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 Table of Contents  
Year : 2017  |  Volume : 14  |  Issue : 2  |  Page : 45-53

Clinical approach to congenital hypothyroidism

Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India

Date of Web Publication26-May-2017

Correspondence Address:
Sunetra Mondal
“Morning Glory,” Golapbag More, Burdwan - 713 104, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/trp.trp_5_17

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Congenital hypothyroidism (CH) is a preventable cause of mental retardation. The principal causes include thyroid dysgenesis and dyshormonogenesis. Central CH is rare. Due to absence of overt symptoms at birth, diagnosis is often delayed. There are some known syndromic associations with extrathyroidal anomalies. Neonatal screening programs help in early detection and categorization of cases requiring immediate treatment or close follow-up. Results of screening tests could guide further tests required for confirmation diagnosis and urgency of replacement therapy. A diagnostic protocol starting with an ultrasonography of thyroid and serum thyroglobulin levels can aid identify the probable underlying etiology and dictate the cases requiring scintigraphy or genetic tests. Early initiation of treatment with oral levothyroxine improves neurocognitive outcomes. Some cases might have transient hypothyroidism and reevaluation at 3 years of age may help in further discontinuation of treatment.

Keywords: Dysgenesis, dyshormonogenesis, screening, thyroglobulin, transient hypothyroidism, ultrasonography

How to cite this article:
Mondal S, Mukhopadhyay P, Ghosh S. Clinical approach to congenital hypothyroidism. Thyroid Res Pract 2017;14:45-53

How to cite this URL:
Mondal S, Mukhopadhyay P, Ghosh S. Clinical approach to congenital hypothyroidism. Thyroid Res Pract [serial online] 2017 [cited 2022 Jun 30];14:45-53. Available from: https://www.thetrp.net/text.asp?2017/14/2/45/207137

  Introduction Top

Congenital hypothyroidism (CH) is one of the most common preventable causes of mental retardation worldwide. The most important actions of thyroid hormones during the antenatal and early postnatal period involve central nervous system (CNS) maturation and are crucial for neurogenesis, dendritic and axonal growth, and neurotransmitter synthesis.[1] Untreated severe CH thus leads to neurological and psych odevelopmental defects, including intellectual disability, spasticity, and disturbances of gait and coordination.[2]

  Epidemiology Top

The prevalence of CH is currently estimated to be about 1 in 2000–3000 live births worldwide versus 1 in 6700 before the advent of universal newborn screening.[2],[3] CH is more common in Asian, Native American, and Hispanic populations and less common in Caucasian and African populations.[4] Increased detection of CH may partly be explained by a 37% increase in Asian births and a 53% increase in Hispanic births.[5],[6] CH is also higher in preterm infants and infants born to older mothers, both of which have increased immensely.[7]

  Indian Scenario Top

The prevalence of CH in India was reported to be 1 in 2640 live births based on the study by Desai et al. in 1997.[8] Three other hospital-based studies quote a prevalence of 1 in 1985 from Hyderabad, 2.1 in 1000 from Kochi, and 1:1221 in Uttar Pradesh.[9],[10],[11] The first multicentric study screening above 1 lakh neonates throughout India was launched by the Indian Council of Medical Research National Task Force Team on New Born Screening at AIIMS, New Delhi (2007–2012), and the preliminary results reveals a much higher incidence of CH all over India of 1 in 1172 live births, particularly in South India (1 in 727).[12]

The incidence of dyshormonogenesis is higher in Indians than worldwide estimates.[13] Diagnosis of CH is also delayed in developing countries including India. The average age at the presentation of CH has been estimated to be 4.1 years based on the study by Virmani et al.[14] As a result, features of long-standing severe hypothyroidism are often present at diagnosis, including classical facies, wide open anterior fontanelle, coarse skin, intelligent quotient (IQ) <40, stunted growth, and even pituitary enlargement on magnetic resonance imaging.[15],[16]

