Journal of Reproduction & Infertility

Journal of Reproduction & Infertility

Exploring the Genetic Diversity of Isolated Hypogonadotropic Hypogonadism and Its Phenotypic Spectrum: A Case Series

Authors
Department of Endocrinology, Gandhi Medical College, Hospital, Hyderabad, India
Abstract
Background: Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder being classified as Kallmann syndrome (KS). The present study was conducted to study the genotype and relative proportion of different genetic mutations in IHH and to assess its correlation with phenotype. Methods: Eleven consecutive subjects presenting to the Department of Endocrinology were retrospectively analyzed during May 2017 to December 2018 with IHH. Phenotypic features and hormonal studies were analyzed along with clinical exome by targeted gene sequencing (Next generation sequencing). Thirty-nine relevant genes were tested in the analysis. Results: Of the 11 patients studied, five had KS and six had nIHH. At diagnosis, mean chronological age was 25 years. There were associated anomalies in KS group including bimanual synkinesia (n=2), unilateral renal agenesis (n=1) and submucosal cleft palate (n=1). Absence or hypoplasia of the olfactory bulb/sulci was found in 4/5 patients with KS. Genetic mutations in KAL1, CHD7, FGFR1, GNRHR, PROKR2, HS6ST1 genes were found in nine of the eleven subjects. Of the five subjects with KS, two had mutations in KAL1 gene. Two siblings who had bimanual synkinesia had CHD7 mutation. The genotype of nIHH subjects (n=6) was more heterogeneous. Conclusion: This study analyzed the clinical, endocrinological, and genetic features in IHH patients. Detectable genetic mutations were seen in a large proportion of cases. A considerable heterogeneity was seen in the genotype with new variants detected. A definite correlation of phenotype-genotype was not possible, and significant overlap was seen between CHD7 and KAl1, and FGFR1 phenotypes.
Keywords

