Cherella and Wassner International Journal of Pediatric Endocrinology (2017) 2017:11 DOI 10.1186/s13633-017-0051-0 REVIEW Open Access Congenital hypothyroidism: insights into pathogenesis and treatment Christine E. Cherella and Ari J. Wassner* Abstract Congenital hypothyroidism occurs in approximately 1 in 2000 newborns and can have devastating neurodevelopmental consequences if not detected and treated promptly. While newborn screening has virtually eradicated intellectual disability due to severe congenital hypothyroidism in the developed world, more stringent screening strategies have resulted in increased detection of mild congenital hypothyroidism. Recent studies provide conflicting evidence about the potential neurodevelopmental risks posed by mild congenital hypothyroidism, highlighting the need for additional research to further define what risks these patients face and whether they are likely to benefit from treatment. Moreover, while the apparent incidence of congenital hypothyroidism has increased in recent decades, the underlying cause remains obscure in most cases. However, ongoing research into genetic causes of congenital hypothyroidism continues to shed new light on the development and physiology of the hypothalamic-pituitary-thyroid axis. The identification of IGSF1 as a cause of central congenital hypothyroidism has uncovered potential new regulatory pathways in both pituitary thyrotropes and gonadotropes, while mounting evidence suggests that a significant proportion of primary congenital hypothyroidism may be caused by combinations of rare genetic variants in multiple genes involved in thyroid development and function. Much remains to be learned about the origins of this common disorder and about the optimal management of less severely-affected infants. Keywords: Congenital hypothyroidism, Genetics, Central hypothyroidism, Mild hypothyroidism Background detection and treatment are indisputable, uncertainty Thyroid hormone is essential for normal growth and remains about mild disease in terms of the neurodeve- neurologic development, particularly in the first few lopmental risk it poses and whether these risks are years of life, and hypothyroidism during this period is a mitigated by treatment [7]. Moreover, despite the leading cause of preventable intellectual disability world- prevalence of congenital hypothyroidism and our suc- wide. The implementation of universal newborn screening cess in treating it, what causes most cases remains a beginning in the 1970’s has been an enormous public mystery. This review discusses important recent develop- health success, virtually eradicating significant intellectual ments in congenital hypothyroidism, focusing on our disability due to severe congenital hypothyroidism in the evolving understanding of its genetics, pathophysiology, developed world. Following this early success, newborn and outcomes. screening programs have implemented increasingly stringent screening strategies over the past few decades. The resulting detection of milder cases of congenital Primary congenital hypothyroidism hypothyroidism is the primary reason for the dramatic Most congenital hypothyroidism is caused by defects in increase in the apparent incidence of congenital the thyroid gland itself (primary hypothyroidism). Causes hypothyroidism from 1:4000 to 1:2000 newborns over of primary congenital hypothyroidism can be broadly clas- the last 20–30 years [1–6].However,unlikeseverecon- sified as failure of the thyroid gland to develop normally genital hypothyroidism, for which the benefits of early (dysgenesis) or failure of a structurally normal thyroid gland to produce normal quantities of thyroid hormone (dyshormonogenesis). Thyroid dysgenesis—which encom- * Correspondence: [email protected] Division of Endocrinology, Boston Children’s Hospital, Harvard Medical passes the spectrum of thyroid agenesis, hypoplasia, and School, 300 Longwood Avenue, Boston, MA 02115, USA ectopy—is the most common cause of congenital © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cherella and Wassner International Journal of Pediatric Endocrinology (2017) 2017:11 Page 2 of 8 hypothyroidism, and its incidence (about 1:4000 infants) preciseroleofNKX2–5 in thyroid dysgenesis remains has not changed significantly over the last several decades to be clarified [8]. [3,5,6].Theunderlyingcauseofthyroiddysgenesis, Mutations in GLIS3 underlie a complex syndrome of however, remains obscure in the vast majority of