childhood thyromegaly: recent developments

T H E J O U R N A L OF

PEDIATRICS 0 C T 0 B E R 1 9 8 1 Volume 99 Number 4

I i

MEDICAL PROGRESS

Childhood thyromegaly: Recent developments

Edward O. Reiter, M.D., Allen W. Root, M.D.,* Kenneth Rettig, M.D.,

and Alfonso Vargas, M.D. , Tampa and St. Petersburg, Fla., and Springfield, Mass.

THYROID ENLARGEMENT is a fairly common abnormality of childhood. Rallison et al 1 noted thyromegaly in 1.8% of 5,179 children aged I1 to 18 years. During a 27-year experience at the Johns Hopkins Hospital, Wil- kins 2 reported 3,I90 children of whom 2.1% had thyromegaly. Between 1973 and 1978, 6% of 1,377 patients evaluated by us were referred because of goiter (Table I). An additional 12 children with thyrotoxic Graves disease also had thyromegaly. The larger proportion of goiter in this series, in comparison to Wilkins' experience, may reflect an increased incidence of this disorder, more frequent referral of the child with thyromegaly, or, as in chronic lymphocytic thyroiditis, more refined diagnostic methods. Our purpose is to review newer aspects of the causes, diagnosis, and management of goiter in the child and adolescent.

From the Departmenis of Pediatrics, University of South Florida College of Medicine, the All Children ~y Hospital, and the Baystate Medical Center, University of Massachusetts Medical School.

Supported by National Foundation-March of Dimes Grants C-199 and 1-632, and by a grant from the Breakfast Optimist's Club, St. Petersburg, Florida. *Reprint address, Department of Pediatrics, AII Children's Hospital, 80t 6th St. South, St. Petersburg, FL 33701.

T H Y R O I D I M M U N O L O G Y

Many aberrations of cellular and humoral immune systems may lead to autoimmune diseases. Broder and Waldmann ~ have recently reviewed cellular immunity, describing both positive and negative regulatory influences which modulate responses to foreign and nonforeign antigens. The B cells, clonal precursors of plasma cells which secrete immunoglobulins, produce surface membrane immunoglobulins with antigenic-bind-

Abbreviations used AMP: CLT: HTACS: LATS: MCT: MEN: PBI: PTU: T3: T3RU: T4: TBG: TRH: TSH: TSIg:

adenosine monophosphate chronic lymphocytic thyroiditis human thyroid adenyl cyclase stimulator long-acting thyroid stimulator medullary carcinoma of the thyroid multiple endocrine neoplasia protein bound iodine propylthiouracil tri-iodothyronine T3 resin uptake thyroxine thyroid-binding globulin thyrotropin-releasing hormone thyrotropin thyroid-stimulating immunoglobulins

0022-3476/81/100507+ 12501.20/0 �9 1981 The C. V. Mosby Co. Vol. 99, No. 4, pp. 507-518

5 0 8 Reiter et al. The Journal of Pediatrics October 1981

Table I. Incidence and distribution of thyroid dysfunction in two pediatric endocrinology clinics

I John Hopkins University*

Duration of study (yr) 27 Total patients 3,190 Thyroid dysfunction 318

Hypothyroidism 202 Hyperthyroidism 44 Euthyroid 72 Thyromegaly 68

Chronic lymphocytic thyroiditis 12 Inborn errors in thyroxine biosynthesis 3 Adenorna 2 Carcinoma 10 Cysts 3 Goitrogen ingestion 5 Goiter of unknown etiology 33

University of South Florida

(10%) (6.3%) (l.4%) (2.3%) (2.t%)

5 1,377

157 (11.4%) 63 (4.6%) 17 (1.2%) 77 (5.6) 84 (6.1%) 46

3 4 1

3O

*Adapted from Wilkins.:

ing sites similar to those eventually released by their plasma cell descendents. The T cells mediate the classic reactions of cellular immunity, including delayed hyper- sensitivity, graft-versus-host reactions and direct cytolytie killing of foreign cells. Although T cells may express surface-binding sites that have antigenic similarities to immunoglobulin heavy chains, normal T cells do not produce conventional immunoglobulins. They do have a crucial role in regulation of humoral responses, however, by acting as potentiators or inhibitors of B-cell transforma- tion into immunoglobulin-secreting plasma cells. Poten- tiating cells are called helper cells whereas those which inhibit cell differentiation are referred to as suppressor ceils.

Tolerance for self-antigen exists but breakdown of such tolerance is potentially quite damaging. Tolerance appar- ently results from the activity of suppressor cells; there is considerable evidence that impaired suppressor T-cell function leads to overt autoimmune disease. Additionally, certain classes of B cells and macrophages inhibit immune responsiveness. Indeed, two or more basic cell types (particularly T cells and macrophages) may be required to interact to develop suppressor cell effects.

The pathogenesis of both Hashimoto thyroiditis and Graves disease has been related to dysfunction of immu- noresponse regulation, specifically impairment of suppressor activity? Such abnormalities may be manifested in several ways. When the surveillance mechanisms become nonfunctional, genetically defined lymphocytes, or clones, which are usually incapable of responding to self-antigens (e.g., thyroid cell membrane antigens) may now destroy the thyroid. Alternatively, those suppressive functions which impair T-cell sensitization to self may be diminished. In this situation, there is reduction of self-

tolerance and subsequent tissue damage. Finally, some evidence suggests that there may be subtle alterations of cell-surface antigens (as in mild viral infections) which may then become recognizable as not-self. An immune response to these abnormal antigens may cross-react with similar self-antigens.

In Hashimoto thyroiditis, cellular immunity, perhaps in concert with some humoral antibodies, leads to thyroid gland destruction; humoral immunity is of greater importance in Graves disease. A primary factor appears to be the development of circulating immunoglobulin antibodies (thyroid-stimulating immunoglobulins) which bind to the TSH receptor or to a very similar receptor on the plasma membrane of thyroid follicle cells. These antibodies have been characterized in many ways, by TSH- displacement assays (binding assays) and by the stimulation of thyroid cell membrane activity (bioassay), as measured by production of cyclic AMP by the adenyl cyclase system. Production of these immunoglobulins against self-antigen may also be related to diminished immunosurveillance. Kidd et al 4 have suggested that stress-associated adrenal corticosteroid secretion may diminish suppressor functions of the T-derived lymphocytes.

Further details regarding immunoglobulin measurements and possible significance are discussed in following sections on Hashimoto thyroiditis and Graves disease.

Chronic lymphocytic thyroiditis (Hashimoto thyroiditis).

