Congenital Hypothyroidism

Abstract

Congenital hypothyroidism is considered the most common neonatal endocrine disorder, with an incidence of 1/3000–1/4000 newborns. It is defined by insufficient synthesis of thyroid hormones from the newborn thyroid. The hormonal deficiency can vary from a slightly low level to a severe deficiency, also called myxedema. It is often a chronic condition caused mainly by thyroid dysgenesis or a defect in the thyroid hormones synthesis (dyshormonogenesis). Less often, it is secondary to abnormal pituitary or hypothalamic control of thyroid function. Considering the major role played by thyroid hormones in the early development of the central nervous system, congenital hypothyroidism is considered the most common condition involved in the etiology of mental retardation in children. Thus, early detection through neonatal screening programs and initiation the earliest possible of thyroid hormone replacement treatment prevent irreversible neurodevelopmental delay and optimize developmental outcome of affected newborns.

1. Introduction

Congenital hypothyroidism (CH) is defined as dysfunction of the hypothalamic-pituitary-thyroid (HPT) axis present at birth, which will generate an insufficient production of thyroid hormones (TH). Axis dysfunction can be of varying degrees, as a result of which the hormonal deficit can vary from mild to severe [1]. It is considered the most common endocrine disorders, reported to occur in 1 in 3000–4000 newborns worldwide [2, 3].

Thyroid hormones play a crucial role in neuronal differentiation, myelination, and synapsis development in the prenatal and newborn periods, regulating early central nervous system development [2, 4, 5]. Thereby, severe undiagnosed and untreated CH is associated with neurological and psychiatric deficits, intellectual disability, spasticity, and impaired gait and coordination [2, 4]. Thyroid hormones are also important for growth during childhood and for normal metabolic functions throughout life [5]. These negative effects of thyroid hormone deficiency on metabolism and growth are reversible by therapy, regardless of when it is initiated. The situation is not the same in the case of cerebral tissue; if the treatment is not initiated as early as possible, the brain damage becomes irreversible [5]. There are studies that have shown the inverse relationship between age at the initiation of treatment (before 3 months) and the intelligence quotient (IQ) level later in life [6]. Despite all that, CH is one of the most common preventable causes of mental retardation [4].

2. Epidemiology

The overall incidence of CH ranges from 1 in 3000 to 1 in 4000 live births, with variation worldwide by geographic location or ethnicity [2, 7]. Before the 1970s, prior to the onset of newborn screening programs, when the diagnosis of CH was made based on clinical manifestations, the incidence ranges between 1;7000 and 1:10,000 [7, 8].

Among racial groups, the incidence is higher in Hispanic, Native American, and Asian population and lower in White and Black infants [2, 7, 8]. Besides, almost all screening programs report a female preponderance, of nearly 1.5 or 2 to 1 female to male ratio, and is also higher in twin births, multiple births, and preterm infants [2, 7].

Over the past few decades, a trend of increasing incidence is observed based on newborn screening programs, with an incidence reported of 1:2000 in ~2000 [2, 8]. The reasons for this rise in the overall incidence of CH are multifactorial: lowering of TSH screening cutoffs in TSH-based screening programs, leading to increased detection of milder cases; earlier discharge from the hospital with screening specimen obtained earlier, closer to the TSH surge after birth; changes in the population demographics (increased births of Asians and Hispanic babies); or increased screening of preterm or low-birth weight infants by improvements in neonatal medicine [2, 8].

3. Etiopathogeny

The HPT axis is a complex neuroendocrine regulatory loop involved in tight regulation of the thyroid function for maintaining a stable level of circulating TH (T4—thyroxine and T3—triiodothyronine) and thus the euthyroid state [9]. At the central level, hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and secretion of pituitary thyrotropin (thyroid-stimulating hormone, TSH). The latter acts at the thyroid level to stimulate all steps of TH biosynthesis and secretion [9]. Conversely, TH controls the TRH and TSH secretion by negative feedback, maintaining physiological levels of central hormones of the HPT axis. In conclusion, reduction of circulating TH levels results in increased TRH and TSH production, whereas the opposite occurs when circulating TH are in excess. It is considered that serum thyroid parameters show substantial interindividual variability and thus that every individual has a unique hypothalamus-pituitary-thyroid axis set point, mainly determined by genetic factors [9].

As we mentioned in the introduction, CH represents a condition characterized by dysfunction of the HPT axis. CH is classified based on [2, 4, 7]:

• Origin—in primary or central/secondary hypothyroidism.

• Severity—in compensated (FT4 levels within the normal range for age) or decompensated (subnormal FT4 levels).

• Duration—in permanent and transient congenital hypothyroidism. In contrast to the permanent form, the transient CH is characterized by a temporary deficiency of thyroid hormones diagnosed at birth, with the possibility of recovery and restoration of euthyroidism in the first months or years of life [7].

