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THYROTOXICOSIS IN CHILDREN Donald Zimmerman, MD, and Aida N. Lteif, MD

The association of goiter and exophthalmos was first recorded in a legal Byzantine text from the third century in which a ”man with bulging eyes and a great walnut round the neck” was d e s ~ r i b e d The . ~ ~ recognition of the disease known as exophthalmic goiter is attributed, however, to Parry.24,87 In 1786 he observed a female patient with palpitations, cardiac enlargement, thyromegaly, and “eyes that were protruded from their sockets.” His record of six cases was not published until 1825, 3 years after his death. Similar patients with “thyroid enlargement,” ”unnatural excitement,” ”lids that were incapable of closing,” and ”eyeballs that were pushed wide from one another and could not be closed” were reported in 1835 by Graves and in 1840 by Von B a s e d o ~ . ~In~1909 , ~ * Osler was the first to hypothesize that the symptoms of Graves‘ disease were caused by the hypersecretion of certain materials by the thyroid gland. Graves’ disease still accounts for most cases of hyperthyroidism in children and adolescents. This review also discusses the less common forms of thyrotoxicosis in the pediatric age group. These rare causes of hyperthyroidism are important to recognize so that proper specific management can be instituted. THYROID PHYSIOLOGY AND FUNCTION IN INFANCY AND CHILDHOOD The thyroid gland derives from the floor of the embryonic pharynx, and its development is largely completed by 10 to 20 weeks‘ gestation. Thyroglobulin production and trapping of iodine occur by the eighth and tenth gestational weeks, respectively. Thyroid hormones and thyroid-stimulating hormone (TSH) are detectable in fetal serum by 12 weeks‘ gestation. The fetal response to exogenous thyrotropin-releasing hormone (TRH) is comparable to that of an adult by 26 to 28 weeks’ gestation. Type I deiodinase is low in the fetus and the

From the Section of General Pediatrics and Pediatric Endocrinology and Metabolism, Mayo Clinic and Mayo Foundation (DZ); Mayo Medical School (DZ); and Mayo Graduate School of Medicine (ANL), Rochester Minnesota

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA

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escape mechanism from the Wolff-Chaikoff block not functional until 36 to 40 weeks’ gestation. Marked changes occur in thyroid physiology at the time of birth in the full-term newborn. An abrupt rise of TSH causes an increase of serum T, and T, within 24 hours of birth followed by a progressive decline over a few weeks.32T, turnover is markedly higher in infancy in comparison with adulthood and somewhat higher in childhood. Whereas T, production rates are approximately 5 to 6 kg/kg/day in infancy, they decrease slowly to 1.5 kg/kg/ day in adulthood. Serum thyroglobulin reaches adult levels by 6 months. The size of the thyroid increases gradually by 1 g/year until age 15 years, when it achieves the adult size of 15 to 20 g.” GRAVES’ DISEASE

Graves’ disease accounts for 10% to 15% of all childhood thyroid disorders. The incidence increases with age and peaks during adolescence. Girls are affected four to five times more frequently than are boys. The clinical triad of hyperthyroidism, ophthalmopathy, and dermopathy is classic, even though dermopathy is rare in the pediatric age group. Pathogenesis

Graves’ disease is an autoimmune disorder that results in the production of antibodies directed against thyroid antigens such as the TSH receptor, thyroglobulin, and thyroid peroxidase. Evidence suggests that the TSH receptor is the primary autoantigen of Graves’ disease. As many as 60% of patients have a family history of autoimmune thyroid disease. Common HLA haplotypes in affected patients are Al, B8, and DR3, suggesting that the genetic component of the pathogenesis may involve regulation of immunity. Immune mechanisms which may contribute to Graves’ disease include suppressor T-cell function permitting thyroid receptor antibody production, breakdown of the idiotypeanti-idiotype network of beta cell immunoregulation,2z,30 abnormal presentation of normally unexposed antigens following thyroid cell destruction or viral invasion, presentation of abnormal antigens that are denaturated or partially degraded, or the presentation of bacterial epitopes such as Yersiniu envelope proteins that cross react with the extracellular domain of the thyrotropin receptor gene.” Work has shown the presence of antibodies to plasmid-encoded proteins of enteropathogenic Yersiniu126and to a human intracisternal type A retroviral parti~le.5~ These investigative leads have not yielded conclusive results. Serologic evidence of retroviral or bacterial exposure together with genetic susceptibility may be the major predisposing factor underlying the pathogenesis of Graves’ disease.58 Clinical Manifestations