Etiology and pathogenesis. Chronic lymphocytic thyroiditis is an inflammatory disorder of unknown etiology which may be associated with euthyroid, hypothyroid, or hyperthyroid states? There is much evidence to support disordered autoimmunity in patients with CLT, thus the

Volume 99 Childhood thyromegaly 5 0 9 Number 4

term autoimmune thyroiditis. Antibodies against thyroglobulin and a microsomal antigen are present in most children with CLT. Sera of patients with CLT may also contain antibodies directed against colloid proteins other than thyroglobulin, the TSH membrane receptor site

(10% of patients), a thyroid nuclear component, T4, and T~? 7 The presence of antithyroid antibodies in subjects without clinical evidence of thyroid dysfunction or goiter (those patients detected in family surveys , those studied because of other associated autoimmune diseases such as diabetes mellitus, collagen vascular disease, primary hypoadrenalism, pernicious anemia, or myasthenia gravis, or those studied because of an associated high incidence with CLT, as in gonadal dysgenesis) indicates lymphocytic infiltration of the gland and is termed symptomless autoimmune thyroiditis. 8

Cytotoxic antithyroid antibodies acting in concert with cellular immune mechanisms may be significant in the development of CLT. 4 Allison 9 has postulated that binding of an antithyroid antibody (IgG) to the thyroid acinar cell permits attachment of cytotoxic killer lymphocytes. Immune complex deposits are demonstrable in the base- ment membranes of thyroid follicles in CLT, 1~ and cellular immunity is abnormal in such patients; there is an increased in vitro mitotic rate of lymphocytes from patients with CLT when exposed to thyroid tissue. Patients with CLT may have a defect in suppressor T-lymphocyte function allowing expression of so-called forbidden clones of immunoglobulin-producing B lym- phocytes2

There is a significant familial incidence of CLT. Many close relatives of patients with CLT have goiter, hypothyroidism, or Graves disease and positive anti-thyroid antibody titers. '1 Recently an association between Hashimoto thyroiditis and cell types HLA-Aw30 and HLA-DRW3 has been demonstrated. 12

Many attempts have been made to identify a specific viral etiology of CLT, but with the exception of rubella 1~ these efforts have been unsuccessful. TM Viruses may act synergistically with disordered immune mechanisms to cause thyroiditis, possibly by altering target tissue anti- genicity or by transiently depressing immune surveillance? Thus, the development of CLT is dependent upon both an inherent genetic predisposition and an environ- mental insult.

The prevalence of CLT may be increasing as the frequency of diagnosis increases. In their survey of 5,179 school children Rallison et aP found thyromegaly due to CLT in 62 children (1.6%) ( M / F = 20/42). Of 290 other- wise normal chiidren, 14 had antithyroglobulin hemag- glutinating antibody t i t e r s> 1:16. '~ Many of these children almost certainly had symptomless autoimmune

thyroiditis, suggesting that the true incidence of CLT in this population approached 5%.

Clinical manifestations. The child with CLT may present with asymptomatic goiter or with symptoms and signs of hypo- or hyperthyroidism. In Rallison's survey, 87% of the children with CLT were clinically euthyroid when identified. In the goitrous form the thyroid may be symmetrically or asymmetrically enlarged, and is firm and nontender with an irregular, "pebbly" capsule. The right lobe is often larger than the left and a pyramidal lobe may be palpable. Generalized, nontender cervical lymphade- nopathy may be present. In patients with symptomless autoimmune thyroiditis the thyroid gland may be normal in size or very slightly enlarged and relatively firm. In such asymptomatic adult subjects, high titers of thyroglobulin (1:25,000) and microsomal (1:32) antibodies may be found; basal TSH values may be above the normal range in 30% and the TSH secretory response to TRH exagger- ated in 40%. 1~ In children the entity of symptomless autoimmune thyroiditis has not been well delineated, although undoubtedly recorded by many observers. We have examined several children with minimal abnormalities on palpation who were clinically and chemically euthyroid, but had positive antithyroid antibody titers. Careful follow-up is necessary because 30% of adults with symptomless autoimmune thyroiditis will become clinically and chemicaiiy hypothyroid within three years after diagnosis. 1;'

Laboratory evaluation. Although the presence of antibodies against thyroid gland components is consistent with the diagnosis of CLT, antibodies may not always be detectable. Rallison et al ~ reported that antithyroglobulin antibodies (1:16) were demonstrable in 76% of children with CLT. However, in our experience and that of others, even low titers (1:4) of antithyroglobulin antibodies may be considered positive in children; the clinical laboratory should be requested to report the observed titers leaving data interpretation to the clinician? 7 A senSitive radioas- say for antithyroglobulin antibodies may detect antibodies in most patients with CLT. 18 It is too early to ascertain if this method has significant advantages over the hemagglutination technique. Because the antimicrosomal titer may be elevated while the antithyroglobulin titer is negative or low, measurement of both antibodies is recommended.

Serum concentrations of T4 in patients with CLT may be elevated, normal, or low. Values indicating a PBI vs thyroxine iodine discrepancy of > 2/~g/dl are consistent with the diagnosis of CLT. Serum levels of TSH may be normal but often are etevated in children with CLT despite normal T4 concentrations? ~ Administration of TRH may evoke excessive TSH secretion, implying that


Table II. Etiology of hyperthyroidism in childhood

. Congenital Transplacental passage of thyroid-stimulating

immunoglobulins Neonatal Graves disease

Acquired Autoimmune disease of the thyroid

Graves disease Chronic lymphocytic thyroiditis

Adenoma Carcinoma Autonomous nodule Multinodular goiter Factitious TSH-secreting pituitary tumor Pituitary resistance to thyroxine

thyroid hormone biosynthesis is inefficient and maintenance of the euthyroid state has been achieved by TSH-stimulated hyperplasia and hypertrophy, secondari- ly implying hypertrophy or hyperplasia (or both) of pituitary thyrotropes. Radionuclide scans may show patchy areas of uptake?" There is enhanced suppressibility of radioiodine uptake by exogenous iodide and abnormal sensitivity to discharge of radioiodide by perchlorate or thiocyanate? ~

Treatment and prognosis. In hypothyroid patients with CLT, replacement therapy with T4 is mandatory. Patients with large goiters, obstructive symptoms, or cosmetic disfigurement should also receive thyroxine in an attempt to reduce thyroid size, although this may not always be successful. Euthyroid children with an increased TSH level or an increased response to TRH are also candidates for treatment. The dose of thyroxine is determined by the clinical response. In adolescents, we initiate therapy with 0.1 rag/day of thyroxine. If thyromegaly does not regress, the dose is increased at three- or six-month intervals by increments of 0.05 mg/day until full TSH-suppressive doses are achieved. The TSH response to TRH may be utilized to determine when TSH suppression has been achieved. Treatment is continued for approximately two years and then withdrawn. Thereafter, recurrence of thyromegaly or development of hypothyroidism indicates the need for resumption of therapy. Children with normal or slightly enlarged thyroid glands, positive antibody titers and normal thyroid function studies may be followed closely without treatment, with periodic assessment of the clinical and chemical status. Administration of thyroxine does not necessarily alter the natural history of euthyroid CLT or hasten resolution of the inflammatory process, regression of the goiter or disappearance of antithyroid antibodies. TM Prevention of adult-onset multinodular goiter is not proven.