Primary CH is caused by damage of the thyroid gland, thereby is characterized biochemical by low TH levels with elevated TSH concentrations [5, 9]. Instead, in central CH, the cause for inadequate TH production is located at the central level (hypothalamus or pituitary) and is defined biochemically by low thyroid hormone concentrations, while TSH is normal, low, or slightly elevated [5, 9]. The slightly elevated TSH concentrations observed in central hypothyroidism can be partly explained by intact immunoactivity but decreased bioactivity [9].

With these in mind, we can conclude that diagnosis of primary hypothyroidism is based on finding of an elevated TSH concentration [9]. Instead, central hypothyroidism may be more difficult to diagnose. It relies on correct interpretation of FT4 concentration using age-specific reference intervals and to recognize when FT4 is too low [9].

3.1 Primary congenital hypothyroidism

Primary CH is caused by a defect in thyroid gland and is the most common form of CH [2, 4, 5]. The majority of primary CH is due to thyroid dysgenesis, summing approximately 80–85% of cases [2, 3, 5]. The remaining 15–20% of cases are due to inborn errors of thyroid hormones biosynthesis, the so-called thyroid dyshormonogenesis [3, 5].

Thyroid dysgenesis encompasses a group of entities including thyroid agenesis (absence of the gland), thyroid ectopy (misplacement of the gland), and thyroid hypoplasia (underdevelopment of the thyroid gland) [2, 3, 5]. Thyroid dysgenesis is almost always sporadic or nonhereditary [2, 10]. However, in 2–5% of cases, mutations in a variety of genes responsible for thyroid gland development have been described [3, 5, 10]. Thus, thyroid dysgenesis can be associated with PAX8 (paired box 8), NKX2–1 (thyroid transcription factor-1), FOXE1 (thyroid transcription factor-2), NKX2–5 (NK2 homeobox 5), HHEX (hematopoietically expressed homeobox), and TSHR (thyroid-stimulating hormone receptor) mutations [2, 3, 5]. Some of these patients have extrathyroidal complications like benign chorea for those with an NKX2–1 variant or urogenital tract malformations in those with a PAX8 variant [7, 10].

Thyroid dyshormonogenesis can also be associated with multiple genetic defects interfering with encoding components of the thyroid hormone biosynthesis machinery like SLC5A5 (sodium/iodide symporter—NIS), TPO (thyroid peroxidase), DUOX2 (Dual oxidase 2), DUOXA2 (Dual oxidase maturation factor 2), SLC26A4 (Pendrin), Tg (Thyroglobulin), and DEHAL1 (Iodotyrosine dehalogenase 1) [3, 5, 10]. These variants cause loss of function, resulting in inadequate thyroid hormone synthesis with or without compensatory goiter [10]. In most of these cases, the CH is isolated. An exception to this in the Pendred syndrome (SLC26A4 variant), in which patients experience sensorineural hearing loss [10]. The genetic defects are often transmitted in an autosomal recessive manner in most cases, but autosomal dominant inheritance has also been reported [3, 10].

Next-generation sequencing (NGS) has brought a major change in understanding the molecular basis of CH, but it also allowed demonstrating a significant overlap in the genetic etiologies in the thyroid dysgenesis and dyshormonogenesis subgroups [10].

While thyroid dysgenesis and dyshormonogenesis cause permanent CH, in a small number of cases (5%), we can have a transient primary CH caused by extrinsic factors [2, 5]. Thus, transplacental passage of maternal anti-thyroid medications (methimazole or propylthiouracil), maternal TSH receptor-blocking antibodies (from a mother with autoimmune thyroid disease), or iodine deficiency or excess can be the causes for transient primary CH factors [2, 5]. Of all these factors, an important role is attributed to iodine, a mineral essential for thyroid hormone biosynthesis [5, 11]. It is worth noting that iodine deficiency remains an important cause of congenital hypothyroidism globally [2, 11]. Compared to an adult, the neonatal thyroid is much more susceptible to iodine deficiency as thyroidal iodide content at birth is extremely low and the daily neonatal iodide turnover is accelerated [11]. Although considerable efforts have been made to reduce the number of iodine-deficient countries in the last 20–25 years, especially through salt iodization, there are still many iodine-deficient areas, including in Europe [7, 11]. On the other hand, exposure of newborns to excess iodine can also result in transient hypothyroidism by interfering with thyroid hormone synthesis via the Wolff-Chaikoff effect [2, 11]. In general, a normofunctional thyroid is capable to “escapes” from the Wolff-Chaikoff effect after around 2 weeks by downregulation of its sodium-iodide symporter from the basolateral membrane and so to decrease its intracellular iodide concentration [11]. Instead, both fetal and neonatal thyroid, especially in preterm infants, cannot escape from the Wolf-Chaikoff effect, making them extremely susceptible to iodine excess [10, 11]. Exposure to excess iodine in this age group, through either iodine-containing antiseptics, radiographic contrast agents, iodine-rich food products (seaweed), iodine-rich supplements, or drugs like amiodarone, can result in blockade of thyroidal iodine transport for weeks to months [2, 7, 10, 11].

