This chapter is, in part, based on the previous version written by Prof. Rosalind Brown. Non endemic congenital hypothyroidism is one of the commonest treatable causes of mental retardation. The association between goitrous hypothyroidism and mental retardation was first noted more than 400 years ago by Paracelsus in 1527, and Thomas Curling first described sporadic nongoitrous hypothyroidism in 1850. However, despite the demonstration by Murray in 1891 that thyroid extract could ameliorate many of the features of untreated cretinism, it was not until the 1970’ that the importance of early treatment in diminishing the neuro-psychological abnormalities of congenital hypothyroidism was demonstrated convincingly (45). The development by Dussault et al of a sensitive and specific radioimmunoassay for the measurement of T4 in dried whole blood eluated from filter paper (and later tests for T4 and TSH using 1/8 ″ discs) provided the technical means to screen all newborns for congenital hypothyroidism prior to the development of clinical manifestations (46). Thus, as summarized by Delange, congenital hypothyroidism includes all the characteristics of a disease for which screening is justified: 1) it is common (4-5 times more common than phenylketonuria for which screening programs were initially developed); 2) to prevent mental retardation, the diagnosis must be made early, preferably within the first few days of life; 3) at that age, clinical recognition is difficult if not impossible; 4) sensitive, specific screening tests and 5) simple, cheap effective treatment are available; and 6) the benefit-cost ratio is highly favorable (approximately 10/1, a ratio that does not include the loss of tax income that would result from impaired intellectual capacity in the untreated, but non-institutionalized, person) (47). Since the development of the first pilot screening program for the detection of congenital hypothyroidism in Quebec in 1972, newborn screening programs have been introduced throughout the industrialized nations and are under development in many other parts of the world. It has been estimated that as of 1999, some 150 million infants had been screened for congenital hypothyroidism worldwide with 42,000 cases detected (46). Although there continues to be some disagreement as to whether minor neuro-intellectual sequelae remain in the most severely affected infants, accumulating evidence suggests that a normal outcome is possible even in the latter group of babies as long as treatment is started sufficiently early and is adequate (48-50). Certainly, the main objective of screening, the eradication of mental retardation, has been achieved. National screening programs are well organized in many developed countries. However, it must be emphasized that approximately 71% of babies worldwide are not born in an area with an established national screening program for CH. The economic burden of disability owing to congenital hypothyroidism is still a significant public health challenge (50a). The prevalence of CH was approximately 1:7000 to 1:10000 in the prescreening era and decreased to1;3000 to 1.4000 in the 1970s and 1980s when the screening programs were applied. Rates ranging from 1:1400 to 1:2800 have been recently reported by screening programs in USA, Canada, Italy, Greece, and New Zealand (50b). Lower TSH cut off values used in the screening programs and changes in birth population partially explained the higher incidence reported. Lower cutoff values for TSH have been adopted in many countries over the years, leading to the identification of milder forms of CH essentially with eutopic thyroid gland (thyroid in situ). Ford and LaFranchi in 2014 (50a) found that lowering the TSH cutoff value from greater than 20-25 uU/mL to greater than 6-10 approximately doubled the incidence of CH. A study from Italy reported that 21.6% of babies with permanent CH had TSH value at screening less than 15 uU/mL (applied between 2000 and 2006, cutoff TSH value ranged from 15 to 7uU/mL in different regions). The frequency of thyroid dysgenesis in this group was 19.6% and TSH levels at confirmation ranged from 9.9 to 708 uU/mL .It is important to remember that in this study TSH value at screening does not discriminate between transient and permanent forms of CH (50c). Harris and Pass reported that CH incidence increased from 1:3373 in 1978 to 1:1415 in 2005 (50d). Changes in the demographics of the birth population in New York partially explained the increased incidence of CH. They found a 23% increase with a birth weight < 1500 gr., 50% increase of twin/multiple births, 41% increase in mothers >30 years of age (50d). Also changes in percentage of races or ethnicity of newborns play a role, as shown in the State of California. In this study, the incidence of CH in Asian Indian is reported to be 1:1200 and in Hispanic 1:1600, versus 1:11000 in Non Hispanic Black (50e). A further study from the Italian Study Group, based on data from the Italian National Registry from 1987 to 2008 showed an increased incidence of both permanent and transient CH, in more recent years (50f). The authors investigated trends in the incidence of CH between the period 1987-1998, and 1999-2008. They found an increasing of 38% (from 1:3200 to 1:2320) of the incidence of permanent CH and of 54% (from1:3000 to 1:1940) including the transient forms in the period 1999-2008. The most important factor was the lowering of cutoff TSH values (from greater than 20 to 7/15 uU/ml since 1999. Moreover an increment of 58% of preterm babies with permanent CH was also reported in the second period. Permanent CH due to thyroid dysgenesis had a slight increase, being the great majority of cases presented with normal/hyperplastic thyroid. A national study from France, including 6622 cases of CH identified from 1982 to 2012 showed that the incidence rate CH due to eutopic glands increased by 4.4 fold in this period, regardless of the screening method adopted. Interestingly, also severe eutopic forms of CH increased by 2.1%. The incidence of dysgenesis did not change (50g). Screening for primary CH worldwide should be performed on the basis of national resources. The aim of neonatal screening is the earliest identification of any form of congenital hypothyroidism, but particularly those patients with severe hypothyroidism in whom disability is greatest if not treated. The identification of Central Congenital Hypothyroidism (CCH) by screening programs is under debate. Two screening strategies for the detection of congenital hypothyroidism have evolved. In the primary T4/backup TSH method, still favored in much of North America and the Netherlands, T4 is measured initially while TSH is checked on the same blood spot in those specimens in which the T4 concentration is low. In the primary TSH approach, favored in most parts of Europe and Japan, blood TSH is measured initially. A primary T4/backup TSH program will detect overt primary hypothyroidism, secondary or tertiary hypothyroidism, babies with a low serum T4 level but delayed rise in the TSH concentration, TBG deficiency and hypothyroxinemia; this approach may, however, miss subclinical hypothyroidism. A primary TSH strategy, on the other hand, will detect both overt and subclinical hypothyroidism, but will miss secondary or tertiary hypothyroidism, a delayed TSH rise, TBG deficiency and hypothyroxinemia. There are fewer false positives with a primary TSH strategy. Both programs will miss the rare