Abstract
Thyroid hormone (TH) is indispensable for brain development in utero and during the first 2–3 years of life, and the negative effects of TH deficiency on brain development are irreversible. Detection of TH deficiency early in life by neonatal screening allows early treatment, thereby preventing brain damage.
Inborn shortage of TH, also named congenital hypothyroidism (CH), can be the result of defective thyroid gland development or TH synthesis (primary or thyroidal CH (CH-T)). Primary CH is characterized by low blood TH and elevated thyroid-stimulating hormone (TSH) concentrations. Less frequently, CH is due to insufficient stimulation of the thyroid gland because of disturbed hypothalamic or pituitary function (central CH). Central CH is characterized by low TH concentrations, while TSH is normal, low or slightly elevated.
Most newborn screening (NBS) programs for CH are primarily TSH based and thereby do not detect central CH. Only a few NBS programs worldwide aim to detect both forms of CH by different strategies. In the Netherlands, we have a unique T4–TSH–thyroxine-binding globulin (TBG) NBS algorithm for CH, which enables the detection of primary and central CH.
Although the necessity of central CH detection by NBS is still under debate, it has been shown that most central CH patients have moderate-to-severe hypothyroidism instead of mild and that early detection of central CH by NBS probably improves its clinical outcome and clinical care for central CH patients with multiple pituitary hormone deficiency. We are therefore convinced that detection of central CH by NBS is of utmost importance.
Introduction
Congenital hypothyroidism (CH) is an inborn disorder of the endocrine system with potentially severe health consequences for the affected individual and was the second disorder to be included in the national newborn screening (NBS) program in the Netherlands. CH is characterized by low blood thyroid hormone (TH) concentrations. When caused by defective thyroid gland development or TH synthesis (primary or thyroidal CH), typically an increased secretion of thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) by the hypothalamus and pituitary gland occurs. Less commonly, insufficient stimulation of the thyroid gland due to defects at the level of the hypothalamus or pituitary causes CH (central CH). In central CH, low serum TH concentrations are accompanied by an inappropriately normal, low or slightly elevated TSH concentration.
TH is indispensable for normal metabolism throughout life, for physical growth during childhood, and for brain development in utero and during the first 2–3 years of life. Although the negative effects of TH deficiency on metabolism and growth are usually reversible, its effects on brain development are not. If not treated shortly after birth, CH causes irreversible brain damage resulting in mental retardation and impaired motor function (1, 2, 3, 4).
Radioimmunoassays, developed in the 1970s, made measurement of blood thyroxine (T4) concentrations in the nanomoles per liter range possible, allowing early-CH detection by NBS. Dussault et al. developed a method to measure total T4 in dried blood spots (DBS), a few years later followed by a method for TSH measurement (5, 6, 7, 8). Given the favorable results from the NBS program in Quebec, Canada – started in April 1974 – and a clear advice from the American Thyroid Association a few years later (9), many countries decided to adopt the total T4-reflex TSH approach in their NBS program for CH. Unfortunately, T4-based screening is not very specific in detecting central CH as low blood T4 concentrations are also found in premature and sick neonates, and in thyroxine-binding globulin (TBG) deficiency, a harmless condition resulting in a high number of false-positive NBS results. With the advent of improved quality of TSH measurement, the majority of countries worldwide changed from T4-reflex TSH or T4 plus TSH to primarily TSH-based NBS for CH. While TSH-based NBS effectively detects primary CH, it does not detect central CH.
After the implementation of the first NBS program for CH in Quebec, Canada, several American states and also France started NBS for CH in the second half of the 1970s. In the Netherlands, NBS for CH screening was added to the existing screening for phenylketonuria (PKU) in 1981 with the measurement of total T4 in all newborns, followed by determination of TSH in newborns with the 20% lowest of T4 concentrations (≤−0.8 standard deviation score (SDS)). In case of a mildly elevated TSH, the screening result is considered inconclusive, and a second screening is performed. As newborns with primary CH are detected based on an elevated TSH, and central CH patients typically have a low T4 with a normal TSH concentration, this T4-reflex TSH strategy was chosen to enable the detection of both types of CH (see Fig. 1).
