Abstract
Congenital hypothyroidism is the most frequent endocrine disorder in neonates. Controversy exists regarding the necessity to adjust current screening programs to also diagnose patients with central hypothyroidism or those with mild forms of congenital hypothyroidism, who have high TSH levels but normal T4 and normal T3 levels (also known as 'subclinical hypothyroidism'). Thyroid hormone replacement should start as soon as the diagnosis is confirmed by measurement of elevated TSH and low serum thyroid hormone levels. Further diagnostic approaches, such as ultrasonography, scintigraphy and measurement of thyroglobulin levels, to determine the subtype of congenital hypothyroidism, should not delay initiation of treatment. Recommendations regarding the initial dosage of levothyroxine vary considerably, and no general accepted guideline exists with regards to initial dosage or optimal time point for dose adjustment according to biochemical parameters. More than 30 years after the introduction of the first neonatal screening programs, mental retardation can be prevented in the majority of children (>90%) with congenital hypothyroidism if therapy is commenced within the first 2 weeks of life, making neonate screening for this disorder the most successful population-based screening test in pediatrics.
Key Points
-
Neonatal screening for primary congenital hypothyroidism is an efficient tool for the secondary prevention of severe mental retardation
-
Diagnosis of primary congenital hypothyroidism is based on detection of an increased TSH concentration in the presence of low T4 levels in serum
-
The differential diagnosis of congenital hypothyroidism includes defects of thyroid hormone synthesis in patients with a normal thyroid gland or goiter and several diseases arising from thyroid transcription factor defects in patients with thyroid dysgenesis
-
Although evidence for particular treatment modalities was not generated in prospective controlled studies, an initial daily dose of >10 μg levothyroxine per kg of body weight is recommended to treat congenital hypothyroidism
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Radwin, L. S., Michelson, J. P., Berman, A. B. & Kramer, B. End results in treatment of congenital hypothyroidism; follow-up study of physical, mental and behavioral development. Am. J. Dis. Child. 78, 821–843 (1949).
Fisher, D. A. et al. Screening for congenital hypothyroidism: results of screening one million North American infants. J. Pediatr. 94, 700–705 (1979).
Illig, R. & Gitzelmann, R. Screening for congenital hypothyroidism. J. Pediatr. 91, 348–349 (1977).
Clerc, J. et al. Scintigraphic imaging of paediatric thyroid dysfunction. Horm. Res. 70, 1–13 (2008).
Bubuteishvili, L., Garel, C., Czernichow, P. & Léger, J. Thyroid abnormalities by ultrasonography in neonates with congenital hypothyroidism. J. Pediatr. 143, 759–764 (2003).
Marinovic, D., Garel, C., Czernichow, P. & Léger, J. Ultrasonographic assessment of the ectopic thyroid tissue in children with congenital hypothyroidism. Pediatr. Radiol. 34, 109–113 (2004).
Maiorana, R. et al. Thyroid hemiagenesis: prevalence in normal children and effect on thyroid function. J. Clin. Endocrinol. Metab. 88, 1534–1536 (2003).
Klein, A. H., Meltzer, S. & Kenny, F. M. Improved prognosis in congenital hypothyroidism treated before age three months. J. Pediatr. 81, 912–915 (1972).
Odell, W. D., Wilber, J. F. & Paul, W. E. Radioimmunoassay of human thyrotropin in serum. Metabolism 14, 465–467 (1965).
Klein, A. H., Agustin, A. V. & Foley, T. P. Jr. Successful laboratory screening for congenital hypothyroidism. Lancet 2, 77–79 (1974).
Dussault, J. H. et al. Preliminary report on a mass screening program for neonatal hypothyroidism. J. Pediatr. 86, 670–674 (1975).
Fisher, D. A. & Odell, W. D. Acute release of thyrotropin in the newborn. J. Clin. Invest. 48, 1670–1677 (1969).
Alm, J., Larsson, A. & Zetterström, R. Congenital hypothyroidism in Sweden. Incidence and age at diagnosis. Acta Paediatr. Scand. 67, 1–3 (1978).
Jacobsen, B. B. & Brandt, N. J. Congenital hypothyroidism in Denmark. Arch. Dis. Child. 56, 134–136 (1981).
Hulse, J. A. Outcome for congenital hypothyroidism. Arch. Dis. Child. 59, 23–29 (1984).
Grosse, S. D. & Van Vliet, G. Prevention of intellectual disability through screening for congenital hypothyroidism: how much and at what level? Arch. Dis. Child. 96, 374–379 (2011).
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.) 289, 1171–1175 (1984).