Another rare form of transient CH can be found in infants with hepatic hemangiomas [7, 12]. Congenital liver hemangiomas are benign vascular tumors affecting 5–10% of infants. These tumors, which can be unifocal, multifocal, or diffuse, can generate a rare form of hypothyroidism also called consumptive hypothyroidism. The pathogenic mechanism involved includes overexpression of deiodinase type 3 by vascular endothelium, a thyroid hormone-inactivating enzyme that converts T4 to reverse triiodothyronine (rT3) and T3 to diiodothyronine [7, 11, 12]. Medical treatment and reduction in tumor burden lead to consumptive hypothyroidism resolution in most cases [11, 12].

3.2 Central or secondary congenital hypothyroidism

This is a less frequently encountered cause of CH [4]. It is generated by insufficient hypothalamic or pituitary stimulation of an otherwise normal thyroid gland, which will result in secondary low serum level of thyroid hormones concentrations [4, 5]. Normally, thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates anterior pituitary thyrotropes cells to secrete TSH. Congenital defects in this system, either from abnormal hypothalamic or pituitary development or from genetic alterations that impair TRH or TSH function, will lead to central congenital hypothyroidism [13]. Based on this, it is classified as central hypothyroidism with isolated TSH deficiency (one-third of cases), or more commonly TSH deficiency associated with other pituitary hormone deficiencies [4, 5, 9, 13]. Through combination of basal and dynamic endocrine investigation, genetic testing, and high-resolution magnetic resonance imaging, it was possible to obtain increasing knowledge about the etiology of central CH [9].

3.2.1 Central congenital hypothyroidism as part of multiple pituitary hormone deficiency

The anterior pituitary lobe or adenohypophysis consists of five specialized cell types involved in secreting of six hormones: thyrotrophs producing TSH, somatotrophs producing growth hormone (GH), corticotrophs producing adrenocorticotropic hormone (ACTH), gonadotrophs producing luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and lactotrophs producing prolactin (PRL) [5, 9]. Multiple pituitary hormone deficiency is an inborn shortage of at least two anterior pituitary hormones, so beside central congenital hypothyroidism, we can meet GH deficiency or ACTH deficiency or central hypogonadism, or all together [5, 14].

Developmental or structural anomalies of the hypothalamus and/or pituitary usually lead to multiple deficits in pituitary hormones [13]. Some of these cases have a genetic basis being attributed to mutations in one of several genes critical for the normal early development of these structures like HESX1, LHX3, LHX4, SOX3, and OTX2 [13, 14]. These genes encodes a series of transcription factors essential for early embryonic brain development [9, 13]. Mutation of these genes are responsible for syndromic features that combine multiple pituitary hormone deficiency with cerebral and extra-cerebral abnormalities [9, 13, 14]. The cerebral structures interested in these conditions are midline brain, eye, inner ear, and the craniofacial structures. So, the newborn can present with holoprosencephaly, septo-optic dysplasia (SOD), absence of corpus callosum, cerebellar malformations, Arnold Chiari malformation, pituitary stalk interruption syndrome (PSIS), cleft lip, or palate and dental malformations [9]. The extra-cerebral structures involved are heart, urinary or gastrointestinal tract, and axial skeleton [9]. When the genetic defects affect transcription factors involved in the final steps of pituitary cellular differentiation, like POU1F1, PROP1, the child will have milder combined pituitary hormone deficiency without other syndromic malformation [9, 13].

Obvious neurological and developmental birth defects will usually lead to an early diagnosis of syndromic multiple pituitary hormone deficiency [9]. In their absence, other neonatal signs that can lead to the diagnosis are hypoglycemia, lethargy, feeding problems, poor weight gain, persistent jaundice, as well as potentially life-threatening adrenal crises due to ACTH deficiency [5]. Also, the male neonates can present with undescended testicles or a micropenis in case of central hypogonadism [5]. It should be mentioned that not all these symptoms are present from birth. So, without screening for central CH, the diagnosis is often delayed until childhood when developmental delay from thyroid hormones deficiency, poor growth secondary to GH deficiency, and delayed pubertal development due to LH/FSH deficiency triggers the diagnosis [5, 9, 14].

3.2.2 Isolated central congenital hypothyroidism

This form is characterized by the presence of an isolated TSH deficiency that leads to the appearance of central congenital hypothyroidism, with an estimated frequency of 1 in 40,000 newborns [5, 9, 15].