A schematic representation of the Dutch stepwise T4–TSH–TBG NBS algorithm for congenital hypothyroidism (CH).
Citation: European Thyroid Journal 12, 4; 10.1530/ETJ-23-0041
An initial period with many false-positive referrals due to low total T4 concentrations in DBS of premature newborns led to the addition of a decision rule in 1982 to refer premature newborns (birth weight ≤2500 g and a gestational age of ≤36 weeks) solely based on their TSH concentration. Since many false-positive results still occurred, discussion regarding the pros and cons of primarily total T4-based NBS for CH remained. TBG deficiency was considered as the main reason for the low total T4 concentrations. After a pilot study, measurement of the TBG concentration in newborns with the 5% lowest of T4 concentrations (≤−1.6 SD) was added to the CH NBS algorithm in 1995 (10). A calculated T4/TBG ratio serves as an indirect measure for free T4, and this effectively lowered the number of false-positive referrals although false-positive referrals due to partial TBG deficiency remained.
This three-step T4-reflex TSH-reflexTBG NBS program effectively detects primary CH with a positive predictive value (PPV) of 55%, which is in agreement with other primary TSH-based screening programs. As we pre-selected the neonates at risk for primary CH based on their T4 concentrations (80% of all neonates do not receive a TSH measurement), very mild primary CH cases with normal T4 concentrations might be missed. This could contribute to the lower incidence of primary CH in the Netherlands compared to other countries (11). The current three-step T4-reflex TSH-reflexTBG NBS program also led to an improved detection of central CH with an incidence of 1:16,404 that appeared much higher than reported in countries with T4-reflex TSH or TSH-based strategies (10).
Recently, we established reference intervals (RIs) for the NBS parameters total T4, TSH, TBG and the total T4/TBG ratio as used in the Dutch NBS. By using the TBG RIs to identify partial TBG deficiency, false-positive referrals were further reduced by approximately 50%. As a result, the Dutch screening algorithm has been adapted to exclude total and partial TBG deficiency (TBG <105 nmol/L blood) and this led to an improvement of the positive predicted value (currently 21%) while maintaining the current sensitivity of central CH detection (12).
Primary congenital hypothyroidism
Primary CH is caused by a defect at the level of the thyroid and is the most common form of CH, with a reported incidence of 1 in 3600 live-born children in the Netherlands (11). Primary CH is mostly (80–85% of the cases) caused by thyroid dysgenesis, a group of entities including absence (thyroid agenesis), misplacement (thyroid ectopy) and hypoplastic development (thyroid hypoplasia) of the thyroid gland. Several genes are involved in the development of the thyroid gland, and mutations in a variety of genes have been described to be associated with dysgenesis (PAX8, NKX2-1, FOXE1, NKX2-5,HHEX and TSHR). Less common (10% of the cases) are inborn errors of TH synthesis, so-called dyshormonogenesis. Disturbed TH synthesis may be due to a defect in iodine trapping, oxidation and organification or coupling (13). Genes involved in thyroid dyshormonogenesis are SLC5A5, TPO, DUOX2, DUOXA2, SLC6A4, Tg and DEHAL1 (see Table 1) (14). A small percentage (5%) is known as transient primary CH and is caused by extrinsic factors such as maternal TSH receptor blocking antibodies, maternal antithyroid drug medication or iodine excess or deficiency. Iodine is a critical component of TH, and hypothyroidism caused by iodine deficiency remains common worldwide (reviewed by Boelen et al. (15)).