infant whose T4 level on initial screening is normal but who later develops low T4 and elevated TSH concentrations. This pattern has been termed “atypical” congenital hypothyroidism or “delayed TSH” and is observed most commonly in premature babies with transient hypothyroidism or infants with less severe forms of permanent disease. In a few regions, a second routine specimen is collected from all births at 2-4 weeks of age (51). Results from the Northwest Regional Screening program, coordinated in Oregon, (USA), that applied this method, have recently been published (51a). In 2014 the European Society for Pediatric Endocrinology, (ESPE) on behalf of all the scientific societies of pediatric endocrinologists worldwide (ESPE,PES, SLEP, JSPE, APEG, APPES, ISPAE) published updated guidelines about screening, diagnosis, and management of congenital hypothyroidism (51b, 51c). According to the ESPE guidelines, the most sensitive test for detecting primary CH is the determination of TSH concentration that detects primary CH more effectively than primary T4 screening (51b,51c). Primary T4 screening with confirmatory TSH testing can detect some cases of CCH, but some cases of mild CH can be missed, depending on the cutoff T4 value used. When available, screening strategies for the identification of CCH are: a) a combination of primary T4 and primary TSH screening, b) a combination of primary T4 screening with secondary TSH testing followed by T4 binding protein determination (TBG). The last one is employed by the Netherlands where, in addition to a primary T4/backup TSH approach, TBG is assessed in those filter paper specimens with the lowest 5% of T4 values (52). The T4/TBG ratio is used as an indirect reflection of the free T4, which is difficult to be measured directly in dried blood spots. This approach has been reported to result in improved sensitivity and specificity in detecting milder cases of primary congenital hypothyroidism that might otherwise be missed. An additional reported advantage was the identification of >90% of infants with central hypothyroidism compared with only 22% with primary T4 screening and none with a primary TSH approach. Since on subsequent testing > 80% of the babies with central hypothyroidism had multiple pituitary hormone deficiencies, a disorder associated with high morbidity and mortality for which effective treatment exists (53,53a), and in view of an apparent frequency (1 in 16,000) similar to that of phenylketonuria (1 in 18,000), the authors have argued that the goals of newborn thyroid screening should be extended to include the detection of babies with central hypothyroidism. Recently a primary FT4 and TSH strategy was applied in Kanagawa Prefecture in Japan. A different method to determine FT4, based on enzyme-immunometric assays in filter paper blood eluates was used. They found a CCH prevalence of 1:31000 infants (53b,53c). Measurement of T4 and/or TSH is performed on an eluate of dried whole blood (DBS) collected on filter paper by skin puncture on day 1-4 of life. Primary CH screening has been shown to be effective for the testing of cord blood or the blood collected on filter paper after the age of 24 hours. Blood is applied directly to the filter paper and after drying the card is sent to the laboratory. The best time to collect blood for TSH screening is 48 to 72 hours of age. The practice of early discharge from the hospital of otherwise healthy full term infants has resulted in a greater proportion of babies being tested before this time. For example, it has been estimated that in North America 25% or more of newborns are now discharged within 24 hours of delivery and 40% in the second 24 hours of life (54). Because of the neonatal TSH surge and the dynamic changes in serum T4 and T3 concentrations that occur within the first few days of life, early discharge increases the number of false positive results. It is important that in the screening laboratory the results of TSH are interpreted in relation to time of sampling. Ethnicity seems to play a role in determining mean TSH values at birth (54a). Physicians caring for infants need to appreciate that there is always the possibility for human error in failing to identify affected infants, whichever screening program is utilized. This can occur due to poor communication, lack of receipt of requested specimens, or the failure to test an infant who is transferred between hospitals during the neonatal period (55). Therefore if the diagnosis of hypothyroidism is suspected clinically, the infant should always be tested (Figure 5). Similarly, as is obvious from the discussion earlier in the chapter, adult normative values, provided by many general hospital laboratories, differ from those in the newborn period and should never be employed. Normal values according to both gestational and postnatal age for cord blood T4, free T4, TBG, T3, reverse T3, and TSH up to 28 days of life (10) are shown in Figure 2. Normal serum levels of Tg in premature and full-term infants (13,14) and normal serum levels of free T4 and TSH in the first week of life (56) have also been published, though it should be noted that precise values may vary somewhat, depending on the specific assays used.  Three month old male infant who was diagnosed clinically when he presented with a history of poor feeding at 3 months of age. The child was born in Puerto Rico prior to the development of newborn screening. Note the dull face, periorbital edema and enlarged tongue. Special categories of neonates with CH can be missed at screening performed at usual time, particularly preterm babies and neonates with serious illnesses and multiple births. Drugs used in neonatal intensive care (i.e., dopamine, glucocorticoids that suppresses TSH), immaturity of hypothalamic-pituitary thyroid axis, decreased hepatic production of thyroid binding globulin, reduced transfer of maternal T4, reduced intake of iodine or excess iodine exposure, fetal blood mixing in multiple births can affect the first sample, and in many center a second specimen is required to rule out CH. (See section thyroid function in infants for more details). Preterm babies have a higher incidence of a unique form of hypothyroidism, characterized by a delayed elevation of TSH. These babies can later develop low T4 and elevated TSH concentrations. This pattern has been termed “atypical” congenital hypothyroidism or “delayed TSH”. Preterm babies with a birth weight of less than 1500 gr. have an incidence of congenital hypothyroidism of 1:300. Survival of even extremely premature babies (<28 weeks of gestation) is around 90% in developed countries, and the incidence of prematurity is around 11.5 % in US and 11.8 % worldwide. So, an increasing subpopulation of preterm babies and high risk newborns deserves a special sight about screening and follow up of CH. In these categories a second specimen 2-6 weeks from the first (ESPE guidelines suggested at about 15 days, or after 15 days from the first) may be indicated: preterm neonates with a gestational age of less than 37 weeks, Low Birth Weight and Very Low Birth Weight neonates and ill and preterm neonates admitted to neonatal intensive care unit, specimen collection within the first 24 hours of life, and multiple births, particularly in the case of same sex twins. The interpretation of the screening results should consider the results of a multiple sampling strategy, the age of sampling and the maturity (GA/birth weight) of the