Knowns and unknowns about congenital hypothyroidism: 2022 update

Abstract.

Several excellent guidelines and expert opinions on congenital hypothyroidism (CH) are currently available. Nonetheless, these guidelines do not address several issues related to CH in detail. In this review, the authors chose the following seven clinical issues that they felt were especially deserving of closer scrutiny in the hope that drawing attention to them through discussion would help pediatric endocrinologists and promote further interest in the treatment of CH.

1. How high should the levothyroxine (L-T4) dose be for initial treatment of severe and permanent CH?

2. What is the optimal method for monitoring treatment of severe CH?

3. At what level does maternal iodine intake during pregnancy affect fetal and neonatal thyroid function?

4. Does serum thyroglobulin differ between patients with a dual oxidase 2 (DUOX2) variants and those with excess iodine?

5. Who qualifies for a genetic diagnosis?

6. What is the best index for distinguishing transient and permanent CH?

7. Is there any cancer risk associated with CH?

The authors discussed these topics and jointly edited the manuscript to improve the understanding of CH and related issues.

Introduction

Several excellent guidelines and expert opinions on congenital hypothyroidism (CH) (1,2,3,4) are currently available. However, clinicians may find it difficult to judge the quality of evidence for specific issues related to CH based on these guidelines and expert opinions.

In this review, we focused on seven clinical issues that have not been addressed in detail in the existing guidelines and are particularly important for clinical practice in Japan (e.g., iodine excess and dual oxidase 2 [DUOX2] variants) or have to do with advances in the study and treatment of CH. These clinical issues do not cover all aspects of CH, but the authors have attempted to address issues for which there is currently no clear-cut, high-evidence support. These discussions may be of practical value because they address concerns relevant to clinical practice.

1. How high should the levothyroxine (L-T4) dose be for the initial treatment of severe and permanent CH?

Long-term complications of severe CH include developmental delay and growth retardation, even with prompt L-T4 replacement (4,5,6). Together with the potential impact of hypothyroidism in utero, the initial L-T4 dose is an important issue.

Several studies suggest that patients with severe CH may not be adequately treated with the previously recommended dose of 6–8 μg/kg/d of L-T4 (7, 8). Thereafter, high-dose and early L-T4 replacement have been shown to achieve adequate development in severe CH (8, 9), and the guidelines since 2000 recommend an initial dose of 10–15 µg/kg/d. However, even early and high-dose L-T4 replacement resulted in a slightly lower intelligence quotient (IQ) in patients with severe CH than in controls (10). Early L-T4 replacement revealed no significant difference between the age at the start of treatment and intelligence prognosis, the latter of which was associated with low T4 levels at the initial visit (10). Thus, the optimal initial L-T4 dose remains an open question in patients with severe CH. This chapter summarizes reports published since 2010 on the initial dose of L-T4 and the long-term prognosis of patients with severe CH.

Since 2010, five neurodevelopmental studies on the initial L-T4 dosage in patients with CH have been published (Table 1) (5, 11,12,13,14). This review classifies the severity of CH by the free T4 (FT4) concentration as severe (< 0.39 ng/dL), moderate (0.39–0.78 ng/dL), and mild (0.78–1.17 ng/dL) in accordance with the most recent guidelines (4). Patients with severe CH had more subtle cognitive and motor impairments than those with mild or moderate CH despite an average initial L-T4 dose of 12.3 μg/kg/d (5). In severe CH, such as athyreosis, poor motor development was reported even with 15 µg/kg/d L-T4 (11), while others showed no difference from healthy siblings, with the equal doses (12). Favorable results have been reported with 10–15 µg/kg/d L-T4 in patients with CH due to ectopic or dyshormonogenesis (11, 12).

Table 1. Summary of neurodevelopmental studies with initial doses of L-T4 in CH patients since 2010.

A previous meta-analysis assessed the relationship between IQ and the initial L-T4 dosage based on CH severity (14). There were 438 patients with CH: 156 with severe CH (initial serum T4 ≤ 2 μg/dL or FT4 ≤ 3 pmol/L), and 282 with moderate or mild CH (initial serum T4 > 2 μg/dL or FT4 > 3 pmol/L). In 157 patients (36%; 47 with severe CH and 110 with mild/moderate CH), treatment was started with an initial dose of >10 μg/kg/d. The meta-analysis assessing found that with an initial dosage < 10 μg/kg/d, patients with severe CH showed a significantly greater decrease in IQ (< 8 μg/kg/d: –6.03; 95% confidence interval [CI]: –9.10, –2.96; 8–10 μg/kg/d: –9.2; 95% CI: –15.07, –3.33) than those with mild to moderate CH. In contrast, a dosage > 10 μg/kg/d was not associated with decreased IQ or quality of life (QOL), even in patients with severe CH (14). Oral administration of high-dose L-T4 shortened the time required for FT4 levels to normalize (12, 14).