Candidate genes and related phenotypes associated with congenital hypothyroidism (CH).
| Gene | Protein | Inheritance | Endocrine phenotype | Associated conditions |
|---|---|---|---|---|
| PAX8 | PAX-8 | AD | CH due to thyroid dysgenesis | Renal hemiagenesis and hypercalciuria |
| NKX2-1 | Thyroid transcription factor-1 | AD | CH due to thyroid dysgenesis | Unexplained respiratory distress, congenital heart defects |
| FOXE1 | Thyroid transcription factor-2 | AD | CH due to thyroid dysgenesis | Bamforth syndrome |
| NKX2-5 | NK2 homeobox 5 | AD | CH due to thyroid dysgenesis | – |
| HHEX | Hematopoietically expressed homeobox | AD | CH due to thyroid dysgenesis | – |
| TSHR | TSH receptor | AD | CH due to thyroid dysgenesis | – |
| SLC5A5 | NIS | AD | CH due to thyroid dyshormonogenesis | – |
| TPO | TPO | AD | CH due to thyroid dyshormonogenesis | – |
| DUOX2 | Dual oxidase 2 | AD | CH due to thyroid dyshormonogenesis | – |
| DUOXA2 | Dual oxidase maturation factor 2 | AD | CH due to thyroid dyshormonogenesis | – |
| SLC6A4, | Pendrin | AD | CH due to thyroid dyshormonogenesis | – |
| Tg | Thyroglobulin | AD | CH due to thyroid dyshormonogenesis | – |
| DEHAL1 | Iodotyrosine dehalogenase 1 | AD | CH due to thyroid dyshormonogenesis | Intellectual deficits |
| TSHβ | TSH | AD | Isolated central CH | – |
| TRHR | TRH receptor | AD | Isolated central CH | – |
| IGSF1 | IGSF1 | XLa | Isolated central CH | Macroorchidism |
| +/−PRL, transient GH | Ovarian cysts | |||
| TBL1X | TBL1X | XL | Mild isolated central CH | Hearing defect |
| IRS4 | IRS4 | XL | Mild isolated central CH | – |
AD, autosomal dominant; CH, congenital hypothyroidism; GH, growth hormone deficiency; PRL, prolactin deficiency; XL, X-linked .
aOne-third of females affected to some degree.
Central congenital hypothyroidism
Central CH results from insufficient hypothalamic and/or pituitary stimulation of an otherwise normal thyroid gland resulting in low serum TH concentrations. The majority of central CH patients have multiple pituitary hormone deficiency (MPHD), i.e., an inborn shortage of at least two anterior pituitary hormones. In approximately one-third of central CH patients, no other pituitary hormone deficiencies are present, referred to as isolated central CH.
Isolated central CH
Isolated central CH may be caused by pathogenic variants in genes involved in signaling pathways of the hypothalamus–pituitary–thyroid axis (see Table 1). Until 2012, only TSHB and TRHR gene variants were reported as very rare causes of isolated central CH, and most cases of isolated central CH remained unexplained. In the last decade, the use of next-generation sequencing techniques has led to the discovery of three new X-linked genetic causes of isolated central CH: IGSF1 (2012), TBL1X (2016), and IRS4 (2018) (15). IGSF1 gene variants seem to be the most frequent cause of isolated central CH followed by variants in TBL1X and IRS4. In a Dutch cohort of 32 cases of isolated central CH we found a genetic cause in 29 cases (17 IGSF1 (15 families), 5 IRS4 (4 families), 5 TBL1X, 1 TSHB, 1 TRHR) (16).
TSH β-subunit gene
Mutations in the TSH β-subunit gene (TSHB) cause severe central CH. Patients have increased α-subunit concentrations, an impaired TSH response to TRH and a hyperplastic pituitary gland on MRI. Although serum TSH concentrations may be within the RI, the profound hypothyroid state of most of the affected patients indicates a total inability to stimulate the TSH receptor (17, 18).
