Acquired hypothyroidism in childhood and adolescence

INTRODUCTION — Hypothyroidism is the most common disturbance of thyroid function in children; acquired hypothyroidism is most often caused by autoimmune thyroiditis [1]. As in adults, acquired hypothyroidism can be caused by both thyroid disease (primary hypothyroidism) and hypothalamic-pituitary disease (central hypothyroidism); furthermore, primary hypothyroidism may be either subclinical (elevated serum thyroid-stimulating hormone [TSH] and normal serum free thyroxine [T4] concentrations) or overt (elevated serum TSH and low serum free T4 concentrations). Whatever its cause, hypothyroidism in children can have deleterious effects on growth, pubertal development, and school performance.

An overview of the clinical manifestations, causes, diagnosis, and treatment of acquired hypothyroidism in children is discussed below. Details about each of the causes are available in linked topics. Evaluation and management of congenital hypothyroidism are discussed separately. Information in this topic pertains to primary hypothyroidism; information on secondary (central) hypothyroidism is presented only when helpful to separate this entity from primary hypothyroidism. (See "Clinical features and detection of congenital hypothyroidism" and "Treatment and prognosis of congenital hypothyroidism" and "Thyroid physiology and screening in preterm infants".)

TERMINOLOGY

●Autoimmune thyroiditis – Autoimmune thyroiditis is the most common cause of acquired hypothyroidism [1]. Synonymous terms include chronic lymphocytic thyroiditis and Hashimoto thyroiditis; for the sake of consistency, this topic will use autoimmune thyroiditis.

●Autoimmune thyroid disease – This is a somewhat broader term, encompassing disorders with autoimmune mechanisms that have a risk of both hypothyroidism (Hashimoto disease) and hyperthyroidism (Graves disease).

CLINICAL MANIFESTATIONS

●Clinical presentation – Presenting features of acquired hypothyroidism in children may include:

•Declining growth velocity/short stature – The most common manifestation of hypothyroidism in children is declining height velocity, often resulting in short stature. The growth delay tends to be insidious in onset, and it may be present for several years before other symptoms occur, if they occur at all [2]. Thus, any child with declining height velocity should be evaluated for hypothyroidism. Skeletal maturation typically is delayed, and therefore, bone age and height age are less than chronologic age [3]. Indeed, because skeletal maturation slows or ceases after the onset of hypothyroidism, the bone age may indicate the age of onset. (See "Diagnostic approach to children and adolescents with short stature".)

•Abnormal pubertal development – Pubertal development is delayed in most adolescent hypothyroid children. However, some children with primary hypothyroidism have sexual precocity, characterized by breast development and vaginal bleeding in girls and macro-orchidism (enlarged testes) in boys, and slightly increased (for age) serum follicle-stimulating hormone (FSH) concentrations. In these cases, the bone age may not be delayed, owing to the effect of sex steroid production. Rarely, patients may present with galactorrhea secondary to hyperprolactinemia associated with their hypothyroidism.

•Functioning in school – Another common feature is altered school performance. Performance often declines, but it improves in some children, perhaps because they are less active and, therefore, less easily distracted and better able to concentrate. One reason for delay in diagnosis is that parents/caregivers see the latter changes as positive.

•Other symptoms – Other symptoms are sluggishness, lethargy, cold intolerance, constipation, dry skin, brittle hair, facial puffiness, and muscle aches and pains. Although hypothyroidism may cause weight gain, this is typically minimal and attributable to fluid retention rather than adiposity. If the cause is hypothalamic or pituitary disease, the child may have headaches, visual symptoms, or manifestations of other pituitary hormone deficiencies. (See "Clinical manifestations of hypothyroidism".)

•Hashimoto encephalopathy – Rarely, an encephalopathy may occur in children or adults with autoimmune thyroiditis. This disorder has been termed Hashimoto encephalopathy and is thought to be an associated autoimmune disorder that is unrelated to thyroid dysfunction or thyroid autoantibodies [4,5]. (See "Hashimoto encephalopathy".)

●Examination findings – In primary hypothyroidism, the most common physical finding at presentation is a diffusely enlarged thyroid gland (goiter). In one series from Turkey, a noticeable goiter was present in 39.5 percent of children with autoimmune thyroiditis [6]. Alternatively, the thyroid gland may be normal in size or not palpable at all. Other abnormalities on physical examination may include short stature; apparent overweight (more fluid retention than obesity); puffy facies with a dull, placid expression; bradycardia; pseudohypertrophy of the muscles; and delayed deep tendon reflexes. Abnormal findings on chest and cardiac auscultation may point to pleural or pericardial effusions [7]. These effusions resolve with levothyroxine treatment. Hypothyroidism should be considered in any child with unexplained pericardial or pleural effusions. There appears to be a higher risk of slipped capital femoral epiphysis in children with acquired hypothyroidism [8].

●Laboratory abnormalities – In addition to characteristic findings on thyroid function testing (see 'Diagnosis' below), patients with primary hypothyroidism also may have hyperlipidemia (most notably hypertriglyceridemia and low high-density lipoprotein [HDL] cholesterol), normocytic or macrocytic anemia, and hyponatremia (infrequently). Rarely, children may present with a myopathy and dramatically elevated serum creatine kinase levels, known as Kocher-Debre-Semelaigne syndrome [9].

●Imaging abnormalities – Primary hypothyroidism may be associated with enlargement of the sella turcica, resulting from secondary hyperplasia of thyrotroph cells [10]. The enlargement may be discovered when cranial imaging is performed for evaluation of short stature. Although pituitary enlargement may be rather pronounced, with the upper convexity of the gland even abutting inferiorly on the optic chiasm, it rarely causes symptoms or signs (in contrast with a pituitary tumor or craniopharyngioma), and it is reversible with levothyroxine therapy. Thus, primary hypothyroidism must be excluded in any child with an enlarged sella turcica. Occasionally, patients with severe hypothyroidism develop pericardial and pleural effusions, which may be presenting features [7]. As noted above, skeletal maturation (bone age) is delayed.