neonate. Two recent papers (56a,56b) showed that a second screen (using a lower TSH cutoff) is able to detect the delayed elevation of TSH that occurs in these babies. Vigone et al (56a) revaluated the children with a diagnosis of CH detected at second screen and treated with L-thyroxine after 2 years of age and found 24% of cases with permanent congenital hypothyroidism, 52% with transient hypothyroidism and 24% with persistent hypertropinemia. Neither screening nor confirmatory TSH levels were able to predict the thyroid function after 2 years of age in these children. Timing of normalization of thyroid hormones is critical for brain development (56c) and treatment should be started immediately if DBS TSH concentration is 40 mUI/l or more, after baseline TSH and FT4 serum determination, because this value strongly suggests decompensated hypothyroidism (56d). If TSH is < 40 mUI/l the clinician may postpone treatment, pending the serum results, for 1-2 days. ESPE guidelines (51b,51c) suggest treatment should be started if venous TSH concentration is persistently >20 mUI/l, even if serum FT4 is normal. Overtreatment can be dangerous for neurocognitive outcome and should be avoided, individualizing the dosage. It is still a matter of debate if treatment can be beneficial in otherwise healthy babies with venous TSH concentration between 6-20 mUI/l and FT4 concentration within the normal limits for age. In these cases, diagnostic imaging is recommended to try to establish a definitive diagnosis. If TSH concentration remains high for more than 3 or 4 weeks, it is possible (in discussion with the family) either starting LT4 supplementation immediately and retesting, off treatment, at a later stage, or retesting two weeks later without treatment. Waiting for larger studies that are able to answer to this question, and given the irreversibility of a possible harm to the child, treating during early childhood and revaluating the thyroid function after myelination of the central nervous system is completed (by 36 to 40 months of age) can be a prudent behavior (56e). LT4 treatment must be started immediately if FT4 or TT4 levels are low, given the known adverse effect of untreated decompensated CH on neurodevelopment and somatic growth. CH is defined on the basis of serum FT4 levels as severe when FT4 is <5 pmol/l, moderate when FT4 is 5 to 10 pmol/l and mild when FT4 is 10 to 15 pmol/l respectively. Determination of serum thyroglobulin (Tg) is useful, if below the detection threshold, to suggest athyreosis or a complete thyroglobulin synthesis defect. Measurement of Tg is most helpful when a defect in Tg synthesis or secretion is being considered. In the latter condition the serum Tg concentration is low or undetectable despite the presence of a normal or enlarged, eutopic thyroid gland. Serum Tg concentration also reflects the amount of thyroid tissue present and the degree of stimulation. For example, Tg is undetectable in most patients with thyroid agenesis, intermediate in babies with an ectopic thyroid gland and may be elevated in patients with abnormalities of thyroid hormonogenesis not involving Tg synthesis and secretion. Considerable overlap exists, and so, the Tg value needs to be considered in association with the findings on imaging. In patients with inactivating mutations of the TSH receptor discordance between findings on thyroid imaging and the serum Tg concentration has been described in some but not all studies (56f). Clinical findings are usually difficult to appreciate in the newborn period except in the unusual situation of combined maternal-fetal hypothyroidism. Many of the classic features (large tongue, hoarse cry, facial puffiness, umbilical hernia, hypotonia, mottling, cold hands and feet and lethargy), when present, are subtle and develop only with the passage of time. In addition to the aforementioned findings, nonspecific signs that should suggest the diagnosis of neonatal hypothyroidism include: prolonged, unconjugated hyperbilirubinemia, gestation longer than 42 weeks, feeding difficulties, delayed passage of stools, hypothermia or respiratory distress in an infant weighing over 2.5 kg (57). A large anterior fontanelle and/or a posterior fontanelle > 0.5 cm is frequently present in affected infants but may not be appreciated. In general, the extent of the clinical findings depends on the cause, severity and duration of the hypothyroidism. Babies in whom severe feto-maternal hypothyroidism was present in utero tend to be the most symptomatic at birth. Similarly, babies with athyreosis or a complete block in thyroid hormonogenesis tend to have more signs and symptoms at birth than infants with an ectopic thyroid, the most common cause of congenital hypothyroidism. Unlike acquired hypothyroidism, babies with congenital hypothyroidism are of normal size. However, if diagnosis is delayed, subsequent linear growth is impaired. The finding of palpable thyroid tissue suggests that the hypothyroidism is due to an abnormality in thyroid hormonogenesis or in thyroid hormone action. Bone maturation reflects the duration and the severity of hypothyroidism. Signs of delayed epiphyseal maturation on knee x-rays, persistence of the posterior fontanelle, a large anterior fontanelle, and a wide sagittal suture all reflect delayed bone maturation. The absence of one or both knee epiphyses has been shown to be related to T4 concentration at diagnosis and to IQ outcome, and is thus a reliable index of intrauterine hypothyroidism. Imaging studies are helpful to determine the specific etiology of CH. Both scintigraphy and ultrasound (US) should be considered in neonates with high TSH concentrations. Ideally, the association of US and scintigraphy gives the best information in a child with primary hypothyroidism. Scintigraphy shows the presence/absence (athyreosis), position (ectopic gland, in any point from the foramen caecum at the base of the tongue to the anterior mediastinum) and rough anatomic structure of the thyroid gland. US, in experienced hands, is a valid tool in defining size and morphology of a eutopic thyroid gland, however, US alone is less effective in detecting ectopic glands. Color Doppler US improves the effectiveness of US (57a). It is important to remember that an attempt to obtain an imaging of the thyroid in a newborn should never delay the initiation of treatment. Scintigraphy should be carried out within 7 days of starting LT4 treatment. Scintigraphy may be carried out with either 10-20 MBq of technetium-99m (99mTc) or 1-2 MBq of iodine-123 (I123). Tc is more widely available, less expensive, and quicker to use than I 123. Scintigraphy with I123, if available, is usually preferred because of the greater sensitivity and because, I123, unlike of technetium-99 is organified. Therefore, imaging with this isotope allows quantitative uptake measurements and tests for both iodine transport defects and abnormalities in thyroid oxidation. An enrichment of the tracer within the salivary gland can lead to misinterpretation, especially on lateral views, but this can be avoided by allowing the infant to feed before scintigraphy, thus empting the salivary glands and keeping the child calm under the camera. The perchlorate discharge test is considered indicative for a organification defect when a discharge of > 10% of I123 administred dose occurs in a thyroid in normal position (when perchlorate is given at 2 hours). Excess iodine intake through exposure (i.e from antiseptic