**4. Diagnostic evaluation**

birth. For all the above reasons, screening has evolved as the best way to detect infants with CH in developed countries. In North America, more than 1400 infants out of the 5 million

The incidence of CH varies from 1 in 4000 to 1 in 1000 in newborn infants as has been reported from various parts of world [5]. Developing countries like India and Iran have a higher incidence of CH [6, 7]. In countries like The US, Canada, New Zealand, Italy, Greece and Argentina the incidence of CH has nearly doubled since the introduction of newborn screening programmes [5, 8–12]. Widespread lowering of screening cutoffs in newborn screening programs [5, 8], increase detection of milder cases of CH, increase screening of higher risk newborn preterm and low birth infants, increased number of birth among Hispanic and of low birth weight [13] are some of the supposed causes that have been proposed as a possible cause for the increase in the incidence of CH. The incidence of CH is higher among Hispanic and Asian individuals and lower in black individuals [10, 13]. There has been a dramatic increase in the incidence of congenital hypothyroidism detected by the newborn screening programs, the incidence has risen from 1:3985 (in 1987) to 1:2273 (in 2002) [14]. This dramatic increase may be attributed to a spurt in the Asian (37%) and Hispanic (53%) births over the same period [13].

Abnormal development of thyroid gland (thyroid dysgenesis) is the most common cause of CH. Thyroid dysgenesis accounts for 85% of cases of CH and is usually sporadic. It has three major forms thyroid ectopy, athyreosis and thyroid hypoplasia. Thyroid ectopy: it is the most common form and accounts for two thirds of cases of thyroid dysgenesis and is twice more common in females [15]. The exact etiology of thyroid dysgenesis is not known but largely its considered a sporadic disease and although the etiology remains elusive in most of cases some mutations in transcription factor genes i.e. TSHR, PAX8, NKX21, FOXE1, that regulate thyroid gland development have been reported, but only 2–5% of cases with thyroid dysgenesis are found to have such genetic mutations [16]. Recently, several other genes have found to be associated with thyroid gland dysgenesis, including NKX25, JAG1 and GLIS3 although each of them contributes to only a small fraction of cases [17–21]. Each of these transcription factors has a role in the development of organ systems too, and mutations of these genes are generally associated with additional congenital defects. In remaining onethird of cases, CH results from absence of thyroid (athyrosis) and thyroid hypoplasia. Dyshormonogenesis, or defects in peripheral thyroid hormone transport, metabolism, or action are accounted in approximately 15% of cases [22]. Defects in thyroid hormone biosynthesis are familial and usually autosomal recessive in inheritance [23]. These include mutations in the genes coding for the sodiumiodide symporter (NIS; SLC5A5), thyroid peroxidase (TPO), thyroglobulin (Tg), apical iodide transporter pendrin (PDS; SLC26A4), iodotyrosine deiodinase (IYD), dual oxidase (DUOX2) and its necessary protein(DUOXA2) [23]. Defective thyroid hormone

newborns screened are diagnosed with CH annually.

**2. Epidemiology**

6 Thyroid Disorders

**3. Etiology**

In countries with newborn screening programs CH is diagnosed after neonatal screening tests. However, only 25% of the world wide birth population has the access and undergoes the said screening tests [26]. For the remaining 75% infants, particularly concentrated in developing countries, clinical suspicion of hypothyroid leads to thyroid function evaluation.

#### **4.1. Newborn thyroid screening protocols**

48–72 h after birth is the ideal time for the newborn screening tests, the reason being that the physiological surge in TSH that occurs after the first hours after birth to a peak serum level of 80 mIU/L slowly starts to decrease over the next several days [27]. Sample taken within 48 h of birth may lead to false positive results whereas screening done in very sick newborn or following blood transfusion may lead to false negative result.

In case of a critically ill new born, preterm birth or in case of a home delivery sample should be collected by 7 days of age. Capillary blood samples taken by heel prick method are placed on circles of specialize filter paper, dried at room temperature, then sent to a centralized laboratory. Second blood sample taken at 2–4 week is a part of the protocol in some screening programs. The additional incidence of CH based on a second screening at 2 weeks of age is approximately 1 in 30,000 [28, 29]. Preterm and LBW infants, critically ill infants, samesex twins, and infants whose initial screen was performed in the first 24 h of life are some examples where a routine second screening must be performed [30].

