Consult the medical resource doctors trust

UpToDate is one of the most respected medical information resources in the world, used by over 360,000 doctors and thousands of patients to find answers to medical questions.

  • Content written by a faculty of over 4,000 physicians from leading medical institutions
  • Unbiased: free of advertising or pharmaceutical funding
  • Evidence-based treatment recommendations
  • Continuously updated to incorporate new medical findings

Clinical features and detection of congenital hypothyroidism

INTRODUCTION

Congenital hypothyroidism, occurring in approximately 1:2000 to 1:4000 newborns, is the most common treatable cause of intellectual disability (mental retardation). There is an inverse relationship between age at diagnosis and intelligence quotient (IQ) later in life, so that the longer the condition goes undetected, the lower the IQ [1]. (See "Intellectual disability (mental retardation) in children: Definition; causes; and diagnosis".)

Most newborn babies with congenital hypothyroidism have few or no clinical manifestations of thyroid deficiency, and the majority of cases are sporadic. As a result, it is not possible to predict which infants are likely to be affected. For these reasons, newborn screening programs in which either thyroxine (T4) or thyrotropin (TSH) are measured in heel-stick blood specimens were developed in the mid-1970s to detect this condition as early as possible [2]. These screening efforts have been largely successful, but more severely affected infants may still have a slightly reduced IQ and other neurologic deficits despite prompt diagnosis and initiation of therapy.

This topic will review the epidemiology, causes, clinical manifestations, and diagnosis of congenital hypothyroidism, and its detection by newborn screening. Treatment and prognosis of this disorder are discussed separately. (See "Treatment and prognosis of congenital hypothyroidism".)

EPIDEMIOLOGY

Data obtained from national and regional screening programs indicate that the incidence of congenital hypothyroidism varies globally. The incidence varies by geographic location and by ethnicity, as illustrated by the following studies:

  • In a study over a 20-year period (1981 to 2002) from a French screening program, the incidence of an elevated TSH value in neonates was 1:10,000 [3]. Of the patients with an elevated screening test, 60 percent had permanent congenital hypothyroidism and the rest had transient hypothyroidism.
  • In a study in the Greek Cypriot population over an 11-year period (1990 to 2000), the incidence of permanent congenital hypothyroidism was 1:1800. Hypothyroidism was initially detected by an elevated TSH value obtained between 3 to 6 days of age [4].
To continue reading this article you need to subscribe.