TRH receptor gene
A far less common genetic cause of central CH is mutations in the TRH receptor gene (TRHR) (19). Despite the absence of TRH signaling in the pituitary, patients with mutations in the TRHR gene have TSH concentrations within the reference range. Furthermore, patients detected at a later age had normal neurological development which implies that during childhood, TH was sufficiently produced. Clinical manifestations predominantly concern growth abnormalities (20).
IGSF1 gene
Another genetic cause of central CH is mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene (21). The IGSF1 gene lies on the X-chromosome and encodes a hypothalamic plasma membrane glycoprotein of which the specific function is still unknown (21). Loss of function mutations in IGSF1 result in central CH, delayed rise of serum testosterone in puberty, adult macroorchidism, obesity, partial GH deficiency and hypoprolactinemia in males. A minority of female heterozygous carriers are also affected. Till now, mutations in IGSF1 are the most common genetic cause of isolated central CH (22).
TBL1X gene
Transducin β-like 1X (TBL1X) is a WD40 repeat-containing protein and an essential subunit of the NCoR/SMRT corepressor complex, the most important TH receptor corepressor complex and involved in T3-regulated gene expression (23). TBL1X is encoded by the TBL1X gene, a gene also located on the X-chromosome. Recently, mutations in the TBL1X gene were identified in patients with mild central CH (24).
Several patients with central hypothyroidism due to mutations in TBL1X were only diagnosed as teenagers or adults having (although not formally tested) normal mental and physical development suggesting sufficient TH concentrations at the cellular level. Therefore, the necessity of TH replacement therapy remains uncertain now, although concentration, energy level and signs of myxoedema of one patient improved after starting T4 replacement therapy, which suggests that she had experienced TH deficiency (24).
IRS4 gene
The Insulin Receptor Substrate 4 (IRS4) gene is involved in the pathogenesis of central hypothyroidism; mutations in IRS4 have been identified in a number of male patients with central CH (25). The IRS4 gene is located on the X-chromosome and encodes a 1257 amino-acid protein that is activated by the insulin, IGF-1, and leptin receptor (26, 27). IRS4 mRNA is expressed in a variety of tissues, including the pituitary gland and hypothalamus (25). At present, the mechanism underlying the central hypothyroidism in patients with IRS4 mutations is unclear (28).
Central CH as part of MPHD
MPHD is an inborn shortage of at least two anterior pituitary hormones (29, 30). Besides TSH, the anterior pituitary lobe produces five other hormones: growth hormone (GH), adrenocorticotrophic hormone (ACTH), the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and prolactin (PRL). Deficiencies of these hormones lead to clinical entities known as GH deficiency, ACTH deficiency and central hypogonadism (30). Neonatal signs of MPHD include hypoglycemia, lethargy, feeding problems, poor weight gain and persistent jaundice (31). In addition, sepsis-like illness and potentially life-threatening adrenal crises can occur due to ACTH deficiency. In male neonates, undescended testicles or a micropenis can be present in case of central hypogonadism. However, clinical signs and symptoms of MPHD are not necessarily present in the neonatal phase, and without screening for central CH, the diagnosis is often delayed until poor growth is noted during childhood (32). Since signs of MPHD are non-specific, pediatricians will be likely to consider more prevalent diagnoses first, for instance, assigning hypoglycemia to prematurity. Indeed, a previous study has shown that despite signs and symptoms of MPHD, the diagnosis of central CH is often missed in the neonatal period (31).
The most common cause of MPHD is a pituitary malformation known as pituitary stalk interruption syndrome (PSIS) consisting of a classic triad of interrupted or absent pituitary stalk, ectopic posterior pituitary and anterior pituitary hypoplasia or aplasia.