preparation), maternal TSH receptor blocking antibodies, inactivating mutation in the TSH receptor and in the sodium/iodide symporter (NIS), and TSH suppression from LT4 treatment can give interfere with the I123 uptake, showing no uptake in the presence of a thyroid in situ (apparent athyreosis). Thyroid ultrasonography is performed with a high frequency linear array transducer (10-15 MHz) and allows a resolution of 0.7 to 1mm. Thyroid tissue is more echogenic than muscle and less echogenic than fat. In the case of absence of the thyroid fat tissue can be misdiagnosed as dysplastic thyroid gland in situ. Distinguish between thyroid hypoplasia and dysplastic non thyroidal tissue in a newborn requires an enormous experience, and reevaluation at later age can result in a different diagnosis (57a). Combining scintigraphy and thyroid ultrasound improve diagnostic accuracy, and helps to address further investigations, including molecular genetic studies. Infants found to have a normal sized gland in situ in the absence of a clear diagnosis should undergo further reassessment of the thyroid axis and imaging at a later age. Replacement therapy with L-thyroxine (L-T4) should be begun as soon as the diagnosis of congenital hypothyroidism is confirmed. In babies whose initial results on newborn screening are suggestive of severe hypothyroidism therapy should be begun immediately without waiting for the results of the confirmatory serum. Severe hypothyroidism is defined by T4 <5 mcg/dL (64 nmol/L) and/or TSH >40 mU, or. accordingly with ESPE guidelines(51g,51k), CH is defined on the basis of serum FT4 levels as severe when FT4 is <5 pmol/l, moderate when FT4 is 5 to 10 pmol/l and mild when FT4 is 10 to 15 pmol/l. As noted above, treatment need not be delayed in anticipation of performing thyroid imaging studies as long as the latter are done within 5-7 days of initiating treatment (before suppression of the serum TSH). Parents should be counseled regarding the causes of congenital hypothyroidism, the importance of compliance and the excellent prognosis in most babies if therapy is initiated sufficiently early and is adequate and educational materials should be provided (58). An initial dosage of 10-15 mcg/kg/day of L-T4 is generally recommended to normalize the T4 as soon as possible. The highest dose is indicated in infants with severe disease, and the lower in those with a mild to moderate form. L-T4 Tablets can be crushed and given via a small spoon, with suspension, if necessary in a few milliliters of water or breast milk or formula or juice, but care should be taken that all of the medicine has been swallowed. Thyroid hormone should not be given with substances that interfere with its absorption, such as iron, calcium, soy, or fiber. Drugs such as antacids (aluminium hydroxide) or infantile colic drops (simethicone) can interfere with L-thyroxine absorption. Many babies will swallow the pills whole or will chew the tablets with their gums even before they have teeth. Reliable liquid preparations are not available commercially in the US, although they have been used successfully in Europe. L-T4 can also be administred in liquid form, but only if pharmaceutically produced and licensed L-T4 solutions are available. A brand name rather a generic formulation of L-T4 is recommended because they are not bioequivalent (58a). The aims of therapy are to normalize the T4 as soon as possible, to avoid hyperthyroidism where possible, and to promote normal growth and development. When an initial dosage of 10-15 mcg/kg is used, the T4 will normalize in most infants within 1 week and the TSH will normalize within 1 month, Subsequent adjustments in the dosage of medication are made according to the results of thyroid function tests and the clinical picture. Often small increments or decrements of L-thyroxine (12.5 mcg) are needed. This can be accomplished by 1/2 tablet changes, by giving an alternating dosage on subsequent days, or by giving an extra tablet once a week. As stated in ESPE guidelines: “ L-T4 alone is recommended as the medication of choice and should be started as soon as possible, no later than two weeks of life or immediately after confirmatory test results in infants identified in a second routine screening test. L-T4 should be given orally. If intravenous administration is necessary, the dose should be no more than 80% of the oral dose”. Serum or plasma FT4 (or TT4) and TSH concentration should be determined at least 4 hours after the last L-T4 administration. TSH should be maintained in the age-specific reference range and FT4 in the upper half of the age- specific reference range. “The first follow up examination is indicated after 1-2 weeks after the start of LT4 treatment and then every 2 weeks until TSH levels are completely normalized and then every 1- 3 months until 12 months of age. Between the age of one and three years, children should undergo frequent clinical and laboratory evaluations (every 2 to 4 months).” Thereafter, evaluations should be carried out every 3 to 12 months until growth is completed. “More frequent evaluations should be carried out if compliance is questioned or abnormal values are obtained. Any reduction of L-T4 dose should not be based on a single increase of FT4 concentration during treatment. “Measurements should be performed after 4-6 weeks any change in the dosage or in the L-T4 formulation”. In hypothyroid babies in whom an organic basis was not established at birth and in whom transient disease is suspected, a trial off replacement therapy can be initiated after the age of 3 years when most thyroxine-dependent brain maturation has occurred, as shown by magnetic risonance imaging studies (56e). Re-evaluation is recommended if the treatment was started in a sick child (i.e. preterm), if thyroid antibodies were detectable, if no diagnostic assessment was completed, and in children who have required no increase in L-T4 dosage since infancy. Re-evaluation is recommended also in the case of a eutopic gland with or without goiter, if not enzyme defects have been detected, if any other cause of transient hypothyroidism is suspected. Re-evaluation is not necessary if venous TSH concentration has risen during the first year of life, due to either LT4 underdosage or poor compliance. To perform a precise diagnosis LT4 treatment is suspended for 4-6 weeks, and biochemical testing and thyroid imaging are carried out. To establish the presence of primary hypothyroidism, without defining the cause, L-T4 dose may be decreased by 20-30% for 2 to 3 weeks. If TSH serum levels rise to > 10 mU/L during this period, the hypothyroidism can be confirmed. Although all are agreed that the mental retardation associated with untreated congenital hypothyroidism has been largely eradicated by newborn screening, controversy persists as to whether subtle cognitive and behavioral deficits remain, particularly in the most severely affected infants (59-64). Both the initial treatment dose and early onset of treatment (before 2 weeks) are important. Time to normalization of circulating thyroid hormone levels, the initial free T4 concentration, maternal IQ, socioeconomic and ethnic status have also been related to outcome (59,62,63,64). The long term problems for these babies appear to be in the areas of memory, language, fine motor, attention and visual spatial. Inattentiveness can occur both in patients who are overtreated and those in whom treatment was initiated late or was