Until 2012, only TSH β-subunit (TSHB) and TRH receptor (TRHR) gene variants were reported as causes of isolated central CH [4, 5, 15]. In the last decade, with the help of NGS techniques, three new X-linked genetic causes of isolated central CH were discovered: Immuno Globulin Super-Family member 1 (IGSF1 in 2012), transducing-beta-like 1 gene (TBL1X in 2016), and insulin receptor substrate-4 gene (IRS4 in 2018) [4, 5, 9, 15]. Of these last three genetic defects identified, IGSF1 gene variants seem to be the most frequent cause of isolated central CH followed by variants in TBL1X and IRS4 [5, 13].

It is considered that this pure form of congenital isolated TSH deficiency has a variant type, namely, combined TSH/prolactin (PRL) deficiency, because TRH receptor signaling affects not only TSH secretion but also PRL secretion in both physiological and pathological conditions [15].

3.2.2.1 TSH β-subunit gene (TSHB)

Thyroid-stimulating hormone or TSH is a glycoprotein hormone consisting of two chains: an alpha and a beta chain. Its structure is very similar to the other glycoprotein hormones produced by the anterior pituitary, LH and FSH, and to human chorionic gonadotropin (hCG), all sharing the same alpha subunit. The β subunit is different for all these hormones, being the one who confers them the biological specificity. TSHB encodes the β subunit of TSH and its mutations cause severe central CH with neonatal onset [5, 9]. Patients shows an elevated α-subunit concentrations, an impaired TSH response to TRH, a normal or high PRL level, and a hyperplastic pituitary gland on MRI [5, 15].

3.2.2.2 TRH receptor gene (TRHR)

A far less common genetic cause of central CH with isolated TSH deficiency is mutations in the TRHR gene. Despite the absence of TRH signaling in the pituitary, patients with mutations in the TRHR gene have normal TSH concentrations but low PRL circulating levels and a blunted TSH/PRL responses to exogenous TRH [5, 14, 15].

3.2.2.3 IGSF1 gene

The IGSF1 gene lies on the X chromosome and encodes a hypothalamic plasma membrane glycoprotein whose functions are not fully known [5]. IGSF1 is expressed at high levels in testes and the pituitary, specifically in thyrotrophs, somatotrophs, and lactotrophs [9]. Mutations in IGSF1 gene are considered the most common genetic cause of isolated central CH [5, 9]. Numerous studies, both in vivo and in vitro, support that IGSF1 deficiency causes central hypothyroidism by impairing expression and downstream signaling of the TRH receptor in pituitary thyrotropes [13]. For this reason, the affected individuals will have a blunted response to exogenous TRH stimulation [13, 14].

The boys with inactivating mutation of IGSF1 will have delayed pubertal rise in testosterone levels, besides central hypothyroidism. As adults, the plasma testosterone levels will remain in the low-normal range and will also have macroorchidism (although testicular enlargement can begin before the onset of puberty), variable hypoprolactinemia and transient growth hormone deficiency [5, 13, 14]. Even if the IGSF 1 deficiency is X-linked, women carrying the mutation can also present with central hypothyroidism and prolactin deficiency but with an apparently normal lactation and late menarche in a minority of cases [13, 14].

3.2.2.4 Neonatal screening

Because thyroid hormone deficiency early in life is harmful to brain, growth, and development and in many cases difficult to recognize shortly after birth, newborn screening (NBS) programs for CH were implemented in many countries worldwide since the 1970s [1, 9]. The introduction of neonatal screening was justified by the fact that the costs of screening and diagnosis are much lower than those necessary for the care of children with intellectual disabilities, during their lifetime [4]. In addition, neonatal screening programs allow early diagnosis, soon after birth, much faster than the moment when signs and symptoms of hypothyroidism become clinically evident [4]. In this way, NBS for CH should be performed in all infants [16]. Prompt diagnosis by NBS leads to an early and adequate treatment, preventing hypothyroidism morbidity and ensuring a grossly normal neurocognitive outcomes in adulthood [4, 16]. Nevertheless, it is estimated that only 25% of the worldwide birth population undergoes screening for CH [7, 8]. A significant percentage of infants worldwide are born in areas that do not have access to neonatal screening, and so, the diagnosis will be made after development of clinical manifestations of hypothyroidism [1, 7, 8, 16]. Furthermore, many of these infants are born in areas of iodine deficiency, increasing their risk of thyroid hormone deficiency [1].

There are different screening strategies for CH worldwide [17], and these are based on [8]:

• Primary determination of TSH, followed by subsequent dosing of T4, when TSH exceeds certain values.

• Initial determination of blood thyroxine (T4) concentrations, with subsequent TSH dosing, when T4 is below certain limits (usually less than the 10th percentile for a given day).

• Simultaneous determination of TSH and T4 values (combined method), this represents the ideal screening approach but involves higher costs.

Each program must develop its own T4 and TSH cutoff for recall of infants with abnormal test results and to use age-related cutoffs, considering rapid changes in TSH and T4 in the first few days of life [7].