However, overtreatment with high-dose L-T4 replacement during initial treatment may have adverse neurodevelopmental consequences. Seven previous studies evaluated the effects of overtreatment with L-T4, although the definition of overtreatment varied, and three of these studies (13, 15, 16) were conducted at the same institution (13,14,15,16,17,18,19). Craven et al. (17) found that an L-T4 dose above 12.5 μg/kg/d may lead to overtreatment, while Tuhan et al. and Vaidyanathan et al. (18, 19) similarly found a risk of overtreatment in patients receiving 12–17 μg/kg/d. In studies on the effects of L-T4 overtreatment, long-term follow-up after a 2-yr postnatal overtreatment period demonstrated lower IQ and increased incidence of attention deficit hyperactivity disorder at 11 yr of age (13, 16). However, Aleksander et al. (14) showed no difference in IQ between patients and their siblings, despite a similar duration of overtreatment. As few studies have compared the initial L-T4 dosage in patients with severe CH, the adverse effects of overtreatment with L-T4 for severe CH are not clearly known.

According to the studies mentioned above and the current guidelines (1,2,3,4), L-T4 10–15 μg/kg/d should be administered as the initial therapy for severe CH during the neonatal period. Patients with severe CH with athyreosis may require 15 μg/kg/d (11, 20). Clinicians should determine the dosage based on the severity of hypothyroidism, history of iodine exposure, maternal thyroid disease, prenatal medications, and the presence of thyroid structural abnormalities. Clinicians should monitor laboratory data and clinical symptoms after the start of L-T4 treatment to avoid underdosing or overdosing.

Answering the present question requires a study of two L-T4 dosages (10–15 and 15 μg/kg/d), ideally in a cohort of patients with comparable disease severity. The endpoints should include not only short-term thyroid function but also long-term neurodevelopmental outcomes.

2. What is the optimal method of monitoring the treatment of severe CH?

Maintaining serum FT4 levels between the mean and upper limit of the normal range in each age group while maintaining serum TSH levels within the normal range has been proposed as a goal of L-T4 replacement therapy for CH (2, 3). The rationale for this recommendation is the negative correlation between serum TSH and FT4 levels. However, T3 is more bioactive than T4, and conversion of T4 into T3 occurs in TSH-producing cells. In type 2 selenodeiodinase gene (DIO2) knockout mice, serum T3 levels did not differ from those of wild-type mice whereas serum T4 and TSH levels were higher, indicating that the conversion from intracellular T4 into T3 is crucial in the feedback regulation of TSH secretion (21). Moreover, approximately 20% of serum T3 is directly derived from the thyroid gland, whereas the remaining 80% is produced by converting T4 (22). Therefore, the regulation of serum TSH levels involves not only the serum T4 levels, but also the serum and local (in TSH-producing cells) T3 levels.

The recommendation to maintain T4 in the upper range is not entirely evidence based (2, 3). Approximately 43% of infants with CH and 10% of children with CH reportedly had high TSH levels relative to FT4, suggesting negative feedback resistance of the hypothalamic–pituitary–thyroid (HPT) axis to serum T4 (23). Indeed, patients with severe CH, such as athyrosis or ectopic thyroid, fail to achieve a normal serum TSH value despite their serum FT4 level exceeding the upper limit of the normal range and their FT3 level being at the lower limit of the normal range. It is still unclear whether monitoring treatment for severe CH should be based on serum TSH or FT4 levels in patients with high TSH levels relative to FT4.

The mechanism underlying the imbalance between serum FT4 and TSH levels in patients with severe CH remains unclear. One possibility is that fetal hypothyroidism may be associated with impaired development of the HPT axis (24). Epigenetic changes in feedback control of the HPT axis have been observed in humans (25). Second possibility is the involvement of T3 in the negative feedback of the HPT axis. Thyroid aplasia or severe hypoplasia may downregulate T3 secretion from the thyroid gland, resulting in a low FT3 level and inadequate TSH suppression, even after L-T4 replacement normalizes the serum FT4 levels (26). Other possibilities include the effect of the timing of blood sampling on the results after oral L-T4 administration. Serum FT4 levels can reportedly increase by up to 20% two–nine hours after L-T4 administration (27).

