ABSTRACT

Thyroid disorders in infancy, childhood and adolescence represent common and usually treatable endocrine disorders. Thyroid hormones are essential for normal development and growth of many target tissues, including the brain and the skeleton. Thyroid hormone action on critical genes for neurodevelopment is limited to specific time window, and even a short period of deficiency of TH can cause irreversible brain damage. During the first trimester of pregnancy fetal brain development is totally dependent on maternal thyroid function. Congenital hypothyroidism is one of the most preventable causes of mental retardation, but early diagnosis is needed in order to prevent irreversible SNC damage. Today more than 70% of the babies worldwide are born in areas without an organized screening program. New insights about genetic causes, screening strategies and treatment of congenital hypothyroidism are reported. Hyperthyroidism in newborns is usually a transient consequence of transplacental passage of TSH receptor stimulating antibodies. Hypothyroidism can be detected in infants born to hyperthyroid mothers, due to transplacental passage of TSH receptor antibodies or hypothalamic-pituitary suppression. In childhood and adolescence autoimmune thyroid disease (AITD) as chronic lymphocytic thyroiditis and Graves’ disease account for the main cause of hypothyroidism and hyperthyroidism, respectively. Incidence of AITD increase from infancy to adolescence. Other autoimmune disorders are frequently associated. An increased risk of thyroid nodules and cancer is suggested. Differentiated thyroid cancer and medullary thyroid carcinoma in childhood and adolescence require specific expertise. Follow up programs are advised for high risk patients as long term survivors of childhood cancer. For complete coverage of this and related areas of Endocrinology, please visit our free online textbook, WWW.ENDOTEXT.ORG.

INTRODUCTION

Thyroid hormone is essential for the growth and maturation of many target tissues, including the brain and skeleton. As a result, abnormalities of thyroid gland function in infancy and childhood result not only in the metabolic consequences of thyroid dysfunction seen in adult patients, but in unique effects on the growth and /or maturation of these thyroid hormone-dependent tissues as well. In most instances, there are critical windows of time for thyroid hormone-dependent development and so the specific clinical consequence of thyroid dysfunction depends on the age of the infant or child. For example, newborn infants with congenital hypothyroidism frequently have hyperbilirubinemia, and delayed skeletal maturation, reflecting immaturity of liver and bone, respectively, and they are at risk of permanent mental retardation if thyroid hormone therapy is delayed or inadequate; their size at birth, however, is normal. In contrast, hypothyroidism that develops after the age of three years (when most thyroid hormone-dependent brain development is complete) is characterized predominantly by a deceleration in linear growth and skeletal maturation but there is no permanent effect on cognitive development. In general, infants with severe defects in thyroid gland development or inborn errors of thyroid hormonogenesis present in infancy whereas babies with less severe defects or acquired abnormalities, particularly autoimmune thyroid disease, present later in childhood and adolescence. In the newborn infant, thyroid function is influenced not only by the neonate ’ s own thyroid gland but by the transplacental passage from the mother of factors that affect the fetal thyroid gland.

In the last several decades, there have been exciting advances in our understanding of fetal and neonatal thyroid physiology, and screening for congenital hypothyroidism has enabled the virtual eradication of the devastating effects of mental retardation due to sporadic congenital hypothyroidism in most developed countries of the world. In addition, advances in molecular biology have led to new insights regarding the early events in thyroid gland embryogenesis and mechanisms of thyroid action in the brain. At the same time, the molecular basis for many of the inborn errors of thyroid hormonogenesis and thyroid hormone action is being unraveled. However, new questions and new challenges arise. In particular, the survival of increasingly small and premature fetuses has resulted in a growing number of neonates with abnormalities in thyroid function and a continuing controversy as to which of these infants require therapy. This chapter will focus on current concepts regarding the ontogenesis of thyroid function in the fetus and will review the major disorders of thyroid gland function in infants and children.

ONTOGENESIS OF THYROID FUNCTION IN THE FETUS AND INFANT

The ontogeny of mature thyroid function involves the organogenesis and maturation of the hypothalamus, pituitary, and thyroid glands as well as the maturation of thyroid hormone metabolism and thyroid hormone action. The placenta also plays a key role in the transfer of hormones and factors other than T4 that impact on thyroid function. In the first half of pregnancy, maternal T4 provides an important source of hormone for the developing fetus. Much of our knowledge derives from work in animal models, particularly sheep and rat. In interpreting these data, it is important to remember potential limitations in these models because of differences both in the structure of the placenta and timing of maturation. For example, the rat thyroid gland is much less mature at birth than its human counterpart and significant maturation of the thyroid gland and of the hypothalamic-pituitary-thyroid axis in this species occurs in the first 2 or 3 weeks after birth in the absence of placental or maternal influence, as compared with the third trimester in human infants.

Thyroid Gland Embryogenesis

Thyroid gland development is extensively reviewed in an earlier chapter and is shown diagrammatically in Figure 1. In brief, the thyroid gland is derived from the fusion of a medial outpouching from the floor of the primitive pharynx, the precursor of the thyroxine (T4)-producing follicular cells, and bilateral evaginations of the fourth pharyngeal pouch, which gives rise to the parafollicular, or calcitonin (C) secreting cells. Commitment towards a thyroid-specific phenotype as well as the growth and descent of the thyroid anlage into the neck results from the coordinate action of a number of transcription factors, including thyroid transcription factor 1 (TTF1, now called NKX2 (1), TTF2 (now called FOXE1) and PAX8 (1,2). Because these transcription factors are also expressed in a limited number of other cell types, it appears to be the specific combination of transcription factors and possibly non-DNA binding cofactors acting coordinately that determine the phenotype of the cell.

Other transcription factors and growth factors that play a role in early thyroid gland organogenesis include HHEX1, HOXA3 (3) and members of the fibroblast growth factor family, i.e., FGF10, but the initial inductive signal is unknown. A role of the neighboring heart primordium in the specification of the thyroid anlage has been postulated. Studies of cadherin expression suggest that the caudal translocation of the thyroid anlage may also arise indirectly, as a result of the growth and expansion of adjacent tissues, including the major blood vessels (4). In late organogenesis, the sonic hedgehog (SHH) gene and its downstream target TBX1 appear to play an important role in the symmetric bilobation of the thyroid (5); SHH also suppresses the ectopic expression of thyroid follicular cells (6).

During caudal migration the pharyngeal region of the thyroid anlage contracts to form a narrow stalk, known as the thyroglossal duct, which subsequently atrophies. Usually no lumen is left in the tract of its descent but, occasionally, an ectopic thyroid and/or persistent thyroglossal duct or cyst form if thyroid descent is abnormal.

Figure 15- 1Approximate timing of thyroid gland maturation in the human fetus.

In the human, embryogenesis is largely complete by 10 to 12 weeks gestation. At this stage, tiny follicle precursors can be seen, iodine binding can be identified and thyroglobulin (Tg) detected in follicular spaces (7,8) . Thyroid hormones are detectable in fetal serum by gestational age 11 to 12 weeks with both thyroxine (T4) and triiodothyronine (T3) being measurable. However, as discussed in further detail below, it is likely that a fraction of the hormones detectable at this early stage is contributed by the mother through transplacental transfer. Thyroid hormones continue to increase gradually over the entire period of gestation as does serum thyroxine-binding globulin (TBG) (9,10) . TBG is present at levels of 100 nmol/L (5 mg/L) at gestational age 12 weeks and progressively increases up to the time of birth, reaching concentrations of 500 nmol/L (25 mg/L). The serum TBG concentrations are higher in the infant then in adult humans as a consequence of placental estrogen effects on the fetal liver. In addition to the increase in total T4 there is also a progressive increase of the free T4 concentration indicating a maturation of the hypothalamic- pituitary- thyroid axis. The increased total T4 / thyrotropin (TSH) and free T4 /TSH ratios also indicate an increased ability of the thyroid gland to respond to TSH due to upregulation of the TSH receptor (11). Whereas the TBG and total T4 levels rise throughout gestation, the concentrations of free T4, and TSH rise until 31 to 34 weeks, declining thereafter to term (12).

Tg can be identified in the fetal thyroid as early as the 5th week, and is certainly present in follicular spaces by 10 to11 weeks, but maturation of Tg secretion takes much longer and it is not known when circulating Tg first appears in the fetal serum (not shown). By the time of gestational age 27 to 28 weeks, however, Tg levels average approximately 100 mg/L, much higher than in the adult and they remain approximately stable until the time of birth (13,14) . Iodide concentrating capacity can be detected in the thyroid of the 10 to 11 week fetus, but maturation of the Wolff-Chaikoff effect (reduction of iodide trapping in response to excess iodide) does not appear until 36 to 40 weeks gestation. Thus the premature fetus is more sensitive than the full term neonate to the thyroid-suppressive effects of iodine exposure.

THYROID FUNCTION IN THE NEONATE, THE INFANT, AND DURING CHILDHOOD

Premature Infants

Thyroid function in the premature infant reflects, in part, the relative immaturity of the hypothalamic-pituitary-thyroid axis that is found in comparable gestational age infants in utero. Following delivery, there is a surge in T4 and TSH analogous to that observed in term infants, but the magnitude of the increase is less in premature neonates (8). In infants <31 weeks, the circulating T4 concentration may not increase and may even fall in the first 1 to 2 weeks of life (37) (Figure 2). This decrease in the T4 concentration is particularly significant in very premature infants, in whom the serum T4 may occasionally be undetectable. In most cases, the total T4 is more affected than the free T4 (38), a consequence of abnormal protein binding and/or the decreased TBG in these babies with immature liver function.

Figure 15-2

Postnatal changes in of T4, free T4, TBG, T3, rT3 and TSH according to gestational age. Values determined in babies born at gestational age of 23-27, 28-30, 31-34 and 37 weeks or more are reported. Note the increase in T4, free T4 and TBG in the full term infant in the first week of life. T3 also rises strikingly, while rT3 and TSH decline. The increase in T4 and free T4 is blunted in infants

The causes of the decrease in T4 observed postnatally in premature infants are complex. In addition to the clearance of maternal T4 from the neonatal circulation, preterm babies have decreased thyroidal iodide stores (39) (a problem of particular significance in borderline iodine-deficient areas of the world), they are frequently sicker than their more mature counterparts, are less able to regulate iodide balance, and they may be treated by drugs that affect neonatal thyroid function (particularly dopamine and steroids). In addition, since the capacity of the immature thyroid to adapt to exogenous iodide is reduced, there is an increase in sensitivity to the thyroid-suppressive effects of excess iodide found in certain skin antiseptics and drugs to which these babies are frequently exposed (see below).

Despite the reduced total T4 observed in some preterm babies, the TSH concentration is not significantly elevated in most of these infants. In some babies, transient elevations in TSH are seen, the finding of a TSH concentration >40 mU/L being more frequent the greater the degree of prematurity. Frank et al found, for example, that the prevalence of a TSH concentration >40 mU/L in very low birth weight, (<1.5 kg), i.e., very premature, infants was 8-fold higher and in low birth weight, (1.5 kg-2.5 kg) neonates 2-fold higher than the prevalence in term babies (40). Whereas in some cases, an elevated TSH concentration may reflect true primary hypothyroidism, in other instances this increase in TSH may reflect the elevated TSH observed in adults who are recovering from severe illness. Such individuals may develop transient TSH elevations that are associated with still reduced serum T4 and T3 concentrations. These have been interpreted as reflecting a “ re-awakening ” of the illness-induced suppression of the hypothalamic pituitary axis. As the infant recovers from prematurity associated illnesses such as respiratory distress syndrome (RDS), a recovery of the illness-induced suppression of the hypothalamic- pituitary- thyroid axis would also occur.

Figure 15-3

Cord blood levels of T4, free T4, TBG, T3, reverse T3 and TSH in the human infant. Note the low T3 and high reverse T3 concentrations as well as the discrepancy between the total T4 and free T4 levels in very premature babies. (Redrawn from Williams et al (10). See text for details).

Somewhat surprisingly, given the relative immaturity of the thyroid gland, serum Tg concentrations are higher in the premature than in the full term infant (41), particularly in those who are sick with respiratory distress syndrome. In view of the attenuated postnatal TSH rise in the latter babies, it is likely that impaired clearance and/or degradation of this glycoprotein from the circulation rather than increased secretion plays an important role.

THYROID DISEASE IN INFANCY

Screening Strategies

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.

Figure 15-4

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.

CAUSES OF PERMANENT CONGENITAL HYPOTHYROIDISM

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).

CAUSES OF TRANSIENT NEONATAL HYPOTHYROIDISM

Transient neonatal hypothyroidism should be distinguished from a ‘false positive’ result in which the screening result is abnormal but the confirmatory serum sample is normal. Causes of transient abnormalities of thyroid function in the newborn period are listed in Table 2. While iodine deficiency, iodine excess, drugs and maternal TSH receptor blocking antibodies are the most common causes of transient hypothyroidism, in some cases the cause is unknown.

HYPERTHYROIDISM

Transient Neonatal Hyperthyroidism

Unlike congenital hypothyroidism which usually is permanent, neonatal hyperthyroidism almost always is transient and results from the transplacental passage of maternal TSH receptor antibodies. Hyperthyroidism develops only in babies born to mothers with the most potent stimulatory activity in serum (86,87,87a). This corresponds to 1-2% of mothers with Graves’ disease, or 1 in 50,000 newborns, an incidence that is approximately four times higher than is that for transient neonatal hypothyroidism due to maternal TSH receptor blocking antibodies (81a). Some mothers have mixtures of stimulating and blocking antibodies in their circulation, the relative proportion of which may change over time. Not surprisingly, the clinical picture in the fetus and neonate of these mothers is more complex and depends not only on the relative proportion of each activity in the maternal circulation at any one time but on the rate of their clearance from the neonatal circulation postpartum. Thus, one affected mother gave birth, in turn, to a normal infant, a baby with transient hyperthyroidism, and one with transient hypothyroidism (87b). In another neonate, the onset of hyperthyroidism did not become apparent until 1-2 months postpartum when the higher affinity blocking antibodies had been cleared from the neonatal circulation (87c). In the latter case, multiple TSH receptor stimulating and blocking antibodies were isolated from the maternal peripheral lymphocytes. Each monoclonal antibody recognized different antigenic determinants (“epitopes”) on the receptor and had different functional properties (87d).

Occasionally, neonatal hyperthyroidism may even occur in infants born to hypothyroid mothers. A prospective study showed that 40% of patients treated for Graves’ disease with radioactive iodine had TRAb detectable after 5 years (87e). In these situations, the maternal thyroid has been destroyed either by prior radioablation, surgery or by coincident destructive autoimmune processes so that potent thyroid stimulating antibodies, present in the maternal circulation, are silent in contrast to the neonate whose thyroid gland is normal (87d). Fetal/neonatal thyrotoxicosis can occur also in newborn from hypothyroid mothers with chronic lymphocytic thyroiditis (87f).

Clinical manifestations

Maternal TSH receptor antibody-mediated hyperthyroidism may present in utero. Fetal hyperthyroidism is suspected in the presence of fetal tachycardia (pulse greater than 160/min) especially if there is evidence of failure to thrive. Obstetric complications are common. Fetal goiter can by monitored by ultrasound. In the neonate infant most often the onset is during the first one-two weeks of life but can occur by 45 days. This is due both to the clearance of maternally-administered antithyroid drug (propylthiouracil, PTU, methimazole or carbimazole) from the infant ’s circulation and to the increased conversion of T4 to the more metabolically active T3 after birth. Rarely, as noted earlier, the onset of neonatal hyperthyroidism may be delayed until later if higher affinity blocking antibodies are also present. In the newborn infant, characteristic signs and symptoms include tachycardia, irritability, poor weight gain, and prominent eyes (Figure 5). Goiter, when present, may be related to maternal antithyroid drug treatment as well as to the neonatal Graves’ disease itself.

Figure 15.5. A

baby with neonatal hyperthyroidism secondary to maternal Graves ‘disease. Note the prominent eyes in the baby and mother in whom Graves’ disease developed after radioiodine therapy for Hodgkin’s disease. In contrast, the father was unaffected.

Rarely, infants with neonatal Graves’ disease present with thrombocytopenia, jaundice, hepatosplenomegaly, and hypoprothrombinemia, a picture that may be confused with congenital infections such as toxoplasmosis, rubella, or cytomegalovirus (87g). In addition, arrhythmias and cardiac failure may develop and may cause death, particularly if treatment is delayed or inadequate. In addition to a significant mortality rate that approximates 20% in some older series, untreated fetal and neonatal hyperthyroidism is associated with deleterious long-term consequences, including premature closure of the cranial sutures (cranial synostosis), failure to thrive, and developmental delay (87h). The half-life of TSH receptor antibodies is 1 to 2 weeks. The duration of neonatal hyperthyroidism, a function of antibody potency and the rate of their metabolic clearance, is usually 2 to 3 months but may be longer.