Patients with CLT and hyperthyroidism may be classi- fied into: a group with low radioiodine uptake, high antithyroid antibody titers, and intense biopsy-proven lymphocytic infiltration of the thyroid gland, and a group with high radioiodine uptake, relatively low antithyroid antibody titers and histologic evidence of both Graves disease and lymphocytic thyroiditis. The first group requires only brief antithyroid treatment since hyperthyroxinemia is transient; the latter population requires prolonged antithyroid treatment. The distinction between Graves disease and the thyrotoxic phase of CLT is becoming increasingly indistinct since similar histologic findings and antithyroid antibodies exist in both diseases.

Other autoimmune disorders which are seen with increased frequency in children with CLT include: diabetes mellitus, hypoadrenocorticism, hypoparathyroidism, myasthenia gravis, and pernicious anemia. Drash et al ~1 found that more than 50% of patients with juvenile diabetes also have thyroid dysfunction. Rotter and Rimoin ~ described considerable heterogeneity among patients with juvenile diabetes mellitus with respect to the frequency of associated autoimmune endocrinopathies. The incidence of abnormalities of carbohydrate metabolism in children with CLT is also substantial. In a study of 21 children with CLT, Winter and Green ~ recorded clinical diabetes mellitus in four and glucose intolerance in two others. Thus, periodic assessment of carbohydrate metabolism should be undertaken in all children with CLT; in patients with diabetes, thyroid function should be evaluated regularly.

Graves disease (Table II). Etiology andpathogenesis. Graves disease (diffuse toxic

goiter) and CLT are different clinical manifestations of an underlying immunologic defect. Antibodies against microsomal antigens, thyroglobulin, or other colloid components acting in concert with "activated" lymphocytes lead to destruction of thyroid follicular cells in CLT. Antibodies against the TSH-receptor site stimulate follicle cells in a manner analogous to TSH, leading to hyperthyroidism. ~ The so-called autonomous thyroid function in Graves disease represents replacement of TSH by TSIg as the primary thyroid stimulator, rather than inherent, independent hyperfunction of the thyroid gland itself. Antibodies to thyroglobulin, microsomal antigens, and the TSH receptor are present in subjects with euthyroid and hyperthyroid Graves disease, as well as in patients with CLT who are euthyroid, hyperthyroid, or hypothyroid. ~- ~- ~ Thus, not all antibodies to the TSH receptor stimulate; some may even inhibit thyroid function. Glands from children with Graves disease and Hashimoto thyroiditis have similar degrees of lymphocyte infiltration


and lymphoid follicle formation, and similar deposition of immunoglobulins.

Many forms of TSIg, specifically IgG moieties, have been demonstrated in the sera of patients with Graves disease. They include long-acting thyroid stimulator, LATS-protector, human thyroid stimulator, human thyroid adenyl cyclase stimulator, thyroid-stimulating antibodies, TSH-binding inhibitor immunoglobulins, and thyrotropin displacement activity. 4 . . . . 6-~o The variable nomenclature reflects the methods by which each activity is determined. LATS is found in less than 50% of patients with Graves disease; use of radioreceptor assays employ- ing thyroid cell TSH membrane receptors has permitted identification of TsIg in 70 to 100%. 4

There is a significant increase in the prevalence of cell types HLA-B8, HLA-Bw35, and HLA-DRw3 in patients with Graves disease?, 31 Type HLA-DRw3 confers a 5.5-fold heightened risk, whereas the increased risk for HLA-B8 is 3.0. These data indicate the importance of familial factors in the development of Graves disease.

Pathophysiology. In Graves disease, thyroid iodide clearance, absolute iodine uptake, iodide transport, and coupling and rate of glandular iodine turnover are greatly increased. The major product is T4 but secretion and turnover rates of T~ are also increased. In some instances T~ is the major circulating thyroid hormone, while the T4 value is normal; this entity known as T6 toxicosis has been characterized in both adults and children? 2, a~ Elevated T~ values are probably responsible for the majority of the clinical manifestations, although an entity term T4 toxicosis (with normal T~ levels) has also been described. ~

Many of the cardiovascular manifestations of hyperthyroidism suggest enhanced beta adrenergic activity, yet serum and urinary levels of epinephrine and norepineph- rine are normal or low, TM a~ and there is normal tissue sensitivity to catecholamines. Although thyroid hormone increases the number of beta adrenergic binding sites on cardiac cell membranes of rats? ' such an increment has not been found in human lymphocytes? ~ Thyroxine and T~ are concentrated in adrenergic nerve endings and may act as neurotransmitters? ~ Thyroid hormones have direct positive chronotropic and ionotropic effects on the heart. ~ Although the mechanisms(s) of action of beta adrenergic blocking agents in the inhibition of the cardiovascular manifestations or thyrotoxicosis is unknown, the clinical utility of these drugs is well established. ~

Clinical manifestations. Thyrotoxicosis may occur in the neonate but is relatively uncommon before 3 years of age. Thereafter the incidence of the disease increases progres- sively and is greatest in the 11- to 19-year age group, particularly in girls (F /M = 4-6/1). The clinical signs and symptoms are well characterized. 4~

Although ophthalmopathy is considered to be unusual in juvenile Graves disease, Barnes and Blizzard 4~ recorded infiltrative eye pathology in 45 of 75 young patients. In 76% of these patients the manifestations were minimal (conjunctival injection, lid fullness, lid lag, increased lacrimation), in 20% moderate (minimal criteria plus exophthalmos of 18 to 23 mm) and in 4% severe (minimal criteria plus exophthalmos of at least 24 mm and extraoc- ular muscle involvement). In 12 patients ophthalmopathy was unilateral. The severity of eye involvement was not correlated with the degree of thyrotoxicosis. After treatment of hyperthyroidism the degree of exophthalmos decreased in the majority of children; in 1% it pro- gressed.

Laboratory evaluation. The circulating concentrations of T4, free T4, T3, and free T3 are elevated in the majority of patients with thyrotoxicosis; that of T3RU is increased as endogenous TBG sites are occupied: TSH levels are usually undetectable and there is no TSH secretory response to TRH. In patients with T~ toxicosis, only serum Ta concentrations are elevated, whereas T~ levels are normal. The T4 and ~[~ values may be elevated in euthyroid patients with excessive TBG (congenital or acquired) or target organ resistance to thyroid hormone. The TSH concentration is increased in thyrotoxic patients with TSH-secreting pituitary adenomas, excessive TRH production, or pituitary resistance to thyroid hormone Radioiodine uptake is increased and not suppressible by Ta.