Although high TSH is often observed in the presence of high T4 as discussed above, the acceptable upper limit of the serum FT4 level required to normalize TSH has yet to be established. A TSH level below the lower detection limit of an assay likely indicates L-T4 overdose. Previous studies have reported conflicting results on this topic. L-T4 overdosing during CH replacement has a negative effect on cognitive function and intellectual development in children (13, 28). However, in their study of 104 patients with permanent CH (P-CH), Aleksander et al. found no association between the frequency of high T4 up to the age of 2 yr and IQ at the age of 10 yr or older (14). They further suggested that the higher T4 levels in CH patients may not represent a state of “overtreatment” but may indicate that more T4 is needed by thyrotrophs to achieve normal T3 levels (14).

Normalization of serum FT3 levels may be important for suppressing serum TSH levels during the treatment of severe CH. In adult post-total thyroidectomy patients, suppressing TSH to a range of 0.03–0.3 μIU/mL during L-T4 replacement reportedly resulted in a normal levels of serum FT3 and metabolic markers equivalent to the preoperative values (29). In patients with CH caused by thyroid aplasia, as in patients undergoing total thyroidectomy, suppression of TSH levels to the range described above may be necessary to achieve an acceptable level of FT3 and metabolic markers. However, Bagattini et al. compared the amount of L-T4 replacement and thyroid function test results in 13 patients with congenital thyroid aplasia (mean age: 21.5 ± 2.1 yr) and 23 patients after a total thyroidectomy (mean age: 24.0 ± 2.7 yr) (24) by examining the daily, weight-based L-T4 dosage and reported that serum TSH and FT4 were significantly higher in patients with athyrosis than in patients after a total thyroidectomy (TSH 1.8 ± 0.8 vs 1.03 ± 0.67 μIU/mL, FT4 1.32 ± 0.18 vs 1.18 ± 0.19 ng/dL) and FT3 levels were not different, despite a higher L-T4 dosage per body weight (2.16 ± 0.36 vs 1.73 ± 0.24 μg/kg/d). This difference was thought to be due to fetal thyroid hormone deficiency, resulting in a shift in the HPT axis setpoint for T4, but the detailed mechanism underlying this difference is still unknown (24).

In summary, the optimal monitoring parameters for severe CH are unknown, and it is unclear whether normalization of serum TSH is the highest priority, what the upper limit of an acceptable FT4 level is, and how high the FT3 level should be maintained. To identify an optimal method for monitoring treatments for severe CH, it is necessary to evaluate the impact of each parameter (TSH, FT4, FT3, FT4 to FT3 ratio, etc.) using intellectual development, anthropometric indicators, and metabolic markers as outcomes.

3. At what level does maternal iodine intake during pregnancy affect fetal and neonatal thyroid function?

Maternal iodine intake affects fetal and neonatal thyroid functions because iodine can cross the placental barrier. Although maternal iodine deficiency is a well-known cause of high TSH levels in newborn screening (NBS) worldwide, neonates with high TSH levels in NBS caused by maternal iodine excess have also been reported in Japan (30, 31).

Excess iodine causes hypothyroidism by downregulating thyroid hormone synthesis, a phenomenon known as the Wolff–Chaikoff effect, which generally resolves within several days in adults whereas fetuses and neonates with immature thyroid glands suffer longer lasting damage (32). Iodine-related fetal and neonatal hypothyroidism is suspected if a goiter is present and may be confirmed with a blood test (33). Because fetal exposure to maternal iodine excess is limited by the gestational period, the resulting hypothyroidism theoretically has a transient clinical course, with P-CH being a rare exception (31, 34).

Transplacental passage of iodine occurs with 1) administration of iodine-containing medicines, 2) intake of iodine-containing supplements or 3) intake of iodine-rich food alone. First, amiodarone, a typical iodine-containing medication, contains 37.5 mg of iodine in a 100 mg tablet formulation. The incidence of neonatal hypothyroidism caused by the administration of 200–1,600 mg of amiodarone during pregnancy is reportedly 23% (35). Since amiodarone is metabolized in the liver and approximately 3.5 mg of inorganic iodine is released into the systemic circulation per 100 mg tablet formulation, 200–1,600 mg of amiodarone is equivalent to 7–56 mg of iodine (36). Potassium iodide is administered to pregnant women with mild Graves’ disease; however, it is not an established treatment. Momotani et al. reported that when pregnant women with mild Graves’ disease were treated with 6–40 mg/d iodine, a relatively low dosage range for adults, only two of 35 fetuses showed elevated TSH with normal FT4 (37).

