The Role of Nuclear Medicine in Congenital Hypothyroidism

Abstract

Nuclear medicine imaging techniques are known as molecular functional radioisotope imaging. It has been used for decades in endocrinology and pediatric clinical practice. Thyroid scintigraphy (TS) results in many cases of congenital hypothyroidism (CH) may not affect the management immediately. However, TS, either Technetium-99 m Pertechnetate (^99mTc-O4) or Iodine-123 (¹²³I), can help establish an etiology for hypothyroidism, including CH that may affect treatment decisions, prognosis, and counseling. Congenital hypothyroidism has potentially devastating neurologic consequences when delayed to manage. Screening CH by measuring Thyroid-Stimulating Hormone (TSH) and or thyroxine hormone (T4) using Radioimmunoassay (RIA) technique will detect CH rapidly, and the case can be treated as soon as possible. This review discusses in vivo and in vitro nuclear medicine techniques and the benefits and limitations of nuclear medicine techniques in evaluating hypothyroidism.

1. Introduction

The inadequate concentration of thyroid hormones present at birth may lead to hypothyroidism, which is known as congenital hypothyroidism (CH) [1]. The condition causes mental retardation and growth failure in newborns [2, 3]. Universal newborn screening has been highly effective in reducing the incidence of CH. However, in regions where prompt diagnosis or treatment may not be readily available, CH still poses a risk for preventable intellectual disability. It is crucial to ensure that all newborns are screened for CH, regardless of geographical location, to facilitate early diagnosis and treatment [4]. With prompt diagnosis and treatment, children with CH can lead healthy everyday lives.

The various forms of CH, including primary (permanent or transient) and secondary, have different etiologies and implications, which can significantly impact treatment planning. Accurate diagnosis and differentiation between the subtypes of CH are crucial for effective treatment planning [5]. Primary CH is caused by thyroid dysgenesis (agenesis, ectopic, hypoplasia), which is present at birth. Another potential cause of primary CH is thyroid dyshormonogenesis, which is a genetic disorder that disrupts the thyroid gland’s ability to produce hormones. Secondary CH is a rare condition due to a deficiency in thyroid-stimulating hormone (TSH) production or secretion by the pituitary gland or hypothalamus. This condition can cause an underactive thyroid gland, leading to symptoms of hypothyroidism, which is known as central hypothyroidism. It is essential to identify the causes of primary congenital hypothyroidism to determine the appropriate treatment and management plan for affected individuals.

Newborn screening tests are commonly used to detect congenital hypothyroidism. The screening measures the levels of TSH in the blood. If TSH levels are elevated, additional testing, such as thyroxine (T4) or T4 initial and secondary TSH tests, is needed. Both screening strategies have similar accuracy in detecting severe primary hypothyroidism [6]. Moreover, thyroid scintigraphy (TS) s a gold standard diagnostic test for determining the etiology of CH, providing a more specific diagnosis [1, 7]. The etiology of CH may play a vital role in determining the disease severity at diagnosis, management therapy, and parents’ counsel on the certainty of lifetime therapy and prognosis [8, 9]. Clinically, CH is divided into distinctive forms: primary (permanent or transient) and secondary. The exact diagnosis and differentiation between the CH subtypes are crucial to effective treatment planning [3, 5]. Thyroid scintigraphy is helpful for re-evaluation to uncover transient or permanent hypothyroidism and the decision to continue or discontinue thyroxine therapy replacement [10]. Additionally, re-evaluation, including thyroid hormone levels and functional thyroid imaging, is vital for those who are born prematurely due to the frequency of transient hypothyroidism to avoid unnecessary extended thyroxine therapy. This review elaborates on nuclear medicine’s role in the screening and diagnosis of congenital hypothyroidism.

2. Incidence

The incidence of CH mostly depends on the newborn screening program [1]. Initially, the incidence was between 3000 and 4000 births when newborn screening was introduced in the 1970s [1, 4]. The incidence of congenital hypothyroidism has nearly doubled in the last decade, with 2000 births [4, 11, 12]. The elevation in the incidence is due primarily to increasing newborn screening and lowering the TSH threshold for diagnosis, which leads to an increasing number of mild cases [11, 13]. However, the incidence of severe congenital hypothyroidism has remained unchanged [4]. Changing demographics may also influence the apparent incidence of this disorder by increasing birth rates [4, 5].