inadequate. In addition to adequate dosage, assurance of compliance and careful long-term monitoring are essential for an optimal developmental outcome. More details about long term follow up are reported in ESPE guidelines (51g,51K). Progressive hearing loss in CH should be recognized and corrected, because strongly influenced the outcome). Recently, extensive reports on long term outcome of congenital hypothyroidism in young adults have been published (64a,64b). In the French cohort of 1202 CH young adults, hearing impairment was found at a mean age of 23.4 years in 9.5% versus 2.5% of general population, and the risk of developing hearing impairment was three times higher in these patients than in general population (64c). Also interesting data about pregnancy outcomes in young women with CH came out from the French cohort (64d). Permanent congenital thyroidal (primary) hypothyroidism can be the consequence of a disorder in thyroid development and/or migration (thyroid dysgenesis), or due to defects at every step in thyroid hormone synthesis (thyroid dyshormonogenesis). Although congenital hypothyroidism (CH) is in the great majority of cases a sporadic disease, the recent guidelines (51g,51k) for CH recommend genetic counseling in targeted cases. Positive family history for CH, association with cardiac or kidney malformation, midline malformation deafness, neurological sigs (i.e., choreoathetosis, hypotonia, any sign of Albright hereditary osteodystrophy, lung disorders, suggest genetic counseling, in order to assess the risk of recurrence and to provide further information about a possible genetic etiology of CH. Recently a targeted next-generation (NGS) panel, covering all exons of the major CH genes, has been proposed as a useful tool to identify the genetic etiology of CH (64e). Lowering TSH cut off value at screening increases the diagnosis of CH with eutopic thyroid. A targeted next-generation (NGS) panel has been applied to patients with CH and thyroid in situ (64f). Unlike in iodine-deficient areas of the world where endemic cretinism continues to be a major health hazard, the majority (85 to 90%) of cases of permanent congenital hypothyroidism in North America, Western Europe and Japan are due to an abnormality of thyroid gland development (thyroid dysgenesis). Thyroid dysgenesis may result in the complete absence of thyroid tissue (agenesis, 20-30%) owing to a defect in survival of the thyroid follicular cells precursors) or it may be partial (hypoplasia); the latter often is accompanied by a failure to descend into the neck (ectopy) mostly located in a sublingual position as a result of a premature arrest of its migratory process. Lowering of cut off TSH values for newborn screening increases the percentage of CH with thyroid in situ. Females are affected twice as often as males. In the United States, thyroid dysgenesis, is less frequent among African Americans and more common among Hispanics and Asians. Babies with congenital hypothyroidism have an increased incidence of cardiac anomalies, particularly atrial and ventricular septal defects (65). An increased prevalence of renal and urinary tract anomalies has also been reported recently (66). Most cases of thyroid dysgenesis are sporadic. Familial cases represent 2%. Discordance between monozigotic twins is inexplained (67). Although both genetic and environmental factors have been implicated in its etiology, in most cases the cause is unknown (67a). The occasional familial occurrence, the higher prevalence of thyroid dysgenesis in babies of certain ethnic groups and in female versus male infants as well as the increased incidence in babies with Down syndrome (68) all suggest that genetic factors might play a role in some patients. Thyroid transcription factors would appear to be obvious candidate genes in view of their important role in thyroid organogenesis and in thyroid-specific gene expression. To date, however, abnormalities in these genes have been found in only a small proportion of affected patients, usually in association with other developmental abnormalities (68a). Thyroid transcription factors (TTF) such as NKX2-1 (or formerly TTF1/TITF1), FOXE1 (Forkhread Box E1, formerly TTF2/TITF2), PAX8 (Paired box gene 8), and NKX2-5, are expressed during early phases of thyroid organogenesis (budding and migration), instead thyroid stimulating hormone receptor gene (TSHR) is expressed during the later phases of thyroid development. All these genes are involved in normal thyroid development and in thyroid dysgenesis. Alternately, epigenetic modifications, early somatic mutations or stochastic developmental events may play a role. Five monogenic forms due to mutations in TSHR, NXK2-1, PAX8, FOXE-1. NXK2-5 have been reported. Monogenic forms represent less than 10% in TD (68a). Thyroid stimulating hormone receptor resistance (TSHR gene #OMIM 603372) Described in 1968, is mostly caused by biallelic inactivating mutations in the TSH receptor gene (TSHR). TSH affects follicular thyroid cell proliferation and many cellular processes, including thyroidal iodine uptake, thyroglobulin iodination, and reuptake of iodinated thyroglobulin. Phenotype varies from mild hyperthyrotropinemia with normal thyroid gland to severe CH with thyroid hypoplasia and absence of tracer uptake at scintigraphy (apparent athyreosis). Inactivating TSHR mutations are the most frequent cause of monogenic TD and non syndromic CH, with prevalence in CH cohorts around 4 % (68b). Clinically a classic and a non-classic TSH resistance form are described, based on different TSHR mutations (68c). Both Gs and Gq proteins are involved Heterozygous non polymorphic TSHR mutations were found in a high frequency (11.8-29%) in children and adolescents with isolated non-autoimmune hyperthyrotropinemia (68d). NKX2-1 (previously TITF-1, TTF-1) gene encodes for a transcription factor of the NK family. It is involved in early development of brain, thyroid and lung. In thyrocytes, NKX2-1 activates the transcription of TG, TPO, TSHR and PDS genes. In the lung is important for the branching of the lobar bronchi and regulates the expression of surfactant proteins in pneumocytes. In the brain, NKX2 is expressed in basal ganglia and forebrain and it is involved in the specification and migration of neurons. Haploinsufficiency of NKX2-1 is responsible for the brain-lung-thyroid (BLT) syndrome (OMIM 610978) characterized by CH, infant respiratory distress syndrome and benign hereditary chorea. NKX2-1 defects occur either as a sporadic cases or as familial cases inherited in an autosomal-dominant manner. The clinical presentation ranges from the complete BLT syndrome (50%) to incomplete forms with brain and thyroid disease (30%) or only benign hereditary chorea (13%), the mildest expression of the syndrome. TD ranges from hypoplasia (about 35%) to normal morphology (>50% of patients) (68e). Recently, a case of BLT syndrome has been reported with thyroid ectopy (68f). The severity of symptoms varies widely, even in families with the same disease causing mutation. In a detailed study (68g) lung disease, if present at birth, manifests as a surfactant deficiency syndrome and can be fatal. Asthma, recurrent pneumonia in childhood, spontaneous pneumothorax, and interstitial lung disease has also been reported. Neurologic forms present with muscular hypotonia in early infancy and psychomotor delay, which progresses to benign hereditary chorea between 1 and 5 years. Additional non