paslier D, Cohen D, Caterina D, Bougueleret L, Dlemarre-Van Der Wall 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. 10.1016/0092-8674(91)90193-3.CrossRefPubMed

16.

Dode C, Levilliers J, Dupont JM, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux 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. 10.1038/ng1122.CrossRefPubMed

17.

Pitteloud N, Zhang C, Pignatelli D, Li JD, Raivio T, Cole LW, Plummer L, Jacobson-Dickman EE, Mellon PL, Zhou QY, Crowley WF: Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA. 2007, 104: 17447-17452. 10.1073/pnas.0707173104.PubMedCentralCrossRefPubMed

18.

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. 10.1016/j.ajhg.2010.08.018.PubMedCentralCrossRefPubMed

19.

Pitteloud N, Acierno JS, Meysing AU, Dwyer AA, Hayes FJ, Crowley WF: 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.CrossRefPubMed

20.

Trarbach EB, Costa EM, Versiani B, de Castro M, Baptista MT, Garmes HM, de Mendonca BB, Latronico AC: Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia. J Clin Endocrinol Metab. 2006, 91: 4006-4012. 10.1210/jc.2005-2793.CrossRefPubMed

21.

Pitteloud N, Acierno JS, 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: 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. 10.1073/pnas.0600962103.PubMedCentralCrossRefPubMed

22.

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 chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 2008, 83: 511-519. 10.1016/j.ajhg.2008.09.005.PubMedCentralCrossRefPubMed

23.

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, Crowley WF, Hoefsloot LH: CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome. Clin Genet. 2009, 75: 65-71. 10.1111/j.1399-0004.2008.01107.x.PubMedCentralCrossRefPubMed

24.

Bianco SD, Kaiser UB: The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2009, 5: 569-576. 10.1038/nrendo.2009.177.PubMedCentralCrossRefPubMed

25.

Semple RK, Topaloglu AK: The recent genetics of hypogonadotrophic hypogonadism - novel insights and new questions. Clin Endocrinol (Oxf). 2010, 72: 427-435. 10.1111/j.1365-2265.2009.03687.x.CrossRef

26.

Miura K, Acierno JS, 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. 10.1007/s10038-004-0137-4.CrossRefPubMed

27.

Miura K, Miura S, Yoshiura K, Seminara S, Hamaguchi D, Niikawa N, Masuzaki H: A case of Kallmann syndrome carrying a missense mutation in alternatively spliced exon 8A encoding the immunoglobulin-like domain IIIb of fibroblast growth factor receptor 1. Hum Reprod. 2010, 25: 1076-1080. 10.1093/humrep/deq006.PubMedCentralCrossRefPubMed

28.

Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PE: Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Hum Mutat. 2008, 29: 6-13. 10.1002/humu.20654.CrossRefPubMed

29.

Cheng A, McDonald NA, Connolly CN: Cell surface expression of 5-hydroxytryptamine type 3 receptors is promoted by RIC-3. J Biol Chem. 2005, 280: 22502-22507. 10.1074/jbc.M414341200.CrossRefPubMed

30.

Ramensky V, Bork P, Sunyaev S: Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 2002, 30: 3894-3900. 10.1093/nar/gkf493.PubMedCentralCrossRefPubMed

31.

Wincent J, Holmberg E, Stromland K, Soller M, Mirzaei L, Djureinovic T, Robinson K, Anderlid B, Schoumans J: CHD7 mutation spectrum in 28 Swedish patients diagnosed with CHARGE syndrome. Clin Genet. 2008, 74: 31-38. 10.1111/j.1399-0004.2008.01014.x.CrossRefPubMed

32.

Wincent J, Schulze A, Schoumans J: Detection of CHD7 deletions by MLPA in CHARGE syndrome patients with a less typical phenotype. Eur J Med Genet. 2009, 52: 271-272. 10.1016/j.ejmg.2009.02.005.CrossRefPubMed

33.

Newberry EP, Boudreaux JM, Towler DA: The rat osteocalcin fibroblast growth factor (FGF)-responsive element: an okadaic acid-sensitive, FGF-selective transcriptional response motif. Mol Endocrinol. 1996, 10: 1029-1040. 10.1210/me.10.8.1029.PubMed

34.