In most patients with Graves’ disease, hyperthyroidism develops insidiously. Symptoms may be minimal over several months. Nervousness, hyperactivity, and a decline in school performance may easily be attributed to other causes. Major clinical manifestations include a goiter, heat intolerance, fatigue, restless sleep, weight loss despite increased appetite, palpitations, tremors, diarrhea, shortened attention span, and proximal muscle weakness. On physical

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examination, thyromegaly is present in more than 95% of cases. The gland is usually diffusely enlarged, smooth, and nontender. There may be a palpable thrill or an audible bruit because of increased blood flow to the thyroid. Other signs include tachycardia, fine tremors, skin warmth and moisture, muscle weakness, increased pulse pressure, and exaggerated deep tendon reflexes. Ophthalmic findings are more common but less severe than in adults with Graves’ disease. They include proptosis, lid lag, lid retraction, stare, chemosis, conjunctival injection, periorbital edema, excess lacrimation, ocular discomfort and pain, and diplopia. Pretibial myxedema is much more common in adults than in children. Height and bone age may be advanced. Costochondral calcifications may be present,lo1and, in neonates, craniosynostosis and mental retardation have been reported. Coexisting diseases include diabetes, Down syndrome, vitiligo, rheumatoid arthritis, nephritis, hyperlipidemia, asthma, and sickle cell disease. Laboratory Findings

In Graves’ disease, circulating levels of T4, T,, and FT, are increased while TSH is suppressed. T, thyrotoxicosis may be seen early in the course of the disease. Measurement of TSH by high-sensitivity assay is most useful, because it permits use of a lower limit of normal values. Thyroid receptor antibodies are usually elevated at diagnosis. These antibodies are commonly measured by two types of assays?2 Receptor assays assess the ability of Graves’ immunoglobulins to inhibit labeled TSH from binding to thyroid membranes. Sensitivity has reached 93% in children with untreated active Graves’ disease.’2 Bioassays assess the ability of immunoglobulin concentrates to stimulate the production of CAMP from thyroid cells and have a sensitivity of 73%. All patients with inactive Graves’ disease have negative findings in this bioassay.yzAntibodies to thyroglobulin, peroxidase, or both are present in the majority of patients. Treatment

The ideal treatment of Graves’ thyrotoxicosis in childhood remains controversial. Results of none of the three available treatment modalities have been shown to be ideal or clearly superior to the others. Antithyroid Medications

Methimazole (MTZ) and propylthiouracil (PTU) are the recommended antithyroid drugs for the long-term treatment of childhood Graves‘ disease in the United States. Carbimazole is available in Europe and in other areas. These drugs inhibit the incorporation of oxidized iodine into tyrosine residues of thyroglobulin and block the coupling of iodotyrosyl residues to form T, and T,. Furthermore, PTU (unlike MTZ or carbimazole) inhibits the peripheral conversion of T4 to T3. The clinical relevance of the immunosuppressive activity of thiourea that is demonstrable in vitro remains controversial.2K,x5 Therapy is generally started with PTU (5 to 7 mg/kg/day) or MTZ (0.5 to 0.7 mg/kg/day), with initial total daily doses reaching 300 to 600 mg/day for PTU and 30 to 60 mg/day for MTZ. When clinical improvement occurs, the dose may be tapered in an attempt to maintain iodothyronine levels in the normal range. Two general methods are used. One method consists of reducing the dose to achieve levels

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of T4 and TSH in the normal range. The advantage of this method is that the dosage, and therefore the side reactions, may be minimized. Another method involves fully suppressing thyroid activity and supplementing with exogenous L-T, to normalize circulating T4 and TSH. This method may give more stable hormonal levels and may optimize the probability of remission.M,76 Medical therapy has a high risk for failure in children with large goiters, a history of previous relapse, thyroxine levels greater than 20 pg/dL, thyroglobulin levels greater than 50 pg/mL, or ~phthalmopathy.'~~,Relapse is also more common in patients with T3-predominant Graves' disease114and possibly in those who receive either low doses or a short course of antithyroid drugsz Children with more than one indicator relapse more frequently. Remission rates range from 30% to 60% (Table 1).Indicators of possible remission include a smaller size of the thyroid gland, a decreased T3 to T4 ratio, a lower early radioiodine uptake, and lower thyroid-stimulating immunoglobulin (TSI) levels.33,y2 Major drawbacks to drug therapy are the failure to achieve remission, noncompliance, and toxicity. Adverse reactions are more common in children (Table 1).Major side effects include agranulocytosis, collagen vascular disease, hepatitis, erythema multiforme, and nephrotic s y n d r ~ m e . ~ Radioactive Iodine