classical features including hypodontia o oligodontia, microcephaly, growth retardation, genitourinary abnormalities, skeletal disorders, and congenital heart defects have been reported in patients with large deletions on chromosome 14, including the NKX2-1 gene and surrounding genes. Interestingly, a more extended phenotype associating hypothalamic symptoms, frequent recurrence of fever without infection, dysrhytmic sleep, and abnormal height in patients with point NKX2-1 mutations was described (68g). So far, 116 NKK2-1 genetic anomalies have been reported worldwide (68h). Paired box gene 8 (PAX8) codes for a TTF of the paired homeodomain transcription factors family. PAX8 is expressed during thyroid organogenesis in the median anlage and in the kidney development. In synergy with NKX2-1, PAX 8 influences the expression of TPO, TG and NIS in thyroid follicular cells. The prevalence of PAX8 mutations in CH patients is about 1%, ranging from 0.3 to 3.4% (68b,68i).Thyroid hypoplasia is the more common phenotype, but athyreosis to normal morphology have also been reported. Thyroid function varies from severe hypothyroidism to mild hypertropinemia, and different phenotypes can be found in the same family. The association with kidney malformations is possible, but remains a facultative sign in CH patients with PAX8 mutations. So far, 29 mutations have been reported (68h). The Forkhead Box 1 E1 (FOXE1) gene encodes for a transcription factor of the forkhead/winged-helix transcription factor family. Foxe1 is expressed in the thyroid primordium, in the pharyngeal endoderm derivates such as the palate and the esophagus and in the hair follicoles (68j). Foxe1 interacts with TG and TPO promoters and with regulatory regions of DUOX2 and NIS genes (68k). The Bamforth-Lazarus syndrome is caused by FOXE1 mutations. It is characterized by CH (usually athyreosis), cleft palate and spinky hair. Bifid epiglottis and choanal atresia can be present. So far, six mutation with loss of function (68h) and 1 mutation with gain of function have been reported in patients with Bamforh-Lazarus syndrome, showing the effect of FOXE1 gene dosage in this disorder (68m). Because an increased prevalence of heart congenital malformations have been reported in CH, genes involved in heart organogenesis as NKX2-5 have been suggested as a cause of CH. NKX2-5, that encodes for a transcription factor with a major role in heart development has been investigated in a cohort of 241 patients with thyroid dysgenesis. Heterozygous missense mutations had been reported in this study in 4 patients with ectopy and athyreosis, and all mutations were transmitted from one of the parents but only 1 patient had minor cardiac phenotype (68n). A major pathogenetic role of NKX2-5 mutations in thyroid dysgenesis has been questioned: given the absence of TD in carriers of NKX2-5 mutations, and the high number of TD patients without mutations. Better defining the role of NKX2-5 in thyroid organogenesis need further studies (68o). Inborn errors of thyroid hormonogenesis (thyroid dyshormonogenesis) are responsible for most of the remaining cases (15%) of neonatal thyroidal hypothyroidism. Unlike thyroid dysgenesis, mostly a sporadic condition, these inborn errors of thyroid hormonogenesis are commonly associated with an autosomal recessive form of inheritance, consistent with a single gene abnormality. DUOX2 mutations can be transmitted in autosomal dominant way. Thyroid dysormonogenesis is caused by genetic defects in proteins involved in all steps of thyroid hormone synthesis (68s) often associated with goiter formation. Goiter can be present in utero or at birth. .A number of different defects have been characterized based on radioiodine uptake and perchlorate test and include: 1) Iodide transport defect (ITD) (SLC5A5, Sodium/Iodide Symporter NIS), that shows failure to concentrate iodide, with low or absent radioiodine uptake, also in salivary glands and gastric mucosa; 2) Iodide organification defect (IOD) with normal radioiodine uptake and altered perchlorate discharge test. In these patients, less than 90% of the iodide is organified and remains stored in the follicles. Total IOD is defined as >90% of the given dose back to the blood. Partial IOD is defined as 10-90% of radioiodine washout after perchlorate application. Total IOD is due to Thyroid peroxidase mutations (TPO) and Dual Oxidase 2 (DUOX2), partial IOD is due to DUOX2, Dual Oxidase Maturation Factor 2 mutations (DUOX2A), SLC26A4, pendrin and TPO defects.
Thyroglobulin TG mutations, iodide recycling defects IYD, Iodothyrosine Deiodinase mutations (DEHAL1). 4) Iodide Transport Defect (OMIM 274400) ITD is rather a rare form and is due a mutation of the Sodium/Iodide Symporter (NIS). The NIS is expressed at the basolateral membrane of the thyrocite and it is responsible for the active iodide uptake through the membrane into the thyrocite (69). This form of hypothyroidism is characterized by goiter and absence of radioiodine uptake. In contrast with athyreosis, uptake is lacking also in salivary glands and in the stomach (white scintigraphy). The severity of hypothyroidism depends on the residual function of the mutated NIS protein, ranging with severe to mild forms, often detected in infancy or childhood. Pendred syndrome is defined by the association of familial profound deafness with multinodular goiter. It is caused by biallelic mutation in the pendrin gene (70-71). Pendred syndrome is the only form of thyroid dyshormonogenesis associated with a malformation. The inner ear presents a characteristic malformation of the cochlea. Congenital hypothyroidism is present in only 30% of cases, goiter occurs often in childhood. Thyroid phenotype is variable. Perchlorate test shows a partial organification defect. Pendred syndrome is the most frequent etiology of familial deafness. SLC264A mutations (mostly in the heterozygous state) have been also described in isolated enlargement of the vestibular aqueduct, with no thyroid disease (71a). More than 150 mutations have been described. Specific mutation cluster in Asia (H723R), and Europe (L236P, T416P, IVS8, 1-GA) (71b). Thyroid peroxidase (TPO) is a heme peroxidase that regulates two rate-limiting step of thyroid hormones synthesis, first the organification of iodide to iodinated thyrosyl residuates such as MIT and DIT, and then the coupling of MIT and DIT to T3 and T4. TPO action needs hydrogen peroxide as the final electron acceptor. Mutations are mostly in the heme-binding domain of the protein, encoded by exons 7-9 (71c). TPO mutations are a common form of thyroid dyshormonogenesis. Severe congenital hypothyroidism with goiter is present in the great part of patients, with a total IOD. Recently, a few patients with partial IOD have been reported (72,72a). DUOX2 (formerly THOX2) and DUOXA2 are components of a nicotinamide adenine dinucleotide phosphate oxidase complex that produces hydrogen peroxide indispensable for TPO action. The first mutation in DUOX2 has been reported in 2002. Heterozygous mutations have been found in a part of the patients, suggesting autosomal dominant and autosomal recessive inheritance both possible in this form (72b). Monoallelic mutations usually cause mild hypothyroidism; biallelic mutations are present in mild to severe hypothyroidism. In some cases, DUOX2 mutations lead to transient congenital hypothyroidism, with normalization of thyroid function at follow up. DUOX2 mutations usually cause partial