Journal Logo

THYROID: Edited by Angela M. Leung and Lewis E. Braverman

Congenital hypothyroidism

recent advances

Wassner, Ari J.; Brown, Rosalind S.

Author Information
Current Opinion in Endocrinology, Diabetes and Obesity: October 2015 - Volume 22 - Issue 5 - p 407-412
doi: 10.1097/MED.0000000000000181
  • Free



Thyroid hormone is critical for normal growth and brain development, and hypothyroidism in infancy is the leading cause of intellectual impairment worldwide. This update will discuss significant new contributions in the area of congenital hypothyroidism since the topic was last reviewed in June 2013 [1]. Particular attention will be given to the emerging understanding of congenital hypothyroidism in patients with a normally located (eutopic) thyroid gland.

Box 1
Box 1:
no caption available


Over the last several years, reports from newborn screening programs around the world have described an increase in the incidence of congenital hypothyroidism. Compared with the rate of 1 : 3000–1 : 4000 when screening was introduced [2], rates ranging from 1 : 1400 to 1 : 2800 have been reported recently by screening programs in many countries including the USA [3], Canada [4], Greece [5], Italy [6], and New Zealand [7]. One factor contributing to this change may be increased screening of patients at higher risk of congenital hypothyroidism, including premature infants [3] and particular ethnic populations such as Hispanics and Asians [7,8]. Methodological changes in newborn screening appear to be another major factor in the rising incidence of congenital hypothyroidism, specifically the widespread lowering of thyroid-stimulating hormone (TSH) screening cut-offs that leads to detection of milder cases [4,6]. In a comprehensive review of newborn screening strategies for congenital hypothyroidism around the world, Ford and LaFranchi [9▪] found that lowering the TSH cut-off from greater than 20–25 mIU/l to greater than 6–10 mIU/l in six national newborn screening programs resulted in a 2.2-fold increase in the average incidence of congenital hypothyroidism (from 1 : 3264 to 1 : 1464) (values recalculated from original data in [9▪]).

Two recent studies have characterized in more detail the factors contributing to the rising incidence of congenital hypothyroidism. In a study of the Argentine newborn screening program over 14 years (1997–2010), the incidence of congenital hypothyroidism increased by 31% (from 1 : 2619 to 1 : 1997), with 42% of the increment attributable directly to a decrease in the screening TSH cut-off from greater than 15 mIU/l to greater than 10 mIU/l [10]. Olivieri et al.[11▪▪] similarly analyzed data from the Italian network of regional newborn screening programs over a 22-year period (1987–2008) during which TSH cut-offs decreased from greater than 20 mIU/l to greater than 7–15 mIU/l. During the study period they observed a 54% increase in the incidence of congenital hypothyroidism (from 1 : 3000 to 1 : 1940), with the change in TSH cut-off accounting for 78% of additional cases detected. Thyroid scintigraphy – performed in both studies in most cases of permanent congenital hypothyroidism – demonstrated that the rising incidence of congenital hypothyroidism was mostly attributable to cases with a eutopic thyroid gland, whereas the incidence of thyroid dysgenesis did not change significantly (Fig. 1) [10,11▪▪]. These studies confirm initial reports that the observed increase in congenital hypothyroidism incidence is driven largely, though not entirely, by the detection of milder cases of congenital hypothyroidism, often with a eutopic thyroid gland [4–6].

The increasing incidence of congenital hypothyroidism is primarily due to a rise in cases with a eutopic thyroid gland, with little change in the rate of thyroid dysgenesis. Data from[4] and [11▪▪].