Laboratory Evaluation

TSH receptor antibodies (TRAb) are Immunoglobulin of G class and freely cross the placenta. Different type of TRAb can be found: TRAb that bind to the TSH receptor and stimulates the production of thyroid hormones, (TSH receptor stimulating antibodies, TSI), TRAb that bind to the TSH receptor, do not stimulate the production of thyroid hormones and can block the binding of TSH (TSH receptor blocking antibodies TBI) .TSH receptor neutral antibodies have also been identified which do not block TSH binding and are unable to stimulate cAMP production (88)..

The receptor binding assays usually used to measure TRAb are not able to distinguish between TSH-receptor stimulating and blocking or neutral antibodies. Bioassays that measure TSI activity based on cAMP on cultured cells can be useful if TRAb are not detectable (88a,88b). The recent guidelines for management of hyperthyroidism (88c) and the updated guidelines for the management of thyroid disease during pregnancy released from the American Thyroid Association ATA (33b) both suggest to anticipate the determination of TRAb in pregnant women with Graves’ disease at 18-22 weeks instead of 20-24 weeks of gestation because a severe case of fetal Graves’ disease has occurred at 18 weeks of pregnancy (88d).

Because of the importance of early diagnosis and treatment, infants at risk for neonatal hyperthyroidism should undergo both clinical and biochemical assessment as soon as possible.

All neonates born from a woman with TRAb positivity in pregnancy should undergo determination of TRAb from cord blood at delivery. If TRAb are negative, the risk to neonatal hyperthyroidism is negligible (Sensitivity is around 100%). FT3, FT4 and TSH determination from cord blood did not predict neonatal hyperthyroidism. Determination of FT4 increase on day 3 to 5 seems to better indicate the onset of hyperthyroidism (88e) Situations that should prompt consideration of neonatal hyperthyroidism are listed in Table 4. A high index of suspicion is necessary in babies of women who have had thyroid ablation because in them a high titer of TSH receptor antibodies would not be evident clinically. Similarly, women with persistently elevated TSH receptor antibodies and with a high requirement for antithyroid medication are at an increased risk of having an affected child. The diagnosis of hyperthyroidism is confirmed by the demonstration of an increased concentration of circulating T4 (and free T4, and T3, if possible) accompanied by a suppressed TSH level in neonatal or fetal blood. The latter can be obtained by cordocentesis if someone experienced in this technique is available. Results should be compared with normal values during gestation. Fetal ultrasonography may be helpful in detecting the presence of a fetal goiter and in monitoring fetal growth. Demonstration in the baby or mother of a high titer of TSH receptor antibodies will confirm the etiology of the hyperthyroidism and, in babies whose thyroid function testing is normal initially, indicate the degree to which the baby is at risk.

TABLE 4SITUATIONS THAT SHOULD PROMPT CONSIDERATION OF NEONATAL HYPERTHYROIDISM

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· Unexplained tachycardia, goiter or stare

· Unexplained petechiae, hyperbilirubinemia, or hepatosplenomegaly

· History of persistently high TSH receptor antibody titer in mother during pregnancy

· History of persistently high requirement for antithyroid medication in mother during pregnancy

· History of thyroid ablation for hyperthyroidism in mother

· History of previously affected sibling

As noted in the case of TSH receptor blocking antibody-induced congenital hypothyroidism, the receptor binding assays are a cost-effective, rapid and technically feasible approach. In general, babies likely to become hyperthyroid have the highest TSH receptor antibody titer whereas if TSH receptor antibodies are not detectable, the baby is most unlikely to become hyperthyroid (87g, 89,89a). In the latter case, it can be anticipated that the baby will be euthyroid, have transient hypothalamic-pituitary suppression or have a transiently elevated TSH, depending on the relative contribution of maternal hyperthyroidism versus the effects of maternal antithyroid medication, respectively (89). Close follow up of all babies with abnormal thyroid function tests or detectable TSH receptor antibodies is mandatory.

Therapy

In the fetus, treatment is accomplished by maternal administration of antithyroid medication. Until recently PTU was the preferred drug for pregnant women in North America, but current recommendations suggest the use of MMI rather than PTU after the first trimester because of concerns about potential PTU-induced hepatotoxicity (123) (discussed under Graves’ disease, below). The goals of therapy are to utilize the minimal dosage necessary to normalize the fetal heart rate and render the mother euthyroid or slightly hyperthyroid.

In the neonate MMI (0.5 to 1.0 mg/kg/day) has been used initially in 3 divided doses. If the hyperthyroidism is severe, a strong iodine solution (Lugol’ s solution or SSKI, 1 drop every 8 hours) is added to block the release of thyroid hormone immediately. Often the effect of MMI is not as delayed in infants as it is in older children or adults, a consequence of decreased intrathyroidal thyroid hormone storage. Therapy with both antithyroid drug and iodine is adjusted subsequently, depending on the response. Propranolol (2 mg/kg/day in 2 or 3 divided doses) is added if sympathetic overstimulation is severe, particularly in the presence of pronounced tachycardia. If cardiac failure develops, treatment with digoxin should be initiated, and propranolol should be discontinued. Rarely, prednisone (2 mg/kg/day) is added for immediate inhibition of thyroid hormone secretion. Measurement of TSH receptor antibodies in treated babies may be helpful in predicting when antithyroid medication can be safely discontinued (87). Lactating mothers on antithyroid medication can continue nursing as long as the dosage of PTU or MMI does not exceed 400 mg or 40 mg, respectively. The milk/serum ratio of PTU is 1/10 that of MMI, a consequence of pH differences and increased protein binding, so one might anticipate less transmission to the infant, but concerns about potential PTU toxicity need to be considered. At higher dosages of antithyroid medication, close supervision of the infant is advisable.

A review about management of neonates born to mothers with Graves’ disease has been recently published (89b).

THYROID DISEASE IN CHILDHOOD AND ADOLESCENCE

Chronic Lymphocytic Thyroiditis

Autoimmune thyroid diseases (AITD) are defined by the lymphocytic infiltration of the thyroid (91). Usually antibodies against thyroid antigens as thyroperoxidase (TPOAb), thyroglobulin (TgAb), and anti-TSH receptor (TRAb) are detectable in serum. Thyroid antibodies in serum correlate with the presence of lymphocytic infiltrate in the thyroid gland. The clinical spectrum of AITD ranges from hypothyroidism to hyperthyroidism and include chronic lymphocytic thyroiditis (CLT) and Graves’ disease. CLT is the most common cause of hypothyroidism in children and adolescents (91,91a).

Graves’ disease and CLT are closely associated and in fact overlapping syndromes .Patients can move from one to the other category, depending upon the stage of their illness. For example, an individual might first be observed with thyroid enlargement and positive antibody tests for anti-thyroglobulin or anti-TPO antibodies, and thus qualify as having CLT. At a later stage, this individual might become hyperthyroid (Hashitoxicosis) and fit in the category of Graves’ disease. Or, the patient with hyperthyroidism might have progressive destruction of the thyroid, or develops blocking antibodies, and become hypothyroid or ultimately develop myxedema.

Incidence

The prevalence of CLT in children and adolescents was reported to be 1.2% by Rallison in 1975 (91b). In this 6 year-survey study 5179 school children were examined in Arizona. Goiter was evaluated by palpation (91b). More recently, a study from Sardinia in 8040 children and adolescents aged 6-15 years reported TPOAb detectable in 2.9% (91c). Similar results were found in Berlin with a prevalence of TPOAb of 3.4% (mean age 11 years) (91d) and in Greece after correction of iodine deficiency. In this study examining 440 children and adolescents aged 5-18 years a prevalence of TPOAb and TgAb was reported to be 4.6% and 4.3% respectively. The prevalence of CLT, confirmed by ultrasound was 2.5% (91e).

In childhood the most common age at presentation is adolescence, but the disease may occur at any age, even infancy. CLT in infancy is rare, but can cause in a short time severe hypothyroidism and permanent damage to CNS if not recognized and treated (85). The female/male ratio in AITD is up to 6:1, but In prepubertal age the female/male ratio is lower than reported in adolescents and adults.

Etiology and Pathogenesis

CLT is thought to be caused by a combination of genetic susceptibility and environmental factors. Both thyroid-specific genes and genes involved in immune recognition and/or response have been identified (91f, 91g). (See chapter Autoimmunity, by A Weetman for an exhaustive information). Some genes are common to both disorders and some tend to predominate only in Graves’ disease. AITD has a striking predilection for females, but in prepubertal age the female/male ratio is lower. A family history of autoimmune thyroid disease (both chronic lymphocytic thyroiditis and Graves’ disease) is found in 30% to 40% of patients. A study about familial clustering of juvenile AITD found thyroid antibodies detectable in 56% of mothers and 25% of fathers. Interestingly, HLA DQ alleles and antibody status in fathers influenced the susceptibility to AITD in children (91h). Siblings recurrence in childhood is 20-30% (91i). AITD are often associated with other autoimmune disorders. The plethora of associations and their familial occurrence indicates that a defect in the immune system may be more likely than primary defects in each organ, as these diseases often share similar genetic associations, including HLA, CTLA-4, PTPN22 and CD25 gene polymorphisms. It is also clear however that there is a difference in the kind of clustering of other autoimmune disease in CLT and Graves’ disease, presumably related to differences between these two types of thyroid disease in genetic predisposition (91j,91k). There is also an increased incidence of CLT in patients with certain chromosomal abnormalities as Down syndrome (91l) Turner syndrome (91m), Klinefelter syndrome (91n) as well as in patients with Noonan syndrome (91o).

Environmental factors as infection, environmental toxins, substances as iodine, selenium, stress, smoking, estrogens, drugs (amiodarone, interferon alfa, lithium) have been suggested as precipitating factors for CLT (91p). The precise environmental trigger has not been yet established. An epigenetic mechanism may be implicated (91q).

Clinical Manifestations

Both goitrous (Hashimoto’s thyroiditis) and nongoitrous (atrophic thyroiditis, also called primary myxedema) as variants of chronic lymphocytic thyroiditis have been distinguished. The term “Hashimoto’s thyroiditis” is often used as a synonymous of CLT, not necessary linked to the presence of goiter (91, 91a). Goiter, present in approximately two-thirds of children with CLT is caused by lymphocytic infiltration that may be extensive, with lymphoid germinal centers, TSH stimulation, or production of antibodies that stimulate thyroid growth (92). Progressive thyroid cell damage, with cell mediated cytotoxicity and follicular cell apoptosis, can change the apparent clinical picture from goitrous hypothyroidism to that of “atrophic” thyroiditis. Atrophic thyroiditis, or primary hypothyroidism/mixedema, is considered to be the end stage of CLT (91).

Children with chronic lymphocytic thyroiditis may be euthyroid, or may have subclinical or overt hypothyroidism. Occasionally, children may experience an initial thyrotoxic phase due to the discharge of preformed T4 and T3 from the damaged gland. Alternatively, as indicated above, thyrotoxicosis may be due to concomitant thyroid stimulation by TSH receptor stimulatory antibodies (Hashitoxicosis).

The onset of hypothyroidism in childhood is insidious. Affected children often are recognized either because of the detection of a goiter on routine examination or because of a poor interval growth rate present for several years prior to diagnosis (92a). Because the deceleration in linear growth tends to be more affected than weight gain, these children can be relatively overweight for their height, although they rarely are significantly obese (Figure 6). If the hypothyroidism is severe and longstanding, immature facies with an underdeveloped nasal bridge and immature body proportions (increased upper-lower body ratio) may be noted. Dental and skeletal maturation are delayed, the latter often significantly. Patients with central hypothyroidism tend to be even less symptomatic than are those with primary hypothyroidism.

Figure 15-6

Sequential changes in physical appearance in a young girl who presented at 15 years of age with amenorrhea and hyperprolactinemia secondary to severe hypothyroidism. Note her poor linear growth since at least 11 years of age.

The classical clinical manifestations of hypothyroidism can be elicited on careful evaluation, though they often are not the presenting complaints. These include sluggishness, lethargy, cold intolerance, constipation, dry skin or hair texture, and periorbital edema. Bradycardia and delayed deep tendon reflexes can be present. In severe, long-standing hypothyroid children pericardial and pleural effusions may occur. School performance is not usually affected, in contrast to the severe irreversible neuro-intellectual sequelae that occur frequently in inadequately treated babies with congenital hypothyroidism. Causes of hypothyroidism associated with a goiter (CLT, inborn errors of thyroid hormonogenesis, thyroid hormone resistance) should be distinguished from non goitrous causes (primary myxedema, thyroid dysgenesis, central hypothyroidism). The typical thyroid gland in a longstanding chronic lymphocytic thyroiditis is diffusely enlarged and has a rubbery consistency. Although the surface is classically described as ’pebbly’ or bosselated, occasionally asymmetric enlargement occurs and must be distinguished from thyroid neoplasia. Alternatively, the thyroid may be normal in size and consistency or not palpable at all. A palpable lymph node superior to the isthmus (“Delphian node”) is often found and may be confused with a thyroid nodule. The thyroid gland, in thyroid hormone synthetic defects, on the other hand, tends to be softer and diffusely enlarged.

In patients with severe hypothyroidism of longstanding duration, the sella turcica may be enlarged due to thyrotrope hyperplasia. There is an increased incidence of slipped femoral capital epiphyses in hypothyroid children. The combination of severe hypothyroidism and muscular hypertrophy which gives the child a “Herculean” appearance is known as the Kocher-Debre-Semelaigne syndrome (92b).

Puberty tends to be delayed in hypothyroid children in proportion to the retardation in the bone age, although in longstanding severe hypothyroidism, sexual precocity has been described. Females with sexual precocity have menstruation, and breast development but relatively little sexual hair. Multicystic ovaries, the etiology of which is unknown, may be demonstrated on ultrasonography. In other cases, galactorrhea or severe menses have been the presenting features. In boys, testicular enlargement may be found (92c). An elevated serum prolactin, the latter possibly due to raised TRH which is known to stimulate prolactin as well as TSH, has been described in some cases, but gonadotropin levels are not consistently elevated. It has been hypothesized that this syndrome of pseudopuberty in hypothyroid patients is due to cross- interaction of the extremely elevated serum TSH with the FSH receptor (92d). Consistent with the latter hypothesis, there is little increase in serum testosterone as might be expected if the FSH, but not luteinizing hormone (LH) receptor is involved and serum gonadotropins are frequently not increased.

Long term follow up studies of children with chronic lymphocytic thyroiditis have suggested that while most children who are hypothyroid initially remain hypothyroid, spontaneous recovery of thyroid function may occur, particularly in those with initial compensated hypothyroidism (93,93a, 93b). A recent five-years prospective study in children and adolescents affected with CLT showed that thyroid dysfunction increased from 27.3% to 47.4% (93c). Therefore, close follow up is necessary.

Although chronic inflammation, leading to neoplastic transformation, is a well-established clinical phenomenon, if CLT can increase the risk for thyroid nodules and thyroid cancer remains controversial. In the past autoimmune thyroiditis has been thought to be protective from thyroid cancer, but several studies both in adults and in children suggested the opposite. Thyroid nodules in healthy children in iodine replete regions are detected in up to 1.6% (94). High prevalence of thyroid nodules, ranging from 13% to 31%, has been reported in children and adolescents with CLT. In a multicentric pediatric retrospective study from Italy, nodules were found in 115/365 patients with CLT (31.5%), and papillary thyroid carcinoma in 11/115 (9.5%) (94a). In a recent study from Turkey, thyroid nodules were detected in 39/300 (13%) of cases of pediatric CLT and papillary thyroid carcinoma was diagnosed in 2 of the 12 cases that underwent FNAB (94b). Recently, in. a retrospective study from United States examining ultrasound characteristic of the thyroid in 154 children and adolescents with goiter, nodules were reported in 20/154 (13%) and PTC in 4/154 (2.5% ) of children. In this study, the same prevalence of nodules (17%) was found in TPOAb positive and TPOAb negative children. Interestingly, one case of PTC was first classified at ultrasound as pseudonodule. Only 15 % of nodules and none of the papillary thyroid carcinoma in these series (PTC) were palpable, although PTC has a diameter ranging from 1.2 to 2.6 cm (94c). A rare variant of PTC, the diffuse sclerosing variant, has also been reported in children with CLT(94d).