IOD, but total IOD is also reported (72c). Mutations in DUOXA2 were described in patients detected by neonatal screening with mild CH. Partial IOD was found in these cases (72d). Thyroglobulin (Tg) is a glycoprotein synthetized by the thyrocytes that serves as a matrix for thyroid hormones synthesis and storage in the follicles (68t). Tg is also in part released in the blood and it is a useful marker of thyroid tissue. In CH, Tg serum determination can differentiate between a true and apparent athyreosis, the last with same residual dysgenetic tissue and Tg detectable. In dyshomonogenesis, Tg levels are low in patients with Tg mutations, but are normal or high in the other defects of hormonogenesis (68t). CH due to Tg mutations is usually severe, with goiter in utero or at birth. Different mechanisms cause hypothyroidism in Tg mutations: a )Tg synthesis defects alter protein synthesis; b) Tg transport defects limit Tg excretion in the follicle; c) a abnormal structure of T impairs coupling of MIT and DIT; d) a large imperfect DNA inversion in Tg gene is a novel cause for CH (72e-72g). DEAHAL 1(IYD) is the enzyme that regulates the recycling of iodide from MIT and DIT to the follicle, thus allowing the synthesis of thyroid hormones. Dietary Iodine is scarce in nature and it is the limitating factor for thyroid hormones synthesis. Failure of DEAHL1 cause iodotyrosine deiodinase deficiency, characterized by hypothyroidism, goiter and mental retardation. It is important to stress that these patients are not detected by neonatal screening for CH, probably because the maternal iodine protect for a period the newborn. Diagnosis is reported between 18 month and 16 years with hypothyroidism and mental retardation (72h). The first mutations in DEAHAL1 has been reported in 2008 (72i). The use of MIT and DIT -as early markers to identify iodotyrosine deiodinase deficiency before mental retardation-is under investigation. Central hypothyroidism (CCH) is caused by an insufficient thyroid hormone biosynthesis due to a defective stimulation by TSH, in the presence of an otherwise normal thyroid. This condition includes all causes of congenital hypothyroidism due to a pituitary or hypothalamic pathology (secondary or tertiary hypothyroidism). CCH was previously considered a very rare disease with a prevalence initially estimated to be 1:100000 in newborns (73). In more recent data, CCH had an incidence that could reach 1:16.000, as shown from results from screening for congenital hypothyroidism applied in the Neetherlands, based on T4/TSH/TBG determination (73a). Also with this sophisticated method of screening, CCH is sometime not identified at birth, because the limiting step is “how low is a low T4”, low enough to be considered an effective cutoff value and allow the determination of TSH and TBG. Many cases are diagnosed in infancy or childhood, if not later in adulthood (73b). The majority of screening programs are based on TSH determination and a high index of suspicion is needed to identify CCH in the preclinical phase. Delayed diagnosis may result in neurodevelopment delay. More than 50% of children with CCH have moderate or severe hypothyroidism, so, if not treated, the risk of neurodevelopmental delay should not be underestimated (73c). In the majority of cases identified early, TSH deficiency is a part of combined pituitary hormone deficiency. A timely correction of ACTH and cortisol deficiency, and/or GH deficiency may avoid life threatening emergencies. CCH can be transient (mostly due to drugs or maternal hyperthyroidism), or permanent. Two forms of non-efficient TSH are known, the first one is very rare and is due to defects in the receptor that regulates the action of TRH on thyrotropes (TRHR), the second form is due to several mutations in the β-subunit of TSH. a)Thyrotropin-releasing hormone receptor (TRHR ) gene defects. TRHR mediates the correct action of TRH on thyrotropes toward the synthesis, glycosylation and secretion of TSH. This is a very rare cause of central hypothyroidism. Mutations in TRHR gene have been described so far in 3 patients from 2 families, the first from Canada, the second from Italy, with autosomal recessive inheritance (73d,73e). Index cases were detected at 9 and 11 years for short stature and symptoms related to hypothyroidism. Neonatal hypothyroidism could not be proven because neonatal screening was based on TSH level. No psychomotor delay or intellectual deficit was reported in these children. TSH was in the low normal range with a suspected low bioactivity; T4 or FT4 were low, TRH test showed no response of TSH and PRL. A compound heterozygosis with 2 different mutations in TRHR gene was found in the Canadian patient. The first mutation in the paternal allele was a premature stop codon R17X that completely inactivated protein function. The second one, on the maternal allele was a complex combination of mutations: 9-nucleotide deletion followed by a point mutation resulting in an in-frame deletion of three aminoacids (Ser115-Thir117) plus a missense change located at the cytoplasmatic end of the transmembrane domain of the receptor (73d).The Italian patient had a homozygous nonsense mutation (pR17X). A novel homozygous missense mutation (P81R) in TRHR has been published in a female infant presented at age 19 days with prolonged jaundice due to isolated hyperbilirubinemia. Thyroid function showed CCH (TSH 2.2 mU/L (RR 0.4-3.5). FT4 7.9 pmol/L (RR10.7-21.8). She was treated with L-thyroxine and at 4 years of age growth and neurological development are in the normal range. The location of the mutated aminoacid (proline 81) in the second transmembrane helix underlines the functional role of this helix in hormone binding and receptor activation (73f). b)TSH β Gene defects TSH is a glycoprotein hormone with an α subunit common with FSH, LH and hCG, and a β-subunit, specific for TSH. Mutations of the β-subunit of TSH are the cause of the most severe forms of central congenital hypothyroidism. All mutations described so far caused central hypothyroidism, either because truncated protein or alterations in key structural features required for heterodimeric integrity occur (74, 74a, 74b). Another consequence of mutations of the β-subunit of TSH is the modification of bioactivity and immunoreacivity of the TSH heterodimer. Diagnosis of central hypothyroidism can be complicated because of impaired TSH immunoreactivity and/or bioactivity. For instance, TSH is not detectable when the heterodimer formation between TSHα and TSH β subunit is completely not allowed from mutations (i.e. p.G49, p.32), in other cases some mutant heterodimeric TSH is present and measurable in an immunoassay dependent manner (i. e. p.Q69, c.373 delT). TSH can be measurable but not shows normal bioactivity (74a). Interestingly, a variant (c223A>G, pR75) causing normal bioactive TSH, but with impaired immunoreactivity has been described (74c, 74d). These individuals are euthyroid, but erroneous diagnosis and inappropriate treatment have been reported. In children affected with CCH due to mutations of the β-subunit of TSH, psychomotor and mental retardation can occur, depending on the time of diagnosis and treatment. Most are clinically diagnosed after 3 months of age because they are not identified by neonatal screening based on increased TSH levels. Hyperplastic pituitary, high levels of serum glycoprotein alfa-subunit and hypoplasic thyroid gland have been reported (74a). Several mutations have been reported, including missense, nonsense and frameshift mutations (74,74a), as well as slice mutations (74b). Recently a homozygous TSHβ mutation was found (74e). A novel missense mutation (c.2T>C) in which a methionin codon, is replaced by a threonine, has been very recently reported in a child with very low levels of TSH (0.45mU/l, (NR 0.4-3.5) and FT4.