UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Clinical features and detection of congenital hypothyroidism

Author
Stephen LaFranchi, MD
Section Editor
Mitchell E Geffner, MD
Deputy Editor
Alison G Hoppin, MD

INTRODUCTION

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

Most newborn babies with congenital hypothyroidism have few or no clinical manifestations of thyroid hormone 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 (thyroid-stimulating hormone [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:

A summary of all screening programs in the United States found that the incidence of congenital hypothyroidism increased from 1:4094 in 1987 to 1:2372 in 2002 [3]. The reasons for the increased incidence are not clear. It is possible that changes in testing cutoffs have led to detection of milder cases. In addition, there is some variation in the incidence among different racial and ethnic groups, and the mix of these groups has changed. A review of the New York program during the years 2000 to 2003 showed that the incidence of congenital hypothyroidism was somewhat lower in white (1:1815) and black infants (1:1902), as compared with Hispanic (1:1559) and Asian infants (1:1016); the overall incidence of congenital hypothyroidism was 1:1601 [3]. In addition, the incidence was nearly double in twin births (1:876) as compared with singletons (1:1765), and even higher in multiple births (1:575). The incidence was higher in preterm infants (<1500 gm; 1:1396) than term infants (>2500 gm 1:1843). Older mothers (>39 years of age) had a higher incidence (1:1328) than younger mothers (<20 years; 1:1703).

                               