Earlier the screening protocol for CH was T4 estimation followed by TSH only if t4 was low however with increasing accuracy of TSH assays on small volumes of blood, initial TSH testing has become the sine qua non of most screening protocols [31]. Both methods allow for the detection of most of the infants having CH but each method has its own merits and demerits. Measuring T4 first and then TSH detects some cases of secondary hypothyroidism and infants that might have "delayed TSH elevation" whereas measuring TSH first and then T4 also detects mild or subclinical forms of hypothyroidism. Broadly speaking, if the screening T4 value is less than 10th percentile of cut off and/or the TSH is greater than 40 mU/L, the infant should be called again for confirmatory serum testing. In cases having "intermediate results," TSH 20–40 mU/L, recommendation is to repeat TSH screening in early second week of life. A TSH value <20 mIU/L is considered as normal.

can be followed with serial filter-paper screening tests until the T4 value becomes normal, or a second blood sample for measurement of serum FT4 and TSH can be obtained. Such infants are usually found to have normal thyroid profile on subsequent screening tests. Their treatment (except those with central hypothyroidism) with LT4 has not yet been shown to

Congenital Hypothyroidism

9

http://dx.doi.org/10.5772/intechopen.81129

Since additional investigations for etiology do not alter the treatment plan they can be delayed. Treatment of CH should never be deferred after confirmation pending the determination of

Thyroid radionuclide uptake and scanning is the most accurate imaging modality to determine the size and location of thyroid tissue. Iodine123 (I123) or sodium pertechnetate 99 m (Tc99m) are tracers of choice as I131 delivers a higher dose of radioactivity. Radionuclide uptake and scan is used to identify thyroid aplasia (absent uptake), hypoplasia (decreased uptake, small gland in a eutopic location) or an ectopic gland. Other conditions not showing any uptake include; TSHβ gene mutations, TSH receptor inactivating mutations, iodide trapping defects and in those with maternal thyrotropin receptor blocking antibodies (TRBAb). Dyshormonogenesis beyond trapping of iodide results in a large gland in a eutopic location with increased uptake on the scan. A perchlorate discharge test can be performed to confirm

When it comes to etiology determination thyroid ultrasound is usually the first modality performed. It confirms thyroid aplasia when radionuclide scan show absent uptake. TSHβ gene mutations, TSH receptor inactivating, iodide trapping defect and maternal TRBAb shows the absence of radionuclide uptake in the presence of thyroid gland in the normal position. Dyshormonogenesis is associated with absent uptake in radionuclide scan and large thyroid in ultrasound. Color Doppler flow may be able to detect up to 90% of cases of ectopic thyroid [37].

Serum thyroglobulin is reflective of the thyroid mass and is usually raised in increased activity of the thyroid gland. In a recent study, Beltrão et al., suggested that color Doppler ultrasound combined with serum thyroglobulin measurement may become very valuable tools for the diagnosis of the cause of CH and will also help minimize more harmful tests, like radionuclide scan [38]. Increased thyroglobulin levels and absent uptake on radionuclide scan suggests presence of thyroid gland along with a TSH receptor inactivating mutation, a trap-

**6. Diagnostic studies to determine an underlying etiology**

**6.1. Thyroid radionuclide uptake and scan**

the diagnosis of dyshormonogenic CH.

**6.3. Serum thyroglobulin (Tg) measurement**

ping defect, or maternal TRBAb, rather than aplasia.

**6.2. Thyroid ultrasound**

be beneficial [36].

etiology.

#### **4.2. Confirmatory serum thyroid testing**

Diagnosis must not be completely and solely reliant on the screening tests only they must be confirmed by serum testing, venipuncture blood should be drawn and serum should be sent for TSH and free T4, or total T4 and T3 resin uptake as some measure of binding proteins. These serum based results must be compared with age normalized values as during the first week of life TSH and T4 are fluctuant [32]. Most confirmatory serum tests could be obtained in first 2 weeks of life, as during this upper TSH range has fallen to an around 10 mU/L.Although all hormones are higher during first week of age they come down to infancy range within 2–4 weeks.
