Ann Pediatr Endocrinol Metab.  2014 Sep;19(3):117-121. 10.6065/apem.2014.19.3.117.

Neonatal screening and a new cause of congenital central hypothyroidism

• Tajima T
• Nakamura A
• Morikawa S
• Ishizu K

• KMID: 2134077
• DOI: http://doi.org/10.6065/apem.2014.19.3.117

Abstract

Congenital central hypothyroidism (C-CH) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin (TSH) stimulation of a normally-located thyroid gland. Most patients with C-CH have low free thyroxine levels and inappropriately low or normal TSH levels, although a few have slightly elevated TSH levels. Autosomal recessive TSH deficiency and thyrotropin-releasing hormone receptor-inactivating mutations are known to be genetic causes of C-CH presenting in the absence of other syndromes. Recently, deficiency of the immunoglobulin superfamily member 1 (IGSF1) has also been demonstrated to cause C-CH. IGSF1 is a plasma membrane glycoprotein highly expressed in the pituitary. Its physiological role in humans remains unknown. IGSF1 deficiency causes TSH deficiency, leading to hypothyroidism. In addition, approximately 60% of patients also suffer a prolactin deficiency. Moreover, macroorchidism and delayed puberty are characteristic features. Thus, although the precise pathophysiology of IGSF1 deficiency is not established, IGSF1 is considered to be a new factor controlling growth and puberty in children.

Keyword

Congenital hypothyroidism (CH); Neonatal screening; Thyrotropin (TSH); IGSF1

MeSH Terms

Adolescent
Cell Membrane
Child
Glycoproteins
Humans
Hypothyroidism*
Immunoglobulins
Infant, Newborn
Neonatal Screening*
Prolactin
Puberty
Puberty, Delayed
Rare Diseases
Thyroid Gland
Thyrotropin
Thyrotropin-Releasing Hormone
Thyroxine
Glycoproteins
Immunoglobulins
Prolactin
Thyrotropin
Thyrotropin-Releasing Hormone
Thyroxine

Figure

• 

  Fig. 1 Speculated function of IGSF1 in pituitary TSH synthesis and secretion. IGSF1 is likely to affect TSH synthesis, secretion and pituitary TRH receptor function. In addition, as IGSF1 is also expressed in hypothalamus, IGSF1 may affect TRH secretion. IGSF1, immunoglobulin superfamily member 1; TSH, thyroid-stimulating hormone; TRH, thyrotropin-releasing hormone. *, Arrowhead indicates that undetermined IGSF1 ligand may interact with IGSF1 on cell surface, and thus may modulate TRH-TRH receptor signaling.

• 

  Fig. 2 Schematic representation of immunoglobulin superfamily member 1.

• 

  Fig. 3 Mutations/deletions of immunoglobulin superfamily member 1. Shaded boxes represent mutations we have described.

Reference

1. LaFranchi SH. Newborn screening strategies for congenital hypothyroidism: an update. J Inherit Metab Dis. 2010; 33(Suppl 2):S225–S233. PMID: 20195902.

2. LaFranchi SH. Approach to the diagnosis and treatment of neonatal hypothyroidism. J Clin Endocrinol Metab. 2011; 96:2959–2967. PMID: 21976744.

3. Lanting CI, van Tijn DA, Loeber JG, Vulsma T, de Vijlder JJ, Verkerk PH. Clinical effectiveness and cost-effectiveness of the use of the thyroxine/thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program. Pediatrics. 2005; 116:168–173. PMID: 15995048.

4. Fujiwara F, Fujikura K, Okuhara K, Tsubaki J, Fukushi M, Fujita K, et al. Central congenital hypothyroidism detected by neonatal screening in Sapporo, Japan (2000-2004): it\'s prevalence and clinical characteristics. Clin Pediatr Endocrinol. 2008; 17:65–69. PMID: 24790365.

5. Tajima T, Jo W, Fujikura K, Fukushi M, Fujieda K. Elevated free thyroxine levels detected by a neonatal screening system. Pediatr Res. 2009; 66:312–316. PMID: 19542904.

6. Adachi M, Soneda A, Asakura Y, Muroya K, Yamagami Y, Hirahara F. Mass screening of newborns for congenital hypothyroidism of central origin by free thyroxine measurement of blood samples on filter paper. Eur J Endocrinol. 2012; 166:829–838. PMID: 22301913.

7. Kelberman D, Dattani MT. Role of transcription factors in midline central nervous system and pituitary defects. Endocr Dev. 2009; 14:67–82. PMID: 19293576.

8. Pfäffle R, Klammt J. Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency. Best Pract Res Clin Endocrinol Metab. 2011; 25:43–60. PMID: 21396574.

9. Tajima T, Ishizu K, Nakamura A. Molecular and clinical findings in patients with LHX4 and OTX2 Mutations. Clin Pediatr Endocrinol. 2013; 22:15–23. PMID: 23990694.

10. Miyai K, Azukizawa M, Kumahara Y. Familial isolated thyrotropin deficiency with cretinism. N Engl J Med. 1971; 285:1043–1048. PMID: 4106196.