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Wed Nov 18 00:00:00 GMT+00:00 2015.
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 ©2016 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 C, et al. Preliminary report on a mass screening program for neonatal hypothyroidism. J Pediatr 1975; 86:670.
  3. Harris KB, Pass KA. Increase in congenital hypothyroidism in New York State and in the United States. Mol Genet Metab 2007; 91:268.
  4. Gaudino R, Garel C, Czernichow P, Léger 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.
  5. 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.
  6. Dorreh F, Chaijan PY, Javaheri J, Zeinalzadeh AH. Epidemiology of congenital hypothyroidism in Markazi Province, Iran. J Clin Res Pediatr Endocrinol 2014; 6:105.
  7. Eugène D, Djemli A, Van Vliet G. Sexual dimorphism of thyroid function in newborns with congenital hypothyroidism. J Clin Endocrinol Metab 2005; 90:2696.
  8. Stoppa-Vaucher S, Van Vliet G, Deladoëy J. Variation by ethnicity in the prevalence of congenital hypothyroidism due to thyroid dysgenesis. Thyroid 2011; 21:13.
  9. Nagasaki K, Asami T, Ogawa Y, et al. A study of the etiology of congenital hypothyroidism in the Niigata prefecture of Japan in patients born between 1989 and 2005 and evaluated at ages 5-19. Thyroid 2011; 21:361.
  10. Fisher DA. Second International Conference on Neonatal Thyroid Screening: progress report. J Pediatr 1983; 102:653.
  11. Devos H, Rodd C, Gagné N, et al. A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations. J Clin Endocrinol Metab 1999; 84:2502.
  12. Castanet M, Polak M, Bonaïti-Pellié 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.
  13. Castanet M, Lyonnet S, Bonaïti-Pellié C, et al. Familial forms of thyroid dysgenesis among infants with congenital hypothyroidism. N Engl J Med 2000; 343:441.
  14. Léger 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. Vilain C, Rydlewski C, Duprez L, et al. Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J Clin Endocrinol Metab 2001; 86:234.
  17. 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.
  18. Narumi S, Muroya K, Asakura Y, et al. Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a population-based cohort of Japanese patients. J Clin Endocrinol Metab 2010; 95:1981.
  19. Carvalho A, Hermanns P, Rodrigues AL, et al. A new PAX8 mutation causing congenital hypothyroidism in three generations of a family is associated with abnormalities in the urogenital tract. Thyroid 2013; 23:1074.
  20. Castanet M, Park SM, Smith A, et al. A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate. Hum Mol Genet 2002; 11:2051.
  21. 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.
  22. Shetty VB, Kiraly-Borri C, Lamont P, et al. NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients. J Pediatr Endocrinol Metab 2014; 27:373.
  23. Baş VN, Ozgelen S, Cetinkaya S, Aycan Z. Diseases accompanying congenital hypothyroidism. J Pediatr Endocrinol Metab 2014; 27:485.
  24. van Trotsenburg AS, Kempers MJ, Endert E, et al. Trisomy 21 causes persistent congenital hypothyroidism presumably of thyroidal origin. Thyroid 2006; 16:671.
  25. Sunthornthepvarakui T, Gottschalk ME, Hayashi Y, Refetoff S. Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med 1995; 332:155.
  26. 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.
  27. Cangul H, Morgan NV, Forman JR, et al. Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism. Clin Endocrinol (Oxf) 2010; 73:671.
  28. Persani L, Gelmini G, Marelli F, et al. Syndromes of resistance to TSH. Ann Endocrinol (Paris) 2011; 72:60.
  29. Lado-Abeal J, Castro-Piedras I, Palos-Paz F, et al. A family with congenital hypothyroidism caused by a combination of loss-of-function mutations in the thyrotropin receptor and adenylate cyclase-stimulating G alpha-protein subunit genes. Thyroid 2011; 21:103.
  30. 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.
  31. 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.
  32. Ladsous M, Vlaeminck-Guillem V, Dumur V, et al. Analysis of the thyroid phenotype in 42 patients with Pendred syndrome and nonsyndromic enlargement of the vestibular aqueduct. Thyroid 2014; 24:639.
  33. 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.
  34. 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.
  35. Muzza M, Rabbiosi S, Vigone MC, et al. The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects. J Clin Endocrinol Metab 2014; 99:E544.
  36. 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.
  37. 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.
  38. Moreno JC, Klootwijk W, van Toor H, et al. Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Engl J Med 2008; 358:1811.
  39. Friesema EC, Grueters A, Biebermann H, et al. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 2004; 364:1435.
  40. 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.
  41. 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.
  42. 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.
  43. 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.
  44. Doeker BM, Pfäffle 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.
  45. Pine-Twaddell E, Romero CJ, Radovick S. Vertical transmission of hypopituitarism: critical importance of appropriate interpretation of thyroid function tests and levothyroxine therapy during pregnancy. Thyroid 2013; 23:892.
  46. 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.
  47. 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.
  48. 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.
  49. 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.
  50. Delange F, Dalhem A, Bourdoux P, et al. Increased risk of primary hypothyroidism in preterm infants. J Pediatr 1984; 105:462.
  51. Zakarija M, McKenzie JM, Eidson MS. Transient neonatal hypothyroidism: characterization of maternal antibodies to the thyrotropin receptor. J Clin Endocrinol Metab 1990; 70:1239.