  1. Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, et al. Expert consensus document: European consensus statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11(9):547-64.
  2. Lewkowitz-Shpuntoff HM, Hughes VA, Plummer L, Au MG, Doty RL, Seminara SB, et al. Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications. J Clin Endocrinol Metab. 2012;97(1):E136-44.
  3. Sykiotis GP, Plummer L, Hughes VA, Au M, Durrani S, Nayak-Young S, et al. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci USA. 2010;107(34):15140-4.
  4. Dodé C, Levilliers J, Dupont JM, De Paepe A, Le Dû N, Soussi-Yanicostas N, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. 2003;33(4):463-5.
  5. Costa-Barbosa FA, Balasubramanian R, Keefe KW, Shaw ND, Al-Tassan N, Plummer L, et al. Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. J Clin Endocrinol Metab. 2013;98:E943-53.
  6. Oliveira LM, Seminara SB, Beranova M, Hayes FJ, Valkenburgh SB, Schipani E, et al. The importance of autosomal genes in Kallmann syndrome: genotype- phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab. 2001;86(4):1532-8.
  7. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17(5):405-24.
  8. Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44(D1):D862-8.
  9. Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA. Online mendelian inheritance in man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 2005;33(Database issue):D514-7.
  10. Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, et al. The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42(Database issue):D1001-6.
  11. Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, et al. Human gene mutation database (HGMDR): 2003 update. Hum Mutat. 2003;21(6):577-81.
  12. Mottaz A, David FP, Veuthey AL, Yip YL. Easy retrieval of single amino-acid polymorphisms and phenotype information using SwissVar. Bioinformatics. 2010;26(6):851-2.
  13. 1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68-74.
  14. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285-91.
  15. Nagasaki M, Yasuda J, Katsuoka F, Nariai N, Kojima K, Kawai Y, et al. Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals. Nat Commun. 2015;6:8018.
  16. Ayers KL, Bouty A, Robevska G, van den Bergen JA, Juniarto AZ, Listyasari NA, et al. Variants in congenital hypogonadotrophic hypogonadism genes identified in an Indonesian cohort of 46, XYunder-virilised boys. Hum Genomics. 2017;11(1):1.
  17. Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2009;5(10):569-76.
  18. Vizeneux A, Hilfiger A, Bouligand J, Pouillot M, Brailly-Tabard S, Bashamboo A, et al. Congenital hypogonadotropic hypogonadism during childhood: presentation and genetic analyses in 46 boys. PLoS One. 2013;8(10):e77827.
  19. Abujbara MA, Hamamy HA, Jarrah NS, Shegem NS, Ajlouni KM. Clinical and inheritance profiles of Kallmann syndrome in Jordan. Reprod Health. 2004;1(1):5.
  20. Quinton R, Duke V, de Zoysa P, Platts A, Valentine A, Kendall B, et al. The neuroradiology of Kallmann’s syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab. 1996;81(8):3010-7.
  21. Zenaty D, Bretones P, Lambe C, Guemas I, David M, Leger J, et al: Paediatric phenotype of Kallmann syndrome due to mutations of fibroblast growth factor receptor 1 (FGFR1). Mol Cell Endocrinol. 2006;254-255:78-83.
  22. Hardelin JP, Julliard AK, Moniot B, Soussi-Yanicostas N, Verney C, Schwanzel-Fukuda M, et al: Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome. Dev Dyn. 1999;215(1):26-44.
  23. Bhagavath B, Xu N, Ozata M, Rosenfield RL, Bick DP, Sherins RJ, et al. KAL1 mutations are not a common cause of idiopathic hypogonadotrophic hypogonadism in humans. Mol Hum Reprod. 2007;13(3):165-70.
  24. Trarbach EB, Costa EM, Versiani B, de Castro M, Baptista MT, Garmes HM, et al. Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia. J Clin Endocrinol Metab. 2006;91:4006-12.
  25. Dode C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler ML, et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2006;2(10):e175.
  26. Cheng MY, Bullock CM, Li C, Lee AG, Bermak JC, Belluzzi J, et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature. 2002;417(6887):405-10.
  27. Brioude F, Bouligand J, Trabado S, Francou B, Salenave S, Kamenicky P, et.al. Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype-phenotype relationships. Eur J Endocrinol. 2010;162(5):835-51.
  28. Jongmans MC, Admiraal RJ, Van Der Donk KP, Vissers LE, Baas AF, Kapusta L, et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. 2006;43(4):306-14.
  29. Bergman JE, de Ronde W, Jongmans MC,Wolffenbuttel BH, Drop SL, Hermus A, et al. The results of CHD7 analysis in clinically well-characterized patients with Kallmann syndrome. J Clin Endocrinol Metab. 2012;97(5):E858-62.
  30. Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, et al. 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 USA. 2011;108(28):11524-9.
  31. Hardelin JP, Dodé C. The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al. Sex Dev. 2008;2(4-5):181-93.
  32. Laitinen EM, Tommiska J, Sane T, Vaaralahti K, Toppari J, Raivio T. Reversible congenital hypogonadotropic hypogonadism in patients with CHD7, FGFR1 or GNRHR mutations. PLoS One. 2012;7(6):e39450.
  33. Beneduzzi D, Trarbach EB, Min L, Jorge AA, Garmes HM, Renk AC, et al. Role of gonadotropin releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. Fertil Steril. 2014;102(3):838-46.e2.
  34. Raivio T, Sidis Y, Plummer L, Chen H, Ma J, Mukherjee A, et al. Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2009;94(11):4380-90.
  35. Nair S, Jadhav S, Lila A, Jagtap V, Bukan A, Pandit R, et al. Spectrum of phenotype and genotype of congenital isolated hypogonadotropic hypogonadism in Asian Indians. Clin Endocrinol (Oxf). 2016;85(1):100-9.
  36. Shin SJ, Sul Y, Kim JH, Cho JH, Kim GH, Kim JH, et al. Clinical, endocrinological, and molecular characterization of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: a single center experience. Ann Pediatr Endocrinol Metab. 2015;20(1):27-33.
  37. Beranova M, Oliveira LM, Bédécarrats GY, Schipani E, Vallejo M, Ammini AC, 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(4):1580-8.