Another iodine-containing medical substance common in Japan is an oil-soluble iodinated contrast medium (ethiodized oil) used in hysterosalpingography (HSG). Post-HSG hypothyroidism has been reported in more than 20 Japanese fetuses and neonates over the past 30 yr (38,39,40). In Japan, the frequency of neonatal hypothyroidism after the use of this contrast medium is 2.4% (39). The low incidence of similar cases of HSG-related fetal or neonatal hypothyroidism in other countries (41) indicates that certain factors may influence hypothyroidism development. The higher incidence reported in Japan is thought to be associated with a high consumption of iodine-rich foods such as seaweed, although this association has not been established. Water-soluble iodinated contrast medium, which has a shorter iodine half-life than the oil-soluble version, is currently recommended for use with HSG in infertile women in Japan (39) although it may still not eliminate the risk of developing thyroid dysfunction. The use of povidone-iodine mouthwash during pregnancy and iodine-containing disinfectants during delivery is also known to cause neonatal hypothyroidism (3). In view of the risk to neonatal thyroid function, iodine-free formulations such as azulene mouthwash and chlorhexidine disinfectant should be used instead.

Second, fetal and neonatal hypothyroidism resulting from the maternal ingestion of nutritional supplements containing large quantities of iodine has also been reported worldwide (33, 42,43,44). In the United States, the use of iodine-containing supplements for healthy infant brain development is encouraged because pregnant women are generally deficient in dietary iodine (45). However, the amount of iodine in health food supplements is not strictly controlled by regulatory authorities such as the Food and Drug Administration and can be quite high (46). Moreover, supplements containing large amounts of potassium iodide (e.g., 12.5 mg in a single tablet) are commercially available in some developed countries. In contrast, pregnant women in Japan normally have sufficient amount of dietary iodine for the reasons described below.

Third, maternal dietary iodine excess alone may lead to fetal and neonatal hypothyroidism. In Japan, where iodine-rich seaweed is consumed in large quantities, Nishiyama et al. reported that maternal iodine excess during pregnancy was observed in 15 of 34 infants who tested positive on CH screening (31). Similar findings have been reported by Asakura et al. (30). However, these reports failed to consider the possibility of co-occurrence of a genetic abnormality causing CH in the infants studied. Further research is needed to investigate whether the frequency of CH increases when excess iodine is added to genetic predisposition.

The upper limit of the daily iodine intake varies by country. The upper limit in healthy adults is 1,100 μg in the United States (47). In contrast, since the daily iodine intake of 1,000–3,000 μg in Japanese adults is not associated with any adverse effects, the upper limit is 3,000 μg for healthy adults (48). A possible reason for the difference between the two countries is that the absorption rate of iodine contained in kelp, a major dietary source of iodine for Japanese people, may be lower than the absorption rate of iodine contained in other foods (49).

The amount of iodine intake in the previously cited study by Nishiyama et al. (31) was 820–3,200 μg/d, suggesting that even a daily maternal iodine intake below the upper limit of 2,000 μg, which is the upper limit for pregnant women in Japan (48), may affect thyroid function in the fetus or neonate. Further research is needed to determine an appropriate upper limit for pregnant Japanese women in the context of post-delivery neonatal thyroid function.

In summary, maternal iodine excess may cause transient fetal and neonatal hypothyroidism. Although the upper intake level in pregnant women is unclear, pregnant women should be made aware of the risks of fetal and neonatal hypothyroidism caused by excessive dietary iodine.

4. Does serum thyroglobulin (Tg) differ between patients with a DUOX2 variant and those with excess iodine?

Both DUOX2 variants and iodine excess are common causes of transient CH (T-CH) with goiter in Japan (31, 50). However, determining which of the two is the cause in a particular case based on physical findings and thyroid function test results alone is difficult. In addition, the diagnosis of iodine excess is not straightforward because iodine excess cannot always be diagnosed by the urinary iodine value due to individual differences in sensitivity to iodine, as hypothyroidism develops only in a small percentage of patients who have received iodinated contrast medium (ethiodized oil) during HSG (39). However, differentiating between DUOX2 variants and iodine excess is important for predicting subsequent follow-ups. Thyroid goiter and hypothyroidism have been reported in adult patients with DUOX2 variants, suggesting a need for long-term follow-up (51).