THYROTOXICOSIS AND HYPERTHYROIDISM

Thyrotoxicosis is defined as the clinical syndrome of hypermetabolism resulting from increased free thyroxine (T4) and/or free triiodothyronine (T3) serum levels (107)). The term thyrotoxicosis is not synonymous with hyperthyroidism, the elevation in thyroid hormone levels caused by an increase in their biosynthesis and secretion by the thyroid gland (Table 6). For example, thyrotoxicosis can result from the destruction of thyroid follicles and thyrocytes in the various forms of thyroiditis, or it can be caused by an excessive intake of exogenous thyroid hormone. It should also be noted that the elevation of free thyroid hormone levels does not always result in thyrotoxicosis in all tissues. In the syndrome of Resistance to Thyroid Hormone (RTH), dominant negative mutations in the thyroid hormone receptor β ( TR β) result in decreased thyroid hormone action in tissues where TRβ is the predominant receptor, for example in the liver and the pituitary, whereas other tissues such as the heart, which express mainly TR α, show signs of increased thyroid hormone action. The determination of the etiology of thyrotoxicosis is of importance in order to establish a rational therapy.

THYROID NODULES AND CANCER

For exhaustive information see also chapters “Thyroid nodules” and “Thyroid cancer “ By F. Pacini and Leslie de Groot in this book.

Recently, the first guidelines specifically elaborated for children with thyroid nodules and differentiated thyroid cancer have been published (114b). Hereditary syndromes (i.e. PTEN related sydromes, DICER1 syndrome, Carney complex, Familial adenomatous polyposis) associated with thyroid cancer in childhood are also been detailed (114b). Medullary thyroid carcinoma guidelines have also been revised, including genetic counseling and modified risk class for children with hereditary MTC (115a).

Thyroid nodules are rare in the first 2 decades of life, but when found, they are more likely to be carcinomatous than are similar masses in adults (115b). Follicular adenomas and colloid cysts account for the majority of benign nodules. Other causes of nodular enlargement include chronic lymphocytic thyroiditis and embryological defects, such as intrathyroidal thyroglossal duct cysts or unilateral thyroid agenesis. Like in adults, the most common form of thyroid cancer in childhood and adolescence is papillary thyroid carcinoma, but other histological types found in the adult may also occur (115c).

A high index of suspicion is necessary if the nodule is painless, of firm or hard consistency, if it is fixed to surrounding tissues or if there is a family history of thyroid cancer. Other worrisome findings include a history of rapid increase in size, associated cervical adenopathy, hoarseness or dysphagia. Even the findings of a cystic component or a functioning nodule, commonly used as favorable signs in adult patients, do not exclude the possibility of neoplasia (115c). Occasionally, thyroid cancer presents in childhood as unexplained cervical adenopathy, or neoplasia is found in patients who also have chronic lymphocytic thyroiditis (115c). The possibility of a rare medullary thyroid carcinoma should be considered if there is a family history of thyroid cancer or pheochromocytoma or if the child has multiple mucosal neuromas and a marfanoid habitus, findings suggestive of multiple endocrine neoplasia (MEN) types 2A and/or 2B (115d).

Children exposed previously to thyroid irradiation comprise a high-risk group. The increased risk of thyroid cancer in adults exposed during childhood to low levels of thyroid irradiation for benign conditions of the head and neck is well known (115e). The increased incidence of both benign and carcinomatous nodules in patients with Hodgkin disease who had received radiotherapy to the neck during childhood is also being documented increasingly (115f, 115g). Thyroid cancer is now known to be the most common second malignancy in childhood survivors of Hodgkin’s and is also seen with increased frequency in leukemia survivors (115h). Similarly, children exposed to high levels of radioactive iodine in the first decade of life or in utero, a consequence of the Chernobyl disaster, are at a markedly increased risk of developing papillary thyroid cancer (113). The risk of thyroid cancer is related to the dose of external irradiation and, unlike the 19 year average latency after low dose irradiation, the average latent period in survivors of Hodgkin disease appears to be only 9 years (115g). In Chernobyl victims, the latency was only 4 years (113). As compared with adults, there appears to be a higher prevalence of gene rearrangements in children with differentiated thyroid cancer, the clinical significance of which is unclear (115h).

Initial investigation of a thyroid nodule includes evaluation of thyroid function and TPO and Tg antibodies. A suppressed serum TSH concentration accompanied by an elevation in the circulating T4 and/or T3 suggests the possibility of a functioning nodule, which can be confirmed with a radionuclide scan. The finding of positive antibodies, on the other hand, usually indicates the presence of underlying chronic lymphocytic thyroiditis, but in some cases, positive antibodies may simply constitute evidence of an immune response to the presence of neoplastic cells. Ultrasonography provides information about whether the nodule is solid or cystic, and whether it is single or multifocal. Fine-needle aspiration biopsy, popular in the investigation of thyroid carcinoma in adults, is gaining increasing acceptance and is now considered to be the procedure of choice in the evaluation of nodules >0.5 cm (115k).

There is an increased incidence of both cervical node involvement and of pulmonary metastases at the time of diagnosis in children with thyroid carcinoma (115c). Nonetheless, the long term cancer specific mortality rate is no greater in children than in adults <40 years of age (115i). Guidelines specifically elaborated for management of children with thyroid nodules differentiated thyroid cancer have been published (114b). Excision of the tumor or lobe is the appropriate treatment for benign tumors and cysts, whereas total thyroidectomy with preservation of the parathyroid glands and recurrent laryngeal nerves is the initial therapy for malignant thyroid tumors. The latter procedure is followed by radioablation if there is evidence of residual gland or tumor after surgery. The issue of prophylactic lymph node dissection is controversial (115h). After radioiodine therapy, the dose of thyroxine is adjusted to keep the serum TSH concentration suppressed (between 0.05 mU/L and 0.1 mU/L in a sensitive assay). Measurement of serum Tg, a thyroid follicular cell-specific protein, is used to detect evidence of metastatic disease in differentiated forms of thyroid cancer, such as papillary or follicular carcinoma. This is best performed after a period (usually 6 weeks) of thyroxine withdrawal or after the exogenous administration of recombinant TSH (115). Measurement of circulating calcitonin is used as a tumor marker for medullary thyroid cancer (MTC), a C-cell derived malignancy (115m). Mutations of the RET protooncogene, detectable in nearly all familial forms of MTC, is of value in screening family members (115e, 115m). In families affected with multiple endocrine neoplasia type 2, screening of children as young as 5 years followed by total thyroidectomy has been successful in curing patients with microscopic MTC, an otherwise highly malignant neoplasm with a poor prognosis (115e). See Medullary Thyroid Carcinoma guidelines for updated genetic counseling and modified risk class for children with hereditary MTC (115a).

Optimal monitoring of patients with a history of thyroid irradiation during childhood remains controversial. Because of the insensitivity of clinical palpation, regular assessment of thyroid function (TSH and, as necessary free T4) as well as ultrasound examinations should be performed. There is evidence that thyroid suppression is associated with a reduction in the development of new nodules after partial surgical resection of an irradiated thyroid gland (115q) but whether it plays any role if the TSH is not elevated or in preventing neoplasia is unknown. Recently, a study that followed a cohort of 4338 5- years survivors of pediatric solid cancer suggested that chemotherapy (nitrosureas), splenectomy, and radiation dose to pituitary gland also play a role in predicting thyroid cancer risk (115r).

A retrospective study on the effects of total body irradiation (TBI) preceding hemopoietic cell transplation in childhood suggested short term and life-long monitoring for thyroid nodules and thyroid cancer in these patients (115s). Although it was a small size, retrospective study they found the time from TBI to thyroid carcinoma detection ranged from 2.2 years to 15.3 years. Follow up programs are advised for long term survivors of childhood cancer.

REFERENCES

1. Missero C, Cobellis G, De Felice M, Di Lauro R. Molecular events involved in differentiation of thyroid follicular cells. Mol Cell Endocrinol. 1998;140:37-43.
2. De Felice M, Di Lauro R. Thyroid development and its disorders: genetics and molecular mechanisms. Endocr Rev. 2004;25:722-46.
3. Manley NR, Capecchi MR. The role of Hoxa-3 in mouse thymus and thyroid development. Development. 1995;121;1989-2003.
4. Fagman H, Grande M, Edsbagge J, Semb H, Nilsson M. Expression of classical cadherins in thyroid development: maintenance of an epithelial phenotype throughout organogenesis. Endocrinology. 2003;144:3618-24.
5. Fagman H, Liao J, Westerlund J, Andersson L, Morrow BE, Nilsson M. The 22q11 deletion syndrome candidate gene Tbx1 determines thyroid size and positioning. Hum Mol Genet. 2007;16:276-85.
6. Fagman H, Grande M, Gritli-Linde A, Nilsson M. Genetic deletion of sonic hedgehog causes hemiagenesis and ectopic development of the thyroid in mouse. Am J Pathol. 2004;164:1865-72.
7. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N Engl J Med. 1994;331:1072-8.
8. Fisher DA, Klein AH. Thyroid development and disorders of thyroid function in the newborn. N Engl J Med. 1981;304:702-12.
9. Thorpe-Beeston JG, Nicolaides KH, McGregor AM. Fetal thyroid function. Thyroid.1992;2:207-17.
10. Williams FL, Simpson J, Delahunty C, et al. Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. J Clin Endocrinol Metab. 2004;89:5314-20.
11. Brown RS, Shalhoub V, Coulter S, et al. Developmental regulation of thyrotropin receptor gene expression in the fetal and neonatal rat thyroid: relation to thyroid morphology and to thyroid-specific gene expression. Endocrinology. 2000;141:340-5.
12. Hume R, Simpson J, Delahunty C, et al. Human fetal and cord serum thyroid hormones: developmental trends and interrelationships. J Clin Endocrinol Metab. 2004;89:4097-103.
13. De Nayer P, Cornette C, Vanderschueren M, et al. Serum thyroglobulin levels in preterm neonates. Clin Endocrinol. 1984;21:149-53.
14. Sobrero G, Munoz L, Bazzara L, et al. Thyroglobulin reference values in a pediatric infant population. Thyroid. 2007;17:1049-54.
15. Roti E, Gnudi A, Braverman LE. The placental transport, synthesis and metabolism of hormones and drugs which affect thyroid function. Endocr Rev.1983;4:131-49.
16. Kester MH, Kaptein E, Van Dijk CH, et al. Characterization of iodothyronine sulfatase activities in human and rat liver and placenta. Endocrinology. 2002;143:814-9.
17. Van der Geyten S, Segers I, Gereben B, et al. Transcriptional regulation of iodothyronine deiodinases during embryonic development. Mol Cell Endocrinol. 2001;183:1-9.
18. Ruiz de Ona C, Obregon MJ, Escobar del Rey F, Morreale de Escobar G. Developmental changes in rat brain 5′-deiodinase and thyroid hormones during the fetal period: the effects of fetal hypothyroidism and maternal thyroid hormones. Pediatr Res. 1988;24:588-94.
19. Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab. 2000;85:3975-87.
20. Ferreiro B, Bernal J, Goodyer CG, Branchard CL. Estimation of nuclear thyroid hormone receptor saturation in human fetal brain and lung during early gestation. J Clin Endocrinol Metab. 1988;67:853-6.

20a. Chan SY, Vasilopoulou E, Kilby MD. The role of the placenta in thyroid hormone delivery to the fetus. Nat Clin Pract Endocrinol Metab. 2009; 5:45-54.

20b. Patel J.Li H, Mortimer RH, Richard K. Delivery of maternal thyroid hormones to the fetus. Trends Endocrinol Metab. 2011;22:164-70.

20c. Burns R, O’Herlihy C, Smyth PP. The Placenta as a Compensatory Iodine Storage Organ. Thyroid. 2011; 21: 541-46.

20d. Burns R, O’Herlihy C, Smyth PP. Regulation of iodide uptake in placental primary cultures. Eur Thyroid J. 2013;2:243-51.

20e. Li H, Patel J, Mortimer RH, Richard K. Ontogenic changes in human placental sodium iodide symporter expression. Placenta. 2012;33:946-8.

21.

Vulsma T, Gons MH, de Vijlder JJ. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med. 1989;321:13-6.

22.

Calvo RM, Jauniaux E, Gulbis B, et al. Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development. J Clin Endocrinol Metab. 2002;87:1768-77.

22a. Contempre B, Jauniaux E, Calvo R, Jurkovic D, Campbell S, de Escobar GM. Detection of thyroid hormones in human embryonic cavities during the first trimester of pregnancy. J Clin Endocrinol Metab.1993; 77:1719-22.

22b. Bernal J. Thyroid hormone receptors in brain development and function. Nat Clin Practice. 2007; 3:249-259.

22c. Rovet JF. The role of thyroid hormones for brain development and cognitive function. Endocr Dev. 2014;26:26-43.

22d. Morreale de Escobar G, Obregon MJ, Escobar del Rey F: Maternal thyroid hormones early in pregnancy and fetal brain development. In: Best Practice & Research in Clinical Endocrinology and Metabolism: The Thyroid and Pregnancy. Editor: Glinoer D 2004; 18:225.

22e. Williams GR. Neurodevelopmental and neurophysiological actions of thyroid hormone. Neuroendocrinol. 2008;20:784-94.

22f. Schroeder AC, Privalsky ML. Thyroid hormones, T3 and T4, in the brain. Front Endocrinol. 2014;5:40. doi: 10.3389/fendo.2014.00040. eCollection 2014.

22g. Bernal J, Guadaño-Ferraz A, Morte B. Thyroid hormone transporters-functions and clinical implications. Nat Rev Endocrinol. 2015;11:406-17.

23.

Meinhold H, Dudenhausen JW, Wenzel KW, Saling E. Amniotic fluid concentrations of 3,3′,5′-tri-iodothyronine (reverse T3), 3,3′-di-iodothyronine, 3,5,3′-tri-iodothyronine (T3) and thyroxine (T4) in normal and complicated pregnancy. Clin Endocrinol.1979;10:355-65.

23a. Seror R, Amand G, Guibourdenche J, Ceccaldi PF, Luton D, Anti-TPO antibodies diffusion through the placental barrier during pregnancy. PloS One. 2014, 9:e84647.

23b. Zimmermann MB. The effects of iodine deficiency in pregnancy and infancy. Paediatr Perinat Epidemiol. 2012; 26 (Supp1):108-117.

24.

Boyages SC. Clinical review 49: Iodine deficiency disorders. J Clin Endocrinol Metab. 1993;77:587-91.

25.

Rovet J, Walker W, Bliss B, Buchanan L, Ehrlich R. Long-term sequelae of hearing impairment in congenital hypothyroidism. J Pediatr. 1996;128:776-83.

26.

de Zegher F, Pernasetti F, Vanhole C, Devlieger H, Van den Berghe G, Martial JA. The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency. J Clin Endocrinol Metab. 1995;80:3127-30.

27.

Matsuura N, Konishi J. Transient hypothyroidism in infants born to mothers with chronic thyroiditis–a nationwide study of twenty-three cases. The Transient Hypothyroidism Study Group. Endocrinol Jpn. 1990;37:369-79.

27a. Hallowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braveman LE. Serum T4 and thyroid antibodies in the United States population (1988-1994): National Health and Nutrition Examination Survay (NHANES III). J Clin Endocrinol Metab. 2002; 489-499.

28.

Man EB, Jones WS, Holden RH, Mellits ED. Thyroid function in human pregnancy. 8. Retardation of progeny aged 7 years; relationships to maternal age and maternal thyroid function. Am J Obstet Gynecol. 1971;111:905-16.

29.

Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med.1999;341:549-55.

29a. Smit BJ, Kok JH, Vulsma T, Briët JM, Boer K, Wiersinga WM. Neurologic development of the newborn and young child in relation to maternal thyroid function. Acta Paediatr. 2000;89:291-5.

29b. Li Y, Shan Z, Teng W, Yu X, Li Y, Fan C, Teng X, Guo R, Wang H, Li J, Chen Y, Wang W, Chawinga M, Zhang L, Yang L, Zhao Y, Hua T. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25-30 months. Clin Endocrinol. 2010;72:825-9.

30.

Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, Vulsma T, Wiersinga WM, Drexhage HA, Vader HL. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol. 1999;50:149-55.

30a. Pop VJ, Brouwers EP, Vader H, Vulsma T, van Baar AL, de Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol. 2003;59:282-8.

30b. Henrichs J, Bongers-Schokking JJ, Schenk JJ, Ghassabian A, Schmidt HG, Visser TJ, Hooijkaas H, de Muinck Keizer-Schrama SM, Hofman A, Jaddoe VV, Visser W, Steegers EA, Verhulst FC, de Rijke YB, Tiemeier H. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab. 2010;95:4227-34.

30c. Suárez-Rodríguez M, Azcona-San Julián C, Alzina de Aguilar V. Hypothyroxinemia during pregnancy: the effect on neurodevelopment in the child. Int J Dev Neurosci. 2012;30:435-8.

30d. Finken MJ, van Eijsden M, Loomans EM, Vrijkotte TG, Rotteveel J. Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring. J Clin Endocrinol Metab. 2013;98:1417-26.

30e. Julvez J, Alvarez-Pedrerol M, Rebagliato M, Murcia M, Forns J, Garcia-Esteban R, Lertxundi N, Espada M, Tardón A, Riaño Galán I, Sunyer J. Thyroxine levels during pregnancy in healthy women and early child neurodevelopment. Epidemiology. 2013;24:150-7.