The use of radioactive iodine for the treatment of Graves' disease in childhood is still controversial. Several studies have failed to demonstrate an increased incidence of leukemia, thyroid cancer, or other malignancies following131 I thera~y.6~ Nonetheless, other studies raise the possibility of a greater frequency of thyroid neoplasms in younger patients, and recent experience with radioiodine exposure near Chernobyl has heightened concerns about the particular susceptibility of children to this effect. No adverse genetic effects have been identified in the offspring of patients treated with radioiodine for Graves' disease in childhood. Both hypoparathyroidism and hyperparathyroidism have been reported in patients following radioiodine therapy. The calculated dose of iodine has varied. At the authors' institution, between 100 and 200 pCi is used per gram of thyroid tissue according to the following formula: Dose

=

Thyroid Weight x 100-200 pCi/g Radioiodine Uptake

Table 1. MEDICAL TREATMENT OF GRAVES' DISEASE Results

Treatment outcome Remission Relapse Complications Granulocytopenia Arthritis

Liver disease Skin rash

Patients (%)

46.8 29.0

5.6 2.3 1.9

8.0

Review of 10 series including 651 children. Data from references 3, 6, 12, 42, 48, 61, 70, 73, 99, and 120.

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Table 2. TREATMENT OF GRAVES’ DISEASE WITH RADIOIODINE Treatment Outcome

Patients (%)

Hypothyroidism Hyperthyroidism controlled Retreatment Benign nodules (histology)

69.0 98.0 12.0 4.4 ~~

Review of 10 series including 550 children. Data from references 19, 21, 34, 36, 42, 47, 61, 97, 102, and 109.

Farrar and Toftz7have suggested the use of a sliding scale of radioiodine for different thyroid volumes. Transient exacerbation of hyperthyroidism may occur but is usually managed successfully with beta-adrenergic blockade. Hypothyroidism eventually develops in more than 50% of patients (Table 2). Low-dose radioiodine treatment decreases the incidence of post-therapeutic hypothyroidism but increases the risks of treatment failure. Radioiodine may be of benefit to poor surgical candidates or to patients with recurrent thyrotoxicosis following thyr~idectomy.‘~~ Surgery

Thyroid surgery is often required for the treatment of childhood Graves’ disease. It is most often performed in patients with large goiters and severe thyrotoxicosis. Subtotal thyroidectomy is the most common procedure. The incidence of recurrent hyperthyroidism correlates with the size of the thyroid remnant. Preoperative therapy consists of Lugol’s solution 10 to 14 days prior to surgery and beta-adrenergic blockers. Some clinicians also employ antithyroid drugs preoperatively. Postoperative complications are summarized in Table 3. NEONATAL GRAVES’ DISEASE Neonatal thyrotoxicosis is an uncommon disorder that occurs in the offspring of women with Graves’ disease or with chronic thyroiditis. It equally affects male and female infants. The prevalence of Graves’ disease in pregnant Table 3. Treatment of Graves’ Disease with Surgety Results Treatment outcome Hypothyroidism Recurrence Complications Hypoparathyroidism Vocal cord paralysis Bleeding Keloid formation Mortality Papillary cancer (histology)

Patients (%) 42.0 10.0

2.0 1.2 0.2 1.7 0.1 (prior to 1948) 1.5

Review of nine series including 555 children. Data from references 5, 6, 12, 42, 58, 73, 99, 107, 120.