Characterization of the circulating thyroid-stimulating immunoglobulins may ultimately prove useful in the evaluation of patients with equivocal findings. The presence of high titers of antithyroglobulin or antimicrosomal antibodies identifies patients with the thyrotoxic phase of CLT, ~

Treatment and prognosis. The thioamides and prc pyl- thiouracil inhibit organifications of iodine and are effec- uve therapeutic agents in the management of children with thyrotoxicosis. Propylthiouracil is administered oral- ly (5 to 7 mg/kg/body weight, 150 mg/m ~ surface area/day)2 The dose of methimazole is one-tenth that of PTU. Treatment is initiated with high doses of PTU C300 to 450 mg/day), divided into three equal amounts and administered every eight hours. Utilization of PTU xs favored because it also blocks peripheral conversion of T4 to T~. After the patient has become euthyroid, the dose of the medication is reduced to one-half to two-thirds of the initial dose. and subsequently readjusted to maintain T4 and T3 levels within the midnormal range. Under some circumstances the maintenance thioamide may be administered only once or twice daily. 4~

Some investigators suggest that PTU dosage be main-


tained at initial suppressive levels and that thyroxine be added to maintain the euthyroid state. ~1, 48 Barnes and Blizzard '~ have described the ease of clinical management with this combined regimen and a remission frequency similar that with thioamide alone. Since the goal of therapy is to maintain normal circulating levels of T,, T~, and TSH, it is important to monitor serum concentrations periodically, particularly if thioamides alone are being employed; increased T3 values in the presence of normal T, concentrations may indicate inadequate thyroid suppression or relapse, whereas elevated TSH levels suggest excessive antithyroid medication. '~, ~

Treatment with antithyroid drugs is continued for 18 to 24 months and then slowly tapered if the patient is euthyroid. In adults, Greet et al 4~ report that antithyroid drugs may be stopped within one to eight months with reasonable success. Relapse, which occurs in 40 to 70% of patients, usually occurs in the first months after stopping therapy, when relapse occurs a second course of thioamide is indicated. If the patient relapses after the second treatment period, subtotal thyroidectomy may be necessary, although long-term drug therapy may finally be successful? ~ The frequency of drug toxicity in patients receiving thioamides has varied from 5 to 45% and includes urticaria, drug fever, and arthralgia. Less common are myalgia, loss of taste, enlargement of lymph nodes or salivary glands, abnormal hair pigmentation, agranulocytosis, autoimmune hemolytic anemia, hepati- tis, arthritis, or a lupus-like syndrome. Other indications for alternative treatment include poor compliance or a primary abnormality (such as neutropenia) precluding drug therapy. In these instances, subtotal thyroidectomy after preparation with propranolol is the procedure of choice.

Propranolol, a beta adrenergic blocking agent which also partially inhibits the peripheral conversion of T, to T~ is a useful adjunctive agent in children, particularly in preparation for surgery? ~ Beta adrenergic blockade decreases heart rate, tremor, restlessness, agitation, heat intolerance, hyperhidrosis, diarrhea, hypercalcemia, and proximal myopathy. Oxygen consumption, metabolic rate, thyromegaly, exophthalmos and (probably) thyroid storm are not affected? ~ . . . . . ~ We have used propranolol in the initial management of hyperthyroxinemia along with PTU and, occasionally, dexamethasone. Such a regimen synergistically lowers the production of T~. '~

In three recently reported series of children with thyrotoxicosis treated with antithyroid drugs,~,'. ~,~~ 264 patients are discussed. In 89 patients treatment had not been completed or follow-up was inadequate. Of the remaining 175 patients, 95 (54%) achieved satisfactory remission on medical therapy alone (the euthyroid state

lasted more than two years after cessation of medication); two patients became hypothyroid. Seventy-four (42%) subjects underwent subtotal thyroidectomy because of noncompliance (25), relapses while on medical therapy (23), drug toxicity (9), or as treatment after drug preparation (17); three patients required a second surgical proce~ dure because of relapse. Four children received ablative radioiodine therapy.

High titers of antithyroglobulin antibodies, reduction in thyroid gland size and low ( < 4%) one-hour radioiodine uptake during therapy are observed more frequently in children who undergo remission while on antithyroid drug therapy compared to those who relapse. 41 The child with an extremely elevated T~ level and with a large gland and one-hour radioiodine uptake > 10% during therapy is unlikely to remit. Restoration of a normal TSH secretory response to T R H is also a favorable indication of remission. A sustained decrease in serum concentrations of thyroglobulin ( < 100 ng/ml) during antithyroid drug therapy is associated with increased likelihood of remission. Unfortunately, each of these indicators of thyroid activity has its predictive errors.

The use of radioiodine 131I in the management of juvenile thyrotoxicosis remains controversial. Fisher 4~ reviewed the results of such therapy in 246 children and recorded remissions in more than 90%, relapses in 9% and development of hypothyroidism in nearly one-half of treated subjects. Eleven patients developed neoplasms of the thyroid (carcinoma [3] and adenoma [8]) after a mean follow-up period of ten years. Freitas et al ~1 treated 51 hyperthyroid children (6 to 18 years Of age) with 3 to 82 mCi of 1~1I. There was one treatment failure. The euthyroid state was achieved in the remaining patients within one or two months after treatment. Hyperthyroidism recurred in two subjects two and 11 years after l~q administration and hypothyroidism occurred in 92%. There were no malignancies of the thyroid or other sites. No significant abnormalities of the offspring of patients treated in this manner have been noted, ~ in keeping with the relatively low total radiation dose (3 rad) to the testes or ovaries when 10 mCi of ~'I are administered to the young adult? 3 Intentionally ablative doses of radionuclide together with replacement thyroxine therapy are used? 4 This approach may decrease the incidence of thyroid neoplasia by fully destroying the hyperplastic thyroid follicles. We reserve this approach for the unique patient in whom medical and surgical therapy may be contrain- dicated, although it is likely that radioiodine will gain more widespread acceptance as further expelience is accumulated.

Subtotal or total thyroidectomy have been recommended as initial procedure in thyrotoxic children after


restoration of the euthyroid state with thioamides. Fish- er40 reviewed the results of this approach in 254 subjects and recorded remission in 85%, and relapse in 13%; permanent hypothyroidism occurred in 24%. Complica- tions of thyroid surgery include transient or permanent hypoparathyroidism, recurrence of thyrotoxicosis and unilateral or bilateral recurrent laryngeal nerve paresis or paralysis. Thyrotoxicosis may recur more than 30 years after initial subtotal thyroidectomy, but the majority of patients will relapse within the early postoperative years. 5~ Because of the relatively high relapse rate (up to 25%) following subtotal thyroidectomy, total thyroidectomy has been advocated as the procedure of choice? ~ Thyrotoxic children are prepared for surgery with thioamide drugs. After the euthyroid state has been restored, iodides (Lugol solution, potassium iodide) are added to the regimen for two weeks prior to surgery in order to decrease glandular vascularity. Recently, propranolol has been used as the only preoperative medication in thyrotoxic adults (an oral dose of 40 mg every six hours for four to seven days pre- and seven days postoperatively)? 7 It is essential that no dose of propranolol be omitted, including the preoperative dose on the morning of surgery. Zonszein et aP ~ found that the rapid onset of action of propranolol allowed surgical flexibility, whereas the biologic half-life was long enough to permit re-institution of oral therapy six to 12 hours postoperatively; small intravenous doses could also be used in the intraoperative period? 7 We have employed this regimen in adolescent patients with satisfactory results.

