Thyrotoxicosis may occur in any age group but is unusual in the first five years of life. The same remarkable preponderance of the disease in females over males is observed in children as in the adult population, and the signs and symptoms of the disease are similar in most respects. Behavioral symptoms frequently predominate in children and produce difficulty in school or problems in relationships within the family. Thyrotoxic children are tall for their age, probably as an effect of the disease. These children are restored to a normal height/age ratio after successful therapy for the thyrotoxicosis. Permanent brain damage and craniosynostosis are reported as complications of early childhood thyrotoxicosis(211.1). Bone age is also often advanced.²¹²

No more is known about the cause of the disease in children than in adults. Diagnosis rests upon eliciting a typical history and signs and upon the standard laboratory test results. Normal values for children are not the same as for adults during the first weeks of life, and these differences, as noted in Chapter 6, should be taken into account.

Therapy of Childhood Graves’ Disease

In some clinics, RAI is used in the treatment of thyrotoxicosis in children. In one report, 73 children and adolescents were so treated. Hypothyroidism developed in 43. Subsequent growth and development were normal. ²¹³ In another group of 23 treated with ¹³¹I, there were 4 recurrences, at least 5 became hypothyroid, and one was found to have a papillary thyroid cancer 20 months after the second dose. ²¹⁴ Safa et al. ⁴⁰ reviewed 87 children treated over 24 years and found no adverse effects except the well-known occurrence of hypothyroidism. Hamburger has examined therapy in 262 children ages 3 - 18 and concludes ¹³¹I therapy to be the best initial treatment. ⁴² Read et al (214.1) reviewed there experience with 131-I over a 36 year period, including six children under age 6, and 11 between 6 and 11 years. No adverse effects on the patients or  their offsprings were found, and they advocate 131-I as a safe and effective treatment.  Nevertheless, most physicians remain concerned about the risks of carcinogenesis, and the experience of Chernobyl has accentuated this concern. This problem was more fully discussed earlier in this chapter. Others believe that the risks of surgery and problems with antithyroid drug administration outweigh the potential  risk of ¹³¹I therapy. This problem was recently critically reviewed by Rivkees et al ^214.1. They point out the significant risks of reaction to antithyroid drugs, and of surgery. Surgery may have a mortality rate in hospital in children of about one per thousand operations, although this may have decreased in recent years. Among problems with radioactive iodide therapy, they note the minimal whole body radiation, possibly worsening of eye disease, and the apparent lack of significant thyroid cancer risk so far reported among children treated with I-131 for Graves’ disease. They assumed that risk would be lower in children after age five, and especially after age ten, and if all thyroid cells were destroyed. They advise using higher doses of radioiodine to minimize residual thyroid tissue, and avoiding treatment of children under age five, but they believe that RAI is a convenient, effective, and useful therapy in children with Graves’ disease. Many physicians remain reluctant to use 131-I in children under age 16-18.

Although ¹³¹I therapy  may gain acceptance, the most common choice for therapy is between antithyroid drugs and subtotal thyroidectomy ^213.1. Proponents of antithyroid drug therapy believe that there is a greater tendency for remission of thyrotoxicosis in children compared to adults and that antithyroid drug therapy avoids the psychic and physical problems caused by surgery in this age group. With drugs the need for surgery (or ¹³¹I) can be delayed almost indefinitely until conditions become favorable.

As arguments against surgery, one must consider the morbidity and possible, although rare, mortality. Surgery means a permanent scar, and the recurrence rate is much higher (up to 15%) than that observed in adults. If the recurrence rate is kept acceptably low by performing near-total thyroidectomies, there is always an attendant rise in the incidence of permanent hypothyroidism, and greater potential for damage to the recurrent laryngeal nerves and parathyroid glands. Damage to the parathyroids necessitates a complicated medical program that may be permanent, and is one of the major reasons for opposing routine surgical therapy in this disease. However Rudberg et al ²¹⁶ reported that, in a series of 24 children treated surgically, only one had  permanent hypoparathyroidism, and two recurred within 12 years. Soreide et al ²⁰³ operated on 82 children and had no post-op nerve palsy, no tetany, nor mortality, and point out that   surgery can provide a prompt, safe, and effective treatment. Childhood Graves’ disease was managed by near-total thyroidectomy in 78 patients of average age 13.8 years as reported by Sherman et al.. Transient hypoparathyroidism and RCN damage were seen. Only three patients required subsequent 131-I treatment. Eighty-five % of those with ophthalmopathy were improved after surgery. The authors conclude that the treatment is safe and effective when performed by experienced surgeons (203.1).Others have pointed out the high relapse rate with all forms of therapy in the pediatric age group.²¹⁴

The main argument favoring surgery is that it may correct the thyrotoxicosis with surety and speed, and result in less disruption of normal life and development than is associated with long-term administration of antithyroid drugs and the attendant constant medical supervision. Often children are unable to maintain the careful dosage schedule needed for control of the disease.

Finally, antithyroid drug therapy is the usual preferable initial therapy in children. Favorable indications for its use are mild thyrotoxicosis, a small goiter, recent onset of disease, and especially the presence of some obvious emotional problem that seems to be related to precipitation of the disease. Antithyroid drug administration necessitates much supervision by the physician and the parents, the permanent remission rate will be 50% or less,²¹⁵ and there is always the possibility of a reaction to the medication.

There is no consensus on secondary treatment. Some physicians favor surgery if the patient and parents seem incapable of following a regimen requiring frequent administration of medicine for a prolonged period or drug reactions occur. A factor that must be remembered in selecting the appropriate course of therapy is the experience of the available surgeon. Lack of experience contributes to a high rate of recurrence, permanent hypothyroidism, or permanent hypoparathyroidism. Other physicians believe the possible but unproven risks of ¹³¹I are more than outweighed by the known risks of operation, and ¹³¹I treatment is increasingly accepted for patients over age 15.