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women is 0.2%. Neonatal hyperthyroidism will develop in 1% to 1.4% of the offspring of these women.’s Asymptomatic women with Graves’ disease and, in rare instances, women with Hashimoto’s thyroiditiP or women not known to have any thyroid disease may give birth to an affected newborn. Neonatal hyperthyroidism results from the transplacental passage of maternal TSI. Newborns seem to be at increased risk when maternal TSI titers are Levels of TSI predictive of the disorder are, however, hard to define, mainly because methods of TSI measurement have changed markedly over the years, and there is no agreed upon international standard for the TSI assay. Zakarija and McKenzie13*have found that, in infants with neonatal hyperthyroidism, a minimum 500% increase in CAMPis present on bioassay of maternal immunoglobulin G with cultured thryoid cells. Fetal hyperthyroidism usually occurs during the second half of pregnancy when the human thyroid becomes fully responsive to TSH. It is most significant, however, in the third trimester because of increased passage of maternal immunoglobulin across the placenta. Fetal thyrotoxicosis leads to tachycardia (defined as a heart rate >160/min), craniosynostosis, frontal bossing, mental retardation, intrauterine growth retardation, premature delivery, and a mortality rate of approximately 16%. To avoid these consequences, pregnant women with elevated levels of TSI need to be treated with PTU, 150 to 300 mg daily, when the fetal heart rate is more than 160/min. Because a high dose of PTU may cause fetal goiter and 45 the dose should be tapered rapidly to the lowest possible dose that can maintain the fetal heart rate below 160/min. PTU is preferable to MTZ, because it decreases the rate of T4 to T3 conversion in peripheral tissues, and because MTZ may be associated with cutis a p l a ~ i a . ~ ~ Thyrotoxic features in the neonatal period include goiter, exophthalmos, tachycardia or arrythmias, flushing, diarrhea, weight loss, hypertension, irritability, tremors, and advanced bone age. Hepatosplenomegaly, jaundice, and thrombocytopenia may also occur. These signs are usually seen within hours of birth but may be delayed up to 10 days when thionamides are administered to the mother and up to 6 weeks when passage of maternal thyroid receptor blocking antibodies occurs. Laboratory findings include elevated thyroxine, FT4, and triiodothyronine and suppressed TSH levels. The duration of the disease correlates with the initial TSI titers in the mother and the time required for their metabolic clearance. It usually averages 2 to 3 months but may last beyond 1 year of age.lr7Neonatal hyperthyroidism requires PTU (5 to 10 mg/kg/day) or MTZ (0.5 to 1 mg/kg/day) with or without iodine (potassium iodide, 1 drop/ day or Lugol’s iodide solution, 1 to 3 drops/day) and beta-adrenergic blockers (propranolol, 1 to 2 mg/kg/day). Successful treatment has also been achieved with the use of oral cholecystographic agents.60,*19 Radioactive iodine is contraindicated. Adequacy of therapy is monitored by measuring thyroid hormone levels and TSH every 2 weeks. Therapy may be stopped after 2 to 3 months or, ideally, until TSI can no longer be detected.”” Breast-feeding is safe when mothers are receiving PTU, but in this situation, it is advisable to check neonatal thyroid function at least once monthly. Patients receiving MTZ are advised against lactation because of its high concentration in breast milk. IODINE-INDUCED HYPERTHYROIDISM

Ingestion of excess iodine may cause hyperthyroidism by increased synthesis and release of T, and T3 in patients with preexisting thyroid autonomy from chronic iodine deficiency or autonomous thyroid nodules and in patients with

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Graves' disease. Iodine-induced hyperthyroidism has been described in adults and even newborns with normal thyroid glands.", lah Impaired autoregulation m the presence of excess iodine has been proposed. The biphasic response to iodine known as the Wolff-Chaikoff effect seems to be altered so that the rise in htrathyroidal iodide concentration results in an increase in hormone synthesis at levels of iodide that would normally turn off the synthesis.lS Exposure to iodide may result from health food preparations (kelp), topical antiseptics (povidone-iodine), and radiographic contrast material and from medications (amiodarone, expectorants). Iodine-induced hyperthyroidism should be suspected when a history of iodine ingestion is obtained and confirmed by findings of low uptake in the thyroid, T4 thyrotoxicosis, normal thyroglobulin levels, and increased urinary iodine levels. T, is normal or mildly elevated, and the T, to T3 ratio is increased. Overiodination of thyroglobulin occurs in the thyroid tissue." Treatment begins with discontinuation of iodine administration. Recovery may take as long as 6 months. A phase of biologic hypothyroidism may precede the return to euthyroidism. Beta-adrenergic receptor blockers may be used. Steroids and thionamides are required at times for treatment of amiodarone-induced thyrotoxicosis.