The responses to therapeutic programs have been examined in relation to levels of various TSIg. Those which reflect a biological stimulatory activity, namely, HTACS and LATS-P, Seem to be very sensitive markers of Graves disease. TM 30. ~, ~ The TSH-displacement assays (around 70% positive) appear less sensitive than the thyroid stimulation assays (80 to 100% positive). Both types of assays yield fewer positive samples in adult patients treated with propylthiouracil or radioiodine? ~-~~ Concentrations of TSIg fall during therapy, so that only 15 to 25% remain positive at the end of treatment. Patients who still demonstrate TSIg at that time have a higher incidence of T3- nonsuppressibility, 59 as well as subsequent clinical relapse? ~ Although exceptions exist, TSIg determinations may be used to monitor therapeutic out- come and perhaps duration of therapy. Discrepancies may relate to assay methods rather than to lack of pathogenic importance.

Mukhtar et aP 1 reported that serum levels of TSIg are significantly reduced in thyrotoxic patients after subtotal thyroidectomy in comparison to values recorded in patients treated with antithyroid drugs or radioiodine.

Table Ill. Classification of thyroid neoplasms

Benign Adenoma

Follicular Papillary Atypical

Teratoma Malignant

Carcinoma Papillary

Pure papillary Mixed papillary and follicular

Follicular Pure follicular Clear cell Oxyphil

Medullary Undifferentiated

Small cell Giant cell

Epidermoid Other

Lymphoma Sarcoma Secondary

Although the mechanism is unclear, surgical ablation may remove a significant source of antigen (the TSH membrane receptor) and hence decrease antibody formation.

Since multiple serum IgG binding-displacement and stimulatory activities are measured present in patients with Graves disease, their correlation with remission may be found to have clinical value. We suggest that identification of the humoral and cellular immune abnormalities in Graves disease may permit specific immunotherapy to supplant thyroid blockade or operative or radionuclide ablation as the treatment of choice for this disease.

Other types of thyromegaly (Table III). Many other causes of thyromegaly including neonatal Graves disease, dyshormonogenesis, and inflammatory and sporadic goiters have been recently reviewed. ~4

Neoplasms (Table IV). In children, 17to 40% of solitary nodules are malignant) 2, 63 Although the likelihood of a thyroid nodule being malignant is higher in a child than in an adult, the incidence of carcinoma in solitary thyroid nodules in childhood may be decreasing. 62 63 The clinical characteristics, standard diagnostic studies, and patholog- ic classifications of thyroid tumors have been described?4. ~5

Etiology. There is a significant association between thyroid neoplasms and ionizing radiation to the head and neck. The high incidence of childhood thyroid carcinoma observed between 1950 and 1970 is now decreasing since


Table IV. Solitary thyroid nodules in (66) children

No.

Thyroid carcinoma Papillary Follicular Mixed

Adenoma Follicular Fetal Embryonal Hurthle cell Toxic

Nodular goiter Thyroiditis Abscess Developmental anomalies, hemiagenesis, ectopia Cysts Fibrous thickening of thyroid capsule Neurofibromatosis Cervical adenitis

23 2 l 1 1

18

28

Adapted from Kirkland et al ~ and Scott and Crawford. ~

the use of head and neck irradiation has declined. However, inasmuch as the carcinogenic effects of irradiation have a prolonged latency, new cases of thyroid cancer continue to appear in young adults. ~ Incidence curves for both malignant and benign lesions of the thyroid are increasing among those in the third and fourth decades of life. ~7 Frohman 6~ surveyed 2,189 young adults who had irradiation to the tonsils and nasopharynx between 1 and 12 years of age; nodular disease of the thyroid was present in 713 (32.6%). Only 50% of the nodules were found by palpation; 96% were detected by scanning with 99mTc pertechnetate. Thyroid carcinoma was found in 33% of patients subjected to surgery with an overall prevalence of 11.2%. The papillary or mixed papillary-follicular carcinomas were frequently multicentric and bilateral with lymph node metastases. Benign and malignant thyroid tumors often coexisted. In a series of 50 patients previously operated upon, recurrent thyroid tumors, many of which were malignant, were recorded in 38%. The majority of those who did not have recurrence had received TSH-suppressive thyroid hormone therapy, suggesting that such a treatment was preventive. Of the patients considered to be normal at the initial examination 10% developed thyroid nodules within three years, indicating the continuing risk in this population. Hempelman et al ~ have reported that, in contrast to a twofold greater incidence of thyroid carcinoma among females in the general population, there is no sex-related increase in postirradiation patients; an exception exists in young adult Jewish women in whom there is a 17-fold greater risk compared to the irradiated population as a whole. In

contrast to the findings of Frohman ~ and Favus et al, 6~ Royce and co-workers 69 were unable to demonstrate a

significant increase in thyromegaly, thyroid nodules, or thyroid carcinoma in 24 persons with a history of head and neck irradiation compared to a control group of 243 nonirradiated subjects.

Most thyroid cancers are TSH dependent, although the number of TSH-binding sites and in vitro metabolic responsiveness to TSH may be decreased in papillary and follicular carcinomas when compared to normal thyroid tissue. TM Undifferentiated thyroid carcinoma, which is not suppressed by thyroid hormones and hence not controlled by TSH, lacks TSH receptors and in vitro biologic responses to TSH. 7~

Diagnosis. A cervical mass in childhood may be thyroid or it may be a lymph node, branchial cleft cyst, heman- gioma, lymphangioma, lymphoma or neurofibroma. A unilateral thyroid mass may represent thyroiditis, hemiagenesis of the thyroid, an ectopic thyroid with compensa- tory enlargement of the remaining tissue, thyroid cyst, adenoma, or carcinomas ~ Evaluation of the child with a thyroid mass requires thorough historical review including inquiry into prior irradiation to the head and neck and exposure to a goitrogen, A rapidly growing nodule, or hoarseness or dysphagia suggest a malignant lesion. The family history may provide evidence of MEN characterized by MCT, pheochromocytoma, and parathyroid hyperplasia (type IIA) or by neuromas of the skin and mucous membranes and a Marfan-like habitus (type IIB).

Neoplastic lesions are usually discrete, but may be firmly bound to surrounding structures. ~ Enlarged metas- tatic cervical lymph nodes are present in 67 to 85% of children with thyroid cancer, and approximately 14% of patients have pulmonary metastases at the time of diagnosis. ~ Since lymph node metastases occur without a palpable thyroid nodule, this diagnosis should be considered in differential diagnosis of chronic cervical adenopathy.