ETIOLOGY — The causes of hypothyroidism in children are listed in the table (table 1). They are similar to those in adults, but iatrogenic hypothyroidism is relatively less common. Most can be identified from the history and physical examination. (See "Disorders that cause hypothyroidism".)

Autoimmune thyroiditis

●Epidemiology and pathogenesis – The most common cause of hypothyroidism in children is autoimmune thyroiditis (also known as chronic lymphocytic or Hashimoto thyroiditis). The autoimmune process typically presents with a goiter, though the thyroid gland may be normal at diagnosis, or even atrophied in a minority. If a goiter is present at diagnosis, it may persist, further enlarge, or regress over time. Autoimmune thyroiditis is more common in girls than boys and more common in White than Black individuals. Among children with this disorder, euthyroid goiter is more common than hypothyroidism [6,11,12]. (See "Approach to acquired goiter in children and adolescents", section on 'Chronic autoimmune thyroiditis (Hashimoto)'.)

In the Third National Health and Nutrition Examination Survey (NHANES III) from 1988 to 1994, 6.3 percent of American adolescents (12 to 19 years of age) had positive antithyroglobulin antibodies (TgAb) and 4.8 percent had positive antithyroid peroxidase antibodies (TPOAb) [13]. The likelihood of detecting TgAb and TPOAb was two times greater in female versus male adolescents. The incidence of antithyroid antibodies was highest in Hispanic adolescents and lowest in Black non-Hispanic adolescents; non-Hispanic White adolescents had an incidence between these two groups. Approximately 2 percent of adolescents had a serum thyroid-stimulating hormone (TSH) >4.5 mU/L, which this study used as a cutpoint to define mild hypothyroidism. While uncommon, hypothyroidism caused by autoimmune thyroiditis has been reported in infants [14].

The natural history of euthyroid autoimmune thyroiditis was illustrated in a report of 160 children (mean age 9.1 years) with elevated titers of antithyroid antibodies who underwent serial measurements of TSH levels [15]. Among 105 children with normal TSH followed for five years, 65 percent remained euthyroid, 9 percent developed mild elevation in serum TSH concentrations (typically 5 to 10 mU/L), and 26 percent developed serum TSH levels twofold above the upper limit of normal (usually >10 mU/L). In a subsequent study of 87 children with elevated antithyroid antibodies and mild TSH elevation (5 to 10 mU/L) followed for three years, 41 percent reverted to euthyroidism (TSH <5 mU/L), 20 percent had persistent mild TSH elevation (5 to 10 mU/L), while 39 percent developed more severe hypothyroidism (TSH >10 mU/L) [16]. Most children with autoimmune thyroiditis remain euthyroid for some time, and only a minority of those with mild TSH elevation progress to overt hypothyroidism.

Different mechanisms can be responsible for thyroid atrophy or goiter formation in these patients [17]. (See "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)".)

•Atrophic thyroiditis is primarily the result of cell-mediated cytotoxicity leading to follicular cell apoptosis; complement-dependent antibody-mediated cytotoxicity may contribute to thyroid damage. TSH receptor-blocking antibodies result in loss of thyroid morphologic integrity, which may be reversible.

•Goitrous thyroiditis may be induced by one of three mechanisms: lymphocytic and plasma cell infiltration (and lymphoid germinal centers), the production of antibodies that stimulate thyroid growth, or excess TSH secretion.

●Disorders associated with autoimmune thyroid disease – Children with some chromosomal disorders or other autoimmune disorders are at increased risk for autoimmune thyroiditis and, to a lesser extent, hypothyroidism. These include Down syndrome (trisomy 21), Turner syndrome, type 1 (autoimmune) diabetes mellitus, celiac disease, and possibly Klinefelter syndrome [18-23]. Because of these associations, children with these disorders should undergo periodic screening for hypothyroidism by measuring serum TSH and free thyroxine (T4) or TSH followed by reflex testing for free T4 if TSH is abnormal. Children whose autoimmune thyroiditis is identified by screening are diagnosed at an earlier stage of the disease, and so have fewer clinical symptoms and signs of hypothyroidism [24].

•Down syndrome – Children with Down syndrome are at increased risk for both congenital and acquired hypothyroidism. Thyroid function tests in infants and older children with Down syndrome often show mild TSH elevation and normal free T4 levels. While these results may indicate subclinical hypothyroidism, TSH levels just above the upper reference range may result from an altered TSH set-point in this population. The cause of acquired hypothyroidism in Down syndrome children is usually autoimmune thyroiditis. The cause of congenital hypothyroidism in Down syndrome infants is not clear, but it does not appear to be autoimmune thyroid disease. There is speculation that the extra chromosome 21 results in genomic dosage imbalance of dosage-sensitive genes interfering with thyroid hormone production. (See "Down syndrome: Clinical features and diagnosis", section on 'Thyroid disease'.)

In one report of children with Down syndrome, 28 percent had positive serum antithyroid antibody titers (mostly TPOAb), 14 percent had subclinical hypothyroidism, 7 percent overt hypothyroidism, and 5 percent hyperthyroidism [18]. In another cross-sectional study of 70 children with Down syndrome, 24 percent were hypothyroid; the percentage increased with age in those with positive serum antithyroid antibody titers [25]. In a longitudinal series, the cumulative incidence of hypothyroidism up to age 25 years was 35 percent [26].

Because of this high prevalence of thyroid disease, children with Down syndrome should be screened throughout the lifespan. The American Academy of Pediatrics recommends screening at birth (newborn screen), at 6 and 12 months, and then annually thereafter [27]. (See "Down syndrome: Management", section on 'Thyroid function'.)