The strategy for selecting neonatal screening tests focuses on detecting all forms of primary CH, mild, moderate, and severe, as early as possible because disability due to primary CH is greatest in patients not treated before 3 months of age [1, 4].

Early in the neonatal screening, when radioimmunoassays developed and made possible measurement of T4 levels from dried blood spots, most programs undertook an initial T4 test, with a follow-up TSH test on infants below a specified T4 cutoff [4, 5, 7]. Unfortunately, T4-based screening is not very specific in detecting central CH and some mild cases of primary CH [4, 5]. Low blood T4 concentrations are also found in premature and sick neonates, as well as in thyroxine-binding globulin (TBG) deficiency [5]. TBG deficiency is an X-linked recessive disorder that occurs in approximately 1:4000 infants, primarily males [7]. It is considered a harmless condition. The infants are usually euthyroid, and treatment is not necessary but can generate a high number of false-positive NBS results [5, 7].

With increasing accuracy of TSH measurement, most countries worldwide changed their screening program from initial T4 test to primarily TSH-based NBS for CH [5, 7]. Nowadays, many screening programs carry out an initial TSH test to detect congenital hypothyroidism [7]. For this reason, TSH levels are determined from blood collected after the first 24 hours and should be the single most important test in any screening program [4]. More accurate and the best “window” for TSH testing for full-term infants is 48–72 hours of age [4, 16]. Blood is spotted onto filter paper after heel prick, allowed to dry, and sent to a centralized laboratory for TSH analysis [4]. The report result may vary according to the NBS program. Thus, some programs report TSH value in serum units while others in whole blood units. TSH results in whole blood unit are approximately one-half of the corresponding serum value. Thereby, the infant whose TSH is >30 mU/L serum (>15 mU/L whole blood) will be recalled for clinical evaluation and serum testing [7]. The reason that the filter paper screening test cutoff is approximately 30 mU/L is because of the TSH surge that occurs shortly after birth [7]. Later, after the first to 2 weeks of life, the TSH range falls to approximately 10 mU/L [7].

There are some programs that use an upper percentile TSH cutoff, for instance, > 97th percentile [7].

As we already mentioned, it is important to use a TSH cutoff adjusted for the infant’s age to avoid false-negative results in those with mild hypothyroidism [16]. And this is important to know especially if a screening sample is collected after the 4 days of life, since TSH decreases sharply during the first week of life [7].

There is a category of neonates, namely, preterm neonates (less than 37 weeks of gestational age); low birth weight (LBW) and very low birth weight, under 1500 grams (VLBW) neonates; infants with Down syndrome; ill neonates admitted to neonatal intensive care; and multiple births, particularly in case of monozygotic twins, that are at risk of transient or permanent CH [4, 16]. The initial screening tests in these newborns may be inappropriate, providing false-negative or false-positive results due to [4]:

• suppression of TSH caused by drug administration,

• hypothalamic-pituitary immaturity,

• fetal blood mixing in multiple births,

• other effects of serious neonatal illnesses

In many centers, for this category, a second screening strategy will be applied, with remeasurement of dried blood spot TSH at about 2–4 weeks of age or as they approach discharge from hospital [4, 7, 16].

It should also be emphasized that while TSH-based NBS effectively detects primary CH, it does not detect central CH [5, 13]. Even though it is a less common condition than primary CH, there are enough evidence to support that neonatal screening for central CH fulfills the criteria for disease screening:

• Central CH is a relatively frequent disease, with an incidence similar to phenylketonuria, condition for which newborn screening was introduced since the 1960s [4, 13].

• Central CH is unlikely to be diagnosed during the neonatal period, without a neonatal screening [5].

• Most central CH patients have moderate-to-severe hypothyroidism instead of mild, based on pre-treatment serum FT4 concentrations [5].

• Screening tests and treatment are available, inexpensive, and effective [4].

• The risks in cases of delayed diagnosis are in for an unfavorable outcome [4, 5].

According to European Society of Pediatric Endocrinology (ESPE) guidelines, the screening strategies for central CH detection are based on two approaches [4]:

• a combination of primary T4 and TSH screening or

• a combination of primary T4 screening with secondary TSH testing followed by thyroxine binding globulin (TBG) determination.

The three-step T4-reflex TSH-reflex TBG NBS program, currently used by the Dutch national health system as a diagnostic strategy, led to an improved detection of central CH with an approximate incidence of 1:16,000, which is much higher than reported in countries with T4-reflex TSH or TSH-based strategies [5, 14].

4. Diagnosis

Diagnosis and treatment should not be based on screening test results alone. That is why all newborns with an abnormal NBS result must be referred to an expert center for immediate measurement of TSH and FT4 in a serum sample, to confirm the diagnosis of CH as soon as possible, preferably within 24 hours [1, 7, 16]. Besides TSH and FT4, it can also measure total T4 and triiodothyronine (T3) uptake to determine the type of hypothyroidism and establish the management approach. Measuring a TBG concentration when T4 is low but FT4 is normal may assist in distinguishing central hypothyroidism from TBG deficiency [16].