Thyroid function is usually normal in children with carcinoma of the thyroid. In patients with differentiated thyroid carcinoma serum levels of thyroglobulin may be elevated and revert to normal values ( < 20 ng/dl) when the tumor is removed. ~3 LoGerfo et aF 4 suggest that serial measurement of thyroglobulin concentrations is useful in following patients for recurrent thyroid malignancies. However, measurement of serum concentrations of thyroglobulin does not detect occult carcinoma55 In patients with MCT, basal levels of calcitonin are often elevated and increase further after stimulation by pentagastrin or calcium. 64 These provocative tests may be employed to screen family members for this disease or for hyperplasia


of calcitonin-secretory cells, the presumptive precursor of MCT. Whenever an index case of MCT is detected, screening of all family members, by measurement of resting and stimulated levels of calcitonin, is essential, both immediately and at yearly intervals thereafter. When an elevated calcitonin value is detected, total thyroidecto-

my is undertaken. Diagnostic approach (Figure) to a child with a thyroid

mass. The presence of a hard, fixed, solid mass (especially in a male), signs of metastases or invasion (hoarseness, cervical adenopathy), rapid growth of the mass, a history of irradiation or a family history of MEN are indications for open surgical biopsy. The combined use of ultrasonography and fine needle aspiration has greatly enhanced diagnostic accuracy and has permitted greater operative selectivity, particularly in adults2 ~' ~ Cystic lesions identified by ultrasonography (echography) may be aspirated percutaneously and the fluid examined cytologically. A small (less than 4 cm in diameter) cystic lesion containing clear yellow fluid is almost always benign. In larger cysts or cysts containing brown or bloody fluid, there is a higher incidence of malignancy. Cysts with malignant cytology or ones that recur, or mixed cystic and solid nodules should be removed surgically. Patients with solid nodules (on ultrasonography) undergo a thyroid scan with 1~ ~bsence of uptake in the area of the nodule (cold) should lead to surgical biopsy and removal. Uptake by the nodule (warm or hot) in the presence of antithyroid antibodies suggests the diagnosis of CLT which may be treated with thyroxine and observed. If the mass does not regress (a decline in size of > 50%) within six or 12 months, the lesions should be excised. If antithyroid antibodies are absent, needle aspiration and cytologic assessment is undertaken. The finding of malignant cells leads to operative intervention. The patient with benign tissue is treated with thyroxine as in CLT.

Treatment. Surgery, radioiodine ablation, and suppressive doses of thyroid hormone have been employed in the treatment of differentiated thyroid carcinoma. ~

In patients with a history of irradiation of the head and neck, careful physical examination of the thyroid, cervical lymph nodes, and salivary glands is indicated yearly. 7~ A discrete thyroid nodule should be removed. In patients with diffuse thyroid enlargement, a radioiodine (~2~I) scan should be performed and suppressive therapy with thyroxine initiated.

Favus et aP 6 and Frohman ~ suggest routine initial thyroid scan in all postirradiation patients, in view of their observation that only 50% of the nodules present may be found by physical examination alone. Repeated scans are not recommended if the initial scan is normal, but periodic physical examination should be done. If scans

MANAGEMENT OF THE CHILD WITH A THYROID NODULE

NODULE

CYSTIC ~ SOLID

ASPIRAT-~E 123, " " ~ N

,~,CO L D" ~'-~'HOT '"

SURGICAL ANTITHYROIO BIOPSY ANTI BODI ES

A S P I R A - T I ~ SUPPRESSIVE CYTOLOGY THERAPY BIOPSY WITH T 4

\o REGRESSION ~,

OBSERVE

Figure. Evaluation of the child with a solitary thyroid nodule.

reveal a nonfunctional area, repeat physical examination by several observers is important. If a nodule can be palpated it should be excised. If the initial scan reveals a hyperfunctioning area, observation at yearly intervals is indicated. Postoperatively, all patients with nodular disease of the thyroid should receive TSH suppressive therapy with thyroxine. The value of prophylactic TSH suppression with thyroid hormone in post-irradiation patients who do not have thyromegaly has not been established and is not recommended at present. In view of the findings of Royce et al, 6~ Utiger 7~ recently recommended that such previously irradiated patients require only periodic physical examination. In his opinion, further studies should be undertaken only if a palpable abnormality is found.

S U M M A R Y

Evaluation of a child with goiter includes .historical review, physical examination, and measurement of serum concentrations of PBI, T4 and T3RU, TSH, and titers of antithyroglobulin and antithyroid microsomal antibodies. If there are no indications for more intensive evaluation such as a history of cervical irradiation, a palpable abnormality of the thyroid gland or unusual laboratory findings (e.g., a significant PBI-thyroxine iodine discrepancy in the absence of a positive antithyroid antibody titer), a trial of TSH-suppressive therapy with thyroxine is undertaken, even if the cause of thyromegaly has not been identified .80 If thyroid size diminishes in the ensuing six to 12 months, treatment is maintained for approximately two years and then discontinued. If the goiter recurs, or if there is impaired thyroid function, treatment is resumed. Periodically, antithyroid antibody titers and indices of thyroid function are determined.

If the goiter does not diminish after a reasonable trial of suppressive therapy with adequate amounts of thyroxine

5 1 6 Reiter et aL The Journal of Pediatrics October 1981

(i.e., those quantities which will inhibit TRH-induced

secretion of TSH), 81 subtotal thyroidectomy is recom-

mended to be certain that an underlying neoplasm has not

been overlooked. A biopsy of the thyroid is not performed

routinely in such children prior to operative therapy.

Almost invariably, examinat ion of the surgical specimen

reveals CLT. Postoperatively, suppressive doses of thyro-

xine are maintained indefinitely. Inasmuch as thyroxine

suppression of TSH secretion is essential in the manage-

ment of patients with thyroid neoplasms, a limited medi-

cal trial, as described, does not place the patient at undue

risk.

The expert secretarial assistance of Mrs. Maria E. Santiago and Mrs. Beverly Mahon is greatly appreciated.

R E F E R E N C E S

1. Rallison M, Dobyns B, Keating F, Rall J, and Tyler F: Thyroid nodularity in.children, JAMA 233:1069, 1975.

2. Wilkins L: Diagnosis and treatment of endocrine disorders of childhood and adolescence, ed 3, Springfield, Ill, 1965, Charles C Thomas, Publisher, pp 7-9.

3. Broder S, and Waldmann TA: The suppressor cell network in cancer, N Engl J Med 229:1281, 1978.

4. Kidd A, Okita N, Row RR, and Volpe R: Immunologic aspects of Graves' and Hashimotos disease, Metabolism 29:80, 1980.

5. Volpe R: Lymphocytic (Hashimoto's) thyroiditis, in Werner SC, and Ingbar SH, editors: The thyroid. A fundamental and clinical text, ed 4, New York, 1978, Harper & Row, Publishers, Inc pp 996-1108.

6. Beall GN, and Solomon DH: Immunologic features of thyroid disease, Postgrad Med 54:181, 1973.

7. Endo K, Kasagi K, Konishi J, Kuno T, Takeda Y, Mori T, and Torizuka K: Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves' and Hashimoto's thyroiditis, J Clin Endocrinol Metab 46:734, 1978.

8. Gordin A, Saarinen P, Pelkonen R, and Lamberg BA: Serum thyrotrophin and the response to thyrotrophin releasing hormone in symptomless autoimmune thyroiditis and in borderline and overt hypothyroidism, Acta Endocri- nol 75:274, 1974.

9. Allison AC: Self-tolerance and autoimmunity in the thyroid, N Engl J Med 295:821, 1976.

10. Kalderon A, and Bogaars H: Immune complex deposits in Graves' disease and Hashimoto's thyroiditis, Am J Med 63:729, 1977.