3. Etiologies

Congenital hypothyroidism is a serious condition that demands immediate attention and treatment. An effective treatment should be based on the root cause. It is interesting to note that thyroid gland abnormalities are the most common culprit behind CH. Congenital hypothyroidism (80%) is due to thyroid abnormalities (dysgenesis 85–90%), which include agenesis (35–40%), ectopic (60–65%), or hypoplastic gland [11, 13, 14, 15]. Additionally, if the thyroid gland visualizes but does not function properly (15%), it can also lead to congenital hypothyroidism (dyshormonogenesis 10%) [3, 14, 15]. Interestingly, several studies reported that 30–40% of CH had an ectopic thyroid gland that showed consistency with a form of dyshormonogenesis [14, 16, 17, 18]. However, pathophysiologically, hypothyroidism can be caused by impaired thyroid gland function (primary hypothyroidism) and also be affected by hypothalamic and pituitary control of the thyroid (central/secondary hypothyroidism).

Thyroid dysgenesis is a relatively common condition that can hinder the thyroid gland’s ability to produce sufficient thyroid hormones. Despite its incidence, the underlying mechanisms of this sporadic disease remain poorly understood [1, 14]. However, it is significant to acknowledge the possibility of a familial component, and genetic mutations or other factors may play a role in its development [14]. Several genes are involved in thyroid development and have been linked to thyroid dysgenesis in some cases [1, 4, 14, 19]. At least 12 genes involved in thyroid dysgenesis and the defects in the biosynthesis of thyroid hormones have been described. However, genetic causes of CH were identified to be only between 2 and 5% [1, 14]. On the other hand, the progressive development of molecular techniques such as next-generation sequencing (NGS) has recently increased the genetic defects associated with CH in the range from 33 to 61.5% [20].

The TSH receptor (TSHR) mutation can result in resistance to TSH and a spectrum of thyroid dysfunctions ranging from elevated TSH levels and normal thyroid hormone levels to congenital hypothyroidism with thyroid hypoplasia, that leads to either sub-clinical congenital hypothyroidism (SCH) or congenital hypothyroidism [21]. Mutations in (TSHR) or genes encoding transcription factors involved in thyroid development (TTF1/NKX2.1, PAX8, FOXE1, NKX2–5, and GLIS3) [1, 20]. Moreover, dyshormonogenesis frequently is caused by defects in the cellular signaling of thyroid hormone synthesis, mutations of thyroglobulin (TG), thyroid peroxidase (TPO), dual oxidase 2 (DUOX2) which associated protein (DUOXA2), the Sodium-Iodide Symporter (NIS) SLC5A5, the apical iodide transporter pendrin (SLC26A4), and iodotyrosine deiodinase (IYD) DEHAL1 [1, 3, 4, 14, 20]. A molecular study using NGS reported severe CH variants in dyshormonogenesis genes in 84.8%, and cases associated with thyroid dysgenesis genes were reported in 13.1% [20]. It contradicts the previously expected distribution of etiological forms. The other study has reported more frequent mutations in dyshormonogenesis genes than in thyroid dysgenesis genes [20]. Additionally, the condition due to the pituitary gland’s inability to produce enough TSH, related to the IGSF1 gene, which is involved in regulating TSH production, and mutations in the IGSF1 gene leading to a deficiency of TSH and subsequent central hypothyroidism [22].

Thyroid hemi-agenesis is a rare clinical condition that entails the absence of one lobe of the thyroid gland while the other remains in a normal position. Research suggests that a unilateral growth defect causes this condition [19]. An early asymmetrical growth defect causes hemi-agenesis and not by regression of the lobe once formed [19]. Notably, the amount of thyroid tissue in hemi-agenesis cases is sufficient to produce normal TH levels, similar to those after a hemi-thyroidectomy. Therefore, this condition may go undiagnosed until the thyroid is examined morphologically for other reasons. Interestingly, the hypoplastic thyroid in the animal study reported that Nkx2-1/Pax8 double-heterozygous-null mice are mostly normal-shaped, but 30% of mutant embryos develop hemi-agenesis almost identical to that seen in the patients. However, functional modification of this gene contributes to asymmetrical thyroid growth in Nkx2-1, and Pax8 mouse embryos has not been elucidated [19].