30f. Vermiglio F, Lo Presti VP, Moleti M, Sidoti M, Tortorella G,Scaffidi G, Castagna MG, Mattina F, Violi MA, Crisà A, Artemisia A, Trimarchi F. Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency:a possible novel iodine deficiency disorder in developed countries. J Clin Endocrinol Metab. 2004;89:6054-60.

30g. Modesto T, Tiemeier H, Peeters RP, Jaddoe VW, HofmanA, Verhulst FC, Ghassabian A. Maternal Mild Thyroid Hormone Insufficiency in Early Pregnancy and Attention-Deficit/Hyperactivity Disorder Symptoms in Children. JAMA Pediatr. 2015;169:838-45.

30h. Román GC, Ghassabian A, Bongers-Schokking JJ, Jaddoe VW,Hofman A, de Rijke YB, Verhulst FC, Tiemeier H. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol. 2013;74:733-42.

30k. Gyllenberg D, Sourander A, Surcel HM, Hinkka-Yli-SalomäkiS, McKeague IW, Brown AS. Hypothyroxinemia During Gestation and Offspring Schizophrenia in a National Birth Cohort. Biol Psychiatry. 2015 19. pii: S0006-3223(15)00520-X.

30i. Ghassabian A, Bongers-Schokking JJ, de Rijke YB, van Mil N, Jaddoe VW, de Muinck Keizer-Schrama SM, Hooijkaas H, Hofman A, Visser W, Roman GC, Visser TJ, Verhulst FC, Tiemeier H. Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: the Generation R Study.Thyroid. 2012; 22:178-86.

30j. Pop VJ, de Vries E, van Baar AL, Waelkens JJ, de Rooy HA, Horsten M, Donkers MM, Komproe IH, van Son MM,Vader HL. Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? J Clin Endocrinol Metab. 1995;80:3561-6.

30l. Wasserman EE, Pillion JP, Duggan A, Nelson K, Rohde C, Seaberg EC, Talor MV, Yolken RH, Rose NR. Childhood IQ, hearing loss, and maternal thyroid autoimmunity in the Baltimore Collaborative Perinatal Project. Pediatr Res. 2012;72:525-30.

30m. Kooistra L, Crawford S, van Baar AL, Brouwers EP, Pop VJ. Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics. 2006;117:161-7.

30n. Mirabella G, Westall CA, Asztalos E, Perlman K, Koren G, Rovet J. Development of contrast sensitivity in infants with prenatal and neonatal thyroid hormone insufficiencies. Pediatr Res. 2005;57:902-7.

30o. Ghassabian A, Bongers-Schokking JJ, Henrichs J, Jaddoe VW, Visser TJ, Visser W, de Muinck Keizer-Schrama SM, Hooijkaas H, Steegers EA, Hofman A, Verhulst FC, van der Ende J, de Rijke YB, Tiemeier H. Maternal thyroid function during pregnancy and behavioral problems in the offspring: the generation R study. Pediatr Res. 2011;69:454-9.

31.

Momotani N, Iwama S, Momotani K. Neurodevelopment in children born to hypothyroid mothers restored to normal thyroxine (T₄) concentration by late pregnancy in Japan: no apparent influence of maternal T₄ deficiency. J Clin Endocrinol Metab. 2012;97:1104-8.

31a. Liu H, Momotani N, Noh JY, Ishikawa N, Takebe K, Ito K. Maternal hypothyroidism during early pregnancy and intellectual development of the progeny. Arch Intern Med. 1994;154:785-7.

31b. Downing S, Halpern L, Carswell J, Brown RS Severe maternal hypothyroidism corrected prior to the third trimester is associated with normal cognitive outcome in the offspring. Thyroid. 2012; 22:625-30.

32.

Lazarus JH, Bestwick JP, Channon S et al. Antenatal thyroid screening and childhood cognitive function. N Engl J Med. 2012; 366:493-501.

32a. Casey B. Effect of treatment of maternal subclinical hypothyroidism or hypothyroxinemia on IQ in offspring. American Journal of Obstetrics & Gynecology. Supplement to JANUARY 2016 Abstr 2 S2.

32b. Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T, Xu YH, Tao FB. Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. J Clin Endocrinol Metab. 2011;96:3234-41.

32c. Korevaar TI, Muetzel R, Medici M, Chaker L, Jaddoe VW, de Rijke YB, Steegers EA, Visser TJ, White T, Tiemeier H, Peeters RP. Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol. 2016; 4:35-43.

32d. Samadi A, Skocic J, Rovet JF. Children born to women treated for hypothyroidism during pregnancy show abnormal corpus callosum development.Thyroid. 2015; 25:494-502.

32e. Lischinsky JE, Skocic J, Clairman H, Rovet J. Preliminary Findings Show Maternal Hypothyroidism May Contribute to Abnormal Cortical Morphology in Offspring. Front Endocrino . 2016;25:7-16.

32f. Williams FL, Watson J, Ogston SA, Visser TJ, Hume R, Willatts P. Maternal and umbilical cord levels of T4, FT4, TSH, TPOAb, and TgAb in term infants and neurodevelopmental outcome at 5.5 years. J Clin Endocrinol Metab. 2013;98: 829-38.

33.

Klein RZ, Haddow JE, Faix JD, et al. Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol. 1991;35:41-6.

33a. Thangaratinam S, Tan A, Knox E, Kiliby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ. 2011; 342:d2616.

33b. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, grobman W, Laurberg P, Lazarus JK, Mandel SJ, Peeters R, Sullivan S. 2016 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2017, Jan 6. doi: 10.1089/thy.2016.0457. [Epub ahead of print]

34.

Abuid J, Stinson DA, Larsen PR. Serum triiodothyronine and thyroxine in the neonate and the acute increases in these hormones following delivery. J Clin Invest..1973;52:1195-9.

35.

Bianco AC, Silva JE. Intracellular conversion of thyroxine to triiodothyronine is required for the optimal thermogenic function of brown adipose tissue. J Clin Invest. 1987;79:295-300.

36.

Houstek J, Vizek K, Pavelka S, et al. Type II iodothyronine 5 ′ -deiodinase and uncoupling protein in brown adipose tissue of human newborns. J Clin Endocrinol Metab. 1993;77:382-7.

37.

Mercado M, Yu VY, Francis I, Szymonowicz W, Gold H. Thyroid function in very preterm infants. Early Hum Dev. 1988;16:131-41.

38.

Nelson JC, Weiss RM, Wilcox RB. Underestimates of serum free thyroxine (T4) concentrations by free T4 immunoassays. J Clin Endocrinol Metab. 1994;79:76-9.

39.

Ares S, Escobar-Morreale HF, Quero J, et al. Neonatal hypothyroxinemia: effects of iodine intake and premature birth. J Clin Endocrinol Metab. 1997;82:1704-12.

40.

Frank JE, Faix JE, Hermos RJ, et al. Thyroid function in very low birth weight infants: effects on neonatal hypothyroidism screening. J Pediatr. 1996;128:548-54.

41.

Kok JH, Tegelaers WH, de Vijlder JJ. Serum thyroglobulin levels in preterm infants with and without the respiratory distress syndrome. I. Cord blood study. Pediatr Res. 1986;20:996-1000.

42.

Thorpe-Beeston JG, Nicolaides KH, Snijders RJ, Felton CV, McGregor AM. Thyroid function in small for gestational age fetuses. Obstet Gynecol. 1991;77:701-6.

43.

Zurakowski D, Di Canzio J, Majzoub JA. Pediatric reference intervals for serum thyroxine, triiodothyronine, thyrotropin, and free thyroxine. Clin Chem. 1999;45:1087-91.

44.

Fisher D. Next generation newborn screening for congenital hypothyroidism? J Clin Endocrinol Metab. 2005;90:3797-9.

44b. Marvin L. Mitchell, Ho-Wen Hsu, Inderneel Sahai and the Massachusetts Pediatric Endocrine Work Group. The increased incidence of congenital hypothyroidism: fact or fancy? Clin Endocrinol. 2011;75:806-10.

45.

Klein AH, Meltzer S, Kenny FM. Improved prognosis in congenital hypothyroidism treated before age three months. J Pediatr. 1972;81:912-5.

46.

Dussault JH. The anedoctal history of screening for congenital hypothyroidism. J Clin Endocrinol Metab. 1999;84:4332-4.

47.

Delange F. Neonatal screening for congenital hypothyroidism: results and perspectives. Horm Res.1997;48:51-61.

48.

Rovet J, Daneman D. Congenital hypothyroidism: a review of current diagnostic and treatment practices in relation to neuropsychologic outcome. Paediatr Drugs. 2003;5:141-9.

50a. Ford G, LaFranchi SH. Screening for congenital hypothyroidism: a worldwide view of strategies. Best Practice & Research Clinical Endocrinology & Metabolism. 2014;28:175-187.

50b. Wassner AJ, Brown RS. Congenital Hypothyroidism: recent advances. Curr Opin Endocrinol Diabetes Obes. 2015, 22:407-412.

50c. Olivieri A, Corbetta C, Weber G, Vigone MC, Fazzini C,Medda E, and The Italian Study Group for Congenital Hypothyroidism. Congenital hypothyroidism due to defects of thyroid development and mild increase of TSH at screening: data from the Italian registry of infants with congenital hypothyroidism. J Clin Endocrinol Metab. 2013; 98:140:3-1408.

50d. Harris KB and Pass KA. Increase of congenital hypothyroidism in New York State and in The United States. Molecular Genetics and Metabolism. 2007; 91:268-277.

50e. Hinton CF, Harris KB, Borgfeld L et al. trends in incidence of congenital hypothyroidism related to select demographic factors: data from the United States , California, Massachussets, New York and Texas. Pediatrics. 2010;125:S37-S47.

50f. Olivieri A, Fazzini C, Medda E. Multiple factors influencing the incidence of congenital hypothyroidism detected by neonatal screening. Horm Res Pediatr. 2015 83:86-93.

50g. Barry Y, Bonaldi C, Goulet V, Coutant R, Leger J, Paty AC, Delmas D, Cheillan D, Roussey M. Increased incidence of congenital hypotiroidism in France from 1982 to 2012: a nationwide multicenter analysis. Ann Epidemiol. 2016;26:100-105.

51.

LaFranchi SH, Hanna CE, Krainz PL, Skeels MR, Miyahira RS, Sesser DE. Screening for congenital hypothyroidism with specimen collection at two time periods: results of the Northwest Regional Screening Program. Pediatrics. 1985;76:734-40.

51a. Ford GA, Denniston S, Sessere D, Skeels MR, LaFranchi SH. Transient versus permanent congenital hypothyroidism after the age of 3 years in infants, detected on the first versus second newborn screening test in Oregon, USA. Horm Res Paediatr. 201616;86(3):169-177

51b. Leger J, Olivieri A, Donaldson M, Torresani T,Krude H, van Vliet G, Polak M, Butler G on behalf of ESPE-PES-SLEP-JSPE-APEG-APPES-ISPAE, and the Congenital Hypothyroidism Consensus Conference Group. European Society for Pediatric Endocrinology Consensus Guidelines on Screening, Diagnosis, and management of congenital hypothyroidism. Horm Res Pediatr. 2014;81:80-103.

51c. Leger J, Olivieri A, Donaldson M, Torresani T, Krude H, van Vliet G, Polak M, Butler G on behalf of ESPE-PES-SLEP-JSPE-APEG-APPE-ISPAE, and the Congenital Hypothyroidism Consensus Conference Group. European Society for Pediatric Endocrinology Consensus Guidelines on Screening, Diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab. 2014; 99:363-384.

52.

Lanting CI, van Tijn DA, Loeber JG, Vulsma T, de Vijlder JJ, Verkerk PH. Clinical effectiveness and cost-effectiveness of the use of the thyroxine/thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program. Pediatrics. 2005;116:168-73.

53.

van Tijn DA, de Vijlder JJ, Verbeeten B, Jr., Verkerk PH, Vulsma T. Neonatal detection of congenital hypothyroidism of central origin. J Clin Endocrinol Metab. 2005; 90:3350-9.

53a. Nesbesio TD, McKenna MP, Nabhan ZM et al. Newborn screening results in children with central hypothyroidism. J Pediatr. 2010;156:990-3.

53b. Adachi M, Soneda A, Asakura Y, Muroya K, Yamagami Y, Hirahara F. Mass screening of newborns for congenital hypothyroidism of central origin by free thyroxine measurement of blood samples on filter paper. Eur J Endocrinol. 2012; 166:829-838.

53c. Soneda, A, Adachi M, Muroya K, Asakura Y, Yamagami Y, Hirahara F. Overall usefulness of newborn screening for congenital hypothyroidism by using free thyroxine measurements. Endocr J 2014; 61:025-1-30.

54.

American Academy of Pediatrics AAP Section on Endocrinology and Committee on Genetics, and American Thyroid Association Committee on Public Health: Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics. 1993;91:1203-9.

54a. Peters C, Brooke I, Ifederu A, Langham S, Hindmarsh P, Cole TJ. Defining the newborn blood spot screening reference interval for TSH: impact of ethnicity. J Clin Endocrinol Metab. 2016; 101:3445-3449.

55.

55. Fisher DA. Effectiveness of newborn screening programs for congenital hypothyroidism: prevalence of missed cases. Pediatr Clin North Am. 1987;34:881-90.

56.

Adams LM, Emery JR, Clark SJ, Carlton EI, Nelson JC. Reference ranges for newer thyroid function tests in premature infants. J Pediatr. 1995;126:122-7.

56a. Vigone MC, Caiulo S, Di Frenna M et al. Evolution of thyroid function in preterm infants detected by screening for congenital hypothyroidism. J Pediatrics. 2014;164: 1296-1302.

56b. LaFranchi SH. Screening preterm infants for congenital hypothyroidism: better the second time around. J Pediatr. 2014; 164:1259-1261.

56c. Zoller RT, Rovet J. Timing of thyroid hormone action in the developing brain: clinical observation and experimental findings. J Neuroendocrinol. 2004:16:809-818.

56d. Spencer CA, LoPresti JS, Patel A et al. Application of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab. 1990;70:453-460.

56e. Parazzini C, Baldoli C, Scotti G, Triulzi F. Terminal zones of myelination: MR evaluation of children aged 20-40 months. Am J Neuroradiol. 2002:23:1669-1673.

56f. Gagne N, Parma J, Deal C, Vassart G, Van Vliet G. Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entities? J Clin Endocrinol Metab. 1998;83:1771-5.

57.

Smith DW, Klein AM, Henderson JR, Myrianthopoulos NC. Congenital hypothyroidism–signs and symptoms in the newborn period. J Pediatr. 1975;87(6 Pt 1):958-62.

57a. Karakoc-Aydiner E, Turan S, Akpinar I, Dede F, Isguven P, Adal E, Guran T, Akcay T, Bereket A. Pitfalls in the diagnosis of thyroid disgenesis by thyroid untrasonography and scintigraphy. Eur J Endocrinol. 2012; 166:43 -48.

58.

Brown RS, LaFranchi S, Rose SR. Patient information page from the hormone foundation. Congenital hypothyroidism. J Clin Endocrinol Metab. 2009;94:1835-6.

58a. Carswell JM, Gordon JH, Popovsky E, Hale A, Brown RS. Generic and brand-name L-thyroxine are not bioequivalent for children with severe congenital hypothyroidism. J Clin Endocrinol Metab. 2013;98: 610-617.

59.

Bongers-Schokking JJ, de Muinck Keizer-Schrama SM. Influence of timing and dose of thyroid hormone replacement on mental, psychomotor, and behavioral development in children with congenital hypothyroidism. J Pediatr. 2005;147:768-74.

60.

Heyerdahl S, Oerbeck B. Congenital hypothyroidism: developmental outcome in relation to levothyroxine treatment variables. Thyroid. 2003;13:1029-38.

61.

Simoneau-Roy J, Marti S, Deal C, Huot C, Robaey P, Van Vliet G. Cognition and behavior at school entry in children with congenital hypothyroidism treated early with high-dose levothyroxine. J Pediatr. 2004;144:747-52.

62.

Rovet JF. In search of the optimal therapy for congenital hypothyroidism. J Pediatr. 2004;144:698-700.

63.

Dimitropoulos A, Molinari L, Etter K, et al. Children with congenital hypothyroidism: long-term intellectual outcome after early high-dose treatment. Pediatr Res. 2009;65:242-8.

64.

Fisher DA. The importance of early management in optimizing IQ in infants with congenital hypothyroidism. J Pediatr. 2000;136:273-4.

64a. Leger J. Congenital hypothyroidism: a clinical update of long-term outcome in young adults. Eur J Endocrinol. 2015;172, R67-R77.