As more cases of congenital hypothyroidism with a eutopic thyroid are diagnosed, an important clinical question is whether these cases are likely to be transient or permanent. Two recent studies provide insight into the natural history of congenital hypothyroidism with a eutopic thyroid gland. In both studies, patients treated for congenital hypothyroidism received a trial off levothyroxine (LT4) at 2–3 years of age. In 43 Korean congenital hypothyroidism patients with a eutopic thyroid gland, LT4 withdrawal demonstrated that 28% had transient congenital hypothyroidism, 51% had permanent congenital hypothyroidism, and the remaining 21% had persistent subclinical hypothyroidism (TSH 5–10 mIU/l) [12]. In a similar French cohort of 32 congenital hypothyroidism patients with a eutopic thyroid gland, Castanet et al.[13] identified transient congenital hypothyroidism in 38%, permanent congenital hypothyroidism in 38%, and persistent subclinical hypothyroidism in 25%. Of note, Castanet et al. included only patients with ‘unexplained’ congenital hypothyroidism, excluding those with defects of iodine organification documented by a perchlorate discharge test. In addition, both studies excluded children born preterm, so these data may not apply to this important population of congenital hypothyroidism patients.

Combining these new data with a prior similar study [14] suggests that among congenital hypothyroidism patients with a eutopic thyroid, roughly equal proportions have transient (35%) or permanent (40%) disease (Table 1). The remaining 25% have persistent hyperthyrotropinemia without overt hypothyroidism, and whether ongoing treatment is necessary in this group remains controversial [15]. Of interest, across all three studies, clinical characteristics – including TSH and free T4 at diagnosis – did not differ between transient and permanent cases of congenital hypothyroidism, and Rabbiosi et al. demonstrated that outcome was independent of whether congenital hypothyroidism at diagnosis was mild (TSH <20 mIU/l) or severe (TSH ≥ 20 mIU/l) [12–14]. A more helpful predictor was the persistence of a daily LT4 requirement above 2 μg/kg [14]. These data reinforce the importance of consistently attempting a trial off therapy at an appropriate age (usually 2–3 years) in patients with a eutopic thyroid, particularly those with a low LT4 requirement.

Table 1
Table 1:
Natural history of congenital hypothyroidism with a eutopic thyroid gland


Recent decades have witnessed striking advances in neonatal care that have dramatically improved the survival of infants born preterm. Such infants are at higher risk than term infants of having congenital hypothyroidism, which occurs in up to 1 in 250 very low birth weight (VLBW) neonates (<1500 g) [16]. Initial data from New England and Quebec suggested that premature newborns did not significantly contribute to increasing rates of congenital hypothyroidism in those regions [3,4]. In contrast, Olivieri et al.[11▪▪] have now reported that preterm infants accounted for about 50% of the total increase in congenital hypothyroidism incidence observed in Italy between 1987 and 2008.

One potential explanation for the discrepancy among studies is that, unlike in Italy, the Quebec screening strategy did not include a mandatory second screening test for preterm or VLBW infants and therefore would have missed cases in whom TSH rise was delayed. This phenomenon appears to be common, occurring in up to 1 in 58 extremely low birth weight (ELBW, <1000 g) infants and 1 in 95 VLBW infants, as compared with 1 in 30 329 infants with birth weight above 1500 g [17]. In these patients, TSH elevation is initially noted at a mean of 22 days and may therefore be missed by a single newborn screen performed at 2–4 days of age.

This concern is substantiated by the recent report of Vigone et al.[18▪], who studied preterm infants with congenital hypothyroidism diagnosed in Lombardy, Italy between 2007–2009. In this region, newborn screening was performed at 2–4 days of age, and repeated at 15–30 days of age in infants born before 33 weeks or under 2000 g. The 24 infants studied had a mean gestational age of 32 weeks and a mean birth weight of 1350 g. Eighteen of 23 (78%) of these infants would likely not have been detected without a repeat screen [18▪].

Interestingly, nearly all infants (21/24) had a eutopic thyroid gland, whereas only three of 24 had thyroid dysgenesis. Of patients with a eutopic gland, the prevalence of transient congenital hypothyroidism (11/21, 52%) was higher than in nonpreterm congenital hypothyroidism patients (Table 1), but a significant minority of patients (5/21, 24%) still had permanent disease. Considering only the 18 patients with delayed TSH rise, five of 18 (28%) had permanent congenital hypothyroidism, similar to the prevalence of 30% reported previously by Mitchell et al.[3] but contrasting with another report in which all cases of congenital hypothyroidism with delayed TSH rise were transient [17]. In summary, the phenomenon of delayed TSH rise may cause some cases of congenital hypothyroidism – including permanent disease – to be missed by screening strategies that do not include repeat testing for preterm and VLBW infants [18▪,19].