Read the rest of this article and others like it

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use (click here) ©2009 UpToDate, Inc.
References Top
  1. Klein, AH, Meltzer, S, Kenny, FM. Improved prognosis in congenital hypothyroidism treated before age three months. J Pediatr 1972; 81:912.
  2. Dussault, JH, Coulombe, P, Laberge, et al. Preliminary report on a mass screening program for neonatal hypothyroidism. J Pediatr 1975; 86:670.
  3. Gaudino, R, Garel, C, Czernichow, P, Leger, J. Proportion of various types of thyroid disorders among newborns with congenital hypothyroidism and normally located gland: a regional cohort study. Clin Endocrinol (Oxf) 2005; 62:444.
  4. Skordis, N, Toumba, M, Savva, SC, et al. High prevalence of congenital hypothyroidism in the Greek Cypriot population: results of the neonatal screening program 1990-2000. J Pediatr Endocrinol Metab 2005; 18:453.
  5. Harris KB, Pass KA. Increase in congenital hypothyroidism in New York State and in the United States. Mol Genet Metab 2007; 91:268.
  6. Eugene, D, Djemli, A, Van Vliet, G. Sexual dimorphism of thyroid function in newborns with congenital hypothyroidism. J Clin Endocrinol Metab 2005; 90:2696.
  7. Fisher, DA. Second international conference on neonatal thyroid screening: progress report. J Pediatr 1983; 102:653.
  8. Devos, H, Rodd, C, Gagne, N, et al. A search for the possible molecular mechanisms of thyroid dysgenesis: Sex rations and associated malformations. J Clin Endocrinol Metab 1999; 84:2502.
  9. Macchia, PE, Lapi, P, Krude, H, et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 1998; 19:83.
  10. Clifton-Bligh, RJ, Wentworth, JM, Heinz, P, et al. Mutation of the gene encoding TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 1998; 19:399.
  11. Vilain, C, Rydlewski, Duprez, L, et al. Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX-8. J Clin Endocrinol Metab 2001; 86:234.
  12. Castanet, M, Lyonnet, S, Bonaiti-Pellie, C, et al. Familial forms of thyroid dysgenesis among infants with congenital hypothyroidism. N Engl J Med 2000; 343:441.
  13. Castanet, M, Polak, M, Bonaiti-Pellie, C, et al. Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors. J Clin Endocrinol Metab 2001; 86:2009.
  14. Leger, J, Marinovic, D, Garel, C, et al. Thyroid developmental anomalies in first degree relatives of children with congenital hypothyroidism. J Clin Endocrinol Metab 2002; 87:575.
  15. Perry, R, Heinrichs, C, Bourdoux, P, et al. Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology. J Clin Endocrinol Metab 2002; 87:4072.
  16. Doyle DA, Gonzalez I, Thomas B, Scavina M. Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2.1. J Pediatr 2004;145:190.
  17. Castanet M, Park SM, Smith A, et al. A novel loss-of-function mutation in TTF-2 is associated with congenital hypothroidism, thyroid agenesis, and cleft palate. Hum Mol Genet 2002;11:2051.
  18. Baris, I, Arisoy, AE, Smith, A, et al. A novel missense mutation in human TTF-2 (FKHL15) gene associated with congenital hypothyroidism but not athyreosis. J Clin Endocrinol Metab 2006; 91:4183.
  19. van Trotsenburg, AS, Kempers, MJ, Endert, E, et al. Trisomy 21 causes persistent congenital hypothyroidism presumably of thyroidal origin. Thyroid 2006; 16:671.
  20. Sunthornthepvarakui, T, Gottschalk, ME, Hayashi, Y, Refetoff, S. Resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med 1995; 332:155.
  21. Narumi, S, Muroya, K, Abe, Y, et al. TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study. J Clin Endocrinol Metab 2009; 94:1317.
  22. Bakker, B, Bikker, H, Vulsma, T, et al. Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). J Clin Endocrinol Metab 2000; 85:3708.
  23. Pohlenz, J, Rosenthal, IM, Weiss, RE, et al. Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site. J Clin Invest 1998; 101:1028.
  24. Vigone, MC, Fugazzola, L, Zamproni, I, et al. Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings. Hum Mutat 2005; 26:395.
  25. Moreno, JC, Bikker, H, Kempers, MJ, et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med 2002; 347:95.
  26. Zamproni, I, Grasberger, H, Cortinovis, F, et al. Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism. J Clin Endocrinol Metab 2008; 93:605.