64b. Leger J, Ecosse E, Roussey M, Lanoe JL, Larroque B. French Congenital hypothyroidism study group. Subtle health impairment and socioeducational attainment in young adult patients with congenital hypothyroidism diagnosed by neonatal screening: a longitudinal population-based cohort study. J Clin Endocrinol Metab. 2011;96:1771-82.

64c. Lichtenberer-Geslin L, Dos Santos S, Hassani Y, Ecosse E, Van Den Abbele T, Leger J. Factors associated with hearing impairment in patient with congenital hypothyroidism treated since the neonatal period: a national population-based study. J Clin Endocrinol Metab. 2013; 98:3644-3652.

64d. Leger J, dos Santos S, larroque B, Ecosse E. Pregnancy outcomes and relationship to treatment adequacy in women treated early for congenital hypothyroidism: a longitudinal population-based study. J Clin Endocrinol Metab. 2015; 100: 800-809.

64e. Lof C, Patyra K, Kuulasmaa T, Vangipurapu J, Undeutsch H, Jaeschke H, Pajunen T, Kero A, Krude H, Biebermann, Kleinau G, Kuhnen P, Rantakari K, Miettinen P, Kirjavainen T, Pursiheimo JP, Mustila T, Jaaskelainen J, Ojaniemi M, Toppari J, Ignatius J, Laakso M, Kero J. Detection of novel gene variants associated with congenital hypothyroidism in a finnish patient cohort. Thyroid. 2016; 26:1215-1224.

64f. Nicholas AK, Serra EG, Cangui H, Alyaarubi S, Ullah I, Schoenmakes E, Deeb A, Habeb AM, AI Maghamsi M, Peters C, Nathwani N, Aycan Z, Saglam H, Bober E, Dattani M, Shenoy S, Murray PG, Babiker A, Willensen R, Thankarmony A, Lyons G, Irwin R, Padidela R, Tharian K, Davies JH, Puthi V, Park SM, Massoud AF, Gregory JW, Albanese A, Pease-Gevers E, Martin H, Brugger K, Maher ER, Chatterje K, Anderson CA, Schoenmakers N. Comprehensive screening of eight known causative genes in congenital hypothyroidism with gland-in-situ. J Clin Endocrinol Metab. 2016; 12:4521-31.

65.

Siebner R, Merlob P, Kaiserman I, Sack J. Congenital anomalies concomitant with persistent primary congenital hypothyroidism. Am J Med Genet. 1992;44:57-60.

66.

Kumar J, Gordillo R, Kaskel FJ, Druschel CM, Woroniecki RP. Increased prevalence of renal and urinary tract anomalies in children with congenital hypothyroidism. J Pediatr. 2009;154:263-6.

67.

Perry R, Heinrichs C, Bourdoux P, et al. Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology. J Clin Endocrinol Metab. 2002;87:4072-7.

67a. Brown RS, Demmer LA. The etiology of thyroid dysgenesis-still an enigma after all these years. J Clin Endocrinol Metab. 2002;87:4069-71.

68.

Fort P, Lifshitz F, Bellisario R, et al. Abnormalities of thyroid function in infants with Down syndrome. J Pediatr. 1984;104:545-9.

68a. Stoupa A, Kariyawasam D, Carre’ A, Polak M. Update of thyroid development genes. Endocrinol Metab Clin N Am. 45:243-246, 2016.

68b. Szinnai G. genetics of normal and abnormal thyroid development in humans. Best Pract Res Clin Endocrinol Metab. 2014; 28:133-50.

68c. Satoshi Narumi and Tobonobu Hasegawa. TSH resistance revised. Endocrine Journal. 2015, 62:393-398.

68d. Calebiro D, Gelmini G, Cordella D et al. Frequent TSH receptor genetic alterations with variable signaling impairment in a large series of children with nonautoimmune isolated hyperthyrotropinemia. J Clin Endocrinol Metab. 2012; 97: E156-160.

68e. Carre A, Szinnai G, Castanet M et al. Five new TTF1/NKX2-1 mutations in brain–lung-thyroid syndrome: rescue by PAX8 synergism in one case. Hum Mol Genet. 2009;18:2266-76.

68f. de Filippis T, Marelli F, Vigone MC, Di Frenna M, Weber G, Persani L. Novel NKX2-1 frameshift mutations in patients with athypical phenotypes of the brain-lung-thyroid syndrome. Eu Thyroid J. 2014; 3: 227-233.

68g. Thowarth A, Schittert-Hubener S , Schrumpf P et al. Comprehensive genotyping and clinical characterization reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum. J Med Genet. 2014;51:375-387.

68h. Stenson PD, Mort M, Ball EV et al. The human gene mutation database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014;133: 1-9.

68i. Narumi S, Muroya K, Asakura Y et al. Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a population-based cohort of Japanese patients. J Clin Endocrinol Metab. 2010: 95: 1981-5.

68j. Fernandez LP, Lopez- Marquez A, Santisteban P. Thyroid transcription factors in development, differentiation and disease. Nat Rev Endocrinol. 2015; 11:29-42.

68k. Fernandez LP, Lopez-Marquez A, Martinez AM, Gomez-Lopez G, Santisteban P l. New insights into FOXE1 functions: identification of direct FOXE1 targets in thyroid cells. PLoS One. 2013, 8:e62849.

68m. Carre A Hamza RT, Kariyawasam D, et al. A novel FOXE1 mutation (R73S) in Bamforth-Lazarus syndrome causing increased thyroid gene expression. Thyroid. 2014:24:649-65.

68n. Dentice M, Cordeddu V, Rosica A et al. Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. J Clin Endocrinol Metab. 2006;91:1428-1433.

68o. Opitz R, Hitz MP, Vandernoot I et al. Functional zebrafish studies based on human genotyping point to netrin-1 as a link between aberrant cardiovascular development and thyroid dysgenesis. Endocrinology. 2015;156:377-388.

68q. Porazzi P, Marelli F, Benato F,de Filippis T,Calebiro D, Argenton F, Tiso N, Persani L . Disruptors of global and JAGGED1 mediated notch signaling affect thyroid morfogenesis in the zebrafish. Endocrinology. 2012; 153:5645-5658.

68r. De Filippis T, Marelli F. Nebbia G, Porazzi P, Corbetta S, Fugazzola L, Gastaldi R, Vigone MC, Biffanti R, Frizziero D, Mandara’ L, Prontera P, Salerno M, Maghnie M, Tiso N, Radetti G, Weber G, Persani L. JAG1 loss- of- function variations as a novel predisposing event in the pathogenesis of congenital thyroid defects. J Clin Endocrinol Metab. 2016;101:861-870.

68s. Knobel M, Madeires-Neto G. An outline of inherited disorders of the thyroid hormone generating system. Thyroid. 2003; 13:771-801.

69.

Portulano C, Paroder-Belenitsky M, Carrasco N. The Na+/I symporter (NIS): mechanism and medical impact. Endocr Rev. 2014;35 :106-149.

70.

Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani F, Nassir E, Baxevanis AD, Sheffied VC, Green ED. Pendred syndrome is caused by mutations in putative sulphate transporter gene (PDS). Nat Genet. 1997;17:411-422.

71.

71. Kopp P. Pendred’s syndrome: identification of the genetic defect a century after its recognition. Thyroid. 1999;9:65-9.

71a. Ladsous M, Vlaeminck-Guillem V, Dumur V, Vincent C, Dubrulle F, Dhanens CM, Wemeau JL. Analysis of the thyroid phenotype in 42 patients with Pendred syndrome and non syndromic enlargement of the vestibular aqueduct. Thyroid. 2014; 24:639-648.

71b. Bizhanova A, Kopp P. Genetics and phenomics of Pendred syndrome. Mol Cell Endocrinol. 2010;322:83-90.

72.

Nascimiento AC, Guendes DR, Santos CS, Knobel M, Rubio IG, Medeiros-Neto G. Thyroperoxidase gene mutations in congenital goitrous hypothyroidism with total and partial iodide organification defect. Thyroid. 2003;13:1145-51.

72a. Delodoey J, Pfarr N, Vuissoz JM, Parma J, Vassart G, Biesterfeld S, Phlenz J, Van Vliet G. Pseudodominant inherence of goitrous congenital hypothyroidism caused byTPO mutations; molecular and in silico studies. J Clin Endocrinol Metab. 2008;93:627-633.

72b. Moreno JC,Bikker H, Kempers MJE, vanTrotsenburg AS, Baas F, deVijlder JJM, Vulsma T, Ris-Stalpers C. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med. 2002; 347:95-102.

72c. Muzza M, Rabbiosi S, Vigone MC, Zamproni I, Cirelio V, Maffini M, Maruca K, Schoenmarkers N, Beccaria L, Gallo F, Park SM, Beck-Peccoz P, Persani L, Weber G, Fugazzola L. The clinical and molecular characterization of patients with dyshormonogenetic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects. J Clin Endocrinol Metab. 2014;99:E544-E553.

72d. Zamproni I, Grasberger H, Cortinovis F, Vigone MC, Chiumello G, Mora S, Onigata K, Fugazzola L, Refetoff S, Persani L, Weber G. Biallelic inactivation of the dual oxidation maturation factor 2 (DUAXA2) gene as a novel cause of congenital hypothyroidism. J Clin Endocrinol Metab. 2008; 93:605-610.

72e. Ieri T, Cochaux P, Targovinik HM, Suzuki M, Shimoda S, Perret J, Vassart G. A 3’splice site mutation in the thyroglobulin gene responsible for congenital goiter with hypothyroidism. J Clin Invest..1991:88:1901-1905.

72f. Medeiros-Neto G, Kim PS, Yoo SE, Vono J, Targovnik H, Camargo R, Hossain SA, Arvan P. Congenital hypothyroid goiter with deficient thyroglobulin. Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones. J Clin Invest. 1996; 98:2838-2844.

72g. Citterio CE, Rossetti LC, Souchon PF, Morales C, Thouvard-Viprey M, Salmon-Musial AS, Mauran PL, Doco-Fenzy M, Gonzales-Sarmiento R, Rivolta CM, De Brasi CD, Targovink HM. Novel mutational mechanism in the thyroglobulin gene: imperfect DNA inversion as a cause for hereditary hypothyroidism. Mol Cell Endocrinol. 2013; 381:220-229.

72h. Iglesias A, Garcia-Nimo L, Cocho de Juan JA, Moreno JC. Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) deficts. Best Prac Res Clin Endocrinol Metab. 2014; 28:151-159.

72i. Moreno JC, Klootwijk W, van Toor H, Pinto G, D’Allessandro M, Leger A, Goundie D, Polak M, Gruters A, Visser TJ. Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Eng J Med. 2008;358:1856-1859.

73.

Fisher DA, Dussault JH, Foley TP, Klein AH, LaFranchi S, Larsen PR, Mitchell ML, Murphey WH, Walfish PG. Screening for congenital hypothyroidism: results of screening one million North American infants. J Pediatr. 1979;94: 700-705.

73a. Lanting CI, van Tijn DA, Loeber JG, Vulsma T, de Vijder JJ, Verkerk PH. Clinical effectiveness and cost-effectiveness of the use of the thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program. Pediatrics. 2005;116:168-173.

73b. Kempers MJ, Lanting CI, van Heijst AF, van Trotsenburg AS, Wiedijk BM. De Vijder JJ,Vulsma T. Neonatal screening for congenital hypothyroidism based on thyroxine, thyrotropin and thyroxine-binding globulin measurement potentials and pitfalls. J Clin Endocrinol Metab.2006; 91:3370-3376.

73c. Zwaveling-Soonawala N, van Trotsenburg AS, Verkerk PH. The severity of congenital hypothyroidism of central origin should not be underestimated. J Clin Endocrinol Metab. 2015:100:E297-E300.

73d. Collu R, Tang J, Castagne’ J, Legace’ G, Masson N, Huot C, Deal C, Delvin E, Faccenda F, Edne KA, Van Vliet G. A novel mechanism for isolated central hypothyroidism: Inactivating mutations in the thyrotropin releasing-hormone receptor gene. J Clin Endocrinol Metab. 1997:82:1561-1565.

73e. Bonomi M, Busnelli M, Beck-Peccoz P, Costanzo D, Antonica F, Dolci C, Pilotta A, Buzi F, Persani L. A family with complete resistance to thyrotropin-releasing hormone receptor gene. N Engl J Med. 2009;360:731-734.

73f. Koulouri O, Nicholas AK, Shoenmakers E, Mokrosinki J, Lane F, Cole T, Kirk J, Farooqi IS, Chatterjee VK, Gurnell M, Shoenmakers N. A novel thyrotropin-releasing hormone receptor missense mutation (P81R) in central congenital hypothyroidism. J Clin Endocrinol Metab. 2016; 101:847-851.

74.

Dacou-Voutekatis C, Feltquate DM, Drakopoulou M, Kourides IA, Dracopoli NC. Familial hypothyroidism caused by a nonsense mutation in the thyroid stimulating hormone beta-subunit gene. Am J Hum Genet. 1990;46:988-993.

74a. Bonomi M, Proverbio MC, Weber G, Chiumello G, Beck-Peccoz P, Persani L. Hyperplastic pituitary gland, high serum glycoprotein hormone alfa-subunit, and variable circulating thyrotropin (TSH) levels as a hallmark of central hypothyroidism due to mutations of the TSH beta gene. J Clin Endocrinol Metab. 2001;86:1600-1604.

74b. Bequadano MS, Ciaccio M, Dujovne N et al. Two novel mutations of the TSH- β-subunit gene underlying congenital central hypothyroidism undetectable in neonatal TSH screening. J Clin Endocrinol Metab. 2010;95:E98-E103.

74c. Drees JC, Stone JA, Reamer CR, Arboleda VF, Huang K, Hrynkow J, Greene DN, Petrie MS, Hoke C, Lorey TS et al. Falsely undetectable TSH in a cohort of Sauth Asian euthyroid patients. J Clin Endocrinol Metab. 2014;99:1171-1179.

74d. PappaT, Johannesen J, Schemberg N, Torrent M, Dumitriescu A, Refetoff S. A TSHB variant with impaired immunoreactivity but intact biological activity and its clinical implications. Thyroid. 2015; 25:869-876.

74e. Hermanns P, Couch R, Leonard N, Klotz C, Pohlenz J. A novel deletion in the thyrotropin β-subunit gene identified by array comparative genomyc hybridization analysis causes central congenital hypothyroidism in a boy originating from Turkey. Horm ResPediatr. 2014;82:201-205.

74f. Nicholas AK, Jaleel S, Kyons E, Shoenmakers E, Dattani MT, Crowne E, Bernhard B, Kirk J, Roche EF, Chatterjee VK, Shoenmakers N. Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland. Clin Endocrinol. 2016; Jun 30 doi:10111/cen. 13149.

75.

Sun Y, Bak B, Schoenmaker N, van Trotsenburg AS, Oostdijk W, Voshol P et al. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet. 2012; 44:1375-1381.

75a. Tajima T, Nakamura A, Ishizu K. A novel mutation of IGSF1 in a Japanese patient of congenital central hypothyroidism without macroorchidism. Endocr J. 2013; 60:245-249.

75b. Nakamura A, Bak B, Silander TL, Lam J, Hotsubo T, Yorifuji T, Ishizu K, Bernard DJ, Tajima T. Three novel IGSF1 mutations in four Japanese patients with X-linked congenital central hypothyroidism. J Clin Endocrinol Metab. 2013;98:E1682-E1691.

75c. Joustra SD, Schoenmakers N, Persani L, Campi I, Bonomi M, Radetti G, Beck-Peccoz P, Zhu H, Davis TM, Sun Y, Corssmit EP, Appelman-Dijkstra NM, Heinen CA, Pereira AM, Varewick AJ, Janssen JA, Endert E, Hennekam RC, Lombardi MP, Mannens MM, Bak B, Bernard DI, Breuning MH, Chatterijee K et al. The IGSF1 deficiency syndrome:characteristics of male and females patients. J Clin Endocrinol Metab. 2013; 98:4942-4952.

75d. Joustra SD, Heinen CA, Schoenmakers N, Bonomi M, Ballieux MO, Turgeon D, Bernard E, Fliers E, van Trotsenburg ASP, Losekoot M, Persani L, Wit JM, Biermasz NR, Pereira AM, Oostdijk W, on behalf of the IGSF1 Clinical Care Group. IGSF1 Deficiency: lessons from an extensive case series and recommendations for clinical management. J Clin Endocrinol Metab. 2016; 101:1627-1636.

75e. Tenenbaum-Rakover Y, Turgeon MO, London S,Hermanns P,Pohlenz J, Bernard DJ, Bercovich D. Familial central hypothyroidism caused by a novel IGSF1 gene mutation. Thyroid. 2016 ;26:1693-1700..

76.

Alatzoglou KS, Dattani MT. Genetic forms of hypopituitarism and their manifestations in neonatal period. Early Hum Dev. 2009;85:705-712.