•Turner syndrome – The prevalence of autoimmune thyroid disease in Turner syndrome increases with increasing age. Autoimmune thyroid disease is more common in Turner girls with an isochromosome Xq or deletion of Xp [28] karyotype as compared with those with a 45,X karyotype. It is rare in young children but rises to approximately 15 percent in adolescents and close to 40 percent in adult women [29,30]. Annual screening for thyroid disease is recommended in all patients with Turner syndrome. (See "Clinical manifestations and diagnosis of Turner syndrome" and "Clinical manifestations and diagnosis of Turner syndrome", section on 'Autoimmune disorders'.)

•Type 1 diabetes mellitus – Among children with type 1 diabetes mellitus, approximately 20 percent have high serum antithyroid antibody concentrations and 5 percent have abnormalities in thyroid function, usually subclinical hypothyroidism [31,32]. Children with type 1 diabetes should be screened for thyroid disease at diagnosis (after metabolic control is established) and then every one to two years thereafter. (See "Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus", section on 'Autoimmune thyroiditis'.)

•Celiac disease – Approximately 10 to 20 percent of individuals with celiac disease have autoimmune thyroiditis, and its clinical course does not appear to be affected by a gluten-free diet [33]. Conversely, approximately 2 to 7 percent of individuals with autoimmune thyroiditis develop celiac disease; the association is weak during childhood and appears to increase with age [34]. However, after excluding children with Down syndrome and type 1 diabetes mellitus, the incidence is similar to that of the general population [35]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'High-risk groups'.)

•Klinefelter syndrome – There is limited information on the risk of thyroid disease; one study reported hypothyroidism in one of eight boys with Klinefelter syndrome [22]. However, another study found a general shift toward lower values in serum free T4 concentrations but no compensatory increase in serum TSH, changes more consistent with central hypothyroidism [23]. (See "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome'.)

•Autoimmune polyglandular syndrome – A few children with autoimmune thyroiditis have or later develop other autoimmune endocrinopathies and, therefore, have an autoimmune polyglandular syndrome [36]. Autoimmune thyroiditis occurs in approximately 10 percent of children with type I autoimmune polyglandular syndrome (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy or Whitaker syndrome); the more common manifestations of this syndrome are hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis. Chronic autoimmune thyroiditis occurs in approximately 70 percent of children with type II autoimmune polyglandular syndrome (Schmidt syndrome), which has as its other major manifestations adrenal insufficiency and autoimmune diabetes. In one study, autoimmune gastritis with antibodies to gastric parietal cells was found in 30 percent of children with autoimmune thyroiditis [37]. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Autoimmune adrenalitis'.)

•Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome – Autoimmune thyroiditis may present in infancy as part of the rare X-linked disorder characterized by autoimmune endocrinopathy, enteropathy, and eczema. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

Disorders with transient hypothyroidism, developing after a short course of hyperthyroidism — These disorders are characterized by hyperthyroidism in the acute phase, often followed by hypothyroidism, then recovery to euthyroidism.

●"Hashitoxicosis" – In a small percentage of children with autoimmune thyroiditis, the initial presentation is characterized by hyperthyroidism of short duration (<3 months), often termed "Hashitoxicosis." In some children, the hyperthyroidism results from production of TSH receptor-stimulating antibodies (TRAb or thyroid-stimulating immunoglobulins [TSI]), followed by autoimmune destruction of the thyroid gland, resulting in hypothyroidism [38]. In other children, the hyperthyroidism results from "destructive" thyroiditis with release of preformed, stored thyroid hormone, followed by hypothyroidism once this storage supply is exhausted. Typically the thyroid gland is not enlarged and is nontender. During the hyperthyroid phase of the form of destructive thyroiditis, radioactive iodine uptake will be low, distinguishing this entity from Graves disease in which the uptake is high. (See "Painless thyroiditis" and "Clinical manifestations and diagnosis of Graves disease in children and adolescents", section on 'Destructive thyroiditis with thyrotoxic phase'.)

●Subacute granulomatous thyroiditis – This disorder, also known as de Quervain disease, is thought to be a viral or postviral syndrome and is characterized by a tender, diffuse goiter, usually without fever or leukocytosis, with high erythrocyte sedimentation rates (ESR), and a brief course of hyperthyroidism (two to six weeks), followed by hypothyroidism and then recovery. These features distinguish it from infectious (suppurative) thyroiditis, which is characterized by pain, fever, and leukocytosis, but usually without hyperthyroidism. Subacute thyroiditis with hyperthyroidism followed by hypothyroidism has been reported with coronavirus disease 2019 (COVID-19) infections [39]. (See "Suppurative thyroiditis in children and adolescents" and "Clinical manifestations and diagnosis of Graves disease in children and adolescents", section on 'Destructive thyroiditis with thyrotoxic phase'.)

Hypothyroidism as a consequence of Graves disease or its treatment — The key characteristic of Graves disease is hyperthyroidism. However, patients who have had Graves disease may ultimately develop hypothyroidism, for several different reasons:

●For children with Graves disease who are treated long term with antithyroid drugs, approximately one-half achieve a true remission, remaining euthyroid after discontinuation of antithyroid drugs. Approximately 10 percent of such children later become hypothyroid, caused by chronic autoimmune thyroiditis with destruction of the thyroid or due to production of a TSH receptor-blocking antibody [40].

●If the Graves disease is treated with radioactive iodine, most children will become hypothyroid, as discussed below. (See 'Other causes' below and "Treatment and prognosis of Graves disease in children and adolescents", section on 'Radioactive iodine'.)

●Similarly, surgical treatment of Graves disease causes permanent hypothyroidism. (See 'Other causes' below.)