Based on data from the initial screening programs in the 1970s, it generally has been accepted that in iodine-sufficient parts of the world congenital hypothyroidism is caused by a defect in thyroid gland formation (dysgenesis) in about 85% of cases, by intrinsic defects of thyroid hormone synthesis (dyshormonogenesis) in the remaining 15%, and rarely by other causes (e.g., maternal TSH receptor-blocking antibodies, iodine deficiency or excess) [20]. The recent changes in patterns of diagnosis have, however, modified the historical distribution of congenital hypothyroidism etiologies in many developed countries. Specifically, in a number of recent studies only 58–69% of permanent congenital hypothyroidism cases are caused by thyroid dysgenesis. The remaining 31–42% of patients have a eutopic thyroid gland consistent with possible dyshormonogenesis [4,10,11▪▪]. Recent data have begun to shed light on new genetic causes of dyshormonogenesis in some of these patients.

Among the known causes of dyshormonogenesis, defects in iodide organification because of mutations in thyroperoxidase are well known but rare (incidence 1 : 66 000) [21]. Another critical element in iodide organification is the dual oxidase (DUOX) system, which is responsible for generating the hydrogen peroxide necessary for this process. Mutations in DUOX2 and DUOX2A have been identified as causes of dyshormonogenetic congenital hypothyroidism [22,23], and the extent to which DUOX2 mutations may contribute to the incidence of congenital hypothyroidism with eutopic thyroid gland has been investigated in several recent studies. In a cohort of 30 congenital hypothyroidism patients with a eutopic thyroid gland and a partial iodide organification defect, Muzza et al.[24▪▪] identified DUOX2 mutations in 11 of 30 (37%) cases. Jin et al.[12] found DUOX2 mutations at a similar rate of 15 of 43 (35%) in a comparable cohort, although iodide organification was not assessed. Both studies conducted in-vitro functional assays to validate the pathogenicity of the identified DUOX2 mutations, an important improvement over some prior studies that have reported DUOX2 variants of unclear pathogenicity. If 30–40% of all congenital hypothyroidism cases are caused by dyshormonogenesis, these results imply that 10–15% of all congenital hypothyroidism cases diagnosed by current screening strategies may be due to defects in DUOX2.

Summarizing the results of several prior studies, Muzza et al.[24▪▪] also showed that congenital hypothyroidism because of DUOX2 mutations is permanent in 65% of cases but transient in 35%, consistent with the fact that DUOX2 defects may result in a clinical spectrum of disease ranging from congenital hypothyroidism to euthyroid goiter in adulthood. These studies also refuted the suggestion that biallelic DUOX2 mutations underlie permanent congenital hypothyroidism, whereas monoallelic mutations cause milder or transient phenotypes. In fact, some patients with biallelic DUOX2 mutations had transient congenital hypothyroidism, whereas some with monoallelic mutations had permanent disease, implying that other genetic or environmental factors likely modify the phenotype of DUOX2 defects [12,24▪▪]. A final important finding of Muzza et al.[24▪▪] was that seven of 11 (64%) of congenital hypothyroidism patients with DUOX2 mutations had a normal TSH (<10 mIU/l) on initial newborn screening and were identified only on repeat screening at 15–30 days of age. This suggests the importance of repeat testing of thyroid function in patients at risk of DUOX2 defects, particularly siblings of patients with known dyshormonogenesis.