Several extrinsic factors can cause hypothyroidism in newborns. Transplacental passage of antithyroid drugs for hyperthyroidism therapy can be the underlying cause of transient congenital hypothyroidism [4, 14]. Pregnancy-related complications such as hypo and hyperthyroidism during pregnancy, placental abruption, or insufficiency have been identified as related to thyroid disorders [5]. Iodine deficiency during pregnancy remains a common cause of neonatal hypothyroidism worldwide, even though iodized salt programs have been implemented. Iodine excess can also cause hypothyroidism, particularly in preterm infants. Additionally, amiodarone for treating maternal and fetal dysrhythmias, including iodinated contrast media, may cause adverse thyroid effects [5, 14]. An understanding of the pathophysiology of congenital hypothyroidism and the condition that affects newborn screening is required to identify, evaluate, and treat this condition in the early stage appropriately.

4. Diagnosis

Rapid detection and immediate management of hypothyroidism are essential for treatment and prevention of long-term health complications. Transient hypothyroidism is around 30% in newborns with the thyroid gland in place [7]. Additionally, determining CH’s etiology at the time of diagnosis is vital. Thyroid scintigraphy and ultrasound tests provide an accurate etiologic diagnosis of differentiated dysgenesis or dyshormonogenesis [2, 7, 11].

Hypothyroidism is diagnosed by measuring the concentration of TSH and total or free thyroxine (T4) [1]. Thyroid hormones circulate and bind to plasma proteins, and their biological action is exerted only by the unbound fraction of the hormone (0.02–0.1%) [14]. The free T4 concentration can be assayed directly or estimated free T4 index [14, 23]. The direct free T4 assay is generally reliable in healthy ambulatory patients. However, it may be inaccurate in patients with severe systemic illness or abnormalities of protein binding, so caution is needed when interpreting such tests in this setting [14].

In the primary hypothyroid case, increasing TSH level is the first detectable abnormality. The free T4 levels fall when severe hypothyroidism occurs [14]. Thyroid stimulating hormone measurement is the most sensitive test for diagnosing primary hypothyroidism and monitoring the treatment. Central hypothyroidism should be suspected when free T4 is low and TSH is in the low or normal range (TSH level is an inappropriate increase in response to low free T4) [14, 23]. During hypothyroidism, T3 is maintained at normal levels until the late stages of the disease. So, measurement of serum T3 or free T3 is generally not helpful in the evaluation of hypothyroidism [14].

The normal TSH and free T4 levels in infants and children differ by age. Therefore, it is essential to use appropriate age-specific reference ranges in interpreting thyroid function tests [14]. However, sometimes, physiologic variations in thyroid hormone production in newborns lead to CH, which typically resolves when the endocrine system matures by age 2–3 years. For this reason, it is common for patients to be taken off treatment whose CH status is not clear at 3 years of age [14]. Moreover, evaluation of a patient’s thyroid status may be affected by numerous medications and by nonthyroidal illness (“euthyroid sick syndrome”) that can mimic true thyroid dysfunction [24].

Some newborns may have false-negative results during initial screening or have a risk for CH, such as preterm, low birth weight, and illness, and need a second screening at 10–14 days of age. Newborns with Down’s syndrome are recommended for level TSH test at the end of the neonatal period [1]. On the other hand, primary T4-algorithms are often at the cost of false-positive referrals due to low T4 caused by nonthyroidal illness or T4-binding globulin (TBG) deficiency [23]. A complete history and physical examination are needed to identify potential confounding factors that influence the level of TSH or T4.

5. Radioimmunoassay

Radioimmunoassay (RIA) is a laboratory technique widely used in the medical field to measure the concentration of various substances in biological samples. The technique uses a mixture of radioisotopes of the measured substance and a specific antibody [25]. Radioimmunoassay has several advantages over other immunoassay techniques, and it is susceptible and specific [25]. The technique can measure various analytes, including hormones, enzymes, and drugs, and provide accurate and precise results. In diagnosing and monitoring CH, RIA can measure TSH and T4 levels. The disadvantage of RIA is the use of radioactive material, which requires special handling and disposal procedures to ensure the safety of laboratory workers and the environment. Additionally, the technique may only be readily available in some laboratory settings.