Tg, along with iodine and peroxidase, is essential for thyroid hormone synthesis. Serum Tg levels increase when thyroid hormone synthesis is impaired because of a congenital organification defect, such as that observed in patients with a TPO or DUOX2 variant. Neonatal hypothyroidism caused by iodine excess also reportedly increases Tg transiently. (42). Serum Tg level is frequently measured at CH diagnosis as a marker of dyshormonogenesis (DH) and iodine excess. However, no previous study has directly compared Tg levels in the two pathological conditions. In this section, we will discuss whether serum Tg levels during the neonatal period can distinguish between these two diseases.

Although there are several ways to answering this question, we reviewed studies analyzing the serum Tg levels in patients with a biallelic DUOX2 variant and those with evident iodine excess-related CH were reviewed. Patients with a DUOX2 variant show a wide clinical spectrum (50, 52, 53); those with a biallelic variant who often present more severe manifestations were considered here. Patients with post-HSG CH were included in the present analysis, as in a previous study by one of the authors (39). Most CH cases detected by HSG using an oil-based contrast medium have been reported in Japan; the patients had severe CH clearly stemming from iodine excess. Finally, patients whose Tg levels were measured during the neonatal period were included, as the Tg levels are normally age-dependent, particularly during the early months of life.

Studies on the characteristics of patients with CH with a DUOX2 variant have reported a high serum Tg level upon diagnosis. Maruo et al. measured Tg levels in 20 of 32 patients with CH with a DUOX2 variant and found it to be above 800 ng/mL in 17 patients (54). Jin et al. reported that serum Tg levels in five of ten patients with CH with a biallelic DUOX2 variant were 20.2, 101, 453, 500, and 1,560 ng/mL (55). Narumi et al. reported that the serum Tg level at diagnosis in three of nine patients with CH with a biallelic DUOX2 variant were 1,600, 1,500, and 710 ng/mL, respectively (56). Muzza et al. examined CH with elevated serum Tg levels or a hyperplastic thyroid gland on ultrasonography (US) and found that 11 of 30 patients harbored a biallelic variant impairing DUOX2 activity. Although the serum Tg value in patients with a DUOX2 variant overlapped with that in patients without the variant, the former had more severe symptoms along with a higher serum Tg level at diagnosis (median: 655 vs 426 ng/mL; range: 403–1,991 vs 54.4–3,000) (57).

With respect to iodine excess, Satoh et al. reported that hypothyroidism developed in five of 212 infants born after HSG (39). The urinary iodine concentration (UIC) in four of the five infants was 1,150, 940, 1,570, and 319 μg/L, which showed a rather large variation but was nonetheless higher than the median UIC of 121.0 μg/L in the first voided urine of Japanese neonates (58). The serum Tg level in two of the five infants was 178.9 and 1,219 ng/mL, respectively (39). Tachibana et al. reported that among 48 infants with a high TSH level on NBS, 15 with high urinary total iodine (> 500 μg/L) and hypothyroidism had Tg levels ranging from 111–7,089 ng/mL (59). This report shows a relationship between urinary iodine and serum Tg level in infants with CH but does not describe the cause of iodine excess or diagnostic criteria.

Previous studies have demonstrated the difficulty in distinguishing between hypothyroidism resulting from a DUOX2 variant or excess iodine based on the Tg level alone. The serum Tg level in neonates with a homozygous or compound heterozygous variant of DUOX2 ranged from 20.2, an extremely low value, to 1,991 ng/mL, and the serum Tg levels in the two neonates with iodine excess were 178.9 and 1,219 ng/mL, respectively, showing that the two causes of hypothyroidism can have overlapping Tg levels (Fig. 1). The differences in the serum Tg levels between the two infants with hypothyroidism due to iodine excess may indicate that the Wolff–Chaikoff effect and/or transfer of iodine to the fetus varies from case to case. The cause of the wide variation in Tg levels associated with DUOX2 variants is currently unknown. Multiple factors are possible, including differences in the severity of DUOX2 variants, presence of other genetic variants, and iodine intake. Since there are few reports of the serum Tg levels in neonates with hypothyroidism caused by excess iodine or a DUOX2 variant, further research is needed before any definitive conclusions can be drawn.

Fig. 1.