  27. Pardo, V, Rubio, IG, Knobel, M, et al. Phenotypic variation among four family members with congenital hypothyroidism caused by two distinct thyroglobulin gene mutations. Thyroid 2008; 18:783.
  28. Moreno, JC, Klootwijk, W, van Toor, H, et al. Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Engl J Med 2008; 358:1811.
  29. Friesema ED, Grueters A, Biebermann H, et al. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 2004;364:1435.
  30. Sijens, PE, Rodiger, LA, Meiners, LC, Lunsing, RJ. 1H magnetic resonance spectroscopy in monocarboxylate transporter 8 gene deficiency. J Clin Endocrinol Metab 2008; 93:1854.
  31. Hanna, CE, Krainz, PL, Skeels, MR, et al. Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program. J Pediatr 1986; 109:959.
  32. Collu, R, Tang, J, Castagné, J, 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.
  33. Medeiros-Neto, G, Herodotou, DT, Rajan, S, et al. A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene. J Clin Invest 1996; 97:1250.
  34. Doeker, BM, Pfaffle, RW, Pohlenz, J, Andler, W. Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin beta-subunit gene follows an autosomal recessive inheritance. J Clin Endocrinol Metab 1998; 83:1762.
  35. van Tijn, DA, de Vijlder, JJ, Vulsma, T. Role of the thyrotropin-releasing hormone stimulation test in diagnosis of congenital central hypothyroidism in infants. J Clin Endocrinol Metab 2008; 93:410.
  36. Kempers, MJ, van Tijn, DA, van Trotsenburg, AS, et al. Central congenital hypothyroidism due to gestational hyperthyroidism: detection where prevention failed. J Clin Endocrinol Metab 2003; 88:5851.
  37. Higuchi, R, Miyawaki, M, Kumagai, T, et al. Central hypothyroidism in infants who were born to mothers with thyrotoxicosis before 32 weeks' gestation: 3 cases. Pediatrics 2005; 115:e623.
  38. Kempers, MJ, van Trotsenburg, AS, van Rijn, RR, et al. Loss of integrity of thyroid morphology and function in children born to mothers with inadequately treated Graves' disease. J Clin Endocrinol Metab 2007; 92:2984.
  39. Delange, F, et al. Increased risk of primary hypothyroidism in preterm infants. J Pediatr 1984; 105:402.
  40. Zakarija, M, McKenzie, JM, Eidson, MS. Transient neonatal hypothyroidism: characterization of maternal antibodies to the thyrotropin receptor. J Clin Endocrinol Metab 1990; 70:1239.
  41. Brown RS, Bellisario RL, Mitchell E, et al. Detection of thyrotropin binding inhibitory activity in neonatal blood spots. J Clin Endocrinol Metab 1993;77:1005.
  42. Iseki, M, Shimizu, M, Oikawa, T, et al. Sequential serum measurements of thyrotropin binding inhibitor immunoglobulin G in transient familial neonatal hypothyroidism. J Clin Endocrinol Metab 1983; 57:384.
  43. Pacaud, D, Huot, C, Gattereau, A, et al. Outcome in three siblings with antibody-mediated transient congenital hypothyroidism. J Pediatr 1995; 127:275.
  44. Bartalena, L, Bogazzi, F, Braverman, LE, Martino, E. Effects of amiodarone administration during pregnancy on neonatal thyroid function and subsequent neurodevelopment. J Endocrinol Invest 2001; 24:116.
  45. Cosman, BC, Schullmger, JN, Bell, JJ, et al. Hypothyroidism caused by topical povidone-iodine in a newborn with omphalocele. J Pediatr Surg 1988; 23:356.
  46. Rodesch, F, Camus, M, Ermans, AM, et al. Adverse effect of amniofetography on fetal thyroid function. Am J Obstet Gynecol 1976; 126:723.
  47. Atwell, TD, Lteif, AN, Brown, DL, et al. Neonatal thyroid function after administration of IV iodinated contrast agent to 21 pregnant patients. AJR Am J Roentgenol 2008; 191:268.
  48. Mouat, F, Evans, HM, Cutfield, WS, et al. Massive hepatic hemangioendothelioma and consumptive hypothyroidism. J Pediatr Endocrinol Metab 2008; 21:701.
  49. Maruo, Y, Takahashi, H, Soeda, I, et al. Transient congenital hypothyroidism caused by biallelic mutations of the dual oxidase 2 gene in Japanese patients detected by a neonatal screening program. J Clin Endocrinol Metab 2008; 93:4261.
  50. Alm, J, Hagenfeldt, Larsson, A, et al. Incidence of congenital hypothyroidism: retrospective study of neonatal laboratory screening versus clinical symptoms as indicators leading to diagnosis. BMJ 1984; 289:1171.