Shifting in screening methods for CH has occurred over time; it is reasonable to evaluate whether such changes might be associated with CH’s observed increasing rate [26]. There was a trend to change the T4-screening method from RIA to the enzyme immunoradiometric assay (EIA) or fluoroimmunoassay (FIA). The change in the laboratory had the most significant impact on the incidence rate of CH because of variations in the sensitivity and specificity of the screening test. However, laboratories that used RIA or either FIA or EIA still increased the CH-incidence rate, indicating that factors other than the T4-screening method also contributed to the CH-incidence rate [26]. Moreover, screening for TSH by FIA resulted in a 20% higher CH-incidence rate than radiochemical methods (RIA/IRMA), and screening for T4 by EIA or FIA methods led to a 38 and 24% higher CH-incidence rate, respectively, than the RIA method [26].

5.1 Thyroid stimulating hormone

Universal newborn screening for congenital hypothyroidism generally begins with measuring TSH and/or T4 in a dried blood spot collected from each infant within a few days after birth [4, 14]. The elevation of TSH with or without low free T4 indicates the presence of congenital primary hypothyroidism. In the case of free T4, it is low, and TSH is normal or low, secondary/central hypothyroidism may be present, and the condition can be challenging to diagnose, particularly in ill or preterm infants [14].

Many variables influence newborn screening results, such as patients’ characteristics and sample collection timing. Blood samples obtained within 24 hours after birth may give false positives due to the surge in TSH secretion (up to 60–80 mIU/L). Preterm Newborns with low birth weight or ill may have altered patterns of thyroid function that may affect newborn screening results, including low free T4 with normal or low TSH that mimics central hypothyroidism or primary hypothyroidism with a delayed rise in TSH that may be missed in early screening [14].

Preterm newborns (<37 weeks) and/or with low birth weight (<2500 g) have a distinct pattern of postnatal thyroid function from the standard weight of term newborns. In this condition, the TSH levels increase slightly and lower free T4 concentrations that may decrease during the first days of life. These conditions are due to multiple factors, including immaturity of the hypothalamic-pituitary-thyroid axis; loss of maternal T4 that would typically be transferred to the fetus in the third trimester; changes in thyroid hormone metabolism; frequent and often severe illness in these newborns; and exposure to medications that may affect thyroid function (such as dopamine, glucocorticoids, and iodine-contained antiseptics) [14]. Naturally, preterm infants frequently result in a state of low T4 (or free T4) without increasing TSH, which resembles central hypothyroidism or nonthyroidal illness [14]. It suggested that hypothyroidism screening is performed by measuring TSH on the second and fifth post-birth to avoid the initial physiological elevation of this hormone after birth [13, 15]. Moreover, the potential presence of TSH receptor-blocking antibodies should be considered in patients with an ectopic thyroid gland, even if there is no history of autoimmune thyroid disease. If TSH receptor antibodies are detected in maternal or newborn serum, they portend a transient condition of hypothyroidism that resolves within 3–4 months [14].

5.2 Thyroxine hormone

North American Newborn Screening (NBS) strategy programs have measured T4 as the initial screening, whereas other countries often measured the concentration of TSH [26]. Elevations in TSH level are a better predictor for CH. However, T4 levels are more stable to physiological variations shortly after birth. Therefore, the T4 measurement was more popular in the initial screening strategy in North American systems affected by early hospital discharge [26]. Initial T4 screening is usually accompanied by second-tier TSH screening to improve screening sensitivity and specificity.

The proportion of specimens with abnormal T4 results was around 10%, followed by retesting to determine the TSH concentrations, and the combined T4 and TSH results were used together to determine the need for early management. The strategies (TSH screening alone or T4 screening with second-tier TSH screening) have provided equivalent case detection [26]. On the other hand, laboratory results from 1991 to 2000 showed that the TSH assay as a newborn screening reported an incidence rate of CH 24% higher than that of laboratories that used a T4 assay [26].

6. Thyroid scintigraphy

Thyroid scintigraphy and Radioiodine uptake (RAIU) tests are functional imaging and widely used methods to evaluate morpho-functional aspects of the thyroid gland. The imaging can quantify the tracer’s spatial distribution and measure thyroid glands’ RAIU and the image results are correlated to the TSH, which shows whether the function is adapted to the physiological stimulus (normal status) or not (hyper- or hypo-function). The advantage of functional imaging is that it reports signals from structures that reflect the functional status of thyroid glands [27]. Therefore, TS remains an essential procedure to identify the etiology of congenital hypothyroidism and is the gold standard diagnostic test for determining the etiology of CH [1, 7].