Dot chart of serum Tg in patients with hypothyroidism with biallelic DUOX2 variants or iodine excess. The left chart shows the DUOX2 variant, and the right chart shows iodine excess. The values were drawn from previous reports (39, 54,55,56,57).

5. Who qualifies for a genetic diagnosis?

Molecular studies focusing on a limited number of candidate genes have been conducted in patients with specific clinical characteristics or family histories. Identification of causative genes (Table 2) helped us to understand the mechanisms of thyroid development and hormone synthesis. Most P-CH cases are subclassified as thyroid dysgenesis (TD) or DH. The overall detection rate of potentially pathogenic variants in the analysis of CH candidate genes in Japan is approximately 20% (56, 60,61,62).

Table 2. Summary of causative genes in congenital hypothyroidism and clinical features.

Most cases of TD are sporadic, and their etiology is unclear. Less than 5% of TD cases are attributable to potentially pathogenic variants of the known genes that regulate thyroid gland development (60). Some patients have extrathyroidal complications. For example, patients with an NKX2-1 variant may experience extra-thyroidal complications, such as benign chorea, whereas those with a PAX8 variant may have urogenital tract malformations (Table 2). Careful phenotypic description of CH patients from both thyroidal and non-thyroidal perspectives is important for identifying a candidate gene.

CH is also associated with several other malformations. Recent genetic studies have identified candidate genes associated with syndromic CH, such as DYRK1A (Down syndrome), TBX1 (22q11.2 deletion syndrome), JAG1 (Alagille syndrome) and KAT6B (Ohdo syndrome, Genitopatellar syndrome) (63,64,65,66,67).

In contrast, most individuals with DH harbor variants in genes encoding known components of the thyroid hormone biosynthesis machinery. These variants cause loss of function, resulting in inadequate thyroid hormone synthesis with or without compensatory goiter. The most frequent gene in the DH group was DUOX2, and the phenotype was usually transient (54, 56). In most cases of DH, the CH is isolated. Pendred syndrome (SLC26A4 variant), in which patients experience sensorineural hearing loss, is an exception to this.

Next-generation sequencing (NGS) has brought about a major change in the conventional approach for diagnosing and understanding the molecular basis of CH by detecting several novel genes involved in the organogenesis of thyroid tissue (68). Furthermore, targeted NGS panels have already provided an efficient means of identifying gene variants in the coding regions of known CH genes (61, 62, 69). Although most cases are monogenic, oligogenic inheritance of CH has also been confirmed using this technology (62, 70). Further studies are required to establish a method for diagnosing oligogenic disorders. NGS approaches have also enabled the screening of genes in large CH populations (irrespective of TD or DH), demonstrating overlapping genetic etiologies in the TD and DH subgroups (71).

Finally, the cost and time required for NGS have decreased over the past several years, and bioinformatics analysis in silico is now widely used (although the accuracy of the analysis is not yet optimal). The authors believe that these trends will continue for some time. Thus, in clinical practice, genetic testing using NGS will soon become a powerful tool for clinicians to identify the genetic etiology of CH.

Although the molecular and genetic mechanisms underlying CH have been elucidated, the exact cause of CH remains obscure in many cases, especially in TD. Whole genome analysis, such as exome analysis, may be considered for research involving undiagnosed cases with multiple congenital anomalies or a family history. The contribution of other genetic and environmental factors should also be considered when attempting to clarify the etiology. The former includes regulatory regions, intronic mutations, and copy number variants in the genes of interest. In the future, alternative mechanisms, such as epigenetic modifications, should be further explored to understand their contribution to CH (72).

6. What is the best index for distinguishing transient and permanent CH?

Clinically, the distinction between P-CH and T-CH is one of the most important concerns for parents of affected children, excluding cases of TD that can be easily diagnosed by US or scintigraphy. Usually, thyroid function test findings are re-evaluated after discontinuing L-T4 treatment at age 3 yr of age or older to differentiate between P-CH and T-CH (2, 3). The latest European consensus guidelines for CH stated that the clinician may consider stopping treatment after 1 yr of age (2). However, these guidelines do not clarify the characteristics of patients in whom treatment may be stopped before the age of 3 yr.