Rastogi, M. V. & LaFranchi, S. H. Congenital hypothyroidism. Orphanet. J. Rare Dis. 5, 17 (2010).
Stoppa-Vaucher, S., Van Vliet, G. & Deladoëy, J. Variation by ethnicity in the prevalence of congenital hypothyroidism due to thyroid dysgenesis. Thyroid 21, 13–18 (2011).
Castanet, M. 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. 86, 2009–2014 (2001).
Hinton, C. F. et al. Trends in incidence rates of congenital hypothyroidism related to select demographic factors: data from the United States, California, Massachusetts, New York, and Texas. Pediatrics 125 (Suppl. 2), S37–S47 (2010).
De Felice, M. & Di Lauro, R. Thyroid development and its disorders: genetics and molecular mechanisms. Endocr. Rev. 25, 722–746 (2004).
Léger, J. et al. Thyroid developmental anomalies in first degree relatives of children with congenital hypothyroidism. J. Clin. Endocrinol. Metab. 87, 575–580 (2002).
Perry, R. et al. Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology. J. Clin. Endocrinol. Metab. 87, 4072–4077 (2002).
van Trotsenburg, A. S. et al. Trisomy 21 causes persistent congenital hypothyroidism presumably of thyroidal origin. Thyroid 16, 671–680 (2006).
Stagi, S., Manoni, C., Salti, R., Cecchi, C. & Chiarelli, F. Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. Horm. Res. 70, 316–318 (2008).
Narumi, S., Muroya, K., Asakura, Y., Adachi, M. & Hasegawa, T. Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a population-based cohort of Japanese patients. J. Clin. Endocrinol. Metab. 95, 1981–1985 (2010).
Al Taji, E. et al. Screening for mutations in transcription factors in a Czech cohort of 170 patients with congenital and early-onset hypothyroidism: identification of a novel PAX8 mutation in dominantly inherited early-onset non-autoimmune hypothyroidism. Eur. J. Endocrinol. 156, 521–529 (2007).
Bamforth, J. S., Hughes, I. A., Lazarus, J. H., Weaver, C. M. & Harper, P. S. Congenital hypothyroidism, spiky hair, and cleft palate. J. Med. Genet. 26, 49–51 (1989).
Clifton-Bligh, R. J. et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat. Genet. 19, 399–401 (1998).
Castanet, M. & Polak, M. Spectrum of human Foxe1/TTF2 mutations. Horm. Res. Paediatr. 73, 423–429 (2010).
Krude, H. et al. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2–1 haploinsufficiency. J. Clin. Invest. 109, 475–480 (2002).
Pohlenz, J. et al. Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. J. Clin. Invest. 109, 469–473 (2002).
Carré, A. et al. Five new TTF1/NKX2.1 mutations in brain–lung–thyroid syndrome: rescue by PAX8 synergism in one case. Hum. Mol. Genet. 18, 2266–2276 (2009).
Guillot, L. et al. NKX2–1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain–Lung–Thyroid Syndrome”. Hum. Mutat. 31, E1146–E1162 (2010).
Breedveld, G. J. et al. Mutations in TITF-1 are associated with benign hereditary chorea. Hum. Mol. Genet. 11, 971–979 (2002).
Dentice, M. et al. Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. J. Clin. Endocrinol. Metab. 91, 1428–1433 (2006).
Macchia, P. E. et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat. Genet. 19, 83–86 (1998).
Meeus, L. et al. Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid. J. Clin. Endocrinol. Metab. 89, 4285–4291 (2004).
Montanelli, L. & Tonacchera, M. Genetics and phenomics of hypothyroidism and thyroid dys- and agenesis due to PAX8 and TTF1 mutations. Mol. Cell Endocrinol. 322, 64–71 (2010).
Biebermann, H., Grüters, A., Schöneberg, T. & Gudermann, T. Congenital hypothyroidism caused by mutations in the thyrotropin-receptor gene. N. Engl. J. Med. 336, 1390–1391 (1997).
Refetoff, S. Resistance to thyrotropin. J. Endocrinol. Invest. 26, 770–779 (2003).
Bizhanova, A. & Kopp, P. Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology 150, 1084–1090 (2009).
Ris-Stalpers, C. & Bikker, H. Genetics and phenomics of hypothyroidism and goiter due to TPO mutations. Mol. Cell Endocrinol. 322, 38–43 (2010).
Moreno, J. C. & Visser, T. J. New phenotypes in thyroid dyshormonogenesis: hypothyroidism due to DUOX2 mutations. Endocr. Dev. 10, 99–117 (2007).
Medeiros-Neto, G., Targovnik, H. M. & Vassart, G. Defective thyroglobulin synthesis and secretion causing goiter and hypothyroidism. Endocr. Rev. 14, 165–183 (1993).