Verloes A: Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A. 2005, 133A: 306-308. 10.1002/ajmg.a.30559.CrossRefPubMed

35.

Fromantin M, Gineste J, Didier A, Rouvier J: Impuberism and hypogonadism at induction into military service. Statistical study. Probl Actuels Endocrinol Nutr. 1973, 16: 179-199.PubMed

36.

Filippi G: Klinefelter's syndrome in Sardinia. Clinical report of 265 hypogonadic males detected at the time of military check-up. Clin Genet. 1986, 30: 276-284.CrossRefPubMed

37.

Sarfati J, Guiochon-Mantel A, Rondard P, Arnulf I, Garcia-Pinero 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, Dode 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. 10.1210/jc.2009-0843.CrossRefPubMed

38.

Laitinen EM, Tommiska J, Dunkel L, Sankilampi U, Vaaralahti K, Raivio T: Idiopathic hypogonadotropic hypogonadism in a mother and her monozygotic twins born after a single embryo transfer. Fertil Steril. 2010, 93: 2074.e13-2074.e16. 10.1016/j.fertnstert.2009.11.013.CrossRef

39.

Riley BM, Mansilla MA, Ma J, Daack-Hirsch S, Maher BS, Raffensperger LM, Russo ET, Vieira AR, Dode C, Mohammadi M, Marazita ML, Murray JC: Impaired FGF signaling contributes to cleft lip and palate. Proc Natl Acad Sci USA. 2007, 104: 4512-4517. 10.1073/pnas.0607956104.PubMedCentralCrossRefPubMed

40.

Dode C, Hardelin JP: Kallmann syndrome. Eur J Hum Genet. 2009, 17: 139-146. 10.1038/ejhg.2008.206.PubMedCentralCrossRefPubMed

41.

Olsen SK, Ibrahimi OA, Raucci A, Zhang F, Eliseenkova AV, Yayon A, Basilico C, Linhardt RJ, Schlessinger J, Mohammadi M: Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity. Proc Natl Acad Sci USA. 2004, 101: 935-940. 10.1073/pnas.0307287101.PubMedCentralCrossRefPubMed

42.

Groth C, Lardelli M: The structure and function of vertebrate fibroblast growth factor receptor 1. Int J Dev Biol. 2002, 46: 393-400.PubMed

43.

Soderlund D, Canto P, Mendez JP: Identification of three novel mutations in the KAL1 gene in patients with Kallmann syndrome. J Clin Endocrinol Metab. 2002, 87: 2589-2592. 10.1210/jc.87.6.2589.CrossRefPubMed

44.

Hu Y, Sun Z, Eaton JT, Bouloux PM, Perkins SJ: Extended and flexible domain solution structure of the extracellular matrix protein anosmin-1 by X-ray scattering, analytical ultracentrifugation and constrained modelling. J Mol Biol. 2005, 350: 553-570. 10.1016/j.jmb.2005.04.031.CrossRefPubMed

45.

Feret H, McDonald-McGinn DM, Santani A, Zackai EH: Expanding the Phenotypic Overlap Between CHARGE and Kallmann Syndromes due to CHD7 Mutations. (Abstract #1671). Presented at the 60th Annual Meeting of The American Society of Human Genetics, November 3, 2010, Washington, DC.

46.

Abreu AP, Trarbach EB, de Castro M, Frade Costa EM, Versiani B, Matias Baptista MT, Garmes HM, Mendonca BB, Latronico AC: Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab. 2008, 93: 4113-4118. 10.1210/jc.2008-0958.CrossRefPubMed

47.

de la Chapelle A: Disease gene mapping in isolated human populations: the example of Finland. J Med Genet. 1993, 30: 857-865. 10.1136/jmg.30.10.857.PubMedCentralCrossRefPubMed

Title: Incidence, Phenotypic Features and Molecular Genetics of Kallmann Syndrome in Finland
Authors: Eeva-Maria Laitinen
Kirsi Vaaralahti
Johanna Tommiska
Elina Eklund
Mari Tervaniemi
Leena Valanne
Taneli Raivio
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2011
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/1750-1172-6-41

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Incidence, Phenotypic Features and Molecular Genetics of Kallmann Syndrome in Finland

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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