Benefits of screening for central CH
In the Netherlands, central CH patients detected by neonatal screening have their first diagnostic blood collection performed at a mean age of 14 days old (33). This is in sharp contrast with countries where central CH is not detected through neonatal screening; one study reported a mean age at endocrine consultation of 16 months (34). The necessity of central CH detection by neonatal screening is under debate. A frequently heard argument against is the relatively mild character of the hypothyroidism, assumed unlikely to cause developmental delay. We showed however that – based on pre-treatment serum FT4 concentrations – most central CH patients have moderate-to-severe hypothyroidism instead of mild (33). Another argument against screening is the assumption that patients with central CH, especially in case of MPHD, are clinically diagnosed based on signs and symptoms such as hypoglycemia, micropenis or undescended testes in boys (35). This, however, is also not the case. In a study of a 20-year Dutch cohort of 154 early-detected central CH patients, a high percentage of patients were hospitalized during the first weeks of life (88% of MPHD patients and 31% of isolated central CH patients) while the diagnosis of central CH was seldom made during these hospital admissions, and approximately half of admitted patients were even discharged without a diagnosis of central CH. In these cases, the diagnosis was only made after notification of an abnormal CH NBS result. These data suggest that without neonatal screening, central CH is unlikely to be diagnosed during the neonatal period. This finding is also supported by studies in clinically detected central CH patients with a mean age at diagnosis of 1.3–2.8 years (31, 34). Thus, in the absence of an NBS program for central CH, hypothyroidism may go untreated for several months or even years with possible negative effect on mental development (36).
Recently, a pilot study in Argentina evaluated an NBS program for CH detecting both primary and central CH (37). This study showed that central CH detection contributed to the improvement of clinical care for central CH patients with MPHD. For countries that are also considering revising their neonatal CH screening methods to detect central CH, data on the neurodevelopmental outcome of early- vs late-detected patients are highly relevant (38).
Unfortunately, those data are scarce. Due to its low prevalence, very few clinical and observational studies on isolated central CH have been reported. Nebesio et al. evaluated retrospectively medical charts of children with central CH seen at a pediatric endocrinology department over a 17-year period, during which the study region’s screening consisted of a combined T4 and TSH measurement. Central CH patients detected by neonatal screening (n = 8) were compared with central CH patients with normal screening results, who were detected during childhood based on clinical grounds (n = 34). Developmental delay, which was assigned based on medical charts, was noted in 25% of early-detected children and 56% of late-detected children (34). Although this difference was not statistically significant, the results from this explorative study should still be considered alarming, showing such a high proportion of central CH patients with developmental delay. These results are also suggestive of a difference in development between early- and late-detected central CH patients.
We recently studied Full Scale Intelligence Quotient (FSIQ) in a cohort of 87 patients with early detected and treated central CH (35 isolated central CH, 52 MPHD) using healthy siblings as controls. While the mean FSIQ in isolated central CH patients was similar to that of siblings, this was not the case for MPHD patients, who scored on average 8 points lower than siblings. Furthermore, more than 10% of MPHD patients had an FSIQ below 70 which is much higher than in the normal population (FSIQ below 70 is 2.3%). Among patients with isolated central CH, an FSIQ below 70 was seen in only one patient (3%) (39). Besides differences in FSIQ, we also observed a lower processing speed and more motor difficulties in both patient groups compared with siblings. These findings may indicate that in central CH, like in primary CH, even a short period of postnatal hypothyroidism may have long-term consequences. Alternatively, these impairments may result from prenatal hypothyroidism or the combination of hypothyroidism during both these periods. Since isolated central CH and MPHD patients were equally affected, the impairment in these two domains seems to be related to TH deficiency per se, rather than the severity of hypothyroidism or the presence of additional pituitary hormone deficiencies. In particular, motor problems are also seen in early-treated patients with primary CH (40, 41).