Iodine deficiency — The most common cause of hypothyroidism worldwide is iodine deficiency (endemic goiter). Although symptomatic iodine deficiency is uncommon in North America because of fortification of salt and presence of iodine in dairy products, the more recent NHANES reported that approximately 15 percent of women of reproductive age in the United States fall into the iodine-deficient category [41]. Isolated case reports describe acquired hypothyroidism due to iodine deficiency in American children, typically caused by a restrictive diet that fails to include sources of iodine, which include iodized salt, fish, kelp, and commercially produced cow's milk [42]. Iodine deficiency and related hypothyroidism were also reported in a substantial proportion of children on chronic parenteral nutrition, which typically does not include iodine [43]. Children for whom parenteral nutrition is their sole source of nutrition should undergo periodic monitoring of iodine status by checking serum TSH every six months. If serum TSH is elevated, then iodine status can be evaluated by measurement of either 24-hour urinary iodine or spot urinary iodine (and creatinine). (See "Iodine deficiency disorders", section on 'Iodine requirements' and "Parenteral nutrition in infants and children".)

Late-onset congenital hypothyroidism — Late-onset congenital hypothyroidism that develops during childhood may appear to be acquired hypothyroidism. This may occur with some forms of thyroid dysgenesis, such as an ectopic gland or with inborn errors of thyroid hormone synthesis (dyshormonogenesis). Subclinical hypothyroidism has been reported in toddlers with pseudohypoparathyroidism type 1A (MIM #103580; caused by a mutation in the GNAS gene), who present with round facies, rapid weight gain, and subclinical ossifications (osteoma cutis) [44]. Hypothyroidism also occurs with pseudohypoparathyroidism type 1B (MIM #603233); this genetic disorder may present with congenital hypothyroidism detected by newborn screening. (See "Clinical features and detection of congenital hypothyroidism", section on 'Etiology'.)

Syndromes associated with acquired hypothyroidism — The hypothyroidism that occurs in the syndromes below presents after birth but is not autoimmune and could represent late-onset presentation of congenital hypothyroidism:

●DiGeorge syndrome – Loss-of-function mutations in genes involved in the embryonic development of both the thyroid and parathyroid gland may result in a combination of hypothyroidism and hypoparathyroidism. The most common of these conditions is DiGeorge syndrome (MIM #188400), caused by a 22q11.2 microdeletion. In a study of 30 DiGeorge syndrome patients 1 to 43 years of age, one-quarter had subclinical hypothyroidism and one patient had overt hypothyroidism [45]. Ultrasound examination showed that most patients with thyroid dysfunction had thyroid hypoplasia. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

●Williams syndrome – Subclinical hypothyroidism is common among young patients with Williams syndrome (MIM #194050; caused by a deletion of genes in the 7q11.23 region, including elastin). In a report of 92 patients with Williams syndrome, 32 percent had subclinical hypothyroidism and none had thyroid autoantibodies [46]. In most cases, thyroid function improves with age. (See "Williams syndrome" and "Microdeletion syndromes (chromosomes 1 to 11)", section on '7q11.23 deletion syndrome (Williams syndrome)'.)

●Prader-Willi syndrome – Thyroid dysfunction is common in children with Prader-Willi syndrome (MIM #176270). In a report of 243 patients younger than 18 years, subclinical hypothyroidism was present in 4 percent, overt hypothyroidism in 2 percent, and central hypothyroidism in 7 percent [47]. In children with subclinical hypothyroidism associated with mild TSH elevation (5 to 10 mIU/L), the elevated TSH may be explained by obesity. (See "Prader-Willi syndrome: Management", section on 'Hypothyroidism'.)

By contrast, the mechanisms of the acquired hypothyroidism associated with Down and Turner syndromes are autoimmune, as discussed above. (See 'Autoimmune thyroiditis' above.)

Other causes

●Excessive iodine ingestion – Hypothyroidism that is reversible can occur as a result of excessive iodine ingestion, eg, from nutritional supplements (kelp, seaweed) or iodine-rich drugs, as noted below. (See "Iodine-induced thyroid dysfunction", section on 'Sources of iodine'.)

●Parenteral or topical iodine – Parenteral or topical exposure to iodine during medical care can also cause hypothyroidism. Hypothyroidism has been reported in up to 25 percent of infants or children with congenital heart disease after exposure to iodinated contrast agents or topical iodine [48,49]. As a result, the US Food and Drug Administration suggests checking thyroid function within three weeks following exposure to iodinated contrast agents in infants and young children up to three years of age [50].

Case reports describe hypothyroidism in children receiving peritoneal dialysis for chronic kidney disease, who developed iodine overload due to chronic exposure to povidone-iodine-impregnated gauze from the transfer set [51]. (See "Disorders that cause hypothyroidism", section on 'Iodine' and "Clinical features and detection of congenital hypothyroidism", section on 'Transient congenital hypothyroidism'.)

●Drugs – Several classes of drugs are associated with hypothyroidism (see "Disorders that cause hypothyroidism", section on 'Drugs'):

•Antithyroid drugs – Hypothyroidism also can occur in patients with hyperthyroidism who are inadvertently overtreated with antithyroid drugs. (See "Treatment and prognosis of Graves disease in children and adolescents".)

•Antiseizure medications – Some antiseizure medications, notably phenytoin and phenobarbital, stimulate hepatic P450 metabolism and excretion of thyroid hormones and so may cause mild hypothyroidism. Other antiseizure medications such as valproate may be associated with abnormal tests of thyroid function (eg, low serum TSH levels), but it is unclear if this reflects a true central hypothyroidism or an artifact of the TSH assay.

•Lithium – Children treated with lithium, eg, for bipolar disorder, may develop hypothyroidism because lithium inhibits thyroid hormone secretion and interferes with the coupling step of thyroid hormone synthesis.

•Immunomodulating or anticancer drugs – Several of the immunomodulating and anticancer drugs, including interferon alfa; tyrosine kinase inhibitors; immune checkpoint inhibitors; and cytokines, such as interlukin-2, affect thyroid function, most commonly producing hypothyroidism [52].