Abramowicz, M. J. et al. Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter. J. Clin. Invest. 90, 1200–1204 (1992).
Kopp, P., Pesce, L. & Solis-S., J. C. Pendred syndrome and iodide transport in the thyroid. Trends Endocrinol. Metab. 19, 260–268 (2008).
Hulur, I. 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. 96, E841–E845 (2011).
Pinsker, J. E., Rogers, W., McLean, S., Schaefer, F. V. & Fenton, C. Pseudohypoparathyroidism type 1a with congenital hypothyroidism. J. Pediatr. Endocrinol. Metab. 19, 1049–1052 (2006).
Beck-Peccoz, P. et al. Syndromes of hormone resistance in the hypothalamic–pituitary–thyroid axis. Best Pract. Res. Clin. Endocrinol. Metab. 20, 529–546 (2006).
Olivieri, A. 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. 87, 557–562 (2002).
Cutler, A. T., Benezra-Obeiter, R. & Brink, S. J. Thyroid function in young children with Down syndrome. Am. J. Dis. Child. 140, 479–483 (1986).
Weisman, Y., Golander, A., Spirer, Z. & Farfel, Z. Pseudohypoparathyroidism type 1a presenting as congenital hypothyroidism. J. Pediatr. 107, 413–415 (1985).
Kempers, M. J. et al. Neonatal screening for congenital hypothyroidism based on thyroxine, thyrotropin, and thyroxine-binding globulin measurement: potentials and pitfalls. J. Clin. Endocrinol. Metab. 91, 3370–3376 (2006).
Hanna, C. E. et al. Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program. J. Pediatr. 109, 959–964 (1986).
Fisher, D. A. Thyroid function and dysfunction in premature infants. Pediatr. Endocrinol. Rev. 4, 317–328 (2007).
Filippi, L., Pezzati, M., Cecchi, A. & Poggi, C. Dopamine infusion: a possible cause of undiagnosed congenital hypothyroidism in preterm infants. Pediatr. Crit. Care Med. 7, 249–251 (2006).
Vincent, M. A., Rodd, C., Dussault, J. H. & Van Vliet, G. Very low birth weight neonates do not need repeat screening for congenital hypothyroidism. J. Pediatr. 140, 311–314 (2002).
Kugelman, A., Riskin, A., Bader, D. & Koren, I. Pitfalls in screening programs for congenital hypothyroidism in premature neonates. Am. J. Perinatol. 26, 383–385 (2009).
Toublanc, J. E. Guidelines for neonatal screening programs for congenital hypothyroidism. Working Group for Neonatal Screening in Paediatric Endocrinology of the European Society for Paediatric Endocrinology. Acta Paediatr. Suppl. 88, 13–14 (1999).
Rose, S. R. et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 117, 2290–2303 (2006).
Elmlinger, M. W., Kühnel, W., Lambrecht, H. G. & Ranke, M. B. Reference intervals from birth to adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free T4, thyroxine binding globulin (TBG) and thyrotropin (TSH). Clin. Chem. Lab. Med. 39, 973–979 (2001).
Lazar, L. et al. Natural history of thyroid function tests over 5 years in a large pediatric cohort. J. Clin. Endocrinol. Metab. 94, 1678–1682 (2009).
Schoen, E. J., Clapp, W., To, T. T. & Fireman, B. H. The key role of newborn thyroid scintigraphy with isotopic iodide (123I) in defining and managing congenital hypothyroidism. Pediatrics 114, e683–e688 (2004).
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. 142, 214–216 (1988).
Brown, R. S. et al. Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies. J. Clin. Endocrinol. Metab. 81, 1147–1151 (1996).
Mengreli, C. et al. Transient congenital hypothyroidism due to maternal autoimmune thyroid disease. Hormones (Athens) 2, 113–119 (2003).
Gruters, A., l'Allemand, D., Heidemann, P. H. & Schürnbrand, P. Incidence of iodine contamination in neonatal transient hyperthyrotropinemia. Eur. J. Pediatr. 140, 299–300 (1983).
Nishiyama, S. et al. Transient hypothyroidism or persistent hyperthyrotropinemia in neonates born to mothers with excessive iodine intake. Thyroid 14, 1077–1083 (2004).
Bernal, J. Thyroid hormones and brain development. Vitam. Horm. 71, 95–122 (2005).
Cassio, A. et al. Treatment for congenital hypothyroidism: thyroxine alone or thyroxine plus triiodothyronine? Pediatrics 111, 1055–1060 (2003).
von Heppe, J. H., Krude, H., L'Allemand, D., Schnabel, D. & Grüters, A. The use of L-T4 as liquid solution improves the practicability and individualized dosage in neonates and infants with congenital hypothyroidism. J. Pediatr. Endocrinol. Metab. 17, 967–974 (2004).