Overall, the long-term cognitive outcome of early-detected central CH patients is reassuring; almost 90% have an FSIQ score that lies within population norm scores. Our study can be considered the first robust study on cognitive outcome in early-treated central CH patients, due to its group size and the use of a standardized outcome measurement. It is also a first step toward uncovering the potential benefits of neonatal screening for central CH. However, to answer the question of whether early detection is beneficial for cognitive outcome and development, additional studies including both early- and late-detected central CH patients are needed. Comparing early- and late-detected patients in a prospective study will present researchers with ethical concerns, but a cross-sectional study including late-detected patients from countries with a TSH-based NBS is feasible. Due to the low prevalence of the disease, international collaboration will be necessary to reach a sufficiently large group. Ideally, future studies should use a design comparable to ours, including siblings as controls, but a study including patients only would also provide valuable information since FSIQ scores can be compared to norm scores. Ultimately comparison of long-term outcomes in early- vs late-detected central CH patients will answer the question of whether neonatal screening programs worldwide should also focus on detecting central CH.
Other NBS programs for central CH
Most NBS programs for CH are based on TSH measurement only, thereby not detecting central CH (42). Only a few NBS programs aim at the detection of both forms of CH by following different strategies. In less than half of the Italian Screening Centers (11 of the 26), newborns are screened by simultaneous measurement of TSH and T4, while in the other centers only TSH is measured (43).
In almost all regions of Japan, NBS is based on TSH measurement, although in some areas TSH and free thyroxine (FT4) are measured simultaneously (44). In case TSH and FT4 are simultaneously measured, central CH was detected although at the cost of a low sensitivity due to the suboptimal FT4 cutoff value (45).
In the United States, the NBS program differs per state; TSH is the primary marker in 22 states, while T4 is the primary marker in 20 states, either always combined with TSH measurement or only if T4 is abnormal. Nine programs screen for both TSH and T4 in all newborns (46). The NBS program in Israel is also based on T4 as a primary marker with additional TSH in case T4 is below the daily tenth percentile. Only neonates with a TSH value >20 mU/L are referred to a pediatrician which means that only primary CH is detected (47).
Conclusion
The unique Dutch T4–TSH–TBG NBS algorithm for CH enables the detection of both primary and central CH by using T4 as the primary marker instead of TSH. The downside of T4 as a primary maker is well known; T4 concentrations are also decreased due to illness or prematurity. Moreover, the total T4 concentration is low in children with a (partial) TBG deficiency. The Dutch algorithm was therefore refined by adding TBG and taking (partial) deficiency into account (10, 12). Currently, this leads to a neonatal screening program with a PPV of 21% and the detection of 10–12 newborns with central CH per year (total number of births in the Netherlands per year: approximately 170,000). Although the necessity of central CH detection by NBS is still under debate, we convincingly showed that most central CH patients have moderate-to-severe hypothyroidism instead of mild (33). Furthermore, results of the first systematic study on the long-term cognitive outcome of earlydetected central CH patients were reassuring; almost 90% have an FSIQ score which lies within population norm scores. In addition, a recent study in Argentina showed that detection of central CH by NBS contributed to the improvement of clinical care for central CH patients with MPHD (38). We are therefore convinced that detection of central CH by NBS is of utmost importance. However, we realize that the difference in PPV between primarily T4-based NBS and an NBS based on TSH is big and therefore an obstacle for changing the NBS approach. This forces us to continuously work on improving our algorithm. We are currently studying the possibility of including additional markers in the algorithm using machine learning techniques in order to further improve the PPV while keeping its sensitivity. Preliminary results are promising.
Recommendations
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Neonatal screening programs should include (total) T4 as a primary marker to allow the detection of patients with central CH.
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Adding TBG to the T4-reflex TSH algorithm prevents unnecessary referrals due to a harmless TBG deficiency.
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Establishing method-specific RIs for T4, TSH and TBG in DBS contributes to the improvement of the screenings algorithm.
Declaration of interest
We declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
AB wrote the manuscript draft and approved the final manuscript. AH, NZS and ASPT read, commented the manuscript draft and approved the final manuscript. All authors contributed to the article and approved the submitted version.
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