•Iodine-rich drugs – Drugs such as amiodarone, expectorants or iodinated contrast agents can cause hypothyroidism. In a study of pediatric and young adult patients treated with amiodarone, 17.3 percent developed subclinical hypothyroidism and 13.7 percent overt hypothyroidism [53]. (See "Disorders that cause hypothyroidism", section on 'Drugs'.)

•Minocycline – Though uncommon, minocycline was reported to be associated with nonautoimmune thyroiditis in nine adolescents out of 423 reviewed patients; thyroid function tests showed thyrotoxicosis in four and hypothyroidism in one patient [54].

●Radioactive iodine therapy – Radioactive iodine is commonly used for treatment of children with Graves disease who do not achieve a permanent remission after a period of treatment with an antithyroid drug. In addition, radioactive iodine is sometimes used as primary therapy for Graves disease. With more current recommendations to treat children with higher doses of radioiodine, hypothyroidism develops by six months after therapy in essentially all treated patients [55,56]. (See "Treatment and prognosis of Graves disease in children and adolescents", section on 'Radioactive iodine'.)

●Thyroidectomy – Some children with Graves disease are treated with surgery (typically subtotal thyroidectomy), which usually causes permanent hypothyroidism. Children who undergo thyroidectomy for thyroid cancer invariably develop hypothyroidism. (See "Treatment and prognosis of Graves disease in children and adolescents", section on 'Surgery' and "Thyroid nodules and cancer in children", section on 'Management'.)

●Exposure to external radiation

•Radiation therapy – Approximately 40 percent of children with tumors of the head and neck region (eg, brain tumors or Hodgkin lymphoma) who are treated with radiation (5000 rad [50 Gy]) develop hypothyroidism during prolonged follow-up [57,58]; the risk is probably life-long. This may be a manifestation of either central hypothyroidism due to irradiation of the pituitary through the cranial fields, or primary hypothyroidism due to irradiation of the thyroid from the spinal fields [58]. In a study of children with brain or head and neck tumors treated with external radiation, approximately 30 percent developed primary hypothyroidism, and approximately 50 percent had evidence of central hypothyroidism [59]. Many of the latter were identified on the basis of a subnormal serum TSH response to thyrotropin-releasing hormone (TRH) or absence of the nocturnal surge in TSH secretion. Other studies report a lower rate of central hypothyroidism, around 10 to 20 percent. Thyroid ultrasonography will show reduced thyroid volume in irradiated patients who develop hypothyroidism [60]. Chemotherapy may increase the risk of hypothyroidism. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Thyroid disorders'.)

Transient suppression of the metabolic activity of thyroid tissue may protect it from injury induced by external radiation. In a small uncontrolled study, 37 children undergoing craniospinal irradiation for medulloblastoma, primitive neuroectodermal tumor, or Hodgkin lymphoma were treated with levothyroxine throughout the radiation treatment at doses designed to suppress thyroid activity [61]. Children in whom the metabolic activity of the thyroid was effectively suppressed during the period of external radiation (as measured by TSH levels of <0.3 mU/L) were less likely to develop long-term hypothyroidism as compared with those in whom thyroid suppression was not achieved (hypothyroidism-free survival 70 versus 20 percent). A similar effect persisted at 20 years follow-up [62]. Randomized trials of this approach will be required to fully examine whether concurrent administration of levothyroxine reduces the risk for radiation-induced hypothyroidism.

•Environmental exposure – Environmental exposure to nuclear radiation does not appear to cause clinically significant thyroid disease, although it can increase the risk for thyroid cancer. Follow-up of 13- to 17-year-old adolescents exposed to nuclear fallout from the Chernobyl accident showed a higher prevalence of TPOAb (6.4 versus 2.4 percent in controls), but thyroid function remained normal [63]. (See "Clinical manifestations, evaluation, and diagnosis of acute radiation exposure".)

●Infiltrative diseases of the thyroid – Any disease that infiltrates the thyroid gland can cause hypothyroidism. In the pediatric age group, notable causes are:

•Cystinosis is a metabolic disease characterized by an accumulation of cystine in different organs and tissues leading to potentially severe organ dysfunction, including end-stage kidney disease. The most severe (infantile) form is characterized by renal dysfunction beginning during infancy. If untreated, many patients develop hypothyroidism, usually during late childhood. (See "Cystinosis", section on 'Infantile cystinosis'.)

•Langerhans cell histiocytosis is a histiocytic disorder that may be seen in all age groups, but is most common in children from one to three years old. The most common manifestations are lytic lesions of the bone and various lesions of the skin and oral mucosa. Rarely, affected patients develop hypothyroidism due to infiltration of the thyroid or central hypothyroidism due to infiltration of the pituitary. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Clinical manifestations'.)

●Hepatitis C infection – In a report of 36 children with chronic hepatitis C infection acquired from their mother, 11.1 percent had subclinical hypothyroidism [64]. This did not appear to be autoimmune thyroiditis, as antithyroid antibodies were negative. A meta-analysis of studies in adults with hepatitis C found a modest independent association with hypothyroidism [65].

●Hemangiomas – Hypothyroidism can occur in infants and young children with large hemangiomas, usually involving the liver [66]. The tumors contain very high levels of type 3 deiodinase activity, which catalyzes deiodination of T4 to reverse triiodothyronine (rT3) and triiodothyronine (T3) to diiodothyronine (T2), resulting in low serum T4 and T3 concentrations. Thyroid hormone production is increased, but not sufficiently to compensate for the large increase in T4 and T3 degradation. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)

●Thyroid hormone resistance – Resistance to thyroid hormone (RTH) is a genetic condition characterized by generalized resistance to thyroid hormone. It is usually caused by mutations in the thyroid hormone receptor beta gene (THRB) and is known as RTH-beta (MIM #188570). Affected children have high serum T4 and T3 concentrations and normal or high TSH. They are usually euthyroid because the elevated thyroid hormone concentrations are able to overcome the nuclear receptor defect. However, they may have some tissue-specific clinical manifestations of hypothyroidism and/or hyperthyroidism because tissues with predominantly beta receptors have impaired sensitivity to thyroid hormone, causing symptoms of hypothyroidism, while tissues with predominantly alpha receptors still respond to the excess thyroid hormone concentrations, causing symptoms of hyperthyroidism. Although the defect is present at birth, most cases are not discovered until later in life, often presenting with goiter and/or symptoms of hyper- or hypothyroidism. RTH-alpha (MIM #614450), caused by mutations in the thyroid hormone receptor alpha gene (THRA), has now been reported in children presenting with growth retardation, delayed bone age, and neurocognitive impairment [67]. (See "Resistance to thyroid hormone and other defects in thyroid hormone action".)