Determining CH’s etiology does not alter initial management, but it provides a prognosis, avoids unnecessary therapy, and optimizes thyroxine therapy [1, 3, 7]. However, it can help distinguish between thyroid agenesis, ectopia, hemigenesis, hypoplasia, and dyshormonogenesis [1, 2, 7, 15]. Visualization of the thyroid gland by scintigraphy depends on the presence and thickness of the functional thyroid tissue [27]. In CH cases, TS should be done under high levels of TSH, and the best time was done before or during the first week of thyroxine therapy [2, 7]. Suppose TS is not performed before the therapy; in that case, the scintigraphy should be done after 3 years, when treatment interruption no longer poses a risk (the critical period of neurocognitive development has passed), or using recombinant TSH to avoid replacement hormone therapy withdrawal [7]. Moreover, TS should never be allowed to delay treatment initiation.

Thyroid scintigraphy generally uses radionuclides such as Technetium-99 m-sodium pertechnetate (^99mTc-O₄) and Iodine-123 (¹²³I). The ^99mTc-O₄ is taken up by follicular cells but is not organified, and it has a six-hour half-life, is a pure gamma emitter, and is cheaper than ¹²³I [27]. Normal TS image using ^99mTc-O₄, as shown in Figure 1. The false positive is caused by the salivary glands’ uptake of ^99mTc-O₄, which may give a falsely positive image for ectopic thyroid (Figure 1A) [2, 3, 8]. On the other hand, Iodine transport via sodium-iodine symporter (NIS) forms extracellular to inside follicular thyroid cells and can be organified [28]. Therefore, ¹²³I can diagnose dysgenesis and dyshormonogenesis and identify organification defects [27]. Iodine-123 has higher accuracy, especially for diagnosing the ectopic thyroid gland [2, 3]. However, it is more expensive and available only in specific clinics, and requires pre-order [2].

Figure 1.

A 17-month-old girl with a history of growth retardation. (A) Thyroid scintigraphy (^99mTc-O₄) showed a normal thyroid gland and the uptake of ^99mTc-O₄ by salivary glands (white arrow). (B) Thyroid agenesis, non-visualized TS, and it confirmed ultrasound image.

6.1 Thyroid dysgenesis

Hypothyroidism due to dysgenesis includes agenesis (35–40%), ectopic (60–65%), or hypoplastic gland [11, 13, 14, 15]. Thyroid agenesis should be considered when no significant uptake of radionuclide appears on the scintigraphy, and the field of view includes the neck and the head, with elevated TSH level as shown in Figure 1B, and it confirmed with the ultrasound image [3]. Dysgenesis with agenesis is permanent hypothyroid. However, about 35% of patients with dysgenesis with a eutopic thyroid gland have transient disease and will not require lifelong therapy [4, 15].

Ectopic thyroid tissue may lie between the tongue, the thyroid bed, or the mediastinum [3, 29]. The relationship between thyroid ectopic and its dysfunction is poorly understood. In some cases, an ectopic thyroid may produce thyroid hormone, but in other cases, the condition may be dysgenic or show diminished thyroid function. The ectopic thyroid gland mainly causes dyshormonogenesis, and in most cases, the thyroid gland is enlarged due to an over-stimulation by increasing TSH levels [2, 3]. Thyroid scintigraphy shows an increasing uptake [2]. Both ^99mTc-O₄ and ¹²³I of TS can detect ectopic glands, but when the ectopic tissue is situated near the mouth, it can be hidden or impeded by oral activity when using ^99mTc-O₄. To accurately pinpoint the molecular defect’s location, identifying eutopic tissue and dyshormonogenesis is best achieved using ¹²³I [3].