THYROID HORMONE INGESTION Deliberate or inadvertent ingestion of thyroid hormones may cause thyrotoxicosis. Signs and symptoms of thyrotoxicosis occur with varying frequency during experimental or prolonged exposure to thyroid hormones. Large doses are often well-tolerated, especially in healthy euthyroid patients.lO, Acute thyroid hormone poisoning occurs most frequently in patients younger than 5 years of age. However, severe toxicity is uncommon in children even after massive ingestion of levothyroxine. The time course of the clinical response is unpredictable. Litovitz and White7' have reported 78 cases of excess levothyroxine (as much as 16 mg) ingestion in children. Patients who ingested less than 1.5 mg and who did not receive gastric lavage were asymptomatic. Symptoms of thyrotoxicosis developed in 5.1% of patients. This may have been the result of the brief exposure to elevated thyroxine levels, inhibition of the peripheral conversion to triiodothyronine, increased disposal rates of T4 and T1, and down regulation of triiodothyronine receptors. Clinical symptoms do not necessarily correlate with plasma T, levels and usually consist of fever, tachycardia, irritability, vomiting, diarrhea, and hyperactivity. Seizures have rarely been reported. The onset of symptoms occurs within 12 to 48 hours after the ingestion levothyroxine but may be as late as 10 days. The thyroid gland is normal or absent on palpation. Laboratory studies reveal that levels of thyroid hormones are elevated while TSH is suppressed. Serum thyroglobulin is low. An elevation of reverse T3out of proportion to serum T4 and T3 has been reported. Radioactive iodine uptake is low. Treatment of thyroiditis factitia is still controversial. Induced emesis and gastric lavage have been used for acute ingestions. Tenenbein and Dean"7 have recommended gastrointestinal decontamination procedures when the ingestion is in excess of 2 mg of levothyroxine. Beta-adrenergic blockers and ipodate are effective when signs of hyperthyroidism develop. Plasmapheresis and exchange transfusion have been recommended for life-threatening situations.@Prophylactic antihyperthyroidism therapy is not recommended. Treatment should be based on clinical findings and not on laboratory values.

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McCUNE-ALBRIGHT SYNDROME

The McCune-Albright syndrome (MAS) is a sporadic disease characterized by the triad of polyostotic fibrous dysplasia, cutaneous pigmentation, and sexual precocity.1mCommon associated endocrinopathies include hyperthyroidism, acromegaly,sOCushing's syndrome, and hyperparathyroidism. Affected tissues originate from the ectoderm, endoderm, or mesoderm. Therefore, it has been postulated that MAS is caused by a somatic dominant mutation that occurs before the development of the trilaminar disk. Cells of affected endocrine glands as well as melanocytes and osteoblasts utilize CAMPin the signaling pathways which are known to stimulate the growth and function of these It is well-known that growth hormone-secreting adenomas and thyroid adenomas have activating mutations in the alpha-subunit of the G protein which lead to inactivation of the intrinsic GTPase activity and, hence, to an increased production of CAMP. These mutations result from the substitution of the amino acid residues arginine 201 and glycine 227 within exon 8 of the Gsa gene.124Similar mutations in the alpha-subunit have been found in MAS. Weinstein and colleagues studied affected tissues from four patients with MAS.lZ1Substitution of cysteine or histidine for arginine at position 201 was present in all affected endocrine tissues. Cells were mosaic for mutant and normal Gsa gene. The investigators were not able to find activating mutations in dysplastic bones and in cafe au lait spots. The random distribution of mutant cells may explain the differing presentation of MAS. Clinically, diffuse enlargement of the thyroid gland occurs early and then evolves into a multinodular Ultrasonographic findings in the thyroid may be abnormal even when no thyroid dysfunction is present." Such abnormalities include thyroid enlargement, inhomogeneous areas, and hypoechoic cystlike lesions." TSH receptor antibodies are absent. TSH is suppressed. TSH response to TRH is blunted, and radioactive iodine uptake is increased. Feuillan and co-workersZvfound that 8 of 19 girls (42%) with MAS had abnormal thyroid function, and that 7 of 18 had thyroid abnormalities on ultrasonography. Six had a serum TSH level that was undetectable or below control range at baseline. Four patients had thyroid enlargement on physical examination. The thyroid disease in MAS seems to have an indolent course. In a study by Hamilton and MalooP3 of hyperthyroidism in MAS, 10 of 16 patients with thyrotoxicosis had goiters that were multinodular by palpation. Toxic multinodular goiter appeared at an average age of 22.9 years. However, a case of neonatal MAS with Cushing's syndrome and hyperthyroidism has been reported.12vHyperthyroidism does not spontaneously remit in MAS. Because antithyroid drugs would need to be continued indefinitely, and because hyperthyroidism often recurs after radioactive iodine therapy, surgical excision is indicated. MUTATION IN THE TSH RECEPTOR GENE