●Central hypothyroidism – Any hypothalamic or pituitary disease can cause central hypothyroidism.

•Acquired causes of central hypothyroidism include hypothalamic or pituitary tumors, the most common of which is craniopharyngioma. The effect of pituitary tumors may either be direct or as a result of therapy. Other causes include Langerhans cell histiocytosis and other infiltrative disorders, other brain tumors, trauma, and radiotherapy, as described above.

•Congenital central hypothyroidism is usually part of congenital hypopituitarism, associated with midbrain developmental defects, such as the syndrome of optic nerve hypoplasia (also known historically as septo-optic dysplasia). Congenital defects, although present at birth, may not be discovered until a few years of age and so may appear to be acquired. Isolated TSH deficiency is most commonly caused by mutations in the IGSF1 gene, and less commonly by mutations in the TSH beta-subunit (TSHB) or TRH receptor (TRHR) genes. (See "Central hypothyroidism".)

DIAGNOSIS — Children suspected to have hypothyroidism should have measurements of serum thyroid-stimulating hormone (TSH) and free thyroxine (free T4; or total T4 plus some assessment of serum binding proteins [eg, triiodothyronine (T3) resin uptake]).

Normal ranges for thyroid function tests — The normal ranges for total and free T4 concentrations are slightly higher in children than in adults (table 2) [68-70]. Questions exist regarding the upper limit of normal for serum TSH concentration. TSH levels have diurnal variation (higher at night, lower during the day), and one series suggests that TSH values measured at 8 AM are more sensitive for the diagnosis of mild primary hypothyroidism as compared with measurements at 4 PM [71]. However, normal ranges that are specific for time of day have not been established. (See "Laboratory assessment of thyroid function".)

Interpretation — Results are interpreted as follows:

●Elevated TSH with low free T4 – TSH elevation >10 mU/L with low free T4 is diagnostic of overt primary hypothyroidism. In children with mild elevations of serum TSH (5 to 10 mU/L), the test should be repeated before making treatment decisions. In addition, some children with secondary (central) hypothyroidism may have a mild TSH elevation (although most patients with central hypothyroidism have normal or low TSH).

●Elevated TSH with normal free T4 – Persistent elevation of TSH with normal free T4 is compatible with "subclinical hypothyroidism." For patients with serum TSH >10 mU/L on two or more occasions, we suggest initiating treatment, particularly if the TSH is trending higher.

For children with mild TSH elevations (5 to 10 mU/L), we perform further evaluation and monitoring to determine whether the TSH elevation persists and whether they are likely to develop clinically important hypothyroidism. TSH often will normalize on repeat testing [72]. We also include testing for antithyroid peroxidase antibodies (TPOAb) and antithyroglobulin antibodies (TgAb). If either of these thyroid antibodies is positive, or if suspicious clinical findings are present, we recommend treatment if repeat serum TSH is still in the 5 to 10 mU/L range. (See 'Further evaluation' below.)

Mild elevation of serum TSH concentration (ie, 5 to 10 mU/L) occurs in 10 to 23 percent of children with obesity, associated with normal or slightly elevated free T3 and normal T4 values [73,74]. Elevated serum leptin, present in children with obesity, stimulates increased transcription of the thyrotropin-releasing hormone (TRH) gene, and so may be the primary factor increasing serum TSH levels. Thus, the elevated TSH levels probably are a consequence rather than a cause of obesity. The elevated TSH levels return to normal after weight loss [75].

●Normal or low serum TSH with low free T4 – These findings indicate central hypothyroidism, particularly if thyroid function tests were obtained in a clinical setting suspicious for central hypothyroidism. Similar results may be found with nonthyroidal illness syndrome. If thyroid function tests are obtained in a patient with acute or chronic illness, they should be repeated after recovery from the illness before making a definitive diagnosis. A few children with central hypothyroidism have slightly high serum TSH concentrations because they secrete immunoreactive but biologically inactive TSH [76].

FURTHER EVALUATION

●Primary hypothyroidism – We recommend that patients with overt primary hypothyroidism (elevated thyroid-stimulating hormone [TSH], low free thyroxine [T4]) be tested for autoimmune thyroiditis by measuring antithyroid peroxidase antibodies (TPOAb) and antithyroglobulin antibodies (TgAb). Approximately 85 to 90 percent of children with autoimmune thyroiditis have positive serum TPOAb titers, while 30 to 50 percent have positive TgAb titers [77]. The presence of TSH receptor-blocking antibodies may explain the development of hypothyroidism in some children, which was found in 9.2 percent of children with autoimmune thyroiditis in one study [78]. However, measurement of TSH receptor-blocking antibodies is not recommended as part of routine care.

In a child with hypothyroidism and positive thyroid antibodies who in addition has a palpable goiter, we suggest an ultrasound examination to obtain baseline characteristics of the goiter. Autoimmune (Hashimoto) thyroiditis typically shows a "moth-eaten" or "Swiss cheese-like" pattern of scattered hypo- or hyperechogenicity (image 1). If the patient has a markedly asymmetric goiter or a palpable nodule, ultrasound examination is important to determine size and echo characteristics of the goiter and nodule and determine if fine-needle aspiration biopsy of the nodule is indicated. In a study of 904 children age 1.2 to 12.8 years with autoimmune thyroiditis, thyroid nodules developed in approximately 20 percent over a mean follow-up period of 4.5 years [79]. In patients with positive thyroid antibodies but without these abnormalities on examination, thyroid ultrasonography is helpful but not always necessary. In a study of 105 children with antibody-positive autoimmune thyroiditis, only one-third showed typical ultrasound changes (scattered hypo- and hyperechogenicity) at diagnosis [80]. During 7- to 14-month follow-up periods, more than one-half of the remaining children developed typical ultrasound changes. (See "Diagnostic testing for hypopituitarism" and "Thyroid nodules and cancer in children".)