An exciting recent discovery has been the identification of a novel iodide transporter, anoctamin 1, which is expressed on the apical surface of human and rat thyrocytes and appears to mediate iodide transport independently of pendrin (SLC26A4) [25,26▪]. SLC26A4 mutations are a known cause of congenital hypothyroidism with sensorineural hearing loss (‘Pendred syndrome’), and although the physiologic role of anoctamin 1 in the human thyroid is not yet clear, it could potentially explain the observation that some patients with SLC26A4 mutations have normal thyroid function [27,28].


In most studies to date, the management of congenital hypothyroidism has been focused on rapid identification and correction of neonatal hypothyroidism, with careful maintenance of euthyroidism particularly during the first few years of critical brain development [29▪▪]. However, a recent study from The Netherlands has suggested the potential risk of overtreatment – rather than undertreatment – on neurodevelopmental outcome in congenital hypothyroidism patients. Bongers-Schokking et al.[30▪▪] assessed the cognitive development of 61 congenital hypothyroidism patients at 2, 6, and 11 years of age, and correlated these results with severity of congenital hypothyroidism, time to TSH normalization, and episodes of overtreatment and undertreatment as defined by either serum fT4 or TSH. Rapid normalization of TSH was associated with a higher mental development index at age 2 years (by 13.3 points out of 100, P < 0.001), but this difference was no longer evident by age 11 years. Unexpectedly, undertreatment of congenital hypothyroidism had no effect on cognitive outcome at any age, whereas overtreatment (defined by elevated fT4 levels) was associated with a significantly lower IQ at age 11 (P = 0.014). Patients who experienced overtreatment for under 3 months had an IQ 13.4 points lower than patients who were never overtreated, and those overtreated for over 3 months had an IQ 17.8 points lower. When overtreatment was defined based on TSH rather than fT4, no effect of overtreatment on cognitive development was observed. The authors suggested that fT4 may be a more sensitive marker of overtreatment than TSH, perhaps because of the relative pituitary resistance to TSH suppression observed in many congenital hypothyroidism patients early in life [31]. These data emphasize the importance of long-term follow-up when assessing cognitive outcome. Although they are provocative, the magnitude of the observed impairment of cognitive development seems quite large for the mild degree of fT4 elevation in overtreated patients, and these findings await validation in additional studies [30▪▪].

More questions about the potential negative effects of excess thyroid hormone were raised by a recent study of preterm infants. Preterm and LBW infants commonly manifest a pattern of low T4 and normal TSH termed ‘transient hypothyroxinemia of prematurity’ (THOP) [32]. Although THOP is associated with poor medical and neurodevelopmental outcomes [33], a causal relationship has not been established, and the few existing trials of treatment for THOP have not demonstrated a clear benefit [34–36]. In this context, Scratch et al.[37▪] attempted to correlate serum fT4 levels in 83 preterm infants (<30 weeks) with a wide range of neurodevelopmental outcomes at 7 years of age. Contrary to expectation, higher fT4 levels over the first 2 weeks of life were associated with poorer verbal learning (P = 0.02) and verbal memory (P = 0.03), and slower reaction time (P < 0.001). A similar but less significant trend was seen with fT4 levels over the first 6 weeks of life. With a mean gestational age among patients of 27.3 weeks, these results echo a prior finding of poorer outcome with LT4 treatment in preterm infants born after 27 weeks gestation [34], and continue to support a cautious approach to treatment for THOP. More broadly, these data and those of Bongers-Schokking et al. are consistent with older studies of the detrimental effects of thyrotoxicosis on neurodevelopment [38] and raise the important question of whether mild excess of thyroid hormone may be as bad (or worse) for the developing brain as inadequate thyroid hormone. More long-term data are surely needed to clarify this critical point.


Emerging data continue to inform our understanding of the epidemiology, pathophysiology, and treatment of congenital hypothyroidism, particularly in milder cases and those with a eutopic thyroid gland that are increasingly being identified. It is hoped that better understanding of the basic physiology of thyroid function and its effects on neurodevelopment will contribute to continuing advances in the management and outcomes of patients with congenital hypothyroidism.