Thyroid hypoplasia cases are considered relatively uncommon, and their diagnosis requires a combination of scintigraphy and ultrasound imaging. Scintigraphy results typically indicate a low uptake of radionuclides and a smaller thyroid gland. At the same time, ultrasound imaging can reveal a modified shape, such as round-shaped lobes, unilobed, or asymmetry in the location of the lobes, as well as a reduction in glandular volume. It is important to note that hypoplasia in permanent hypothyroid cases may present with a customarily located gland in 15% of cases. However, relying on a single imaging technique can result in false-positive or false-negative results. Therefore, a comprehensive approach using complementary techniques is recommended for a more accurate diagnosis [3].

6.2 Dyshormonogenesis

Dyshormonogenesis accounts for about 10% of cases of CH and reflects a defect in any of the steps in thyroid hormone synthesis [3]. The non-visualized thyroid gland in TS, but displayed in ultrasound, maybe a dyshormonogenesis due to the presence of thyroid-blocking antibodies (maternal autoimmune thyroid disease), a genetic change in the TSH-gene and loss of NIS function that caused a defect of iodide uptake (Figure 2) [1, 13, 15, 30]. Other causes of iodine defect uptake can be thyroid gland prematurity, prior medication of thyroid hormone, or a central type of congenital hypothyroidism in addition to thyroid aplasia [11]. The thyroid may be eutopic in cases of a partial block of thyroid hormonogenesis, and auditory evoked potentials may be needed to diagnose some forms of thyroid dyshormonogenesis (Pendred syndrome, Hollander syndrome), especially when there is a family history of hearing loss [15].

Figure 2.

A 10-year-old boy was diagnosed with dyshormonogenesis with an elevation of TSH level (>100 μIU/mL) and a low level of FT4 (0.4 ng/dL). (A) Thyroid scintigraphy is non-visualized of the thyroid gland. (B) The image of ultrasonography showed normal thyroid glands in the thyroid bed.

The scintigraphy thyroid in dyshormonogenesis can be classified into three types of defects. Type 1 defects are characterized by impaired function at the basal membrane/loss of NIS expression, resulting in low to blunted radionuclide uptake despite high TSH plasma levels. Late ¹²³I images are more often positive than ^99mTc-O₄ images. The defective thyrotropin receptor (R-TSH) is often associated with thyroid hypoplasia or reflects maternal autoantibodies’ transient blockade of the thyrotropin receptor. Defective (R-TSH) or abnormal NIS expression yields no radionuclide uptake at the thyroid and stomach level. Type 2 defects are characterized by impaired function at the apical membrane, responsible for reduced iodide organification. Both scintigraphy and uptake are high and rise quickly in an enlarged thyroid. The perchlorate discharge test is positive with a washout value >10% (partial) and > 50% (complete) organification defect [3, 31]. Total organification defects are most often due to a mutation in the TPO gene. Partial defects occur in minor thyroid peroxidase (TPO) abnormalities and Pendred syndrome (abnormal pendrin) [3, 31]. Type 3 defects are post-organification defects, including a goiter with pre-served uptake and a normal organification process (negative per-chlorate discharge test). Indeed, iodide, which has entered the organification process, cannot be chemically displaced by perchlorate. Mutations in the thyroglobulin (Tg) gene are more common than other abnormalities, such as defective pinocytic resorption of the Tg. Finally, DEHAL1 produces a secondary iodine-deficient state due to excessive renal losses of Iodine in MIT and DIT [3].

6.3 Radiopharmaceutical administration and image acquisition

Scintigraphy images provide the function of thyroid glands by using ^99mTc-O₄ or ¹²³I [1, 7]. The image acquisition was 15 minutes after administration of ^99mTc-O₄ intravenous. It is inexpensive and well tolerated; no complications have been reported [7, 10]. Other centers preferred to use ¹²³I, a more physiologic agent that addresses the thyroid gland’s global function and can be administered intravenously or orally. The image acquisition can occur within 0.5–24 hours after ¹²³I administration [3, 7, 10]. We should not use ^99mTc-O4 for uptake measurement because it is not organified. So, it is not suitable to quantify the radionuclide uptake.

It is essential to determine the appropriate radiopharmaceutical dose examinations. High doses may lead to increased radiation exposure without improving diagnostic sensitivity or accuracy, while low doses may not allow for adequate examination. In that case, the minimum amount of activity necessary for a satisfactory diagnosis is administered in the shortest possible time. Adhering to this principle will avoid unnecessary radiation exposure in newborns/infants. The activity dose radionuclides for thyroid examination are 1.1 MBq (0.03 mCi)/kg, with a minimum dose of 7.5 MBq (0.2 mCi) for 99mTc-O4, and 0.025–0.03 mCi (0.9–1.1 MBq) for ¹²³I. The average thyroid dose is less than 5 mSv/MBq (18.5 rem/mCi) [7, 29].