  Etiology Top

CH can be classified as transient and permanent CH. While permanent CH requires life-long treatment, transient CH refers to a state of temporary deficiency of thyroid hormone, discovered at birth, which normalizes within the first few months or years of life. Permanent CH can be further classified into permanent primary and secondary (or central). Rarely, transient primary CH has also been reported.[17] Primary CH results from aberration of embryologic development of thyroid gland (dysgenesis) which accounts for 85% of cases or an inborn error of thyroid hormone synthesis (dyshormonogenesis) in 10%–15% of cases. Secondary or central hypothyroidism at birth results from a deficiency of thyroid-stimulating hormone (TSH). Congenital TSH deficiency may rarely be an isolated problem (caused by mutations in the TSH-beta subunit gene), but commonly it is associated with other pituitary hormone deficiencies, as part of congenital hypopituitarism. Peripheral hypothyroidism is a separate entity and results from defects of thyroid hormone transport, metabolism, or action. [Table 1] summarizes the etiology.[18]
Table 1: Etiology of congenital hypothyroidism

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  Permanent Congenital Hypothyroidism Top

Thyroid dysgenesis

Thyroid dysgenesis arises due to disruption in any of the developmental steps necessary for transformation of pluripotent stem cells to functional thyrocytes resulting in a spectrum of abnormalities ranging from athyreosis, hypoplasia, and hemiagenesis to eutopic thyroid without normal thyroid function.

True athyreosis (30%) is the severest form of thyroid hormone deficiency with highest TSH levels and no measurable thyroglobulin (TG).[17] Hypoplastic thyroid can present with isolated hyperthyrotropinemia alone. Thyroid ectopy which results due to block in thyroid migration from foramen cecum to its final position accounts for two-thirds of cases of thyroid dysgenesis and is more common in females. Patients can suffer from severe hypothyroidism or can be euthyroid at birth.[18]

Hence, in a case of documented CH, if ultrasonography (USG) fails to detect the presence of thyroid gland or its remnants and if TG is undetectable, then there is limited role of scintigraphy in the workup of CH.

Thyroid-stimulating hormone resistance

Mutations in the TSH receptor gene lead to thyroid hypoplasia with low or undetectable TG. Pseudohypoparathyroidism Type 1a, caused by mutations in the Gs alpha, results in defective TSH signaling.[18]

Thyroid dyshormonogenesis

Thyroid dyshormonogenesis can be associated with goiter formation which is, however, a rare finding in newborns. The sodium iodide symporter (NIS) mediates iodide accumulation in the thyrocyte, and iodide is released into the follicle by the SLC26A4 protein on the apical membrane. The thyrocyte synthesizes and releases TG into the follicular lumen. Iodide is oxidized and bound to tyrosine residues on the TG protein, leading to mono- and di-iodotyrosines (MIT and DIT) which are coupled to form thyroxine (T4) and to a lesser extent triiodothyronine (T3). Iodination and coupling are catalyzed by thyroid peroxidase (TPO), whose activity depends on hydrogen peroxide generated by dual oxidase 2 (DUOX2) and DUOX maturation factor 2 (DUOXA2). T4 and T3 are released into blood while thyrocytes recycle the iodide bound to MIT, DIT by the iodotyrosine dehalogenase (IYD/DEHAL1).[18],[19] Mutations in genes encoding these proteins cause different forms of dyshormonogenesis.

The mode of inheritance of all forms is autosomal recessive, except DUOXA2 which is transmitted in an autosomal dominant fashion. No associated malformations are present except for deafness in pendrin mutations.

TPO mutations are the most common while TG mutations are the most severe with goiter often present at birth.[20]

Secondary or central hypothyroidism

Congenital central hypothyroidism results from defects of TSH production; usually as a part of congenital hypopituitarism. Mutations in genes regulating pituitary gland development, which include HESX1, LHX3, LHX4, PIT1, and PROP1, have been reported to cause familial hypopituitarism. Rarely, isolated TSH deficiency caused by mutations in the TSH-beta subunit gene, and thyrotropin-releasing hormone (TRH) resistance, resulting from mutations in the TRH receptor gene lead to TSH deficiency alone.