If the NBS TSH is >40 mIU/L, levothyroxine (L-T4) treatment should be initiated immediately after drawing the confirmatory serum sample, without waiting for the results [1, 16]. Such a value is highly suggestive of moderate-to-severe primary CH [1]. CH severity can be also assessed clinically (symptomatic hypothyroidism), biologically, respectively, based on knee X-ray and thyroid imaging results [4].

The infant with abnormal NBS result should be evaluated by a physician (primary care provider or pediatric endocrinologist) that should [16]:

• Obtain a complete history, including prenatal maternal thyroid status, maternal medications, and family history

• Perform a complete physical examination of the newborn.

The clinical symptoms and signs of symptomatic CH include sleepiness and not waking for feeds, poor and slow feeding, cold extremities, prolonged neonatal jaundice, lethargy, hypotonia, macroglossia, umbilical hernia, and dry skin with or without a puffy face [4]. Persistence of the posterior fontanelle, a large anterior fontanelle, and a wide sagittal suture all reflect delayed bone maturation, which can be further documented by knee X-ray [4]. The absence of one or both knee epiphyses is a reliable index for the severity of intrauterine hypothyroidism [1, 4]. Also, it has been shown to be related to T4 concentration at diagnosis and neurodevelopmental and IQ outcome [1, 4].

Biologically, based on plasma FT4 concentrations, it possible to construct a scale of CH severity in [4]:

• Severe—FT4 levels <5 pmol/l,

• Moderate—FT4 levels between 5 and < 10 pmol/l, or

• Mild—FT4 levels >10–15 pmol/l

Although it does not change initial treatment, it is recommended to determine the etiology of CH at the time of diagnosis using thyroid radionuclide uptake and scan, ultrasonography, serum thyroglobulin, and test for thyroid autoantibodies or urinary iodine excretion [1]. However, this approach should never delay the start of treatment in newborns with CH [1, 8, 16].

1. Thyroid scintigraphy—using Technetium-99 m (^99mTc) or iodine-123 (¹²³I) is the most accurate diagnostic test for determining the etiology of CH, allowing to define the size and location of any thyroid tissue [1, 8]. ¹³¹I delivers a higher dose to the thyroid and total body and should not be used [7]. For an accurate scintigraphic examination, it should only be performed when the TSH is elevated and thus before or within the first 2–3 days after initiating of L-T4 treatment [16].

   ^99mTc is more widely available, less expensive, faster in use (image acquisition after 15 minutes), and has a shorter half-live than ¹²³I but is not organified and the images are of lower quality than with ¹²³I [1]. The latter isotope adds more information about organification process and exposes infants to a lower dose of whole-body irradiation than ^99mTc (3–10 uCi/kg vs. 50–250 uCi/kg body weight) [1]. Radionuclide uptake and scanning identify thyroid aplasia, hypoplasia (decreased uptake, small gland in a eutopic location), or an ectopic gland (small gland located somewhere between the foramen cecum and over the thyroid cartilage) [8].

   A large gland with increased uptake is compatible with a dyshormonogenesis, one of the inborn errors of thyroid hormone production beyond trapping of iodide [7, 8]. In such cases, ¹²³I uptake can be followed by a perchlorate discharge test [1, 7]. The test consists in administration of sodium perchlorate with thyroid activity measured before and 1 hour afterward [1]. The perchlorate discharge test is considered positive when discharge of ¹²³I is more than 10% of the administered dose [1].

   Absence of uptake can be seen in thyroid aplasia and also with TSHβ gene mutations, TSH receptor-inactivating mutations, iodide-trapping defects, or with maternal thyrotropin receptor-blocking antibodies (TRB-Ab) [7].

2. Thyroid ultrasonography—it is an important diagnostic tool for determining the presence of the thyroid gland, its location, size, and echotexture, but it is less accurate than radionuclide scan for detection of an ectopic thyroid gland [1, 8]. Identifying a large gland on thyroid ultrasonography can guide the diagnostic towards a case of dyshormonogenesis [7].

3. Serum Tg determination—it reflects the amount of thyroid tissue, and it is generally elevated with increased thyroid activity [7]. It can be helpful in further evaluation of infants with absent radionuclide uptake [7, 8]. In cases of true thyroid aplasia, serum thyroglobulin levels are absent [7]. Together with the perchlorate discharge test, it provides useful information for targeted genetic testing to diagnose the various forms of CH caused by dyshormonogenesis [1].

4. Serum TRB-Ab determination—it may be useful in case of absent radionuclide uptake and a small or normal eutopic gland determined by ultrasonography, in an infant born to a mother with autoimmune thyroid disease [8]. TRB-Ab can cross the placenta and block TSH binding, inhibiting fetal thyroid gland development and function [7].