Financial support and sponsorship


Conflicts of interest

R.S.B. has been a consultant to AbbVie, Inc., but no longer serves in this role. A.J.W. has no conflict of interest to disclose relevant to the content of this review.


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest


1. Wassner AJ, Brown RS. Hypothyroidism in the newborn period. Curr Opin Endocrinol Diabetes Obes 2013; 20:449–454.
2. Fisher DA, Dussault JH, Foley TP Jr, et al. Screening for congenital hypothyroidism: results of screening one million North American infants. J Pediatr 1979; 94:700–705.
3. Mitchell ML, Hsu HW, Sahai I. The increased incidence of congenital hypothyroidism: fact or fancy? Clin Endocrinol (Oxf) 2011; 75:806–810.
4. Deladoey J, Ruel J, Giguere Y, Van Vliet G. Is the incidence of congenital hypothyroidism really increasing? A 20-year retrospective population-based study in Quebec. J Clin Endocrinol Metab 2011; 96:2422–2429.
5. Mengreli C, Kanaka-Gantenbein C, Girginoudis P, et al. Screening for congenital hypothyroidism: the significance of threshold limit in false-negative results. J Clin Endocrinol Metab 2010; 95:4283–4290.
6. Corbetta C, Weber G, Cortinovis F, et al. A 7-year experience with low blood TSH cutoff levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism (CH). Clin Endocrinol (Oxf) 2009; 71:739–745.
7. Albert BB, Cutfield WS, Webster D, et al. Etiology of increasing incidence of congenital hypothyroidism in New Zealand from 1993–2010. J Clin Endocrinol Metab 2012; 97:3155–3160.
8. Hinton CF, Harris KB, Borgfeld L, 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 2010; 125 (Suppl 2):S37–S47.
9▪. Ford G, LaFranchi SH. Screening for congenital hypothyroidism: a worldwide view of strategies. Best Pract Res Clin Endocrinol Metab 2014; 28:175–187.

Comprehensive review of global trends in newborn screening and diagnosis of congenital hypothyroidism.

10. Chiesa A, Prieto L, Mendez V, et al. Prevalence and etiology of congenital hypothyroidism detected through an argentine neonatal screening program (1997–2010). Horm Res Paediatr 2013; 80:185–192.
11▪▪. Olivieri A, Fazzini C, Medda E. Collaborators. Multiple factors influencing the incidence of congenital hypothyroidism detected by neonatal screening. Horm Res Paediatr 2015; 83:86–93.

The rising incidence of congenital hypothyroidism consists largely of milder cases with eutopic thyroid gland due to decreased TSH cut-offs and increased diagnosis of congenital hypothyroidism in preterm infants.

12. Jin HY, Heo SH, Kim YM, et al. High frequency of DUOX2 mutations in transient or permanent congenital hypothyroidism with eutopic thyroid glands. Horm Res Paediatr 2014; 82:252–260.
13. Castanet M, Goischke A, Leger J, et al. Natural history and management of congenital hypothyroidism with in situ thyroid gland. Horm Res Paediatr 2015; 83:102–110.
14. Rabbiosi S, Vigone MC, Cortinovis F, et al. Congenital hypothyroidism with eutopic thyroid gland: analysis of clinical and biochemical features at diagnosis and after re-evaluation. J Clin Endocrinol Metab 2013; 98:1395–1402.
15. Grosse SD, Van Vliet G. Prevention of intellectual disability through screening for congenital hypothyroidism: how much and at what level? Arch Dis Child 2011; 96:374–379.
16. Larson C, Hermos R, Delaney A, et al. Risk factors associated with delayed thyrotropin elevations in congenital hypothyroidism. J Pediatr 2003; 143:587–591.
17. Woo HC, Lizarda A, Tucker R, et al. Congenital hypothyroidism with a delayed thyroid-stimulating hormone elevation in very premature infants: incidence and growth and developmental outcomes. J Pediatr 2011; 158:538–542.
18▪. Vigone MC, Caiulo S, Di Frenna M, et al. Evolution of thyroid function in preterm infants detected by screening for congenital hypothyroidism. J Pediatr 2014; 164:1296–1302.