cases. congenital hypothyroidism, neonatal diabetes mellitus, Thyroid dysgenesis usually occurs sporadically, with only and variable other abnormalities including congenital 2–5% of cases being attributable to identifiable genetic glaucoma, developmental delay, hepatic fibrosis, and mutations (Fig. 1). Nevertheless, the known genetic causes polycystic kidneys [12, 13]. GLIS3 is highly expressed in of thyroid dysgenesis provide an important window into the thyroid, and congenital hypothyroidism in patients basic thyroid ontogeny. The thyroid-stimulating hormone with GLIS3 mutations may be associated with either thy- receptor (TSHR) and the transcription factors PAX8, roid dysgenesis or a eutopic but histologically abnormal NKX2–1,andFOXE1 are all expressed in the developing thyroid gland [13]. GLIS3 may act as a transcriptional thyroid, and disruption of any of these genes can lead to activator or repressor, but its precise role in thyroid de- failure of normal thyroid gland formation [8]. These velopment and function remains to be determined. Some transcription factors also play important roles in other de- patients with GLIS3 mutations require unusually high veloping tissues, and mutations in each may be associated doses of levothyroxine to normalize serum thyroid with additional syndromic features such as renal abnor- stimulating hormone (TSH) levels [13, 14], which could malities (PAX8), interstitial lung disease and chorea imply an additional effect of GLIS3 on central regulation (NKX2–1), or cleft palate, bifid epiglottis, choanal atresia, of the hypothalamic-pituitary-thyroid (HPT) axis. and spiky hair (FOXE1)(Table1). Recently, genetic variants in CDCA8 (also called Several other genes implicated in thyroid dysgenesis BOREALIN) were identified in a study of three consan- offer additional insights into the mechanisms of thyroid de- guineous families with thyroid dysgenesis [15]. This gene velopment. The transcription factor NKX2–5 is expressed is expressed in the thyroid and is known to play a key in the developing heart and thyroid, and NKX2–5 muta- role in the chromosomal passenger complex that tions are associated with congenital cardiac abnormalities. stabilizes the mitotic spindle during cell division. Deletion of NKX2–5 in mice causes thyroid agenesis, sug- Interestingly, however, the CDCA8 variants detected gesting that this transcription factor plays an important in these patients do not appear to affect mitosis but role in thyroid development, but to what degree this rather impair cell migration and adhesion in vitro. finding extends to humans is not clear. Heterozygous vari- Thus, the potential mechanistic role of CDCA8 in thy- ants in NKX2–5 are found in some individuals with thyroid roid dysgenesis is still unclear, and the range of thy- dysgenesis[9,10];however,thepathogenicityofthesevari- roid phenotypes observed in patients carrying CDCA8 ants is unclear since they do not consistently cosegregate variants is broad, ranging from thyroid agenesis or ectopy with thyroid disease in families [9] and some may not to euthyroid individuals with asymmetric thyroid lobes or impair protein function in vitro [11]. Therefore, the thyroid nodules. Hypothalamic/ Pituitary Development Hypothalamus TRH / TSH HESX1 signaling LHX3 TRH TRHR LHX4 TSHB SOX3 IGSF1 OTX2 Pituitary TBL1X PROP1 LEPR POU1F1 TSH Thyroid Thyroid Hormone Development Synthesis TSHR Thyroid TG PAX8 TPO NKX2-1 DUOX2 FOXE1 DUOXA2 NKX2-5 T4, T3 SLC5A5 JAG1 SLC26A4 GLIS3 IYD CDCA8 Fig. 1 Genes associated with congenital hypothyroidism. TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone; T4, thyroxine; T3, triiodothyronine Cherella and Wassner International Journal of Pediatric Endocrinology (2017) 2017:11 Page 3 of 8 Table 1 Clinical features of genetic syndromes associated with congenital hypothyroidism Primary congenital hypothyroidism Central congenital hypothyroidism PAX8 Renal abnormalities IGSF1 Macro-orchidism, delayed pubertal testosterone rise, PRL deficiency, transient GH deficiency NKX2–1 Interstitial lung disease, chorea TBL1X Hearing deficits FOXE1 Cleft palate, bifid epiglottis, choanal atresia, LEPR Severe early-onset obesity, delayed puberty spiky hair (Bamforth-Lazarus syndrome) NKX2–5 Congenital heart disease POU1F1 Combined pituitary hormone deficiency GLIS3 Neonatal diabetes mellitus, congenital glaucoma, PROP1 Combined pituitary hormone deficiency developmental delay, hepatic fibrosis, polycystic kidneys JAG1 Alagille syndrome (variable