11. McConahey W: Hashimoto's thyroiditis, Med Clin North Am 56:885, 1972.

12. Moens H, and Farid NR: Hashimoto's thyroiditis is associated with HLA-DRw3, N Engl J Med 299:133, 1978.

13. Ziring P, Gallo G, Finegold M, Burnovici-Kline E, and Ogra-Pearay O: Chronic lymphocytic thyroiditis. Identifica- tion of rubella virus antigen in the thyroid of a child with congenital rubella, J PEDIATR 90:419, 1977.

14. Nieburg P, and Gardner L: Thyroiditis and congenital rubella syndrome, J PEDIAT• 89:675, 1975.

15. Gordin A, and Lamberg BA: Natural course of symptomless autoimmune thyroiditis, Lancet 2:1234, 1975.

16. Rallison M, Dobyns B, Keating F, Rall J, and Tyler F: Occurrence and natural history of chronic lymphocytic thyroiditis in children, J PEDIATR 86:675, 1975.

17. Loeb P, Drash A, and Kenny F: Prevalence oflow-titer and negative antithyroglobulin antibodies in biopsy proved Hashimoto's thyroiditis, J PEDIATR 82:17, 1973.

18. Hopwood NJ, Rabin BS, Foley TP, and Peake RL: Thyroid antibodies in children and adolescents with thyroid disorders, J PEDIATR 93:57, 1978.

19. Fisher D, Oddie T, Johnson D, and Nelson J: The diagnosis of Hashimoto's thyroiditis, J Clin Endocrinol Metab 40:795, 1975.

20. Fisher DA: Thyroid physiology and function tests in infants and childhood: Function tests, in Werner SC, and Ingbar SH, editors: The thyroid, a functional and clinical text, ed 4, New York, 1978, Harper & Row, Publishers, Inc., pp 384-388.

21. Drash AL, Becker DJ, Vitlapando S, Hopwood NJ, Foley TP, Robin B, and Peake R: The incidence of clinical and subclinical thyroid and adrenal disease and their association with antibodies to endocrine tissues, in children with juvenile diabetes mellitus (JDM), J PEDIATR 93:310, 1978.

22. Rotter JI, and Rimoin DL: Heterogenity in diabetes mellitus-update 1978. Evidence for further genetic heterogenity within juvenile-onset insulin-dependent diabetes mellitus, Diabetes, 27:599, 1978.

23. Winter RJ, and Green OC: Carbohydrate homeostasis in chronic lymphocytic thyroiditis: Increased incidence of diabetes mellitus, J PEDIATR 89:401, 1976.

24. Smith BR, and Hall R: Thyroid-stimulating immunoglobulins in Graves' disease, Lancet 2:427, 1974.

25. SolomOn DH, Chopra IJ, Chopra U, and Smith FS: Identification of subgroups of euthyroid Graves' ophthalmopathy, N Engl J Med 296:181, 1977.

26. McKenzie JM, and Zakarija M: LATS in Graves' disease, Rec Prog Horm Res 33:29, 1977.

27. Adams DD, and Kennedy TH: Evidence to suggest that LATS-protector stimulates the human thyroid gland, J Clin Endocrinol Metab 36:517, 1971.

28. Orgiazzi J, Williams DE, Chopra IJ, and Solomon DH: Human thyroid adenyl cyclase-stimulating activity in immunoglobulin G of patients with Graves' disease, J Clin Endocrinol Metab 42:341, 1976.

29. O'Donnell J, Trokoudes K, Silverberg J, Row R, and Volpe R: Thyroid displacement activity of serum immunoglobulins from patients with Graves' disease, J Clin Endocrinol Metab 46:770, 1978.

30. Shishiba Y, Miyachi Y, Takashi M, and Ozawa Y: LATS- protector activity in thyrotoxicosis measured by thyroidal intracellular colloid droplet formation, J Clin Endocrinol Metab 46:841, 1978.

31. Farid NR, Sampson L, Noel EP, Barnard JM, Mandeville R, Larsen B, Marshall WH, and Carter ND: A study of human leukocyte D locus related antigens in Graves' disease, J Clin Invest 63:108, 1979.

32. Harland PC, McArthur RG, and Fawcett DM: T3 toxicosis in children, Acta Paediatr Scand 66:525, 1977.

33. Weis EB, Oberg G, and Rosenthal JM: T3 thyrotoxicosis in a child, Am J Dis Child 132:374, 1978.

34. Turner JG, Brownie BE, Sadler WA, and Jensen CA: Does T, toxicosis exist? Lancet 1:1292, 1975 (letter).

35. Coulombe P, Dussault JH, and Walker P: Plasma catechol-


amine concentrations in hyperthyroidism and hypothyroidism, Metabolism 25:973, 1976.

36. Bayliss RI, and Edwards DM: Urinary excretion of free catecholamines m Graves' disease, J Endocrinol 49:167, 1971.

37. Blonde L, and Skeleton CL: Hyperthyroidism and cardiovascular disease: Concepts and management, Cardiovasc Med 3:1145, 1978.

38. Williams RS, Guthrow CE, and Lefkowitz RJ: B-adrenergic receptors of human lymphocytes are unaltered by hyperthyroidism, J Clin Endocrinol Metab 48:503, 1979.

39. Zonszein J, Santangelo RP, Mackin JF, Lee TC, Coffey R J, and Canary JJ: Propranolol therapy in thyrotoxicosis. A review of 84 patients undergoing surgery, Am J Med 66:411, 1979.

40. Fisher DA: Hyperthyroidism: Pediatric aspects, in Werner SC, and Ingbar SH, editors: The thyroid. A fundamental and clinical text, ed 4, New York 1978, Harper & Row, Publishers, Inc., pp 805-813.

41. Barnes HV, and Blizzard RM: Antithyroid drug therapy for toxic diffuse goiter (Graves'): Thirty years experience in children and adolescence, J PEDIATR 91:313, 1977.

42. Sato T, Takata I, Taketani T, Saida K, and Nakajima H: Concurrence Of Graves' disease and Hashimoto's thyroiditis, Arch Dis Chil d 52:951, 1977.

43. Greer MA: Antithyroid drugs in the treatment of thyrotoxicosis, Thyroid Today 3:1, 1980,

44. Golden MP, Kaplan SA, Lippe BM, and Lee WP: Value of simultaneous T3, T4, and TSH measurements for management of Graves' disease in children, Pediatrics 59:762, 1977.

45. Greer MA, Kammer H, and Bouma O J: Short-term antithyroid drug therapy for the thyrotoxicosis of Graves' disease, N Engl J Med 297:173, 1977.

46. Collen RJ, Landaw EM, Kaplan SA, and Lippe BM: Remission rates of children and adolescents with thyrotoxicosis treated with antithyroid drugs, Pediatrics 65:550, 1980.

47. Zwillich CW, Matthau M, Potts DE, Alder R, Hofeldt F, and Weil IV: Thyrotoxicosis. Comparison of effects of thyroid ablation and beta adrenergic blockade on metabolic rate and ventilatory control, J Clin Endocrinol Metab 46:491, 1978.