Many studies have reported that the L-T4 dosage is a useful predictor of the clinical course of hypothyroidism (Table 3) (73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89). Most reports revealed a significant difference at the age of 1 yr, at which the mean L-T4 dosage for P-CH and T-CH was 3.1–4.5 µg/kg/d and 1.9–3.4 µg/kg/d, respectively (74, 76, 78, 80, 83, 84, 86, 87). Because of the variations among the studies and the overlap in the mean values of the two groups, complete distinction between the groups based on the L-T4 dosage was not possible. Three reports suggested the possibility of predicting the clinical course of hypothyroidism at the age of 1 yr based on receiver operating characteristic (ROC) analysis (77, 84, 85). The area under the curve (AUC) of the ROC curves was 0.61–0.73 at the age of 1 yr. A L-T4 dosage exceeding 4.7–4.9 µg/kg/d and below 1.7–1.8 µg/kg/d at the age of 1 yr may help predict P-CH and T-CH, respectively (77, 85). The specificity of these cut-off values was 97–100%. At older ages, both the sensitivity and specificity were higher, with the AUC of the ROC curves being 0.73–0.80 at the age of 2 yr and 0.82–0.83 at the age of 3 yr (77, 85).

Table 3. L-T4 dosage per body weight as predictor of P-CH and T-CH.

Some researchers have reported that predicting P-CH and T-CH was possible at the age of 90–180 d (79, 83). However, the sensitivity and specificity of the L-T4 dosage as a predictor tended to be lower in younger populations. As age 90–180 d is too early to discontinue L-T4, this conclusion may be difficult to apply in clinical practice.

Two additional parameters for discriminating between P-CH and T-CH have been reported. First, Yamamura et al. suggested that an increase in the L-T4 dosage at age ≥ 3 yr is useful for distinguishing P-CH from T-CH (89). Second, the TSH level at diagnosis also reportedly had a predictive value (76, 83), although other reports showed no significant difference in TSH levels between P-CH and T-CH (73,74,75, 77, 80, 84, 85, 87, 89). Some studies have examined the Tg levels at diagnosis, albeit in only in a few subjects (75, 78).

Recently, Mehran et al. developed a model for predicting P-CH and T-CH development in patients up to 1 yr of age based on a forward stepwise multivariable logistic regression analysis of 1,047 patients with CH (90). The equation for predicting P-CH risk included confirmed TSH levels, total T4 < 8.2 μg/dL, increased L-T4 requiring dosage up to the age of 1 yr, 6-mo duration of TSH >10 μIU/mL, parental consanguinity, and a family history of thyroid disease. This prediction model had a significantly greater diagnostic value than TSH or total T4 level alone.

It is unclear for how long patients with suspected T-CH should be followed up after L-T4 discontinuation. In our previous study, patients with CH were followed up till the age of 15 yr or older (85), whereas the duration of observation after L-T4 discontinuation was < 1 yr in almost all other studies (73,74,75,76,77,78,79,80,81, 83,84,85,86,87). In patients with P-CH in our study, the longest L-T4-free period after discontinuation was 1.2 yr (85). This indicates that some patients may require L-T4 administration again within approximately 1 yr. The length of follow-up after L-T4 discontinuation should be longer than 1 yr. However, few studies besides ours have been designed to observe patients for more 1 yr after L-T4 discontinuation.

To better understand whether the L-T4 dosage is a useful prediction, a prospective study investigating not only thyroid function, but also the physical and mental development, of patients with CH is warranted. The increased use of genetic testing has clarified the spectrum of clinical expressions and the genotype–phenotype correlation. In particular, patients with a DUOX2 variant should be analyzed separately because they are usually treated for short periods despite having severe hypothyroidism during the neonatal and early postnatal periods (54).

In conclusion, the L-T4 dosage is one of the best means of differentiating P-CH from T-CH. The L-T4 dosage at 1 yr of age had an especially high diagnostic accuracy with high sensitivity and specificity. The addition of some other factors may improve the diagnosis of P-CH and T-CH.

7. Is there any cancer risk associated with CH?

Several cases of thyroid cancer as a complication of CH with or without neonatal hypothyroidism were reviewed, including patients with DH or TD, and the mechanism of carcinogenesis. There are a few previous reports of thyroid cancer in patients with CH caused by DH, which did not include genetic analysis (91,92,93,94,95). Recently, thyroid cancer complicated by DH stemming from variants of TG (96,97,98,99,100), TPO (101, 102), NIS (103), and PDS (104, 105) have been reported (Table 4). These cancers can develop at various ages but are most common in middle-aged individuals and can be aggressive (91,92,93,94,95,96,97,98,99,100,101,102,103,104,105). Few cancer-driver gene variants have been identified in thyroid cancer associated with DH (Table 4), although the presence of such variants is generally required for carcinogenesis (106).