For children suspected of having a late-onset form of congenital hypothyroidism, other diagnostic studies may be appropriate, as discussed elsewhere. (See "Clinical features and detection of congenital hypothyroidism".)

●Subclinical hypothyroidism – In patients with subclinical hypothyroidism (elevated TSH with normal free T4), it may be helpful to test for TPOAb and TgAb. Those with positive antithyroid antibodies have autoimmune thyroiditis and are at risk to develop overt hypothyroidism over time. The decision to treat depends on the presence of likely clinical features of hypothyroidism, the degree of TSH elevation, and changes in TSH and free T4 over time (see 'Treatment and prognosis' below). In children with obesity, mild elevations of TSH are common, and may not warrant antibody testing if free T4 is normal.

In patients with no evidence of autoimmune thyroiditis (normal TPOAb and TgAb), persistently elevated TSH may be caused by mutations in the TSH receptor gene (TSHR), causing resistance to TSH (MIM #275200). In one study, TSH receptor mutations were found in 29 percent of patients with nonautoimmune subclinical hypothyroidism [81]. Many of these patients have a fully compensated defect, in which case they remain euthyroid and do not require treatment. Others have a partially compensated defect and may become hypothyroid over time. (See "Resistance to thyrotropin and thyrotropin-releasing hormone", section on 'Resistance to thyroid-stimulating hormone'.)

Occasionally, elevations of TSH with normal free T4 are caused by confounders that affect assay measurement of TSH, such as heterophile antibodies or macro-TSH [82,83].

●Central hypothyroidism – Children with confirmed central hypothyroidism should undergo cranial imaging with contrast, preferably magnetic resonance imaging, and tests for other pituitary hormone deficiencies. (See "Central hypothyroidism".)

TREATMENT AND PROGNOSIS

Indications for levothyroxine — Levothyroxine is the recommended treatment for children with primary or central hypothyroidism. The goals of treatment are to restore normal growth and development, including pubertal development.

For patients with subclinical hypothyroidism, treatment decisions often depend on the degree of thyroid-stimulating hormone (TSH) elevation. For those with TSH levels >10 mU/L, there is general agreement to treat, based on expert opinion. There is some controversy about the need to treat children with mild subclinical hypothyroidism, characterized by TSH elevations between 5 and 10 mU/L. If there are clinical features likely to be associated with hypothyroidism, such as a decreasing height velocity, presence of a goiter, positive antithyroid antibodies, or metabolic complications such as dyslipidemia [84], most clinicians would treat until growth and puberty are complete, and then reevaluate thyroid function. Regardless, these patients should be monitored periodically, and treatment initiated if greater abnormalities in thyroid hormones develop. (See 'Diagnosis' above.)

Levothyroxine dose — Initial treatment is started with levothyroxine at the following doses, given by mouth, once daily:

●Age 1 to 3 years – 4 to 6 mcg/kg body weight

●Age 3 to 10 years – 3 to 5 mcg/kg

●Age 10 to 16 years – 2 to 4 mcg/kg

Alternatively, the replacement dose can be calculated as a function of body surface area, in which case, the dose at any age is approximately 100 mcg/m²/day. Body surface area can be determined from height and weight using a calculator (calculator 1).

Levothyroxine in pill form has been the established and effective treatment for decades. Levothyroxine in gel capsule or liquid formulations is now available for treatment. Some studies show benefit of these latter preparations in patients with malabsorption or interfering medications. However, given the unfavorable cost-effectiveness and only weak evidence to support these other preparations [85], pills remain our first choice for treatment.

For most children, therapy should be initiated with a levothyroxine dose in the middle of the appropriate range for age, though an initial dose at the lower end of the range may be used in children with subclinical hypothyroidism and central hypothyroidism. The dose is then adjusted based on thyroid hormone measurements, as described below. Children clear levothyroxine more rapidly than adults; as a result, the weight-adjusted daily replacement dose is higher.

In children with longstanding hypothyroidism, rapid correction of hypothyroidism may be associated with untoward effects, in particular on behavior and an increased risk of pseudotumor cerebri. In these cases, we recommend a slower up-titration to full dosing, for example one-quarter of the estimated full dose for four to six weeks, then advancing by a one-quarter dose increase every four to six weeks, such that full dosing is achieved by 12 to 16 weeks.

Monitoring and dose adjustment — For children with acquired primary hypothyroidism, serum TSH and free T4 should be checked six to eight weeks after initiation of treatment and then every 6 to 12 months. Thyroid function tests should be obtained six to eight weeks after any dose change or if the patient develops any clinical manifestations suspicious for hypo- or hyperthyroidism. The levothyroxine dose is adjusted to maintain TSH and free T4 (or T4) in the normal reference range for age. Because the free T4 reference range varies according to the assay method, clinicians need to determine the range for their specific laboratory. Because the levothyroxine dose gradually increases as children grow, we target TSH in the lower one-half and free T4 in the upper one-half of the reference range to anticipate these changes; however, as long as both values are in the normal range, we judge the levothyroxine dose to be appropriate.

For children with central hypothyroidism, only measurement of serum free T4 or T4 is generally required for dose monitoring. We recommend maintaining the free T4 in the upper one-half of the reference range. As an example, if the normal free T4 reference range is 0.8 to 1.8 ng/dL (10 to 23 pmol/L), the corresponding optimal free T4 range would be between 1.3 and 1.8 ng/dL (16 to 23 pmol/L). Serum TSH, if checked, is usually low or undetectable in treated children with central hypothyroidism, so this test generally is not useful for monitoring these patients.