  51. Vulsma, T, Gons, MH, deVijlder, JJM. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 1989; 321:13.
  52. Shoham, I, Aricha-Tamir, B, Weintraub, AY, et al. Fetal heart rate tracing patterns associated with congenital hypothyroidism. Am J Obstet Gynecol 2009; 201:48.
  53. Law, WY, Bradley, DM, Lazarus, JH, et al. Congenital hypothyroidism in Wales (1982-1993): demographic features, clinical presentation and effects on early neurodevelopment. Clin Endocrinol 1998; 48:201.
  54. Van Vliet, G, Larroque, B, Bubuteishvili, L, et al. Sex-Specific Impact of Congenital Hypothyroidism due to Thyroid Dysgenesis on Skeletal Maturation in Term Newborns. J Clin Endocrinol Metab 2003; 88:2009.
  55. LaFranchi, SH, Murphey, WH, Foley, TP Jr, et al. Neonatal hypothyroidism detected by the Northwest Regional Screening Program. Pediatrics 1979; 63:180.
  56. Olivieri, A, Stazi, MA, Mastroiacovo, P, et al. A population-based study on the frequency of additional congenital malformations in infants with congenital hypothyroidism: data from the Italian Registry for Congenital Hypothyroidism (1991-1998). J Clin Endocrinol Metab 2002; 87:557.
  57. Siebner, R, Merlob, P, Kaiserman, I, Sack, J. Congenital anomalies concomitant with persistent primary congenital hypothyroidism. Am J Med Genet 1992; 44:57.
  58. Roberts, HE, Moore, CA, Fernhoff, PM, et al. Population study of congenital hypothyroidism and associated birth defects, Atlanta, 1979-1992. Am J Med Genet 1997; 71:29.
  59. Al-Jurayyan, NA, Al-Herbish, AS, El-Desouki, MI, et al. Congenital anomalies in infants with congenital hypothyroidism: is it a coincidental or an associated finding? Hum Hered 1997; 47:33.
  60. Kumar, J, Gordillo, R, Kaskel, FJ, et al. Increased prevalence of renal and urinary tract anomalies in children with congenital hypothyroidism. J Pediatr 2009; 154:263.
  61. Rose, SR, Brown, RS, Foley, T, et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006; 117:2290.
  62. LaFranchi, SH, Hanna, CE, Krainz, PL, et al. Screening for congenital hypothyroidism with specimen collection at two time periods: results of the Northwest Regional Screening Program. Pediatrics 1985; 76:734.
  63. Asami, T, Otabe, N, Wakabaysahi, M, et al. Congenital hypothyroidism with delayed rise in serum TSH missed on newborn screening. Acta Paediatr Jpn 1995; 37:634.
  64. van Tijn, DA, de Vijlder, JJ, Verbeeten, B Jr, et al. Neonatal detection of congenital hypothyroidism of central origin. J Clin Endocrinol Metab 2005; 90:3350.
  65. Lanting, CI, van Tijn, DA, Loeber, JG, et al. 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.
  66. Leonardi, D, Polizzotti, N, Carta, A, et al. Longitudinal study of thyroid function in children with mild hyperthyrotropinemia at neonatal screening for congenital hypothyroidism. J Clin Endocrinol Metab 2008; 93:2679.
  67. Larson, C, Hermos, R, Delaney, A, et al. Risk factors associated with delayed thyrotropin elevations in congenital hypothyroidism. J Pediatr 2003; 143:587.
  68. Fisher, DA. Euthyroid low thyroxine (T4) and triiodothyronine (T3) states in prematures and sick neonates. Pediatr Clin North Am 1990; 37:1297.
  69. Mandel, SH, Hanna, CE, Boston, BA, et al. Thyroxine-binding globulin deficiency detected by newborn screening. J Pediatr 1993; 122:227.
  70. Muir, A, Daneman, D, Daneman, A, et al. Thyroid scanning, ultrasound and serum thyroglobulin in determining the origin of congenital hypothyroidism. Am J Dis Child 1988; 142:214.
  71. Schoen, EJ, Clapp, W, To, TT, Fireman, BH. The key role of newborn thyroid scintigraphy with isotopic iodide (123I) in defining and managing congenital hypothyroidism. Pediatrics 2004; 114:e683.
  72. Takashima, S, Nomura, N, Tanaka, H, et al. Congenital hypothyroidism assessment with ultrasound. AJNR Am J Neuroradiol 1995; 16:1117.
  73. Ohnishi, H, Sato, H, Noda, H, et al. Color Doppler ultrasonography: diagnosis of ectopic thyroid gland in patients with congenital hypothyroidism caused by thyroid dysgenesis. J Clin Endocrinol Metab 2003; 88:5145.
white circle LOG IN
white circle DEMO