Nonautoimmune hereditary hyperthyroidism is a rare disorder caused by mutations in the thyrotropin receptor gene on the long arm of chromosome 14. The thyrotropin receptor gene belongs to the superfamily of G protein-coupled transmembrane receptors. Germline mutations causing autosomal dominant nonimmune hereditary hyperthyroidism have been identified in two families from the northern part of France (Nancy and Reims)."' Tyrosine to cysteine substitution is present in the gene encoding the seventh transmembrane region of the receptor in the first family and an alanine to valine substitution in the

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gene encoding the third transmembrane region in the second.z6Kopp and coworkers62have reported on a patient with congenital hyperthyroidism who was heterozygous for a new germline cell activating mutation of the TSH receptor gene. Molecular analysis of the patient's leukocytes and thyroid tissue revealed substitution of leucine for phenylalanine in the sixth transmembrane region of the receptor?* These mutations may induce a change in position of transmembrane helices and thereby activate the receptor with subsequent generation of CAMP, which is known to stimulate the growth and function of thyrocytes. Activating mutations of Gscu, Gia, or of rus oncogenes have not been identified in neonatal hyperthyroidism. The diagnosis should be suspected when the maternal history is negative for thyroid disease. Diffuse goiter is present on palpation. Levels of T4, FT4, and T3 are increased while TSH is suppressed. Tnyrotropin receptor stimulating antibodies are not present. Early recognition of the disorder is essential, because its onset during fetal development may lead to severe and irreversible consequences when left untreated. PITUITARY RESISTANCE TO THYROID HORMONES

In 1967 Refetoff and colleagues93described the first two cases of generalized thyroid hormone resistance (GTHR) in two siblings who had a syndrome combining deaf-mutism, stippled epiphyses, goiter, and high protein-bound iodide.93 Selective pituitary resistance to thyroid hormones (PRTH) leading to peripheral stigmata of thyrotoxicosis was reported in 1975 by Gershengorn and Weint r a ~ bGRTH . ~ ~ is an autosomal dominant disorder caused by mutations within the T3-bindingdomain of the thyroid receptor beta gene (TXP) on chromosome 3.% In vitro studies suggest that the mutant-type receptors inhibit wild-type receptor action (dominant negative leading to target gene resistance to the thyroid hormone action. Because a significant degree of clinical overlap exists between these two entities: and after the demonstration of mutations in the T,-binding domain of the TRP gene in few patients with PRTH,SZ,94 there might be reason to believe that PRTH constitutes a form of GRTH in which pituitary hyposensitivity to thyroid hormones predominates over peripheral tissue hyposensitivity. Other researchers have implicated a defective type I1 5' deiodinase in the pathogenesis of PRTH.94 Signs and symptoms of hyperthyroidism, hypothyroidism, or euthyroidism have been documented in GRTH. Tachycardia in GRTH may represent a normal response of the myocardium to thyroid hormone acting via a normal alphareceptor. In PRTH, there is an appropriate response of peripheral tissues to excess thyroid hormones so that features of thyrotoxicosis are preponderant. In both cases, laboratory studies show elevated T,, FT4, and TJ, and unsuppressed TSH. Radioiodine uptake is increased. Exogenous T3 administration leads to an equally impaired but significant basal and stimulated TSH suppression in GRTH and PRTH. Resistance to thyroid hormones needs to be differentiated from thyroid-binding globulin excess in which free thyroid hormone levels are usually normal. Resistance to thyroid hormones should also be differentiated from TSHsecreting tumors in which a disproportional secretion of alpha-subunit is present. Partial suppression of basal TSH level after T3 administration in patients with GRTH, PRTH, and TSH-secreting tumors occurs in 90%, 88%, and 25% of cases, respectively." Most patients with GRTH require no treatment. Some may benefit from treatment with T, or T,. The T3 analog 3,5,3'-triiodothyroacetic acid (Triac) has been used in therapy of resistance to thyroid hormones. Triac has a higher

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affinity for thyroid receptor beta-1 in comparison with T, and more effectively overcomes the dominant negative effect relative to T, by mutant receptor beta-1 than does T3.lI5It also inhibits pituitary TSH secretion without having peripheral thyromimetic consequences. Its beneficial effect has been variable. Bromocriptine and the somatostatin analogue octreotide may be administered, but TSH secretion often escapes from their inhibitory Treatment of resistance to thyroid hormones requires careful monitoring during the period of active growth. TSH-SECRETING ADENOMAS