  52. 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.
  53. 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.
  54. Pacaud D, Huot C, Gattereau A, et al. Outcome in three siblings with antibody-mediated transient congenital hypothyroidism. J Pediatr 1995; 127:275.
  55. 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.
  56. Cosman BC, Schullinger JN, Bell JJ, Regan JA. Hypothyroidism caused by topical povidone-iodine in a newborn with omphalocele. J Pediatr Surg 1988; 23:356.
  57. Rodesch F, Camus M, Ermans AM, et al. Adverse effect of amniofetography on fetal thyroid function. Am J Obstet Gynecol 1976; 126:723.
  58. Thaker VV, Leung AM, Braverman LE, et al. Iodine-induced hypothyroidism in full-term infants with congenital heart disease: more common than currently appreciated? J Clin Endocrinol Metab 2014; 99:3521.
  59. Linder N, Sela B, German B, et al. Iodine and hypothyroidism in neonates with congenital heart disease. Arch Dis Child Fetal Neonatal Ed 1997; 77:F239.
  60. Smerdely P, Lim A, Boyages SC, et al. Topical iodine-containing antiseptics and neonatal hypothyroidism in very-low-birthweight infants. Lancet 1989; 2:661.
  61. US Food and Drug Administration 11/17/15: FDA Drug Safety Communication: FDA advises of rare cases of underactive thyroid in infants given iodine-containing contrast agents for medical imaging http://www.fda.gov/Drugs/DrugSafety/ucm472782.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery (Accessed on November 18, 2015).
  62. Connelly KJ, Boston BA, Pearce EN, et al. Congenital hypothyroidism caused by excess prenatal maternal iodine ingestion. J Pediatr 2012; 161:760.
  63. 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.
  64. Bourjeily G, Chalhoub M, Phornphutkul C, et al. Neonatal thyroid function: effect of a single exposure to iodinated contrast medium in utero. Radiology 2010; 256:744.
  65. Mouat F, Evans HM, Cutfield WS, et al. Massive hepatic hemangioendothelioma and consumptive hypothyroidism. J Pediatr Endocrinol Metab 2008; 21:701.
  66. 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.
  67. Hulur I, Hermanns P, Nestoris C, et al. A single copy of the recently identified dual oxidase maturation factor (DUOXA) 1 gene produces only mild transient hypothyroidism in a patient with a novel biallelic DUOXA2 mutation and monoallelic DUOXA1 deletion. J Clin Endocrinol Metab 2011; 96:E841.
  68. Alm J, Hagenfeldt L, Larsson A, Lundberg K. Incidence of congenital hypothyroidism: retrospective study of neonatal laboratory screening versus clinical symptoms as indicators leading to diagnosis. Br Med J (Clin Res Ed) 1984; 289:1171.
  69. Vulsma T, Gons MH, de Vijlder JJ. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 1989; 321:13.
  70. 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.e1.
  71. 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 (Oxf) 1998; 48:201.
  72. 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.
  73. LaFranchi SH, Murphey WH, Foley TP Jr, et al. Neonatal hypothyroidism detected by the Northwest Regional Screening Program. Pediatrics 1979; 63:180.
  74. 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.
  75. Siebner R, Merlob P, Kaiserman I, Sack J. Congenital anomalies concomitant with persistent primary congenital hypothyroidism. Am J Med Genet 1992; 44:57.
  76. 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.
  77. 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.
  78. 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.
  79. Ford G, LaFranchi SH. Screening for congenital hypothyroidism: a worldwide view of strategies. Best Pract Res Clin Endocrinol Metab 2014; 28:175.
  80. Centers for Disease Control and Prevention (CDC). CDC Grand Rounds: Newborn screening and improved outcomes. MMWR Morb Mortal Wkly Rep 2012; 61:390.
  81. American Academy of Pediatrics, Rose SR, Section on Endocrinology and Committee on Genetics, American Thyroid Association, et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006; 117:2290.
  82. Léger J, Olivieri A, Donaldson M, et al. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab 2014; 99:363.
  83. Asami T, Otabe N, Wakabayashi M, et al. Congenital hypothyroidism with delayed rise in serum TSH missed on newborn screening. Acta Paediatr Jpn 1995; 37:634.
  84. Nebesio TD, McKenna MP, Nabhan ZM, Eugster EA. Newborn screening results in children with central hypothyroidism. J Pediatr 2010; 156:990.
  85. 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.
  86. Larson C, Hermos R, Delaney A, et al. Risk factors associated with delayed thyrotropin elevations in congenital hypothyroidism. J Pediatr 2003; 143:587.
  87. Fisher DA. Euthyroid low thyroxine (T4) and triiodothyronine (T3) states in prematures and sick neonates. Pediatr Clin North Am 1990; 37:1297.
  88. 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.
  89. Mandel S, Hanna C, Boston B, et al. Thyroxine-binding globulin deficiency detected by newborn screening. J Pediatr 1993; 122:227.
  90. Muir A, Daneman D, Daneman A, Ehrlich R. Thyroid scanning, ultrasound, and serum thyroglobulin in determining the origin of congenital hypothyroidism. Am J Dis Child 1988; 142:214.
  91. 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.
  92. Supakul N, Delaney LR, Siddiqui AR, et al. Ultrasound for primary imaging of congenital hypothyroidism. AJR Am J Roentgenol 2012; 199:W360.
  93. Takashima S, Nomura N, Tanaka H, et al. Congenital hypothyroidism: assessment with ultrasound. AJNR Am J Neuroradiol 1995; 16:1117.
  94. Chang YW, Lee DH, Hong YH, et al. Congenital hypothyroidism: analysis of discordant US and scintigraphic findings. Radiology 2011; 258:872.
  95. 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.
  96. Dias VM, Campos AP, Chagas AJ, Silva RM. Congenital hypothyroidism: etiology. J Pediatr Endocrinol Metab 2010; 23:815.