Peripheral defects in thyroid hormone metabolism

A mutation in a gene encoding monocarboxylate transporter 8 impairs the passage of T3 into neurons and has been reported in to cause an X-linked hypothyroidism associated with mental retardation characterized by elevated serum T3 levels, low T4, and normal TSH. It is known as Allan–Herndon–Dudley syndrome.[21],[22]

Peripheral resistance to the action of thyroid hormone due to mutations in genes encoding thyroid hormone receptor beta are dominantly inherited and affected individuals are only rarely hypothyroid. Circulating T3 and T4 are mildly elevated without suppression of TSH. These infants are usually not detected by newborn screening.[18]

Transient central hypothyroidism

Transient CH could result from iodine deficiency, transplacental passage of maternal TSH-binding inhibitory antibodies, and maternal exposure to radioiodine, iodine, or antithyroid drugs, neonatal iodine exposure, liver hemangiomas (expressing large amounts of Type 3 iodothyronine deiodinase leading to consumptive type of hypothyroidism)[23] or mutations in DUOX2 (THOX2) and DUOXA2. Rarely, premature TSH estimation (on the first day of life) may lead to an erroneous diagnosis due to a physiological TSH surge. A transient low T3 syndrome may be seen in neonates with prematurity, malnutrition, and stress (especially surgical), a syndrome similar to adult nonthyroidal illness.[24]

In an Indian study by Nair et al. on 36 children aged >3 years, thyroid hormone supplementation could be discontinued in 50% of children diagnosed with CH.[25]

In these cases, it is better to institute T4 replacement until it becomes apparent that the dose needs not be increased to curtail the TSH levels or till the child is 3 years old, when it is safe to stop therapy for 4–6 weeks to assess the need for continued replacement.[26]

  Clinical Features Top

Symptoms of CH are mostly subtle. History of prolonged gestation, maternal autoimmune thyroid disease or an iodine deficient diet or inadvertent radioactive iodine treatment during pregnancy should be taken.[18] An overtly hypothyroid infant would have birth weight greater than the 19th percentile and could present with umbilical hernia, macroglossia, cold or mottled skin, posterior fontanelle >5 mm, persistent jaundice (due to lack of maturation of glucuronyl transferase), poor feeding, and hoarse cry.[27] Few with dyshormonogenesis may have a palpable goiter. Bradycardia, hypotonia with delayed reflexes is rare.

  Congenital Malformations Top

Distinct clinical phenotypes can provide clues to underlying gene mutations as summarized in [Table 2].[28],[29]
Table 2: Syndromic associations of congenital hypothyroidism

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  Screening Top

It has been confirmed that CH screening is successful in normalizing the cognitive outcomes of children with severe primary CH and the lifetime costs of care for children with severe intellectual disability far exceeds the costs of screening, thus emphasizing its need for worldwide implementation.[30] Although routinely adapted in many developed and developing nations, still, only 25% of worldwide birth population today undergo screening for CH.[30]

[Figure 1] and [Figure 2] illustrate the current recommendations for screening and algorithm for confirmatory diagnosis and treatment following screening, respectively.[18],[28],[31]
Figure 1: Recommendations for neonatal screening for congenital hypothyroidism

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Figure 2: Algorithm for confirmation of diagnosis and treatment following screening test results

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  Diagnostic Evaluation Top

A diagnostic approach based on biochemical tests and imaging could differentiate the etiologic types and subtypes of CH.[32],[33] Diagnostic studies generally do not alter treatment decisions which are mainly based on serum thyroid function tests. However, findings may have treatment implications in infants with borderline serum test results, for example, discovery of a form of thyroid dysgenesis.[34] In addition, they help separate transient from permanent cases and facilitates the choice of genetic tests required.

The role of nuclear medicine in diagnostic evaluation of CH cannot be overemphasized, and prior studies have shown it to detect accurately the most common causes of permanent CH.[35] Scanning with 10–20 MBq (0.27–0.54 mCi) of 99m Tc is favored as it can be done in 20 min in contrast to 1–2 MBq (0.027–0.054 mCi) of I 123 that takes several hours, is more expensive and less widely available.[36] However, I 123 is more specifically taken up by the thyroid gland thus giving a clearer picture and is almost mandatory when a perchlorate discharge test is planned. For eutopic thyroid glands, a discharge of >10% of the administered I 123 dose when perchlorate is administered at 2 h indicates an organification defect (positive perchlorate discharge test).[36] Although scintigraphy may be postponed until reevaluation of the diagnosis at 3 years of age, it is easier to perform in a sleepy infant. However, delay in imaging should not delay treatment.