Hypersecretion of TSH from a pituitary adenoma is a rare cause of hyperthyroidism in childhood. Only a few cases have been reported to date. The youngest reported patients with thyrotropin-secreting tumor were 11 years of age.?,84 These adenomas may secrete excess prolactin, growth hormone, and alpha-subunit besides TSH.'04 Secretion of alpha-subunit is seen in most cases and in amounts greater than TSH. TSH-secreting adenomas may lead to secondary hypopituitarism and diabetes insipidus. They are usually large because of their aggressive features, and because their diagnosis is often delayed. The length of time from the onset of initial treatment for the hyperthyroidism to the recognition of the pituitary tumor was almost 6 years in a 13-year-old female. In another case, pituitary adenoma was diagnosed, but the diagnosis of hyperthyroidism was delayed until after surgical resection.? The clinical presentation consists of signs and symptoms of hyperthyroidism, visual complaints, and headaches. Laboratory studies are remarkable for increased levels of T4,FT,, and T, with inappropriately normal or increased TSH. Immunoradiometric assays should be performed in attempt to separate euthyroid from suppressed serum TSH values. An elevated TSH alpha level or a TSH alpha/TSH molar ratio greater than 1 is seen in most adult patients.Io4,lo5In at least two recorded pediatric cases, alphasubunit levels were normal', 63 (Table 4). Pituitary tumors secreting TSH need to be differentiated from thyroid hormone resistance, because TSH values are elevated or normal in both. In a large number of TSH-secreting adenomas, and in contrast to thyroid hormone Table 4. CLINICAL AND LABORATORY FEATURES OF NINE PEDIATRIC PATIENTS WITH HYPERTHYROIDISM OWING TO TSH-SECRETING TUMOR ClinicallLaboratory Characteristics

Number of Patients (%)

Goiter Sex Male Female Visual fields defect Ophthalmopathy Elevation of T4 or T, TSH normal or elevated TSH nonresponsive to TRH Alpha-subunit elevated Elevated growth hormone

818 (100)

Data from references 4, 7, 63, 84, 89, 90, 108, 111 , and 131

519 (55) 419 (45) 418 (50) 418 (50) 919 ( 1 00) 919 ( 1 00) 215 (40) 214 (50) 216 (33)

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resistance, TRH administration fails to increase TSH secretion. However, normal TSH response after TRH stimulation has been reported in two adolescent girls with thyrotropin-secreting adenomas. Imaging studies of the head are often pivotal. In the majority of cases, surgical removal is incomplete and TSH excess persists even after additional pituitary irradiation. Earlier diagnosis would likely make the tumors easier to cure. Octreotide has been shown to be effective in decreasing TSH levels.9oTumor shrinkage is observed in one-third of octreotidetreated patients.16,l7 Normalization of thyroid hormone levels with persistent elevation of serum TSH is occasionally seen. Bromocriptine has no beneficial effect. THYROID MASSES

Hyperthyroidism caused by multinodular goiter is exceedingly rare in the pediatric age group. It is most commonly seen in the context of MAS but has also been reported in a few ~ h i l d r e n , ” ~ mostly , ~ ~ , ’ ~females, who did not have any feature suggestive of MAS. Leger and c o - w ~ r k e r shave ~ ~ reviewed the records of 17 children who underwent surgery for multinodular goiter. Hyperthyroidism occured in two of the cases. Cardiovascular manifestations were the most common indications of hyperthyroidism in all reported cases. Subtotal thyroidectomy has been the treatment of choice for children and adolescents. Autonomous hyperfunctioning solitary thyroid nodules occur predominantly in adults.4O.95 Only 2.2% to 8.6% of the patients are less than 20 years of age at diagnosis. Most affected patients are females. Young children and adolescents with autonomous nodules are usually clinically euthyroid. The incidence of hyperthyroidism secondary to these functional nodules increases with age. Thyrotoxicosis has been reported, however, in a child as young as 22 months.K2 In a clinical review of nodular goiters, Hayles and colleagues50 found that adenomatous goiter was associated with thyrotoxicosis in only 1 of 68 cases. Harnb~rger,~ reviewed 349 cases of autonomously functioning thyroid nodules. Toxic lesions were seen in 12.5% of patients younger than 20 years of age in comparison with 56.5% of patients more than 60 years of age. Most toxic nodules were at least 3 cm in diameter’ (Table 5 ) . Laboratory findings suggestive of subclinical hyperthyroidism are not uncommon with normal levels of T,, FT4, and TSH in addition to elevated serum T3 concentrations and blunted TSH response to TRH.86These solitary hyperfunctioning nodules are usually benign adenomas, but cases of primary carcinomas occuring in functioning thyroid nodules are described. The association of hyperthyroidism with carcinoma of Table 5. CLINICAL AND LABORATORY FEATURES OF NINE PEDIATRIC PATIENTS WITH CLINICAL HYPERTHYROIDISM OWING TO SOLITARY NODULE