The image acquisition is taken in an immobilized supine position with head extension, which can use a particular design mattress or the newborn/infant in sleep [29]. A low-energy, high-resolution for ^99mTc-O₄ and a high- or medium-energy collimator are available for imaging ¹²³I [7, 10, 29]. A medium-energy collimator produces a superior image quality than the high-sensitivity or ultra-high-resolution collimators for ¹²³I [29]. The best image is obtained with a pinhole collimator [29].

7. Perchlorate discharge test

Iodine is captured at the basal pole by active transport using NIS as a co-transporter, and then transported to the apical pole of thyrocytes, where it is fixed (organified) to thyroglobulin tyrosine residues, leaving no free iodide in the thyrocyte [28]. Iodide accumulates in the thyrocytes if organification is defective. In this case, sodium perchlorate, which is also captured by thyroid cells but not organified, competes with iodide and chases it out of the cells [2, 7]. Perchlorate discharge tests and genetic mutation studies might be helpful for the identification of the type of dyshormonogenesis [2, 3].

The effect of sodium perchlorate is evaluated before and 1 hour after its administration. Perchlorate does not alter iodine uptake in the normal newborn; therefore, the test is negative. The test is positive when iodine uptake is reduced by defective organification. Iodine uptake is measured before and after perchlorate. A 10% iodine uptake change is considered significant [7]. It can reach 98% in children with no iodide or ganification. Defective organification is usually permanent because of a defect in a gene involved in organification (the TPO and DUOX2/DUOXA2 genes in 470% of cases) [7]. However, it can also be transient following iodine overload due to povidone-iodine disinfection before maternal surgery (e.g., cesarean). Monitoring of thyroid function and thyroxine dose adjustment is recommended in all forms of hypothyroidism associated with an ectopic thyroid gland. In a French study of 71 neonates with CH with a positive result for the perchlorate test, CH was transient in 11 cases. Only one of the 11 children had a discharge showing a change exceeding 90% [7].

8. Ultrasonography

Thyroid scintigraphy and ultrasound are complementary for the evaluation of CH. Thyroid scintigraphy is highly sensitive for detecting ectopic thyroid tissue, and ultrasound helps assess gland size and morphology. Ultrasound may be beneficial for confirming the presence of non-functioning thyroid tissue [29]. Detecting the causes of thyroid dysgenesis and differentiating them from dyshormonogenesis can be effectively achieved through ¹²³I scintigraphy and ultrasonography [13, 29]. The absence of radionuclide uptake and ultrasound result confirms thyroid aplasia.

Meanwhile, ultrasound may help ensure the presence of non-functioning thyroid tissue due to TSHb gene mutations, TSH receptor inactivating mutation, defected iodide trapping, or maternal TRB-Ab [13, 29]. An abnormal positioning and larger-than-normal thyroid gland in ultrasound may indicate dyshormonogenesis [2, 13]. Additionally, a study reported that utilizing thyroid ultrasound with color Doppler flow can identify up to 90% of cases of ectopic thyroid [32].

9. Conclusion

Nuclear medicine offers a range of advantages, such as in-vitro and in-vivo diagnostic tools. However, using radionuclides can be limiting as they are only sometimes widely available. RIA for newborn screening is a relatively simple and susceptible method. Additionally, TS can assist in identifying the cause of congenital hypothyroidism and differentiating types of dyshormonogenesis. This safe and clinically meaningful procedure maximizes the information available for accurate diagnosis and optimal treatment. The scintigraphy provides insight into the relationship between clinical and genetic factors in CH, and it can help clinicians determine the certainty of lifetime therapy for children with a dysplastic thyroid or the possibility of later discontinuing therapy for children with an ectopic thyroid. If the thyroid gland is absent or ectopic, parents can be advised that the newborn will require lifetime thyroid therapy. However, suppose the thyroid gland is in the normal position. In that case, permanent treatment may not be necessary if the condition is transient, as demonstrated by controlled withdrawal of the thyroid at an older age.