USG of the thyroid with a high-frequency linear transducer (10–15 MHz) can be used to investigate the presence, size, echotexture, and structure of a thyroid gland in situ. It has been debated that ultrasound is prone to movement artifacts, is observer-dependent with misdiagnosis of nonthyroidal tissue in thyroid fossa as a dysplastic thyroid gland and most importantly does not identify ectopic thyroid glands.[37],[38]

However, recent studies report that color flow Doppler can detect ectopic thyroid tissue in 90% of cases.[39] In addition, in situ ations where radionuclide uptake and scan show absent uptake, but a gland is actually present (TSH beta gene mutations, TSH receptor inactivating mutation, iodide trapping defect, maternal thyroid receptor blocking antibody [TRB-Ab]), USG may show a eutopic thyroid gland. In resource-limited settings, it could well be the first-line investigation guiding the need for more elaborate investigations, including scintigraphy.

Serum Thyroglobulin (Tg) levels reflect the amount of thyroid tissue and are useful in cases of absent radionuclide uptake where increased Tg suggests that thyroid gland is present and that the neonate may have a TSH receptor inactivating mutation, a trapping defect, or maternal TRB-Ab.[40]

Maternal TRB-Ab determinations are recommended in mothers with known autoimmune thyroid disease and a previous child having transient CH. Urinary iodine estimation is necessary only in infants born in areas of endemic iodine deficiency.[28]

A skiagram demonstrating the absence of knee epiphyses indicate prenatal hypothyroidism and has prognostic value on neurocognitive development.[18]

[Figure 3] shows a diagnostic algorithm suitable for resource-limited scenario starting with USG thyroid and serum TG estimation.
Figure 3: Diagnostic algorithm for congenital hypothyroidism

Click here to view

  Endemic Cretinism Top

Endemic cretinism occurring in regions of severe iodine deficiency is manifested by two major clinical patterns - myxedematous and neurological or with combined features of both. Neurologic manifestations include various degrees of mental retardation, spastic diplegia, and deaf-mutism and are believed to result from maternal iodine deficiency causing prenatal CNS insult.[41] However, they often have transient hypothyroidism postnatally. By contrast, myxedematous cretins have more permanent and severe postnatal thyroid hormone deficiency and in addition to neurological signs, are dwarfed, sexually immature, with marked myxedema.[42] Infantile hypothyroidism is more frequent at 5–7 years of age than at birth or during the 1st year.[42] Concurrent selenium deficiency could be a major determinant of the severity of iodine deficiency.[43] Endemic cretinism is now rare in India due to nationwide iodine fortification of salt.

  Treatment Top

The goal of therapy is to rapidly restore and maintain clinical and biochemical euthyroidism so that these children develop physically and mentally to the best of their genetic potential. Levo-T4 (LT4) administered orally is the treatment of choice.[28] Pharmaceutically produced and licensed LT4 solutions are available in selected areas. A brand rather than a generic formulation is recommended.[28]

LT4 should be taken in the morning, before feeding, and in the same time daily avoiding nutritional supplements such as soy protein formulas or drugs that interfere with LT4 absorption. Caution should be taken with administration of Vitamin D due to reports of Vitamin D hypersensitivity.[44]

The recommended initial LT4 dose set forth by the American Academy of Pediatrics and the European Society for Paediatric Endocrinology is 10–15 μg/kg/day.[28],[31] The highest initial dose is reserved for infants with very low pretreatment total T4 or free T4 concentration. LT4 must be started within first 2 weeks of life and immediately after confirmatory test results in infants identified in a screening test.[31] The dose requirement decreases to 4–5 μg/day by 5 years due to decreased rate of T4 turnover.[45] Conversely, the rate of weight gain decreases rapidly in early infancy so the starting dose need not be changed for several months.[45]

  Monitoring of Treatment Top

[Table 3] summarizes the recommendations for monitoring of treatment of CH.[18],[28]
Table 3: Recommendations on monitoring of treatment of congenital hypothyroidism

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  Prognosis Top

There is evidence that age of onset of treatment, starting LT4 dose, and severity of hypothyroidism each plays an important role in neurocognitive outcome.[18] Strict compliance at least during initial 3 years must be ensured for normal brain development. However, noncompliance beyond the first 3 years might also affect cognitive performance.[18]

  Assessment of Permanence of Hypothyroidism Top

Reevaluation of the thyroid axis is recommended in cases, in which no etiological diagnostic assessment was carried out during early infancy and/or when treatment was started in the context of the infant being ill/preterm.

