Ann Pediatr Endocrinol Metab.  2020 Sep;25(3):192-197. 10.6065/apem.1938148.074.

Dizygotic twin sisters with normosmic idiopathic hypogonadotropic hypogonadism caused by an FGFR1 gene variant

• Choe J
• Kim JH
• Kim YA
• Lee J

• KMID: 2507563
• DOI: http://doi.org/10.6065/apem.1938148.074

Abstract

Isolated hypogonadotropic hypogonadism (IHH) is a rare genetic disorder that is clinically and genetically heterogeneous. It is characterized by absent or incomplete pubertal development owing to an isolated defect in the production, secretion, or action of gonadotropin-releasing hormone. The incidence of IHH is estimated at 1:30,000 in males and 1:125,000 in females. Although the vast majority of IHH cases are sporadic, some X-linked recessive, autosomal dominant, and autosomal recessive modes of inheritance have been described. IHH can be classified into Kallmann syndrome with anosmia and normosmic IHH. Here, we report dizygotic twin sisters with normosmic IHH who showed short stature and absence of puberty as a result of a variant of the FGFR1 gene. They had a normal sense of smell, and brain magnetic resonance imaging (MRI) showed well-defined olfactory bulbs. The older sister and the twins' mother had cleft palate, while the younger sister did not. The mother had menarche at the age of 16 years after hormonal replacement owing to delayed puberty. Molecular analysis of the FGFR1 gene identified a missense variant c.874C>G (p.His292Asp) in the twins and their mother. Herein, we described the clinical heterogeneity observed in the 2 affected twins who carry an identical variant in the FGFR1 gene. Further studies of the effects of modifier genes and epigenetic factors on the expression of FGFR1, as well as the various clinical manifestations of its mutations, are warranted.

Keyword

Idiopathic hypogonadotropic hypogonadism; Gonadotropin-releasing hormone; Puberty

Figure

• 

  Fig. 1. Pedigree of the cases.

• 

  Fig. 2. Exome sequencing for genetic analysis. (A) Heterozygous missense variant c.874C>G (p.His292Asp mutation) was found in the FGFR1 gene of patient 1 (the older sister of the dizygotic twin). (B) The same missense variant was found in the FGFR1 gene of patient 2 (the younger sister of the dizygotic twin). (C) The same missense variant was found in the FGFR1 gene of the mother. (D) Mutant sites in the FGFR1 gene of the father were validated to be wild-type.

Reference

References

1. Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2009; 5:569–76.

2. Iovane A, Aumas C, de Roux N. New insights in the genetics of isolated hypogonadotropic hypogonadism. Eur J Endocrinol. 2004; 151 Suppl 3:U83–8.

3. Topaloglu AK. Update on the genetics of idiopathic hypogonadotropic hypogonadism. J Clin Res Pediatr Endocrinol. 2017; 9:113–22.

4. 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; 20:27–33.

5. 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.

6. Seminara SB, Oliveira LM, Beranova M, Hayes FJ, Crowley WF Jr. Genetics of hypogonadotropic hypogonadism. J Endocrinol Invest. 2000; 23:560–5.

7. Beate K, Joseph N, Nicolas de R, Wolfram K. Genetics of isolated hypogonadotropic hypogonadism: role of GnRH receptor and other genes. Int J Endocrinol. 2012; 2012:147893.

8. Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, et al. Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet J Rare Dis. 2011; 6:41.

9. Silveira LF, Latronico AC. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013; 98:1781–8.

10. Cho JH, Jeong YS, Lee YJ, Hong SC, Yoon JH, Kim JK. The Korean version of the Sniffin' stick (KVSS) test and its validity in comparison with the cross-cultural smell identification test (CC-SIT). Auris Nasus Larynx. 2009; 36:280–6.

11. Sam S, Frohman LA. Normal physiology of hypothalamic pituitary regulation. Endocrinol Metab Clin North Am. 2008; 37:1–22. vii.

12. 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.

13. Hoffman AR, Crowley WF Jr. Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med. 1982; 307:1237–41.

14. Crowley WF Jr, Pitteloud N, Seminara S. New genes controlling human reproduction and how you find them. Trans Am Clin Climatol Assoc. 2008; 119:29–37. discussion37-8.

15. Pitteloud N, Meysing A, Quinton R, Acierno JS Jr, Dwyer AA, Plummer L, et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol. 2006; 254-255:60–9.

16. Trarbach EB, C osta EM, Versiani B, de C astro 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.

17. 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; 92:1155–8.

18. 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; 94:4380–90.

19. Tsai PS, Gill JC. Mechanisms of disease: insights into X-linked and autosomal-dominant Kallmann syndrome. Nat Clin Pract Endocrinol Metab. 2006; 2:160–71.

20. Boehm U, Bouloux PM, Dattani MT, de Roux N, Dode C, Dunkel L, et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015; 11:547–64.