76a. Brown RS, Bhatia V, Hayes E. An apparent cluster of congenital hypopituitarism in central Massachusetts: magnetic resonance imaging and hormonal studies. J Clin Endocrinol Metab. 1991;72:12-8.

76b. Dattani ML, Martinez-Barbera J, Thomas PQ, et al. Molecular genetics of septo-optic dysplasia. Horm Res. 2000; 53 Suppl 1:26-33.

76c. Machinis K, Pantel J, Netchine I, et al. Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet. 2001;69:961-8.

76d. Parks JS, Brown MR. Transcription factors regulating pituitary development. Growth Horm IGF Res. 1999;9 Suppl B:2-8; discussion -11.

77.

Refetoff S, Bassett JH, Beck-Peccoz P et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport and metabolism. Thyroid. 2014; 24:407.

77a. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev. 1993; 14:348-399.

77b. Weiss RE, Balzano S, Scherberg NH, Refetoff S. Neonatal detection of generalized resistance to thyroid hormone. Jama. 1990;264:2245-50.

77c. Bochukova E, Schoenmakers N, Agostini E, et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med. 2012;366:243-9.

77d. Moran C, Chatterje K, Resistance to thyroid hormone due to defective thyroid hormone receptor alpha. Best Pract Res Clin Endocrinol Metab. 2015; 29: 647.

77e. Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet. 2004;74:168-75.

77f. Friesema EC, Gruters A, Biebermann H, Krude H, von Moers A, Reeser M, Barrett TG, Mancilla EE, Svensson J, Kester MH, Kuiper GG, Balkassmi S, Uitterlinden AG, Koehrle J, Rodien P, Halestrap AP, Visser TJ. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 2004; 364:1435-1437.

77g. Allan W, Erdon CN, Dudley FC. Some exemples of the inheritance of mental deficiency apparently sex-linked idiocy and microcefaly. Am J Ment Defic. 1944, 48:325.

77h. Dumitrescu AM, Liao XH, Abdullah MS, et al. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet. 2005;37:1247-52.

78.

l’Allemand D, Gruters A, Beyer P, Weber B. Iodine in contrast agents and skin disinfectants is the major cause for hypothyroidism in premature infants during intensive care. Horm Res. 1987;28:42-9.

79.

Brown RS, Bloomfield S, Bednarek FJ, Mitchell ML, Braverman LE. Routine skin cleansing with povidone-iodine is not a common cause of transient neonatal hypothyroidism in North America: a prospective controlled study. Thyroid.1997;7:395-400.

80.

Cheron RG, Kaplan MM, Larsen PR, Selenkow HA, Crigler JF, Jr. Neonatal thyroid function after propylthiouracil therapy for maternal Graves’ disease. N Engl J Med. 1981;304:525-8.

81.

Mitsuda N, Tamaki H, Amino N, Hosono T, Miyai K, Tanizawa O. Risk factors for developmental disorders in infants born to women with Graves disease. Obstet Gynecol. 1992;80(3 Pt 1):359-64.

81a. Brown RS, Bellisario RL, Botero D, et al. Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies. J Clin Endocrinol Metab. 1996;81:1147-51.

81b. Brown RS, Keating P, Mitchell E. Maternal thyroid-blocking immunoglobulins in congenital hypothyroidism. J Clin Endocrinol Metab. 1990;70:1341-6.

81c. Connors MH, Styne DM. Transient neonatal ‘athyreosis’ resulting from thyrotropin-binding inhibitory immunoglobulins. Pediatrics. 1986;78:287-90.

82.

Mandel SH, Hanna CE, LaFranchi SH. Diminished thyroid-stimulating hormone secretion associated with neonatal thyrotoxicosis. J Pediatr. 1986;109:662-5.

83.

Deming DD, Rabin CW, Hopper AO, Peverini RL, Vyhmeister NR, Nelson JC. Direct equilibrium dialysis compared with two non-dialysis free T4 methods in premature infants. J Pediatr. 2007;151:404-8.

83a van Wassener-Leemhuis A, Ares S, Golombek S, Kok J, Paneth N, Kase J, LaGamma E. Thyroid hormone supplementation in preterm infants born before 28 weeks of gestational age and neurodevelopmental outcome at age 36 months. Thyroid. 2014; 24:1162-1169.

83b. Hollanders JJ, Israels J, van del Pal SM, Verkerk PH, Rotteveel J, Finken MJ, Duch POPS-19 collaborative study group. No Association Between Transient Hypothyroxinemia of Prematurity and Neurodevelopmental Outcome in Young Adulthood. J Clin Endocrinol Metab. 2015; 100:4648-53.

83c. Williams FL, Visser TJ, Hume R. Transient hypothyroxinaemia in preterm infants. Early Hum Dev. 2006;82:797-802.

83d. van Wassenaer AG, Kok JH, de Vijlder JJ, et al. Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks’ gestation. N Engl J Med. 1997;336:21-6.

83e. van Wassenaer AG, Westera J, Houtzager BA, Kok JH. Ten-year follow-up of children born at <30 weeks’ gestational age supplemented with thyroxine in the neonatal period in a randomized, controlled trial. Pediatrics. 2005;116:e613-8.

84.

Williams FL, Ogston SA, van Toor H, Visser TJ, Hume R. Serum thyroid hormones in preterm infants: associations with postnatal illnesses and drug usage. J Clin Endocrinol Metab. 2005;90:5954-63.

85.

Foley TP, Jr., Abbassi V, Copeland KC, Draznin MB. Brief report: hypothyroidism caused by chronic autoimmune thyroiditis in very young infants. N Engl J Med. 1994;330:466-8.

85a. Verbansky JW, Chatila TA. Immune dysregulation, Poliendocrinopathy, Enteropathy, X linked (IPEX) and IPEX related disorders: an evolving web of heritable autoimmune disease. Curr Opin Pediatr. 2013; 25:708-714.

85b. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Med Genet. 2002;39:537-45.

85c. Huang SA, Tu HM, Harney JW et al. Severe hypothyroidism caused by type 3 iodothyronine dieiodinase in infantile hemangiomas. N Eng J Med. 2000;343: 185-9.

85d. Balatz AE, Athanassaki I, Gunn SK, Tatevian N, Huang SA, Haymond MW, Karaviti L. Rapid resolution of consumptive hypothyroidism in a child with hepatic hemangioendothelioma following liver transplantation. Ann Cli Lab Sc. 2007;37:280-284.

86.

Zakarija M, McKenzie JM. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves’ disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab. 1983;57:1036-40.

87.

Skuza KA, Sills IN, Stene M, Rapaport R. Prediction of neonatal hyperthyroidism in infants born to mothers with Graves disease. J Pediatr. 1996;128:264-8.

87a. Abeillon-du Payret, Chikh K, Bossart N, Bretones P, Gaucherand P, Claris O, Charrie’ A, Raverot V, Orgiazzi J, Borzon- Chazot F, Bournaud C. Predictive value of maternal second-generation thyroid-binding inhibitory immunoglobulin assay for neonatal autoimmune hyperthyroidism. Eur J Endocrinol. 2014, 171:451-460.

87b. Fort P, Lifshitz F, Pugliese M, Klein I. Neonatal thyroid disease: differential expression in three successive offspring. J Clin Endocrinol Metab. 1988;66:645-7.

87c. Zakarija M, McKenzie JM, Munro DS. Immunoglobulin G inhibitor of thyroid-stimulating antibody is a cause of delay in the onset of neonatal Graves’ disease. J Clin Invest. 1983;72:1352-6.

87d. Kohn LD, Suzuki K, Hoffman WH, et al. Characterization of monoclonal thyroid-stimulating and thyrotropin binding-inhibiting autoantibodies from a Hashimoto’s patient whose children had intrauterine and neonatal thyroid disease. J Clin Endocrinol Metab. 1997;82:3998-4009.

87e. Launberg P, Wallin G, Tallstedt L, Abraham-Nording M, Lundell G, Terring O. TSH-receptor autoimmunity in Graves’ disease after therapy with antithyroid –drugs, surgery or radioiodine: a 5 year prospective randomized study. Eur J Endocrinol. 2008; 158:69-75.

87f. Kiefier FW, Kierbemass-Screhof K, Steiner M, Worda C, Kaisprian G, Tanja D, Kahaly G, Gess A. Fetal/neonatal thyrotoxicosis in a newborn from a hypothyroid woman with Hashimoto thyroiditis, J Clin Endocrinol Metab. 2017;102:6-9.

87g. Neal PR, Jansen RD, Lemons JA, Mirkin LD, Schreiner RL. Unusual manifestations of neonatal hyperthyroidism. Am J Perinatol. 1985;2:231-5.

87h. Daneman D, Howard NJ. Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years. J Pediatr. 1980;97:257-9.

88.

Morshed SA, Ando T, Latif R, Davies TF. Neutral antibodies to the TSH receptor are present in Graves' disease and regulate selective signaling cascades. Endocrinology. 151:5537-49, 2010.

88a. Barbesino G, Tomer Y. Clinical utility of TSH receptor antibodies. J Clin Endocrinol Metab. 2013;98:2247-2255.

88b. Diana T, Brown RS, Bossowski A, Segni M, Niedziela M, Konig J, Bossowka A, Ziora K, Smith J, Pitz S, Kanitz M, Kahaly GJ. Clinical relevance of thyroid-stimulating autoantibodies in pediatric Graves’ disease. A multicenter study. J Clin Endocrinol Metab. 2014;99:1648-1655.

88c. Ross DS, Burch HB, Cooper DS, Greenlee MC, Launberg P, Maia AL, Rivkees S, Samuels M, Sosa JA, Stan MN, Walter MA. 2016 American Thyroid Association Guidelines for Diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis.Thyroid.. 2016;2:1343-1421.

88d. Donnelly MA, Wood C, Casey B, Hobbins J, Barbour LA. Early severe fetal Graves disease in a mother after after thyroid ablation and thyroidectomy. Obstetric Gynecol. 2015; 125:141-152.

88e. Besancon A, Beltrand J, Le Gac I, Luton D, Polak M. Management of neonates born to women with Graves’ disease: a cohort study. Eur J Endocrinol. 2014;170:855-862.

89.

Matsuura N, Konishi J, Fujieda K, et al. TSH-receptor antibodies in mothers with Graves’ disease and outcome in their offspring. Lancet. 1988;1:14-7.

89a. Tamaki H, Amino N, Aozasa M, et al. Universal predictive criteria for neonatal overt thyrotoxicosis requiring treatment. Am J Perinatol. 1988;5:152-8.

89b. Van der Kaay D, Wasserman JD, Palmert MR. Management of neonates born to mothers with Graves’ disease. Pediatrics. 2016;137:e20151878.

90.

de Roux N, Polak M, Couet J, et al. A new mutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism. J Clin Endocrinol Metab. 1996;81:2023-6.

90a. Holzapfel HP, Wonerow P, von Petrykowski W, Henschen M, Scherbaum WA, Paschke R. Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J Clin Endocrinol Metab. 1997;82:3879-84.

90b. Schwab KO, Gerlich M, Broecker M, Sohlemann P, Derwahl M, Lohse MJ. Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism. J Pediatr. 1997;131:899-904.

90c. Kopp P, Muirhead S, Jourdain N, Gu WX, Jameson JL, Rodd C. Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281–>isoleucine) in the extracellular domain of the thyrotropin receptor. J Clin Invest .1997;100:1634-9.

90d. Gruters A, Schoneberg T, Biebermann H, et al. Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor. J Clin Endocrinol Metab. 1998;83:1431.

90e. Paschke R, Niedzela M, Vaidya B, Persani L, Rapaport B, Leclere J. The management of familial and persistent sporadic non-autoimmune hyperthyroidism caused by thyroid stimulating hormone receptor germline mutations. Eur Thyroid J. 2012;1:142-147.

90f. Yoshimoto M. Nakayama M, Baba T, Uehara y, Nikawa N, Ito M, Tsuji Y. A case of neonatal McCune Albright syndrome with Cushing syndrome and hyperthyroidism. Acta Paediatr Scand. 1991;80:984-987.

91.

Davies TF, Amino N. A new classification for human autoimmune thyroid disease. Thyroid. 1993; 3: 331-333,

91a. Fisher DA, Pandian MR, Carlton E. Autoimmune disease: an expanding spectrum. Pediatr Clin North Am. 1987; 34: 907-18.

91b. Rallison ML, Dobyns FR, Keating FR, Rall JE, Tyler FH, Occurrence and natural history of chronic lymphocytic thyroiditis in childhood. J Pediatr. 1975; 86: 675-82.

91c. Loviselli A, Veluzzi F, Mossa P, Cambosu MA, Secci G, Atzeni F, Taberlet A, Balestrieri A, Martino E, Grasso L, Songini M, Bottazzo GF, Mariotti S. Sardinian Schoolchildren Study Group. The Sardinian Autoimmunity Study: 3. Studies on circulating antithyroid antibodies in Sardinian schoolchildren: relationship to goiter prevalence and thyroid function.Thyroid. 2001;1: 849-57.

91d. Kabelitz M, Liesenkotter KP, Stach B, Willigerodt H, Stablen W, Singendok W, Jager-Roman E, Litzenborger H, EhnertB, Gruters A. The prevalence of anti-thyroid peroxidase antibodies and autoimmune thyroiditis in children and adolescents in an iodine replete area. Eur J Endocrinol. 2003;48:301-307.

91e. Kaloumenou I, Mastorakos G, Alevizaki M, Duntas LH, Mantzou E, Ladopoulos C, Antoniou A, Chiotis D, Popassotiriou I, Chousos GP, Dacou-Voutetakis-C. Thyroid autoimmunity in schoolchildren in an area with long-standing iodine sufficiency: correlation with gender, pubertal stage, and maternal thyroid autoimmunity. Thyroid. 2008;18:747-58.

91f. Davies TF. Really significant genes for autoimmune thyroid disease do not exist–so how can we predict disease? Thyroid. 2007;17:1027-9.

91g. Brown RS. Autoimmune thyroid disease: unlocking a complex puzzle. Curr Opin Pediatr. .2009;21:523-8.

91h .Segni M, Pani MA, Pasquino AM, Badenhoop K. Familial clustering of juvenile thyroid autoimmunity: higher risk is conferred by human leukocyte antigen DR3-DQ2 and thyroid peroxidase antibody status in fathers. J Clin Endocrinol Metab 2002; 87: 3779-82.

91i.Segni M, Wood J, Pucarelli I, Toscano V, Toscano R, Pasquino AM. Clustering of autoimmune thyroid diseases in children and adolescents: a study of 66 families. J Pediatr Endocrinol Metab. 2001, 14 Supp 5:1271-5.

91j. Wiebolt J, Achterbergh R, den Boer A, van der Leij S, Marsch E, Suelmann B, de Vries R, van Haeften TW. Clustering of additional autoimmunity behaves differently in Hashimoto's patients compared with Graves' patients. Eur J Endocrinol. 2011;164:789-94.

91k. Jenkins RC, Weetman AP. Disease associations with autoimmune thyroid disease. Thyroid. 2002;12:975-986.

91l. Karlsson B, Gustafsson G, Ivarson SA, Anneren G, Thyroid dysfunction in Down’s syndrome: relation to age and thyroid autoimmunity. Arch Dis Child. 1998;79:243-245.

91m. Eisheikh M, Wass JA, Conway GS. Autoimmune thyroid disease in women with Turner ‘s syndrome-the association with karyotype. Clin Endocrinol. 2001; 55:223-226,

91n. Seminog OO, Seminog AB, Yeates D, Goldacre MJ. Associations between Klinefelter’s syndrome and autoimmune diseases: English national recortd linkage studies. Autoimmunity. 2015;48: 125-280.

91o. Quaio CR, Carvalho JF, da Silva CA, Bueno C, Brasil AS, Pereira AC, Jorge AA, Malaquias AC, Kim CA, Bertola DR. Autoimmune disease and multiple autoantibodies in 42 patients with RASopathies. Am J Med Genet. 2012; 158A: 1077-82.

91p. Brent GA. Enviromental exposures and autoimmune thyroid disease. Thyroid. 2010;20:755-761.

91q. Eshler DC, Hasam A, Tomer Y. Cutting edge: the etiology of autoimmune thyroid disease. Clin Rev Allergy Immunol. 2011; 41:190-197.

92.

Brown RS. Immunoglobulins affecting thyroid growth: a continuing controversy. J Clin Endocrinol Metab. 1995;80:1506-8.

92a. deVries L, Bulvik S, Philllip M. Chronic autoimmune thyroiditis in children and adolescents at presentation and during long-term follow up. Arch Dis Child. 2009; 94:33-7.

92b. Najjar SS. Muscular hypertrophy in hypothyroid children: the Kocher-Debre-Semelaigne syndrome; a review of 23 cases. J Pediatr. 1974;85:236-9.