Table 4. Summary of case reports of thyroid dyshormonogenesis with gene variants associated with thyroid cancer.

The mechanisms implicated in the development of thyroid cancer in patients with thyroid DH are not yet fully understood. Constant and prolonged TSH stimulation may result in goiter, thyroid nodules, or thyroid cancer (91, 97, 100, 107,108,109). TSH is a growth factor of thyroid epithelial cells that can promote thyroid nodule formation and cancer progression (100). A higher serum TSH concentration was found in children and adolescents with differentiated thyroid cancer than in those with benign thyroid nodules (109). In contrast, a large, multinodular goiter can develop despite early treatment with L-T4, resulting in normal TSH levels (99, 102). Cancer in the absence of elevated serum TSH levels indicates that genetic and environmental factors other than TSH levels may play a role in oncogenesis, and the precise cancer risk in CH patients who receive L-T4 replacement therapy from early infancy is currently unknown.

The frequency of thyroid cancer in patients with a TG variant is higher than that in the general populations (96). Hishinuma et al. reported thyroid cancer in 11 of 25 patients with a TG variant (44%) (110). Most of these patients were diagnosed before the initiation of NBS and had normal thyroid function at diagnosis. Some patients with TG variants may have TSH levels in the normal range, possibly because of sustained TSH-stimulated thyroid growth, which partially compensates for thyroid hormone production (96, 111). It is not yet clear whether early L-T4 treatment can prevent the development of thyroid cancer; however, early L-T4 treatment in patients with TG abnormalities who were diagnosed positive as positive for NBS did not develop goiter, suggesting that early LT4 treatment may prevent thyroid cancer development (96). As a mechanism of carcinogenesis in TG abnormalities, abnormal folding and transport of Tg protein to the Golgi apparatus has been suggested to result in retention of the abnormal proteins in the endoplasmic reticulum (ER), which may trigger carcinogenesis due to ER stress in patients with TG variants. (110, 112).

Biochemical evidence suggests that thyroid peroxidase (TPO) may promotes oncogenesis. TPO reduces hydrogen peroxide (H₂O₂) and attaches iodine to the tyrosyls residues in Tg. In the context of pathological TPO deficiency, H₂O₂ produced by DUOXs can diffuse through the apical membrane of thyrocytes and reach the nucleus directly or via redox signaling pathways, possibly activating intracellular NADPH oxidase 4 (NOX4) in the nucleus and ER. The presence of NOX4 in the perinuclear region might increase nuclear oxidative stress and promote DNA damage and genomic instability (113, 114). However, there are no reports of a higher frequency of cancer in TPO variant cases than that in the general population.

Several studies of patients with thyroid hemi-agenesis (THA), defined as the absence of one thyroid lobe, reported thyroid cancer as a complication of this condition (Supplementary Table 1), even in patients as young as 14 yr of age (115). Cancer occurs more frequently in female, than in male, probably because the frequency of THA is higher among female patients (116) and develops at approximately the same rate in the right and left residual lobes. To the best of our knowledge, no case of hypothyroidism has ever been reported in a patient with cancer associated with THA. It is unclear whether the frequency of thyroid cancer in THA patients is higher than that in the general population.

Many cases of thyroid cancer were associated with ectopic thyroid (Supplementary Table 2). Massine et al. summarized 28 cases of lingual thyroid cancer that occurred between the ages of 18 and 86 yr, before 2000 (117). Carcinoma arising from the lingual thyroid are rare, with an incidence of approximately 1% (117, 118). The risk of malignant transformation is no more likely than that in orthotopic thyroid, and the risk factors (ionizing radiation, family history, etc.) are the same (117). Thus far, genetic analysis of transcription factors in patients with ectopic thyroid cancer has failed to yield any significant findings.

In conclusion, the risk of thyroid cancer may be higher in patients with a TG variant, but it remains unknown whether the occurrence rate of cancer in other DH and TD patients is not higher than that in the general population. Careful follow-up with physical examination and US is necessary, especially in patients with poorly controlled disease and resulting prolongation of TSH elevation or in patients with thyroid nodules or a goiter. Determining the cancer risk associated with CH with thyroid DH and TD is difficult because of the rarity of pediatric thyroid cancer and the requirement for long-term follow-up to achieve meaningful endpoints.

Conflict of interests

The authors have no conflicts of interest.