ClinicaULaboratory Characteristics

Percentage of Patients

Sex Male Female Elevation of T, and T, Elevation of T, only Size of nodule >3 cm Data from references 1, 23,37,55,82, 91, 116.

0 100 56 44 71

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the thyroid has been infrequently reported.’12In a review of 602 cases of thyroid cancer in children, Winship and Rosvo11128found only three cases of thyroid cancer that were treated for laboratory confirmed hyperthyroidisrn.lz8None of Nishiyama and colleagues7 patients with thyroid cancer presented with hypert h y r o i d i ~ mAt , ~ ~the Mayo Clinic between 1909 and 1962, only one patient with Graves’ disease was found to have a papillary thyroid c a r ~ i n o m a Hyperthy.~~ roidism rarely results from thyroid cancer, because even well-differentiated carcinomas are much less efficient than normal thyroid tissue in synthesizing hormones. Evidence of metastatic disease is often present in adults with hyperthyroidism owing to thyroid cancer.88 Spontaneous resolution of hyperfunctioning thyroid nodules has been reported but is unlikely.95 Surgical adenectomy is the treatment of choice in children,3I because a low dose of radiation in the surrounding normal thyroid tissue may have a carcinogenic effect when radioiodine is given for ablation of an autonomous nodule. Subtotal or total thyroidectomy is indicated if thyroid carcinoma is found. THYROIDITIS

Hyperthyroidism may be secondary to several thyroiditis syndromes, including chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), acute thyroiditis, and subacute t h y r ~ i d i t i s It . ~was ~ probably Polowe in 1934 and then Eden and Trotter in 1942 who reported the first cases of thyrotoxicosis caused by pathologically proven Hashimoto’s thyroiditis. Mild hyperthyroidism may occur early in the course of the disease, but most patients are either euthyroid or hypothyroid. Five to ten percent of children and nearly 6% of adults known to have Hashimoto’s thyroiditis present with thyrotoxicosis. Hypothyroidism eventually develops in hyperthyroid patients with Hashimoto’s thyroiditis. Positive thyroid-stimulating immunoglobulins and ophthalmopathy may be present. It has been suggested that hyperthyroidism is caused by stimulating antibodies or by the release of thyroid hormones after cell lysis? Subacute thyroiditis may occur in two forms. The first form, painful granulomatous thyroiditis, also called de Quervain’s disease, is typically preceded by an upper respiratory tract illness and is associated with malaise, fever, and severe pain in the thyroid area. The thyroid gland is tender and normal to slightly enlarged in size.Il3 The erythrocyte sedimentation rate is elevated and the leukocyte count normal. TSH is supressed whereas T4, T3, and thyroglobulin levels are elevated. Radioiodine uptake is low during the thyrotoxic phase. In 40% of cases, antithyroid antibodies are transiently present. This disease is selflimited, running its course over a period of 2 to 5 months. The second fprm, painless lymphocytic thryoiditis, is usually not associated with increased levels of antithyroid antibodies. The erythrocyte sedimentation rate is normal to mildly elevated. The levels of total thyroxine and total triiodothyronine are elevated in the early stages of the disease. In both forms, signs and symptoms of hyperthyroidism can be managed effectively with beta-adrenergic blockers. Glucocorticoids are used for the relief of severe clinical symptoms. Acute thyroiditis is rare in childhood. Classic clinical features include fever, sore throat, painful thyroid swelling, a left-sided mass, and erythema of the overlying skin. A pyriform sinus fistula is found in 96% of cases. Thyroid function studies are abnormal in approximately 2.5% of affected children. Surgical incision and drainage are often required in addition to appropriate antibiotic treatment.

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SUMMARY Graves‘ disease is the predominant cause of hyperthyroidism i n the pediatric age group. Other disorders must be recognized, however, because adequate management relies on a precise diagnosis. Careful monitoring of the thyroid status is required d u r i n g this active phase of growth and development.

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