Adverse effects — Treatment with levothyroxine is generally well tolerated and has minimal adverse effects. Considerations are:

●Patients with longstanding hypothyroidism are at risk for developing pseudotumor cerebri shortly after initiation of levothyroxine treatment (see recommendation for slower up-titration of levothyroxine dosing (see 'Levothyroxine dose' above)) [86]. Children with persistent headaches or vision changes should contact their clinician. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis".)

●Children with more chronic (or severe) hypothyroidism also are at higher risk of temporary poorer school achievement and hyperactivity at initiation of treatment [87].

●Prolonged excessive doses of levothyroxine should be avoided. The potential consequences of overtreatment vary with age: Infants with open cranial sutures may develop craniosynostosis, and older children may develop adverse behavior changes and lower school performance [87].

●Treatment does not lead to substantial changes in weight or body mass index for most children [88].

●Both undertreatment (hypothyroidism) and overtreatment can affect bone mineral density [89]. On the other hand, at least one study found no difference in bone density at diagnosis or after long-term levothyroxine therapy in adolescent girls with subclinical hypothyroidism compared with normal girls [90].

Course — Once levothyroxine therapy is started, it probably is best to continue treatment until growth and pubertal development are complete. At that time, if there is a question of permanency of hypothyroidism (for example, in children with subclinical hypothyroidism), it can be addressed by discontinuing levothyroxine and measuring serum TSH one month later.

Hypothyroidism caused by autoimmune thyroiditis is not invariably permanent; some children treated for several years have persistently normal thyroid function after levothyroxine treatment is discontinued [91,92]. In a review of seven observational studies of children with subclinical hypothyroidism followed for an average duration of 4.3 years, approximately one-third became euthyroid, one-third had persistent subclinical hypothyroidism, and in one-third the hypothyroidism worsened, with some progressing to overt hypothyroidism [93]. Worsening of hypothyroidism tended to be associated with the degree of initial TSH elevation and presence of antithyroid peroxidase antibodies (TPOAb) and antithyroglobulin antibodies (TgAb).

Height outcomes — Children whose hypothyroidism is diagnosed and promptly treated prior to puberty typically have good catch-up growth and normal adult height outcomes, unless they have other causes of short stature. For children who are diagnosed and treated just before or during puberty, and who have longstanding chronic hypothyroidism, adult height may be diminished; the height deficit ranges from 8 to 14 cm [3,94]. Use of a lower initial dose of levothyroxine has been suggested as a strategy to avoid overly rapid acceleration of skeletal maturation, which could lead to loss of adult height [3]. However, the efficacy of this strategy is challenged by a study that reported no correlation between slow or rapid correction of hypothyroidism and skeletal maturation [95]. In the same study, use of other growth-promoting therapies such as gonadotropin-releasing hormone agonists and growth hormone failed to improve adult height outcome [95].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypothyroidism" and "Society guideline links: Pediatric thyroid disorders".)

SUMMARY AND RECOMMENDATIONS

●Causes – Acquired hypothyroidism is the most common abnormality of thyroid function in children and is most often caused by autoimmune thyroiditis. In the United States, 6 percent of adolescents have positive antithyroid antibodies and 2 percent have an elevated serum thyroid-stimulating hormone (TSH). Other causes of hypothyroidism in children are listed in the table (table 1). (See 'Autoimmune thyroiditis' above.)

●Clinical manifestations – Many children with acquired hypothyroidism, particularly those with subclinical hypothyroidism, will be asymptomatic. In those with overt disease, clinical features include declining height velocity, short stature, and/or the presence of a goiter. Adolescents may also have signs of pubertal delay. (See 'Clinical manifestations' above.)

●Evaluation – Patients with symptoms or findings on physical examination compatible with hypothyroidism should be evaluated with measurements of serum TSH and free thyroxine (T4) concentrations, and the results should be compared with age-specific normal values (table 2). If another etiology is not obvious, we recommend testing for antithyroid peroxidase antibodies (TPOAb) and antithyroglobulin antibodies (TgAb) because autoimmune thyroiditis is the most common cause. (See 'Diagnosis' above.)

●Diagnosis – TSH elevations >10 mU/L with low free T4 is diagnostic of overt primary hypothyroidism. In children with milder elevations (TSH 5 to 10 mU/L), the test should be repeated before making treatment decisions. This is because TSH levels are normal in up to 70 percent of such patients when the test is repeated. Moreover, mild elevation of TSH is common in children with obesity and does not warrant thyroid hormone replacement. (See 'Diagnosis' above.)

●Treatment – Patients with clinical and laboratory evidence of hypothyroidism require replacement therapy with levothyroxine. The goals of treatment are to restore normal growth and development and correct associated clinical manifestations of hypothyroidism. We also suggest levothyroxine treatment for patients with subclinical hypothyroidism that is confirmed by repeat testing (Grade 2C) to prevent any untoward effects on growth and development. (See 'Indications for levothyroxine' above and 'Levothyroxine dose' above.)

•Monitoring and dose adjustment – Thyroid function tests should be monitored and levothyroxine dose adjusted to maintain TSH and free T4 (or T4) in the normal reference ranges for age. Once growth and pubertal development are complete, if there is a question of permanency of hypothyroidism, levothyroxine treatment can be discontinued and thyroid function reevaluated. (See 'Monitoring and dose adjustment' above and 'Course' above.)

•Adverse effects – Children with chronic (or severe) hypothyroidism sometimes develop transient problems with school achievement and hyperactivity at initiation of treatment. Prolonged excessive doses of levothyroxine can cause craniosynostosis in infants and adverse behavioral changes in older children. (See 'Adverse effects' above.)