Conrad, S. C., Chiu, H. & Silverman, B. L. Soy formula complicates management of congenital hypothyroidism. Arch. Dis. Child. 89, 37–40 (2004).
Bolk, N., Visser, T. J., Kalsbeek, A., van Domburg, R. T. & Berghout, A. Effects of evening vs morning thyroxine ingestion on serum thyroid hormone profiles in hypothyroid patients. Clin. Endocrinol. (Oxf.) 66, 43–48 (2007).
Hrytsiuk, I., Gilbert, R., Logan, S., Pindoria, S. & Brook, C. G. Starting dose of levothyroxine for the treatment of congenital hypothyroidism: a systematic review. Arch. Pediatr. Adolesc. Med. 156, 485–491 (2002).
Léger, J., Larroque, B. & Norton, J. Influence of severity of congenital hypothyroidism and adequacy of treatment on school achievement in young adolescents: a population-based cohort study. Acta Paediatr. 90, 1249–1256 (2001).
Rovet, J. F. Children with congenital hypothyroidism and their siblings: do they really differ? Pediatrics 115, e52–e57 (2005).
Oerbeck, B., Sundet, K., Kase, B. F. & Heyerdahl, S. Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults. Pediatrics 112, 923–930 (2003).
Dubuis, J. M. et al. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment. J. Clin. Endocrinol. Metab. 81, 222–227 (1996).
Salerno, M. et al. Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism. Thyroid 12, 45–52 (2002).
Bongers-Schokking, J. J. & de Muinck Keizer-Schrama, S. M. Influence of timing and dose of thyroid hormone replacement on mental, psychomotor, and behavioral development in children with congenital hypothyroidism. J. Pediatr. 147, 768–774 (2005).
Selva, K. A., Harper, A., Downs, A., Blasco, P. A. & Lafranchi, S. H. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. J. Pediatr. 147, 775–780 (2005).
Dimitropoulos, A. et al. Children with congenital hypothyroidism: long-term intellectual outcome after early high-dose treatment. Pediatr. Res. 65, 242–248 (2009).
Boileau, P., Bain, P., Rives, S. & Toublanc, J. E. Earlier onset of treatment or increment in LT4 dose in screened congenital hypothyroidism: which as the more important factor for IQ at 7 years? Horm. Res. 61, 228–233 (2004).
Grüters, A. & Krude, H. Update on the management of congenital hypothyroidism. Horm. Res. 68 (Suppl. 5), 107–111 (2007).
Corbetta, C. et al. A 7-year experience with low blood TSH cutoff levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism (congenital hypothyroidism). Clin. Endocrinol. (Oxf.) 71, 739–745 (2009).
Mengreli, C. et al. Screening for congenital hypothyroidism: the significance of threshold limit in false-negative results. J. Clin. Endocrinol. Metab. 95, 4283–4290 (2010).
Korada, S. M. et al. Difficulties in selecting an appropriate neonatal thyroid stimulating hormone (TSH) screening threshold. Arch. Dis. Child. 95, 169–173 (2010).
Kreisner, E., Schermann, L., Camargo-Neto, E. & Gross, J. L. Predictors of intellectual outcome in a cohort of Brazilian children with congenital hypothyroidism. Clin. Endocrinol. (Oxf.) 60, 250–255 (2004).
Kemper, A. R., Ouyang, L. & Grosse, S. D. Discontinuation of thyroid hormone treatment among children in the United States with congenital hypothyroidism: findings from health insurance claims data. BMC Pediatr. 10, 9 (2010).
Wong, S. C., Ng, S. M. & Didi, M. Children with congenital hypothyroidism are at risk of adult obesity due to early adiposity rebound. Clin. Endocrinol. (Oxf.) 61, 441–446 (2004).
Salerno, M. et al. Long-term cardiovascular effects of levothyroxine therapy in young adults with congenital hypothyroidism. J. Clin. Endocrinol. Metab. 93, 2486–2491 (2008).
Ng, S. M., Anand, D. & Weindling, A. M. High versus low dose of initial thyroid hormone replacement for congenital hypothyroidism. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD006972. doi:10.1002/14651858.CD006972.pub2 (2009).
Author information
Authors and Affiliations
Contributions
Both authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Grüters, A., Krude, H. Detection and treatment of congenital hypothyroidism. Nat Rev Endocrinol 8, 104–113 (2012). https://doi.org/10.1038/nrendo.2011.160
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrendo.2011.160