5. Urinary iodine determination—it a measure that approximates iodine intake [7]. It can be useful in an infant with CH born in an area of endemic iodine deficiency or if there is a history of excess iodine exposure [7, 8].

5. Management

As we mentioned in the introduction, CH is one of the most common treatable causes of mental retardation [2, 7]. Also, there are studies that have shown that the timing of therapy is crucial to neurologic outcome [6, 7]. But even when it is diagnosed early, neurologic development may suffer if treatment is not optimized in the first 3 years of life [7].

According to the ESPE consensus guidelines, treatment of infants with severe primary CH should be with L-T4 in dose of 10–15 μg/kg per day [4]. Treatment should be started as soon as possible, no later than the first 2 weeks of life or immediately after confirmatory serum test results [1, 4]. The goal of L-T4 treatment is to obtain a rapid normalization of serum FT4 and TSH levels, preferably within 2–4 weeks from initiation, to improve neurocognitive outcomes [16]. Infants with moderate primary CH should be treated with an initial dose of ~10 μg/kg per day, and for infants with mild form, we can use even a lower starting dose (5–10 μg/kg) [1].

Oral L-T4 administration is preferred, either in the form of tablets that are crushed and suspended in 2–5 milliliters of water, breast milk/nonsoy-containing formula or as an oral solution [4, 16]. It can be taken in the morning or evening, either before feeding or with food, and it should be administered in the same way every day [4, 16]. The bioavailability of oral L-T4 is about 50–80% [1, 4]. It is mainly absorbed in the proximal small intestine, and this process can be influenced by food presence (soy, fiber) or minerals (calcium, iron). For this reason, simultaneously administration should be avoided [1, 4, 16]. In cases where oral administration is not an option, L-T4 can be administered intravenously in a smaller dose, approx. 75–80% of the enteral dose [4, 16].

The newborn’s family must receive verbal and written instructions from the endocrinologist or their primary care provider regarding appropriate method for administering L-T4, the substances that can interfere with L-T4 absorption, and the importance of adherence to the treatment plan, including regular follow-up, to ensure a normal neurocognitive development and growth [1, 4, 16].

The follow-up evaluation (clinical evaluation and TSH, FT4 measurements) should take place 1–2 weeks after the start of L-T4 treatment with subsequent evaluation every 2 weeks until complete normalization of serum TSH [1]. Thereafter, the evaluations can be made [1]:

• Every 1–3 months until the age of 12 months.

• Every 2–4 months between 12 months and 3 years,

• Every 3–6 months until growth is completed.

Monitoring is important being useful in avoiding under or overdosing [1, 10, 16]. It should be mentioned that the collection of TSH and FT4 must be performed before, or at least 4 hours after the last L-T4 administration [1]. The therapeutic targets are [16]:

• Maintaining a serum TSH in the age-specific reference range, usually between 0.5 and 5 mIU/L after 3 months of life;

• Maintaining a serum FT4 levels in the upper half of the age-specific reference range.

Regardless of the etiopathogenic form of CH (primary or central), the treatment consists of hormone replacement with L-T4. The biggest differences between the two forms are the L-T4 starting dose and how the treatment is monitored [1]. Although central CH can be a severe condition, most cases are classified as mild to moderate with an FT4 at diagnosis between 5 and 15 pmol/L [1, 5]. For this reason, the usual recommended dose of L-T4 is 5–10 μg/kg, but it can be increased to 10–15 μg/kg in severe cases [1, 17]. Once the replacement therapy is started, patients should be monitored based on FT4 levels at the same intervals as done with primary hypothyroidism [1, 9], the goal being the maintenance of FT4 levels in the reference ranges for age [1, 9, 14]. When FT4 is around the lower limit of the reference interval, especially when is associated with a TSH >1.0 mU/L, undertreatment should be considered. Inversely, when serum FT4 is around or above the upper limit of the reference interval, particularly if associated with clinical signs of thyrotoxicosis, or a high T3 concentration then overtreatment should be considered, excluding the situation in which L-T4 was administered just before blood withdrawal [1].

Considering that central HC is most often associated with other pituitary hormone deficits, it must be taken into account that L-T4 initiation should be start after exclusion of a concomitant cortisol deficit [14, 17]. In those with concomitant adrenal insufficiency or when its presence cannot be excluded, L-T4 supplementation should be started after adequate glucocorticoid supplementation, to prevent induction of an adrenal crisis [14]. Also, both estrogens and GH influence thyroid hormone transport and metabolism; this is why sex steroid and GH deficiencies can mask an underlying central CH, while the introduction of these replacement therapies often requires an uptitration of L-T4 dose [14]. Taking all these data into account, particular attention should be given to patients with central CH as part of multiple pituitary hormone deficiency whenever new replacement therapies are added or modified [14].