92c. Hopwood NJ, Lockhart LH, Bryan GT. Acquired hypothyroidism with muscular hypertrophy and precocious testicular enlargement. J Pediatr. 1974;85:233-6.

92d. Anasti JN, Flack MR, Froehlich J, Nelson LM, Nisula BC. A potential novel mechanism for precocious puberty in juvenile hypothyroidism. J Clin Endocrinol Metab. 1995;80:276-9.

93.

Maenpaa J, Raatikka M, Rasanen J, Taskinen E, Wager O. Natural course of juvenile autoimmune thyroiditis. J Pediatr. 1985;107:898-904.

93a. Moore DC. Natural course of ‘subclinical’ hypothyroidism in childhood and adolescence. Arch Pediatr Adolesc Med. 1996;150:293-7.

93b. Lazar L, Frumkin RB, Battat E, Lebenthal Y, Phillip M, Meyerovitch J. Natural history of thyroid function tests over 5 years in a large pediatric cohort. J Clin Endocrinol Metab. 2009;94:1678-82.

93c. Aversa T, Corrias A, Salerno MC, Tessaris D, Di Mase R, Valenzise M, Corica D, De Luca F, Wasniewka M. Five-years prospective evaluation of thyroid function test evolution in children with Hashimoto’s thyroiditis presenting with either euthyroidism or subclinical hypothyroidism. Thyroid. 2016, 26:1450-1456.

94.

Hayashida N,Imaizumi M, Shimura H, Okubo N, Asari Y, Nigarawa T, Midorikava Sm Kotani K, Nakaji S, Otssuru A, Akamizu T, Kitaoka M, Suzuki S, Taniguchi N, Yamashita S, Takamura N. Thyroid ultrasound findings in children from three Japanese prefectures: Aomori, Yamanashi and Nagasaki. Plos One. 2013,8:e83220.

94a. Corrias A, Cassio A, Weber G, Mussa A, Wasniewska M, Rapa A, Gastaldi R, Einaudi S, Baronio F, Vigone MC, Messina MF, Bal M, Bona G, De Santis C; for the study for thyroid diseases of the Italian Society for Pediatric Endocrinology and Diabetology. Thyroid nodules and cancer in children and adolescents affected by autoimmune thyroiditis. Arch Pediatr Adolesc Med. 2008; 162:526-531.

94b. Keskin M, Savas-Erdeve S, Aycan Z. Co-existence of thyroid nodule and thyroid cancer in children and adolescents with Hashimoto thyroiditis: a single-center study. Horm Res Pediatr. 2016; 85:181-187.

94c. Kambalpalli M, Gupta A, Prasad UR, Francis GL. Ultrasound characteristics of the thyroid in children and adolescents with goiter: a single center experience. Thyroid. 2015; 25:176-182.

94d. Jeong SH, Hong HS, Lee FH, Kwak JJ. Papillary thyroid carcinoma arising in children and adolescent Hashimoto’s thyroiditis: ultrasonographic and pathologic findings. Int J Endocrinolol. 2016, 2397690.

94e. Gilani BB, MacGillivray MH, Voorhess ML, Mills BJ, Riley WJ, MacLaren NK. Thyroid hormone abnormalities at diagnosis of insulin-dependent diabetes mellitus in children. J Pediatr. 1984;105:218-22.

94f. Kakleas K, Soldatou A, Karachaliou F, Karavanaki K. Associated autoimmune diseases in children and adolescents with type 1 diabetes. Autoimmunity Reviews. 2015; 14:781-797.

95.

Neufeld M, Maclaren N, Blizzard R. Autoimmune polyglandular syndromes. Pediatr Ann. 1980;9:154-62.

95a. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350:2068-2079.

95b. Betterle C, Greggio NA, Volpato M. Clinical review 93: Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab. 1998;83:1049-55.

95c. Kordonouri O, Harmann R, Deiss D, Wilms M, Gruters-Kieslich A. Natural course of autoimmune thyroiditis in type 1 diabetes: association with gender, age, diabetes duration and and puberty. Arch Dis Child. 2005; 90:411-414.

95d. Bright GM, Blizzard RM, Kaiser DM, Clarke WL. Organ-specific autoantibodies in children with common endocrine disease. J Pediatr. 1982; 100:8-14.

95e. Dost A, Roher TR, Frolich-Reitherer E, Bollow E, Karges B, Bockmann A, Harmann J, Holl RW: DPV initiative and the German Competence Network Diabetes Mellitus. Horm Res Paediatr. 2015; 84: 190-8.

95f. Naiyer AJ, Shah J, Hernandez L, Kim SY, Ciaccio EJ, Cheng J, Manavalan S, Bhagat G, Green PH. Tissue transglutaminase antibodies in individuals with celiac disease bind to thyroid follicles and extracellular matrix and may contribute to thyroid dysfunction. Thyroid. .2008;18:1171-8.

95g. Roy A, Laszowska M, Sundstrom J, Lebwohl B, green PH, Kampe O, Ludvigsoon JF. Prevalence of celiac disease in patients with autoimmune thyroid disease: a meta-analysis. Thyroid. 2016; 26:880-90.

95h. Kurien M, Mollazadegan K, Sanders DS, Ludvigssson JF. Celiac disease increased risk of thyroid disease in patients with type 1 diabetes: a nationwide cohort study. Diab Care. 2016 39:371-375.

95i. Virili C, Bassotti G, Santaguida MG, Iourio R, Del Duca SC, Mercuri V, Pocarelli A, Gargiulo P. Gargano L, Centanni M. Atypical celiac disease as a cause of increased need for thyroxine: a systematic study. J Clin Endocrinol Metab. 2012; 97:E419-22.

95j. Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD, Heward JM, Manji N, Allahabadia A, Armitage M, Chatterjee KV, Lazarus JH, Pearce SH, Vaidya B, Gough SC, Franklyn JA. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med. 2010;123:183.e1-9.

95k Irvine WJ, Davies SH, Teitelbaum S, Delamore IW, Williams AW. The clinical and pathological significance of gastric parietal cell antibody. Ann NY Acad Sci.1965; 124:657-91.

95l. Segni M, Borrelli O, Pucarelli I, Delle Fave G, Pasquino AM, Annibale B. Early manifestations of gastric autoimmunity in patients with juvenile autoimmune thyroid diseases. J Clin Endocrinol Metab. 2004; 4944-8.

96.

Scott HS, Heino M, Peterson P, et al. Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. Mol Endocrinol.1998;12:1112-9.

96a. Ferre EM, Rose SR, Rosenzweig SD, Burbelo PD, Romito KR, Niemela JE, Rosen LB, Break TJ, Gu W, Hunsberger S, Browne SK, Hsu AP, Rampertaap S, Swamydas M, Collar AL, Kong HH, Lee CR, Chascsa D, Simcox T, Pham A, Bondici A, Natarajan M, Monsale J, Kleiner DE, Quezado M, Alevizos I, Moutsopoulos NM, Yockey L, Frein C, Soldatos A, Calvo KR, Adjemian J, Similuk MN, Lang DM, Stone KD, Uzel G, Kopp JB, Bishop RJ, Holland SM, Olivier KN, Fleisher TA, Heller T, Winer KK, Lionakis MS. Redifined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. JCI insight. 2016;1(13):e88782.

96b. Jenkins RC, Weetman AP. Disease associations with autoimmune thyroid disease. Thyroid. 2002; 12:975-986.

96c. Fallahi P, Ferrari SM, Ruffilli I, Elia G, Biricotti M, Vita R, Benvenga S, Antonelli A. The association of other autoimmune diseases in patients with autoimmune thyroiditis: Review of the literature and report of a large series of patients. Autoimm Rev. 2016;15:1125-1128.

96d. Stagi S, Giani T, Simonini G, Falcini F. Thyroid function, autoimmune thyroiditis and coeliac disease in juvenile idiopathic arthritis. Reumatology. 2005; 44:517-20.

96e. Kroon MW, Vrijman C, Chandeck C, Wind BS, Wolkerstofer A, Luiten RM, Bos JD, Geskus RB, van Trosenburg P, van der Veen JP. High prevalence of autoimmune thyroiditis in children and adolents with vitiligo. Horm Res Paediatr. 2013;79:137-44.

96f. Noso S, Park C, Babaya N, Hiromine Y, Harada T, Ito H, Taketomo Y, Kanto K, Oiso N, Kawada A, Suzuki T, Kawabata Y, Ikegami H. Organ specificity in autoimmune diseases: thyroid and islet autoimmunity in alopecia areata. J Clin Endocrinol Metab. 2015; 100:1976-1983.

96g. Leznoff A, Josse RG, Denburg J, Dolovich J. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol. 1983;119:636-40.

96h. O’Regan S, Fong JS, Kaplan BS, Chadarevian JP, Lapointe N, Drummond KN. Thyroid antigen-antibody nephritis. Clin Immunol Immunopathol. 1976;6:341-6.

96i. Segni M, Pucarelli I, Truglia S, Turriziani I, Serafinelli C, Conti F. High prevalence of antinuclear antibodies in children with thyroid autoimmunity. J Immunol Res 2014, 150239.

96j. Manetti L, Lupi I, Morselli L, Albertini S, Cosottini M, Grasso L, Genovesi M, Pinna G, Mariotti S, Bogazzi F, Bartalena L, Martino E. Prevalence and functional significance of antipituitary antibodies in patients with autoimmune and non-autoimmune thyroid diseases. J Clin Endocrinol Metab. 2007.92:2176-81.

96k. De Bellis A, Bellastella G, Maiorino MI, Aitella E, Lucci E, Cozzolino D, Bellastella A, Bizzarro A, Giugliano D, Esposito K, Italian Autoimmune Hypophysitis network group. Longitudinal behavior of autoimmune GH deficiency: from childhood to transition age. Eur J Endocrinol. 2016;174:381-7.

97.

Mehta A, Hindmarsh PC, Stanhope RG, Brain CE, Preece MA, Dattani MT. Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children?. J Clin Endocrinol Metab. 2003;88:5696-703.

97a. Feingold SB, Smith J, Houtz J, et al. Prevalence and functional significance of thyrotropin (TSH) receptor blocking antibodies in children and adolescents with chronic lymphocytic thyroiditis. J Clin Endocrinol Metab. 2009;94: 4742-8.

97b. Brown RS, Alter CA, Sadeghi-Nejad A. Severe unsuspected maternal hypothyroidism discovered after the diagnosis of thyrotropin receptor-blocking antibody-induced congenital hypothyroidism in the neonate: failure to recognize and implication to the fetus Horm Res Pediatr. 2015; 83:132-8.

98.

Pedersen OM, Aadal NP, Larssen TB, Varhuag JE, Myking O, Vik-Mo H. The value of ultrasonography in predicting autoimmune thyroid disease. Thyroid. 2000, 10:251-259.

99.

Rovet JF, Daneman D, Bailey JD. Psychologic and psychoeducational consequences of thyroxine therapy for juvenile acquired hypothyroidism. J Pediatr. 1993;122:543-9.

99a. Van Dop C, Conte FA, Koch TK, Clark SJ, Wilson-Davis SL, Grumbach MM. Pseudotumor cerebri associated with initiation of levothyroxine therapy for juvenile hypothyroidism. N Engl J Med.1983;308:1076-80.

99b. Lomenick JP, El-Sayyid M, Smith WJ. Effect of levo-thyroxine treatment on weight and body mass index in children with acquired hypothyroidism. J Pediatr. 2008. 152:96-100.

99c. Rivkees SA, Bode HH, Crawford JD. Long-term growth in juvenile acquired hypothyroidism: the failure to achieve normal adult stature. N Engl J Med. 1988;318:599-602.

100.

Salerno M, Capalbo D, Cerbone M, De Luca F. Subclinical hypothyroidism in childhood- current knowledge and open issues. Nat Rev Endocrinol. 2016; 734-746.

100a. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. Jama. 2004;291:228-38.

100b. Taylor P, Razvi S, Pearce Sh, Colin D. A Review of the clinical consequences of variation in thyroid function whitin the reference range. J Clin Endocrinol Metab. 2013; 98: 3562-3571,

100c. Ittermann T, Thamm M, Wallschofski H, Rettig R, Volzke H. Serum thyroid-stimulating hormone levels are associated with blood pressure in children and adolescents. J Clin Endocrinol Metab. 2012; 97:828-834.

100d. Witte T, Ittermann T, Thamm M, Ribiet NB, Votzke H. Association between serum thyroid stimulating hormone levels and serum lipids in children and adolescents: a population-based study on german youth. J Clin Endocrinol Metab. 2015;100:2090-7.

100e. Nader NS, Bahn RS, Johnson ,MD, Weaver AL, Singh R, Kumar S. Relationships between thyroid function and lipid status or insulin resistance in a pediatric population. Thyroid. 2010;20:1333-1339.

100f. McLeod DS, Watters KF, Carpenter AD, Landenson PW, Cooper DS, Ding EL. Thyrotropin and thyroid cancer diagnosis: a systematic review and dose-response meta-analysis. J Clin Endocrinol Metab. 2012; 97:2682-2692.

100g. Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaydya B. European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014; 3: 76-94.

101.

Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med. 1995;333:1688-94.

101a. McCowen KC, Garber JR, Spark R. Elevated serum thyrotropin in thyroxine-treated patients with hypothyroidism given sertraline. N Engl J Med. 1997;337:1010-1.

101b. Delange FM. Iodine Deficiency. In: Braverman LE, Utiger,R.D., ed. Werner & Ingbar’s The Thyroid. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2000.

101c. Pacaud D, Van Vliet G, Delvin E, et al. A Third World endocrine disease in a 6-year-old North American boy. J Clin Endocrinol Metab. 1995;80:2574-6.

101d. Donadieu J, Rolon MA, Thomas C, et al. Endocrine involvement in pediatric-onset Langerhans ’ cell histiocytosis: a population-based study. J Pediatr. 2004;144:344-50.

102.

Hauser P, Zametkin AJ, Martinez P, et al. Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone. N Engl J Med. 1993;328:997-1001.

102a. Bercu BB, Orloff S, Schulman JD. Pituitary resistance to thyroid hormone in cystinosis. J Clin Endocrinol Metab. 1980;51:1262-8.

103.

van der Gaag RD, Drexhage HA, Wiersinga WM, et al. Further studies on thyroid growth-stimulating immunoglobulins in euthyroid nonendemic goiter. J Clin Endocrinol Metab. 1985;60:972-9.

104.

Rother KI, Zimmerman D, Schwenk WF. Effect of thyroid hormone treatment on thyromegaly in children and adolescents with Hashimoto disease. J Pediatr. 1994;124:599-601.

105.

Svensson J, Ericsson UB, Nilsson P, Olsson C, Jonsson B, Lindberg B, Ivarsson SA. Levothyroxine treatment reduces thyroid size in children and adolescents with chronic autoimmune thyroiditis. J Clin Endocrinol Metab. 2006. 91:1729-34.

106.

Smith SL, Pereira KD Suppurative thyroiditis in children. A management algorithm. Pediatr Emerg Care. 2008; 24:764-767.

106a. Greene JN. Subacute thyroiditis. Am J Med. 1971:51:97.

106b. Paes JE, Burman KD,.Cohen J, Franklyn J, McHemry CR, Shoham S, Kloos RT. Acute bacterial suppurative thyroiditis: a clinical review and expert opinion. Thyroid. 2010; 20:247-255.

106c. Mali VP, Prabhakaran K. Recurrent acute thyroid swellings because of pyriform sinus fistula. J Pediatr Surg. 2008;43:e27-30.

106d. Radfar N,Kenny FM, Larsen PR. Subacute thyroiditis in a lateral thyroid gland:evaluation of the pituitary-thyroid axis during the acute distructive and the recovery phases. J Pediatr. 1975; 87:34.

107.

Braverman L, Utiger R: Introduction to thyrotoxicosis. In: Braverman L, Utiger R eds. The Thyroid. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 453-455, 2005.

107a. Graves RJ: Clinical lectures. London Med Surg J (pt 2):516, 1835.

107b. Kjaer H, Andersen SM, Hansen D. Increasing incidence of juvenile thyrotoxicosis in Denmark: a nationwide study, 1998-2012. Horm Res Paediatr. 2015;84: 102-107.

107c. Shulman DI, Muhar I, Jorgensen EV, Diamond FB, Bercu BB, Root AW. Autoimmune hyperthyroidism in prepubertal children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy. Thyroid. 1997;7:755-60.

107d. Segni M, Leonardi E, Mazzoncini B, Pucarelli I, Pasquino AM. Special features of Graves ’ disease in early childhood. Thyroid. 1999;9:871-7.

107e. Goday-Arno A, Cerda-Esteva M, Flores-Le-Roux JA, Chillaron-Jordan JJ, Corretger JM, Cano-Perez JF. Hyperthyroidism in a population with Down syndrome (DS). Clin Endocrinol. 2009;71:110-4.