Permanent CH can be assumed if:[18]

  • thyroid gland is absent/ectopic
  • dyshormonogenesis has been demonstrated as the cause (except DUOXA2) or
  • if at any time during the 1st year of life, TSH rises above 20 mU/L.

Reevaluation is usually done after the age of 3 years though earlier reevaluation may be indicated in newborns in whom TPO or TSH receptor antibodies are detectable in the blood; and when a eutopic, normally sized gland is found.[28]

If a precise diagnosis is sought, LT4 should be phased out over 4–6-weeks and a full reevaluation carried out at the end of this. If the clinician wishes just to establish the presence or absence of primary hypothyroidism, LT4 dose may be decreased by 30% for 2–3 weeks. If an increase in TSH concentration to >10 mU/L is observed during this period, continuing hypothyroidism can be assumed and treatment reinstituted.[28] One novel approach is the use of recombinant TSH to make the diagnosis of CH without requiring withdrawal of thyroid hormone.[46]

  Antenatal Diagnosis Top

Antenatal diagnosis is possible by sampling of fetal cord blood and amniotic fluid for TSH. Cases have undergone treatment through intra-amniotic injections of 250 mcg of LT4 weekly with good psychomotor developmental outcome and shrinking of goiter; however, there are no systematic studies.[1],[47] However, newborn screening with early treatment has improved outcomes to such an extent that the necessity of antenatal treatment is questionable given the risks associated.

  Unresolved Issues Top

Despite extensive research, a number of questions remain unanswered with results of recent trials raising newer controversial issues. Newborn screening poses most of the ambiguities in existing practice including cutoffs, reliability of methods, and ideal timing. Lowered TSH threshold, coupled with the large number of premature neonates have contributed to the surge in the incidence of CH. However, issues are being raised that this results in detection of infants with such mild subclinical hypothyroidism that little to no benefit is derived from early detection and treatment. Given the increased rate of hospital discharge within 24 h, there is an increased rate of false positives with primary TSH assay.[48]

Recognition of transient hypothyroidism and discontinuation of treatment is another area of difficulty. There is lack of universally accepted TSH end-points for trials of T4 withdrawal in children treated for mild CH. In addition, lack of appropriate reference range for TSH in premature and LBW children who have periods of mild hypothyroxinemia and/or fluctuating TSH elevations during the perinatal period poses difficulty in deciding whether to treat without a definitive diagnosis or to temporize and continue to repeat thyroid function tests indefinitely.[49]

Given that only 2% of thyroid dysgenesis are claimed to be familial, genetic diagnosis in cases with thyroid dysgenesis is deemed less important. However, higher incidence in certain racial and ethnic groups, in preterm infants, in twin and multiple births, and in older mothers points toward undiscovered genetic and epigenetic as well as stochastic factors.[50] In addition, the approximate 2:1 female:male ratio, (more apparent with ectopic glands than with thyroid agenesis) points to undiscovered genetic factors, perhaps linked to autoimmuity.

Another issue raised is the adequacy of the recommended initial dosage of 10–15 μg/kg/day for severe CH. Members of the New Zealand program designed T4 dosages according to the etiology, namely, 10 μg/kg/day for dyshormonogenesis, 12 μg/kg/day for ectopia, 15 μg/kg/day for athyreosis.[51] Such a regimen would probably rationalize for differences in severity of CH. Again, concerns exist regarding the potential risks of overtreatment including attention-deficit disorder and lower IQ at adolescence.[52] However, in a prospective trial with newborns randomized to high-dose (50 μg/day) versus low-dose (37.5 μg/day) LT4, higher full-scale IQ scores were observed in children who had received the higher initial dose.[53],[54]

Finally, despite quite a high reported prevalence of neonatal hypothyroidism in India, and the known benefits of neonatal screening programs of CH, TSH screening is not yet deemed mandatory, and a properly implemented neonatal screening program for CH at all levels of health care is definitely the need of the hour.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]

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