48. Erikson M, Rubenfeld S, Garber AJ, and Kohler PO: Propranolol does not prevent thyroid storm, N Engl J Med 296:263, 1977.

49. Croxson MS, HalI TD, and Nicoloff JT: Combination drug therapy for treatment of hyperthyroid Graves' disease, J Clin Endocrinol Metab 45:623, 1977.

50. Vaidya VA, Bongiovanni AM, Parks JS, Tenore A, and Kirkland RT: Twenty-two years experience in the medical management of juvenile thyrotoxicosis, Pediatrics 54:565, 1974.

51. Freitas JE, Swanson DP, Gross MD, and Sisson JC: Iodine-131: Optimal therapy for hyperthyroidism in children and adolescents, J Nuclear Med 20:847, 1979.

52. Schumacher OP, and Safa AM: Long-term follow up results in children and adolescents treated with radioactive iodine (131-I) for hyperthyroidism, Pediatr Res 12:366A, 1978.

53. Gorman CA, and Robertson JS: Gonadal radiation dose and its genetic significance in radioiodine therapy of hyperthyroidism, J Nucl Med 17:826, 1976.

54. Wise RH, Ahmad A, Burnett RB, and Harding PE: Inten- tional radioiodine ablation in Graves' disease, Lancet 2:1231, 1975.

55. Kalk WJ, Durback D, Kantor S, and Levin J: Post thyroidectomy thyrotoxicosis, Lancet 1:291, 1978.

56. Perzik SL: Total thyroidectomy in Graves' disease in children, Pediatr Surg 11:191, 1976.

57. Toft AD, Irvine W J, Sinclair I, McIntosh D, Seth J, and Cameron EHD: Thyroid function after surgical treatment of thyrotoxicosis, N Engl J Med 298:643~ 1978.

58. Ozawa Y, Maciel RMB, Chopra IJ, Solomon DH, and Beall GN: ReIationships among immunoglobutin markers in Graves' disease, J Clin Endocrinol Metab 48:381, 1979.

59. Kuzuya N, Chiu SC, tkeda H, Uchimura H, Ito K, and Nagataki S: Correlation between thyroid stimulators and 3,5,3', triiodothyronine suppressibility in patients during treatment for hyperthyroidism with thioamide drugs: Com- parison of assays by thyroid stimulating and thyrotropin displacing activities, J Clin Endocrinol Metab 48:706, 1979.~

60. Teng CS, and Yeung RTT: Changes in thyroid stimulating antibody activity in Graves'disease treated with antithyroid drug and its .(elationship to relapse: A prospective study, J Clin Endocrinol Metab $0:144, 1980,

61. Mukhtar ED, Smith BR, Pyle GA, Hall R, and Vice P: Relation of thyroicl stimulating.immunoglobulins to thyroid function drugs and effects of surgery, radioiodine, and antithyroid drugs, Lancet 1:713, 1975.

62. Kirkland RT, Kirkland JL, Rosenberg HS, Harberg FJ, Librick L, and Clayton GWi Solitary thyroid nodules in 30 children and a report of a child with a thyroid abscess, Pediatrics 51:85, 1973.

63. Scott MD, and Crawford JD: Solitary thyroid nodules in childhood: Is the incidence of thyroid carcinoma declining? Pediatrics 58:521, 1976.

64. Root AW, Rettig K, Vargas A, and Reiter EO: The Thyroid: Recent advances in normal and abnormal physiology, Adv Pediatr 26:441, 1979.

65. Winship T, and Rosvall RV: Thyroid carcinoma in childhood and adolescence, Final report on a 20-year study, Clin Proc Child Hosp DC 26:327, 1970.

66. Favus M J, Schneider AB, Stauchura ME, Arnold JE, Ryo US, Pinsky SM, Coleman M, Arnold M J, andFrohman LA: Thyroid cancer occurring as a late consequence of head and neck irradiation. Evaluation of 1056 patients, N Engl J Med 294:1019, 1976.

67. Hempelman LH, Hall W J, Phillips M, Cooper R A, and Ames WR: Neoplasms in persons treated with x-rays in infancy: fourth survey in 20 years, J Nail Cancer Inst 55:519, 197/5.

68. Frohman LA: Radiation-induced thyroid cancer, presented at the Post-graduate Assembly of the Endocrine Society, Miami Beach, Fla., October 23-27, 1978~ pp 326-336.

69. Royce PC, Mackay BR, and Disabella PM: Value of postirradiation screening for thyroid nodules. A controlled study of recalled patients, JAMA 242:2675, 1979.

70. Clark OH, and Castner B J: Thyrotropin "receptors" in normal and neoplastic human thyroid tissue, Surgery 85:624, 1979.

71. Field JB, Bloom (3, Chou MCY, Kerins ME, Larsen PR, Kotani M, Kariya T, and Decker A: Effect of thyroid- stimulating hormone on human thyroid carcinoma and

$1 8 Reiter et al. The Journal of Pediatrics October 1981

adjacent normal tissue, J Clin Endocrinol Metab 47:1052, 1978.

72. Hopwood NK, Carroll RJ, Kenny FM, and Foley TP: Functigning thyroid masses in childhood and adolescence. Clinical, surgical and pathological correlations, J PrDIATR 89:710, 1976.

73. Van Herle A, and Uller R: Elevated serum thyrog!obulin. A marker of metastases in differentiated thyroid carcinoma, J Clin Invest 56:272, 1975.

74. LoGerfo P, Stillman T, Colacchio D, and Feind C: Serum thyroglobulin and recurrent thyroid cancer, Lancet 1:881, 1977.

75. Schneider A, Favu.s M, Stachura M, Arnold J, Yun Ryo M, Pinsky S, Coleman M, Arnold M, and Frohman L: Plasma thyroglobulia in detecting thyroid carcinoma after childhood head and neck irradiation, Ann Intern Med 86:29, 1977.

76. Wang CA, Vickey AL, and Maloof F: The role of needle

biopsy in evaluating solitary cold thyroid nodules, Excerpta Med 378:568, 1975.

77. Walfish PG, Hazani E, Strawbridge HTC, Miskin M, and Rosen IB: Combined ultrasound and needle aspiration cytology ~n the assessment and management of hypofunc~ tioning thyroid nodule, Ann Intern Med 8'7:270, 1977.

78. Irradiation-related thyroid cancer, DHEW Publication No. (NIH) 77-1120 pp 3-27.

79. Utiger RD: Is external irradiation a risk factor for thyroid disease and thyroid carcinoma? JAMA 242:2702, 1979.

80. Mosier HD: Euthyroid goiter: Diagnosis and management, in Gardner LI, editor: Endocrine and genetic diseases of childhood and adolescence, 2 ed, Philadelphia, I975, WB Saunders Company, pp 329-330.

81. Hoffman DP, Surks MI, Oppenheimer JH, and Weitzman ED: Response to thyrotropin-releasing hormone: An objec- tive criterion for the adequacy of thyrotropin suppression therapy, J Clin Endocrinol Metab 44:892, 1977.

childhood thyromegaly: recent developments

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