Congenital hypothyroidism with delayed TSH rise is frequently not detected on initial newborn screening.

19. LaFranchi SH. Screening preterm infants for congenital hypothyroidism: better the second time around. J Pediatr 2014; 164:1259–1261.
20. LaFranchi SH. Approach to the diagnosis and treatment of neonatal hypothyroidism. J Clin Endocrinol Metab 2011; 96:2959–2967.
21. 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; 85:3708–3712.
22. 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; 347:95–102.
23. 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; 93:605–610.
24▪▪. 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–E553.

Congenital hypothyroidism due to DUOX2 mutations may be transient or permanent and may not be detected on initial newborn screening.

25. Iosco C, Cosentino C, Sirna L, et al. Anoctamin 1 is apically expressed on thyroid follicular cells and contributes to ATP- and calcium-activated iodide efflux. Cell Physiol Biochem 2014; 34:966–980.
26▪. Twyffels L, Strickaert A, Virreira M, et al. Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte. Am J Physiol Cell Physiol 2014; 307:C1102–1112.

Like pendrin, anoctamin 1 mediates apical iodine transport in rat and human thyrocytes in vitro.

27. 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; 24:639–648.
28. Kopp P. Mutations in the Pendred Syndrome (PDS/SLC26A) gene: an increasingly complex phenotypic spectrum from goiter to thyroid hypoplasia. J Clin Endocrinol Metab 2014; 99:67–69.
29▪▪. Leger J, Olivieri A, Donaldson M, et al. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Horm Res Paediatr 2014; 81:80–103.

Consensus guidelines on the diagnosis and management of congenital hypothyroidism.

30▪▪. Bongers-Schokking JJ, Resing WC, de Rijke YB, et al. Cognitive development in congenital hypothyroidism: is overtreatment a greater threat than undertreatment? J Clin Endocrinol Metab 2013; 98:4499–4506.

Overtreament of congenital hypothyroidism, defined by elevated serum free T4, was associated with decreased IQ at 11 years of age, whereas undertreatment had no effect on cognitive outcome.

31. Fisher DA, Schoen EJ, La Franchi S, et al. The hypothalamic-pituitary-thyroid negative feedback control axis in children with treated congenital hypothyroidism. J Clin Endocrinol Metab 2000; 85:2722–2727.
32. La Gamma EF, Paneth N. Clinical importance of hypothyroxinemia in the preterm infant and a discussion of treatment concerns. Curr Opin Pediatr 2012; 24:172–180.
33. Delahunty C, Falconer S, Hume R, et al. Levels of neonatal thyroid hormone in preterm infants and neurodevelopmental outcome at 5 1/2 years: millennium cohort study. J Clin Endocrinol Metab 2010; 95:4898–4908.
34. van Wassenaer AG, Kok JH, de Vijlder JJ, et al. Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks’ gestation. N Engl J Med 1997; 336:21–26.
35. van Wassenaer AG, Westera J, Houtzager BA, Kok JH. Ten-year follow-up of children born at <30 weeks’ gestational age supplemented with thyroxine in the neonatal period in a randomized, controlled trial. Pediatrics 2005; 116:e613–e618.
36. van Wassenaer-Leemhuis A, Ares S, Golombek S, et al. Thyroid hormone supplementation in preterm infants born before 28 weeks gestational age and neurodevelopmental outcome at age 36 months. Thyroid 2014; 24:1162–1169.
37▪. Scratch SE, Hunt RW, Thompson DK, et al. Free thyroxine levels after very preterm birth and neurodevelopmental outcomes at age 7 years. Pediatrics 2014; 133:e955–e963.

Higher serum free T4 is correlated with poorer developmental outcome in preterm infants.

38. Daneman D, Howard NJ. Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years. J Pediatr 1980; 97:257–259.

congenital hypothyroidism; eutopic; prematurity; preterm; thyroid

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.