(<5.1 pmol/l (NR 13.8-22.5). This child was diagnosed at 3.5 months of age because feeding difficulties, somnolence, constipation and severe growth retardation. She was treated with L-thyroxine with a good response in growth, but she has severe neurodevelopmental deficits, with bilateral sensorineural deafness, nistagmus, motor and language development delay at age of 10. She was on autistic/Asperger spectrum and needed special education at school (74f). IGSF1 (immunoglobulin (Ig) superfamily member1) gene mutations were described in 2012 as a cause of central hypothyroidism, with an incidence of about 1:100.000 (75,75a). IGSF1 gene is located on X chromosome (Xq26.1) and encodes for a plasma membrane glycoprotein that is mainly expressed in the pituitary, brain and testes. Several pathogenetic mutations in IGSF1 gene have been reported so far (75,75a,75b). An extensive case series, expanding the clinical phenotype has been published very recently (75c,75d). The first patient was diagnosed by neonatal screening in the Neetherlands where a screening program for congenital hypothyroidism that includes T4 determination (T4/TBG/TSH) is applied. Many other cases of central hypothyroidism were identified in this family and in others with an age at diagnosis ranging from 3 weeks to 69.9 years (75). Typical phenotype in adult males includes central hypothyroidism and macroorchidism (>30 ml by Prader orchidometer). Hypoprolactinemia and GH deficiency can be present. GH deficiency is usually transient and detectable in childhood. Body mass index tends to be elevated. Testicular volume is normal in childhood and increases at a normal age in puberty, but the testosterone rise is delayed, as well as the pubertal growth spurt and the appearance of secondary sexual characteristics. Thyroid volume is small, TSH is usually detectable, TSH response to TRH is diminished. No clear correlation genotype-phenotype has been established. IGSF1 gene is located on X chromosome. Male are affected but 1/3 of females heterozygous carriers shows a milder phenotype, with central hypothyroidism, delayed menarche, mild prolactin deficiency and benign ovarian cysts sometime requiring surgical resection. Recently a familial form of isolated central hypothyroidism with neurological phenotypes due to a novel IGSF1 gene mutation has been reported from Israel (75e). Central congenital hypothyroidism can be a component of combined pituitary hormone deficiency. This form represents the majority of cases detected by the neonatal screening when T4 determination is used (73b). Early diagnosis in these cases helps to prevent dangerous hypoglycemic and adrenal crisis due to associated GH and ACTH deficiency. TSH deficiency can be present at diagnosis or occurs later, as a component of an evolving phenotype. In a minority of patients, mutations of known transcriptor factors (i.e POU1F1 ,PROP1,HESX1,LHX3,LHX4,SOX3 and OTX2) that are involved in pituitary development can be identified (76) (See Table 1). Mutations in early transcriptor factors cause developmental abnormalities, i.e., septo-optic dysplasia, midline defects, holoprosencephaly, ocular or skeletal defects, intellectual impairment, associated with variable hypopituitarism. Mutations in HESX1, OTX2 and SOX3 have been found in patients with septo-optic dysplasia and TSH deficiency (76). TSH deficiency in association with other pituitary hormone deficiencies may be associated with abnormal midline facial and brain structures (particularly cleft lip and palate, and absent septum pellucidum and/or corpus callosum) and should be suspected in any male infant with microphallus and persistent hypoglycemia (76a). One of the more common of these syndromes, septo-optic dysplasia, has been related in some cases to a mutation in the HESX 1 homeobox gene in some cases (76b). Other genetic causes of congenital hypopituitarism include molecular defects in the genes for the transcription factors LHX3 (76c), LHX4, POU1F 1 (76d) or PROP 1 (76d). POU1F 1 (Pit-1 in mice) is essential for the differentiation of thyrotrophs, lactotrophs and somatotrophs while PROP 1, a homeodomain protein that is expressed briefly in the embryonic pituitary, is necessary for POU1F 1 expression. For complete coverage of this and related areas visit the chapter entitled: “Defects of thyroid hormone transport in serum” by Samuel Refetoff, MD in this book. Inherited abnormalities of the iodothyronine-binding serum proteins include TBG deficiency (partial or complete), TBG excess, transrethyretin (TTR) (prealbumin) variants and familial dysalbuminemic hyperthyroxinemia (FDH). In these conditions the concentration of free hormones is unaltered, but the abnormal total thyroxine concentrations can be misleading during neonatal screening and in the evaluation of thyroid function. For complete coverage of this and related areas visit the chapter entitled: “Impaired sensitivity to thyroid hormone: defects of transport, metabolism and action” by.Alexandra M. Dumitrescu, MD and Samuel Refetoff, MD, in this book. Impaired sensitivity to thyroid hormone, previously known as “reduced sensitivity to thyroid hormone”, include defects in thyroid hormone action, transport and metabolism. They are classified in a)Thyroid hormone cell membrane transport defect (THCMTD),b) thyroid hormone metabolism defect (THMD) and c) thyroid hormone action defect that include Resistance to thyroid hormone (RTH) (77).The first defect, recognized almost 50 years ago, produces reduced sensitivity to TH and was given the acronym RTH, for resistance to thyroid hormone (77a, 77b). Its major cause, found in more than 3,000 individuals, is mutations in the TH receptor ß (THRB) gene. More recently mutations in the THRA gene were found to produce a different phenotype owing to the distinct tissue distribution of this TH receptor (77c, 77d). Two other gene mutations, affecting TH action, but acting at different sites have been identified in the last 10 years. One of them, caused by mutations in the TH cell-membrane transporter MCT8, with decreased T4 uptake into brain cells produces severe psychomotor defects (77e,77f). In this syndrome, first described as Allan Herdon Dudley syndrome, (77g) mutations in the monocarboxylate transporter 8 (MCT 8 gene, located on the X-chromosome), have been associated with male- limited hypothyroidism and severe neurological abnormalities, including global developmental delay, dystonia, central hypotonia, spastic quadriplegia, rotary nystagmus and impaired gaze and hearing (77e, 77f). Heterozygous females had a milder thyroid phenotype and no neurological defects. A defect of the intracellular metabolism of TH, identified in 11 members from 9 families, is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases (77h). Knowledge of the molecular mechanisms involved in mediation of TH action allows the recognition of the phenotypes caused by genetic defects in the involved pathways. While these defects have opened the avenue for novel insights into thyroid physiology, they continue to pose therapeutic challenges.
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