107f. Rapoport B, Chazenbalk GD, Jaume JC, McLachlan SM. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr Rev. 1998;19:673-716.

107g. Smith BR, Sanders J, Furmaniak J. TSH receptor antibodies. Thyroid. 2007;17:923-38.

107h. Sanders J, Evans M, Premawardhana LD, et al. Human monoclonal thyroid stimulating autoantibody. Lancet. 2003;362:126-8.

107i. Sanders J, Miguel RN, Bolton J, et al. Molecular interactions between the TSH receptor and a thyroid-stimulating monoclonal autoantibody. Thyroid. 2007;17:699-706.

107j. Rapoport B, McLachlan SM. The thyrotropin receptor in Graves’ disease. Thyroid .2007;17:911-22.

107k. Williams RC, Jr., Marshall NJ, Kilpatrick K, et al. Kappa/lambda immunoglobulin distribution in Graves’ thyroid-stimulating antibodies. Simultaneous analysis of C lambda gene polymorphisms. J Clin Invest. 1988;82:1306-12.

108.

Segni M, Gorman CA. The aftermath of childhood hyperthyroidism. J Pediatr Endocrinol Metab. 2001; Suppl 5 1277-82.

108a. Goldstein SM, Katowitz WR, Modhang T, Katowitz JA. Pediatric Thyroid-Associated Orbitopathy: The children’s hospital of Philadelphia experience and literature review. Thyroid. 2008;18:997-999.

108b. Nucci P, Brancato R, Bandello F, Alfarano R, Bianchi S. Normal exophtalmometric values in children. Am J Opthal 1989;108:582-584.

108c. Liu GT, Helher KL, Katowitz JA, Kazim M, Moazami G, Moshang T, Teener JW, Sladeky J, Volpe NJ, Galetta SL. Prominent proptosis in childhood thyroid eye disease. Opthalmology. 1996;103:779-784.

108d. Durairaj VD, Bartley GB, Garrity JA. Clinical features and treatment of Graves’ opthalmopathy in pediatric patients. Opthal Plast Reconstr Surg 2006; 22:7-12.

109.

Sterling K, Refetoff S, Selenkow HA. T3 thyrotoxicosis due to elevated serum triiodothyronine levels. JAMA​. 1970;213:571-5.

109a. Harvengt J, Boizeau P, Chevenne D, Zenaty D, Paulsen A, Simon D, Crepon SG, Alberti C, Carel JC, Leger J. Triiodothyronine- predominant Graves’ disease in childhood:detection and therapeutic inplications. Eur J Endocrinol. 2015; 172: 715-23.

109b. Ruiz M, Rajatanavin R, Young RA, Taylor C, Brown R, Braverman LE, Ingbar SH. Familial dysalbuminemic hyperthyroxinemia: a syndrome that can be confused with thyrotoxicosis. N Engl J Med. 1982;306:635-9.

109c. Mariotti S, Martino E, Cupini C, et al. Low serum thyroglobulin as a clue to the diagnosis of thyrotoxicosis factitia. N Engl J Med. 1982;307:410-2.

109d. Kaguelidou F, Alberti C, Castanet M, Guitteny MA, Czernichow P, Leger J. Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of anthythyroid drug treatment. J Clin Endocrinol Metab. 2008; 93:3817-3826.

110.

Ichiki Y, Akahoshi M, Yamashita N, et al. Propylthiouracil-induced severe hepatitis: a case report and review of the literature. J Gastroenterol. 1998;33:747-50.

110a. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl. 2004;10:1018-23.

110b. Rivkees SA, Mattison DR. Ending propylthiouracil-induced liver failure in children. N Engl J Med. 2009;360:1574-5.

110c. Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein IL, Laurberg P, McDougall IR, Rivkees SA, Ross D, Sosa JA, Stan MN. The Role of Propylthiouracil in the Management of Graves’ Disease in Adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid. 2009;19:673-4.

110d. Okuno A, Yano K, Inyaku F, Suzuki Y, Sanae N, Kumai M, Naitoh Y. Pharmacokinetics of methimazole in children and adolescents with Graves’ disease. Acta Endocrinol.1987. 115:112-118.

110e. Rivkees SA. Pediatric Graves’ disease: management in the post-propilthyuracil era .Inter J Pediatr Endocrinolol. 2014; 10:1-10.

110f. Smith J, Brown RS. Persistence of thyrotropin (TSH) receptor antibodies in children and adolescents with Graves’ disease treated using antithyroid medication. Thyroid. 2007;17:1103-7.

110g. Fenzi G, Hashizume K, Roudebush CP, DeGroot LJ. Changes in thyroid-stimulating immunoglobulins during antithyroid therapy. J Clin Endocrinol Metab. 1979;48:572-6.

110h. Teng CS, Yeung RT. Changes in thyroid-stimulating antibody activity in Graves’ disease treated with antithyroid drug and its relationship to relapse: a prospective study. J Clin Endocrinol Metab. 1980;50:144-7.

110i. Bliddal H, Kirkegaard C, Siersbaek-Nielsen K, Friis T. Prognostic value of thyrotrophin binding inhibiting immunoglobulins (TBII) in longterm antithyroid treatment, 131I therapy given in combination with carbimazole and in euthyroid ophthalmopathy. Acta Endocrinol. 1981;98:364-9.

110j. Collen RJ, Landaw EM, Kaplan SA, Lippe BM. Remission rates of children and adolescents with thyrotoxicosis treated with antithyroid drugs. Pediatrics. 1980;65(3):550-6.

110k. Leger J, Gelwane G, Kaguelidou F et al. Positive impact of long-term antithyroid drug treatment on the outcome of children with Graves disease: natural long-term cohort study. J Clin Endocrinol Metab. 2012; 97:110-9.

110l. Hashizume K, Ichikawa K, Sakurai A, et al. Administration of thyroxine in treated Graves’ disease. Effects on the level of antibodies to thyroid-stimulating hormone receptors and on the risk of recurrence of hyperthyroidism. N Engl J Med. 1991;324:947-53.

110m. McIver B, Rae P, Beckett G, Wilkinson E, Gold A, Toft A. Lack of effect of thyroxine in patients with Graves’ hyperthyroidism who are treated with an antithyroid drug. N Engl J Med 1996;334:220-4.

111.

Rivkees SA, Sklar C, Freemark M. Clinical review 99: The management of Graves’ disease in children, with special emphasis on radioiodine treatment. J Clin Endocrinol Metab. 1998;83:3767-76.

111a. Rivkees SA, Stephenson K, Dinauer C. Adverse events associated with methimazole therapy of Graves’ disease in children. Int J Pediatr Endocrinol. 2010; 176970.

111b. Wada N, Mukai M, Kohono M, Notoya A, Ito T, Yoshioka N. Prevalence of serum anti-myeloperoxidase antineutrophil cytoplasmatic antibodies (MPO-ANCA) in patients with Graves’ disease trated with prophilthyuracil and thiamazole. Endocr J. 2002; 49: 329-334.

111c. Guma M, Salinas I, Reverter JL, Roca J, Valls-Roc M, Juan M, Olive’ A. Frequency of antineutrophil cytoplasmic antibody in Graves’ disease patients treated with methimazole. J Clin Endocrinol Metab. 2003, 88:2141-6.

111d. Tajiri J, Noguchi S, Murakami T, Murakami N. Antithyroid drug-induced agranulocytosis. The usefulness of routine white blood cell count monitoring. Arch Intern Med. 1990;150:621-4.

111e. van Veenendaal NR, Rivkees SA. Treatment of pediatric Graves’ disease is associated with excessive weight gain. J Clin Endocrinol Metab. 2011; 96:3257-63.

111f. Mazzaferri EL. Thyroid cancer and Graves’ disease. J Clin Endocrinol Metab. 1990; 70:825-829.

111g. Dobyns BM, Sheline GE, Workman JB, Tompkins EA, McConahey WM, Becker DV. Malignant and benign neoplasm of the thyroid in patients treated for hyperthyroidism: a report of the cooperative thyrotoxicosis therapy follow-up study. J Clin Endocrinol Metab. 1974; 38:976-988.

112.

Sherman J, Thompson GB, Lteif A, et al. Surgical management of Graves disease in childhood and adolescence: an institutional experience. Surgery. 2006;140:1056-61. Discussion 61-2.

112a.Tuggle CT, Roman SA, Wang TS, Thomas DC, Uldelsman R, Ann Sosa J. Pediatric endocrine surgery: who is operating on our children? Surgery. 2008; 144:869-877, Discussion 877.

112b. Kundel A, Thompson GB, Richards ML, Qiu LX, Cai Y, Schwenk FW, Lief AN, Pittock ST, Kumar S, Tebben PJ Hay ID, Grant CS. Pediatric endocrine surgery: a 20 year experience at the Mayo Clinic. J Clin Endocrinol Metab. 2014. 99: 399-406.

112c. Beuer CK, Solomon D, Donovan P, Rivkees SA, Udelsman R. Effect of patient age on surgical outcome for Graves’ disease: a case control study of 100 consecutive patients at a high volume thyroid surgical center. Int J Pediatr Endocrionol. 2013;1: 9856.

113.

Nikiforov Y, Gnepp DR, Fagin JA. Thyroid lesions in children and adolescents after the Chernobyl disaster: implications for the study of radiation tumorigenesis. J Clin Endocrinol Metab. 1996;81:9-14.

113a. Safa AM, Schumacher P, Rodriguez-Antunez A. Long-term follow-up results in children and adolescents treated with radioactive iodine (131-Iodine). N Engl J Med. 1975; 292:167-171.

113b. Holm LE, Dahlqvist I, Israelsson A, Lundell GM. Malignant thyroid tumors after 131-iodine therapy. N Engl J Med. 1980; 303:188-191.

113c. Hamburger JI. Management of hyperthyroidism in children and adolescents. J Clin Endocrinol Metab. 1985; 60:1019.

113d. Hayek A, Chapman E, Crawford JD. Long-term results of treatment of thyrotoxicosis in children and adolescents with radioactive iodine. N Engl J Med .1970; 283:949, 953.

113e. Franklyn JA, Maisonneuve P, Sheppard M, Betteridge PB.Bovie P. Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study. Lancet. 1999;353:2111-5

113f. Starr P, Jaffe HL, Oettinger L Jr. Late results of 131-I treatment of hyperthyroidism in seventy-three children and adolescents. J Nucl Med.1964; 5:81-9.

113g. Kogut MD, Kaplan SA, Collipp PJ, Tiamsic T, Boyle D. Treatment of hyperthyroidism in children. N Engl J Med.1965; 272:217-22.

113h. Read CH Jr, Tansey MJ, Menda Y. A 36-year retrospective analysis of the efficacy and safety of radioactive iodine in treating young Graves’ patients. J Clin Endocrinol Metab. 2004;89:4229-33.

113i. Rivkees SA, Dinauer C. An optimal treatment for pediatric Graves’ disease is radioiodine. J Clin Endocrinol Metab. 2007;92:797-800.

113j. Rivkees SA. Controversies in the management of Graves’ disease in children. J Endocrinol Invest. 2016;39:1247-1257.

114.

Ly S, Frates MC, Benson CB, Peters HE, Grant FD, Drubach LA, Voss SD, Feldman HA, Smith JR, Barletta J, Hollowell M, Cibas ES, Moore FD, Modi BM, Shamberger RC, Huang SA. Features and outcome of autonomous thyroid nodules in children: 31 consecutive patients seen at a single center. J Clin Endocrinol Metab. 2016;101:3856-3862.

114a. Niedzela M, Breborowicz D, Trejster E, Koeman E. Hot nodules in children and adolents in western Poland from 1996 to 2000: clinical analysis of 31 patients. J Pediatr Endocrinol Metab. 2002;15:823-830.

114b. Francis GL, Waguenspack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, Dinauer CA, Hamilton J, Hay ID, Luster M, Parisi MT, Rachmiel M, Thompson GB, Yamashita S. Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid. 2015:716-759.

114c. Gershergorn MC, Weintraub BD. Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone. A new syndrome of “inappropriate secretion of TSH”. J Clin Invest. 1975;56:633-642.

114d. Beck-Peccoz P, Lania A, Beckers A, Chatterrjee K, Wernau JL. European Thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. Thyroid J. 2013;2-76-82.

114e. Daly AF, Tichomirova MA, Petronians P, Heliovaara E, Jaffrain-Rea ML, Barlus R et al. Clinical characteristics and therapeutic responses.in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab. 2010; 95:E373-E383.

114f. Misra M, Levitsky LL, Lee MM. Transient hyperthyroidism in an adolescent with hydatidiform mole. J Pediatr. 2002;140:362-6.

114g. Hershman JM. Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and throphoblastic tumors. Thyroid. 1999; 9:653-657.

115a. Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robison B, Rosental MS, Santoro M, Schulberger M, Shah M, Waguespack SG, American Thyroid Association Guidelines task force on medullary thyroid carcinoma. Thyroid. 2015; 25:567-610.

115b. Hung W, Anderson KD, Chandra RS, et al. Solitary thyroid nodules in 71 children and adolescents. J Pediatr Surg. 1992;27:1407-9.

115c . Schlumberger M, De Vathaire F, Travagli JP, et al. Differentiated thyroid carcinoma in childhood: long term follow-up of 72 patients. J Clin Endocrinol Metab. 1987;65:1088-94.

115d . Flannery TK, Kirkland JL, Copeland KC, Bertuch AA, Karaviti LP, Brandt ML. Papillary thyroid cancer: a pediatric perspective. Pediatrics 1996;98(3 Pt 1):464-6.

115e. Lairmore TC, Frisella MM, Wells SA, Jr. Genetic testing and early thyroidectomy for inherited medullary thyroid carcinoma. Ann Med. 1996;28:401-6.

115f. Sarne D, Schneider AB. External radiation and thyroid neoplasia. Endocrinol Metab Clin North Am. 1996;25:181-95.

115g. Healy JC, Shafford EA, Reznek RH, et al. Sonographic abnormalities of the thyroid gland following radiotherapy in survivors of childhood Hodgkin’s disease. Br J Radiol. 1996;69:617-23.

115h. Soberman N, Leonidas JC, Cherrick I, Schiff R, Karayalcin G. Sonographic abnormalities of the thyroid gland in longterm survivors of Hodgkin disease. Pediatr Radiol. 1991;21:250-3.

115k. Dinauer CA, Breuer C, Rivkees SA. Differentiated thyroid cancer in children: diagnosis and management. Curr Opin Oncol. 2008;20:59-65.

115i. Waguespack SG, Francis G. Initial management and follow up of differentiated thyroid cancer in children. J Natl Compr Canc Netw. 2010; 8:1289-300.

115l. Gharib H, Goellner JR. Fine-needle aspiration biopsy of thyroid nodules. Endocr Pract .1995;1:410-7.

115m. Zimmerman D, Hay ID, Gough IR, et al. Papillary thyroid carcinoma in children and adults: long-term follow-up of 1039 patients conservatively treated at one institution during three decades. Surgery. 1988;104:1157-66.

115o. Ladenson PW, Braverman LE, Mazzaferri EL, et al. Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma. N Engl J Med. 1997;337:888-96.

115p. Wohllk N, Cote GJ, Evans DB, Goepfert H, Ordonez NG, Gagel RF. Application of genetic screening information to the management of medullary thyroid carcinoma and multiple endocrine neoplasia type 2. Endocrinol Metab Clin North Am. 1996;25:1-25.

115q. Fogelfeld L, Wiviott MB, Shore-Freedman E, et al. Recurrence of thyroid nodules after surgical removal in patients irradiated in childhood for benign conditions. N Engl J Med. 1989;320:835-40.

115r. de Vathaire F¹, Haddy N¹, Allodji RS¹, Hawkins M¹, Guibout C¹, El-Fayech C¹, Teinturier C¹, Oberlin O¹, Pacquement H¹, Diop F¹, Kalhouche A¹, Benadjaoud M¹, Winter D¹, Jackson A¹, Bezin Mai-Quynh G¹, Benabdennebi A¹, Llanas D¹, Veres C¹, Munzer M¹, Nguyen TD¹, Bondiau PY¹, Berchery D¹, Laprie A¹, Deutsch E¹, Lefkopoulos D¹, Schlumberger M¹, Diallo I¹, Rubino C. Thyroid Radiation Dose and Other Risk Factors of Thyroid Carcinoma Following Childhood Cancer. J Clin Endocrinol Metab. 2015 ;100:4282-90.

115s. Vivanco M¹, Dalle JH, Alberti C, Lescoeur B, Yakouben K, Carel JC, Baruchel A, Léger J. Malignant and benign thyroid nodules after total body irradiation preceding hematopoietic cell transplantation during childhood. Eur J Endocrinol. 2012 ;167):225-233.