11. Hayashizaki Y, Hiraoka Y, Endo Y, Miyai K, Matsubara K. Thyroid-stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the beta-subunit. EMBO J. 1989; 8:2291–2296. PMID: 2792087.

12. Collu R, Tang J, Castagne J, Lagace G, Masson N, Huot C, et al. A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab. 1997; 82:1561–1565. PMID: 9141550.

13. Bonomi M, Busnelli M, Beck-Peccoz P, Costanzo D, Antonica F, Dolci C, et al. A family with complete resistance to thyrotropin-releasing hormone. N Engl J Med. 2009; 360:731–734. PMID: 19213692.

14. Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, Voshol P, et al. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet. 2012; 44:1375–1381. PMID: 23143598.

15. Tajima T, Nakamura A, Ishizu K. A novel mutation of IGSF1 in a Japanese patient of congenital central hypothyroidism without macroorchidism. Endocr J. 2013; 60:245–249. PMID: 23363888.

16. Nakamura A, Bak B, Silander TL, Lam J, Hotsubo T, Yorifuji T, et al. Three novel IGSF1 mutations in four Japanese patients with X-linked congenital central hypothyroidism. J Clin Endocrinol Metab. 2013; 98:E1682–E1691. PMID: 23966245.

17. Joustra SD, Schoenmakers N, Persani L, Campi I, Bonomi M, Radetti G, et al. The IGSF1 deficiency syndrome: characteristics of male and female patients. J Clin Endocrinol Metab. 2013; 98:4942–4952. PMID: 24108313.

18. Mazzarella R, Pengue G, Jones J, Jones C, Schlessinger D. Cloning and expression of an immunoglobulin superfamily gene (IGSF1) in Xq25. Genomics. 1998; 48:157–162. PMID: 9521868.

19. Robakis T, Bak B, Lin SH, Bernard DJ, Scheiffele P. An internal signal sequence directs intramembrane proteolysis of a cellular immunoglobulin domain protein. J Biol Chem. 2008; 283:36369–36376. PMID: 18981173.

20. Bernard DJ, Chapman SC, Woodruff TK. Inhibin binding protein (InhBP/p120), betaglycan, and the continuing search for the inhibin receptor. Mol Endocrinol. 2002; 16:207–212. PMID: 11818494.

21. Bernard DJ, Burns KH, Haupt B, Matzuk MM, Woodruff TK. Normal reproductive function in InhBP/p120-deficient mice. Mol Cell Biol. 2003; 23:4882–4891. PMID: 12832474.

22. Chapman SC, Bernard DJ, Jelen J, Woodruff TK. Properties of inhibin binding to betaglycan, InhBP/p120 and the activin type II receptors. Mol Cell Endocrinol. 2002; 196:79–93. PMID: 12385827.

23. Barclay AN. Membrane proteins with immunoglobulin-like domains: a master superfamily of interaction molecules. Semin Immunol. 2003; 15:215–223. PMID: 14690046.

24. Xu Z, Jin B. A novel interface consisting of homologous immunoglobulin superfamily members with multiple functions. Cell Mol Immunol. 2010; 7:11–19. PMID: 20081873.

25. Ohtani H, Nakajima T, Akari H, Ishida T, Kimura A. Molecular evolution of immunoglobulin superfamily genes in primates. Immunogenetics. 2011; 63:417–428. PMID: 21390552.

26. Babu K, Hu Z, Chien SC, Garriga G, Kaplan JM. The immunoglobulin super family protein RIG-3 prevents synaptic potentiation and regulates Wnt signaling. Neuron. 2011; 71:103–116. PMID: 21745641.

27. Irintchev A, Schachner M. The injured and regenerating nervous system: immunoglobulin superfamily members as key players. Neuroscientist. 2012; 18:452–466. PMID: 21903634.

28. Yu XM, Gutman I, Mosca TJ, Iram T, Ozkan E, Garcia KC, et al. Plum, an immunoglobulin superfamily protein, regulates axon pruning by facilitating TGF-β signaling. Neuron. 2013; 78:456–468. PMID: 23664613.

29. Malaguti A, Della Casa C, Castorina S, Martelli AM, Roti E, Martino E, et al. Molecular mechanisms for pituitary thyrotroph cell growth. J Endocrinol Invest. 2004; 27(6 Suppl):151–167. PMID: 15481817.

30. Shibusawa N, Yamada M, Hirato J, Monden T, Satoh T, Mori M. Requirement of thyrotropin-releasing hormone for the postnatal functions of pituitary thyrotrophs: ontogeny study of congenital tertiary hypothyroidism in mice. Mol Endocrinol. 2000; 14:137–146. PMID: 10628753.

31. Inokuchi M, Matsuo N, Takayama JI, Hasegawa T. Tracking of BMI in Japanese children from 6 to 18 years of age: reference values for annual BMI incremental change and proposal for size of increment indicative of risk for obesity. Ann Hum Biol. 2011; 38:146–149. PMID: 20632778.