As we mentioned before, some patients with a positive NBS for CH have transient congenital hypothyroidism and will receive hormone replacement treatment. Predictive factors that increase the likelihood of a transient or permanent disease are listed in Table 1 [1, 17].

Transient CH	Permanent CH
Sex (more often in boys); Low birthweight; Neonatal morbidity requiring intensive care; Race/ethnicity (more often in nonwhite patients); Less severe CH at diagnosis (assessed by screening or diagnostic TSH or FT4)	Prematurity; Other congenital abnormalities; A family history of thyroid disease; Abnormal thyroid morphology (thyroid hypoplasia at diagnosis); TSH elevation >10 mU/L after the age of 1 year; A higher L-T4 dose requirement

Table 1.

Predictive factors that increase the likelihood of a transient or permanent CH.

If the diagnosis has not been fully confirmed at the time of the initial evaluation of the newborn, a trial of L-T4 therapy should be considered at 3 years of age, particularly if the patient is adequately treated with a low dose of L-T4 (<2 mcg/kg/day) [16]. At that time, the serum levels of TSH and FT4 will be determined after 4 weeks of stopping L-T4 treatment [1, 16, 17]:

• If TSH and FT4 levels remain in the age-specific reference range, then transient CH is confirmed.

• If the TSH >10 mIU/L and/or FT4 is low, permanent CH is confirmed and L-T4 therapy should be reinstituted.

• If TSH is mildly elevated (greater than the age-specific reference range, but <10 mIU/L) and FT4 is normal, TSH and FT4 levels should be repeated in another 4–8 weeks.

According to the ESPE guide, it is considered that there is sufficient evidence to support early treatment withdrawal to assess the necessity of further treatment and this can be considered and done from the age of 6 months onward, particularly in patients with a gland in situ, a negative first-degree family history of CH, or in those requiring a low L-T4 dose [1]. And thus, it will be an early identification of children who do not require long-term treatment.

6. Prognosis

Most children with CH identified early and treated appropriately will have a normal level of neurocognitive development and school performance, with a significant reduction/even disappearance of intellectual disability (defined by an IQ <70) [1]. However, subtle cognitive and motor deficits and low school performance may persist in patients with severe CH despite early and appropriate treatment. These may reflect prenatal brain damage caused by thyroid hormone deficiency in utero, damage that is not fully recovered by postnatal treatment [1]. These children may exhibit reduced hippocampal volume and abnormal cortical morphology, which may account for subtle and specific deficits in memory, language, sensorimotor, and visuospatial function [1]. In addition, thyroid hormones play an important role in the development of cochlear and auditory function; thus, subjects with CH have a three times higher risk of developing a hearing deficit, compared to the general population, a fact that can negatively affect the development of speech, school performance, and quality of life [1]. So, it is estimated than 20–25% of adolescents with CH will associate mild and subclinical hearing loss, despite early and appropriate L-T4 treatment [1].

It is also worth mentioning that poor socioeconomic status with poor adherence to treatment or excessive treatment in the first months of life, considered a critical period for brain development, may also affect cognitive outcome and can be associated with school-age attention deficit and lower IQ scores.

Children and adolescents with primary CH due to dyshormonogenesis may have an increased risk of developing goiter and thyroid nodules and may even have an increased risk of malignancy [1]. These cancers can develop at various ages but are most common in middle-aged individuals and can be aggressive [10]. The mechanisms implicated in the development of thyroid cancer in patients with thyroid dyshormonogenesis are not fully understood; presumably, constant and prolonged stimulation by TSH, a growth factor for thyroid epithelial cells, may result in goiter, thyroid nodules, or thyroid cancer [10]. Thus, they will require periodic follow-up with physical examination and ultrasound evaluation, especially in patients with poorly controlled disease, to identify nodules that will require fine needle biopsy to exclude thyroid carcinoma [1, 10].

We previously mentioned that patients with severe hypothyroidism associate delayed skeletal maturation, however, in the first months of life, treatment with L-T4 rapidly normalizes bone maturation. Nevertheless, excessive L-T4 treatment can increase bone turnover with greater bone resorption than formation, resulting in progressive bone loss [1].

Body mass index and composition are generally normal in children and adults with CH; still about 40% of young adults have a tendency and increased risk of being overweight or obese. Therefore, lifestyle interventions including diet and exercise and good adherence to treatment should be encouraged to avoid metabolic abnormalities and maintain an optimal cardiovascular health [1].

7. Conclusions

The neurodevelopmental outcome in children with CH is highly dependent on early diagnosis and therapy. Newborn screening for CH has been a great success story, and it is desirable it will continue to expand worldwide. And so, by its extension to a larger birth population that undergoes comprehensive screening, it will be possible to identify new mechanisms involved in the etiopathogenesis of this condition. Besides an early identification, we should also keep in mind that compliance with hormonal substitution and the therapeutic regimen can influence the long-term prognosis; this is why the maintenance of treatment adherence should be promoted throughout life.