If antithyroid drugs are chosen as primary therapy, the patient is initially given a course of treatment for one or two years, according to the dosage schedule shown in Table 11-9. The dosage of PTU needed is usually 120 - 175 mg/m² body surface area daily divided into three equal doses every eight hours. Methimazole can be used in place of PTU; approximately one-tenth as much, in milligrams, is required. During therapy the dosage can usually be gradually reduced. Many patients will be satisfactorily controlled by once-a-day treatment. Although the plasma half-life of methimazole in children is only 3-6 hours, the drug is concentrated in the thyroid and maintains higher levels there for up to 24 hours after a dose ^215.1.

The program is similar to that employed in adult thyrotoxicosis. It is sensible to see the child once each month, and at that time to make sure that the program is being followed and progress made. Any evidence of depression of the bone marrow should prompt a change to an alternative drug or a different form of treatment, as discussed below.

At the end of one or two years the medication is withdrawn. If thyrotoxicosis recurs, a second course of treatment lasting for one year or more may be given. A decrease in the size of the goiter during therapy is good evidence that a remission has been achieved. Progressive enlargement of the gland during therapy implies that hypothyroidism has been produced. This enlargement can be controlled by reduction in the dose of antithyroid drug or by administration of replacement thyroid hormone. There is no adequate rule for deciding when medical therapy has failed. After courses of antithyroid drug therapy totaling two to four years and attainment of age 15, if the patient still has not entered a permanent remission it is probably best to proceed with surgical or ¹³¹I treatment. Barrio et al (215.1) reported on truly long term antithyroid drug therapy, which achieved 40% remissions in pediatric patients, with average time to remission of 5.4 years. Non-remitters were cured by RAI or surgery.

Occasionally a drug reaction develops while the condition is being controlled with an antithyroid drug. A change to another thiocarbamide may be satisfactory, but patients should be followed carefully. If a reaction is seen again, or if severe neutropenia occurs, it is usually best to stop antithyroid drug therapy and (1) give potassium iodide and an agent such as propranolol and to proceed with surgery, or (2) to give ¹³¹I. RAI therapy will be necessary if surgery is contraindicated by uncontrollable thyrotoxicosis,for whatever reason, or with prior thyroidectomy. If surgery is elected, the patient should be prepared with an antithyroid drug such as PTU in a dosage and duration sufficient to produce a euthyroid state, and then should be given iodide for seven days before surgery. Lugol's solution, or a saturated solution of potassium iodide, 1 or 2 drops twice daily, is sufficient to induce involution of the gland.

Bossowski et al recently reported outome of treatment in 14 children (4 boys, 10 girls) aged 3.4-7.5 yr. At diagnosis, all patients had weight loss, hyperkinetic activity, tachycardia, difficulty sleeping, and poor concentration and 11 presented with proptosis. Four patients developed long-term neuropsychological problems. There was a family history in 7 cases. All patients had goiters. Height was increased with median (range) height; 1.25 standard deviation score (SDS) (-0.2-5.24) and body mass index (BMI) was decreased; -0.48 SDS (-1.65-1.26). Bone age was advanced in 4 of 5 children, who had assessments. Initial treatment was with carbimazole or propylthiouracyl. T4 was added in 6 patients. Normalisation of serum T4 occurred at 4 months (1- 9) and TSH at 7 months (3-24) after start of therapy. Treatment was discontinued after a minimum of 2 yr in 11 patients, relapse occurring in 9. Median duration of total therapy was 58 months (18-132). During adolescence, 4 patients had curative therapy by surgery (no.=2) or radioiodine (no.=2). Disturbance of growth, behavioral difficulties and infrequent spontaneous remission are key features of Graves' disease in early childhood. (Bossowski AT, Reddy V, Perry LA, Johnston LB, Banerjee K, Blair JC, Savage MOClinical and endocrine features and long-term outcome of Graves' disease in early childhood.J Endocrin Invest 30:388-392,2007)Thyrotoxicosis in children has been recently reviewed(215.2)

Table 11-9.

* Metrically minded physicians can divide weight by 2 to approximate kilograms.
  Surface area in square meters.

Intrauterine and Neonatal Thyrotoxicosis

Thyrotoxicosis in utero is a rare but recognized syndrome occurring in pregnant women with very high TSH-R stimulating Ab in serum, due to transplacental passage of antibodies, or can develop in the neonate. It is possible to screen for this risk by assaying TSAb in serum of pregnant women with known current or prior Graves' Disease. Intra-uterine thyrotoxicosis causes fetal tachycardia, failure to grow, acceleration of bone age, premature closure of sutures, and occasionally fetal death. Multiple sequential pregnancies with this problem have been recorded. Clinical diagnosis is obviously inexact.  Antithyroid drugs can be given, but control of the dosage is uncertain.²¹⁷   Propylthiouracil is  considered to be the safest drug to use, because of fetal anomalies attributed to methimazole exposure in early pregnancy(217.1). Luton et al (217.1) recently provided their extensive experience in managing these difficult cases. Measurement of TSAb is important. Patients with negative TSAb assay, and not on ATD, rarely have any fetal problem. Mothers with positive TSAb or on ATD must be monitored by following maternal hormone and TSH levels, fetal growth , heart rate, and by ultrasound for evidence of goiter or other signs of fetal hyper- or hypothyroidism.  If maternal hormone levels are low and TSH elevated, with fetal goiter and evidence of hypothyroidism, ATD therapy is reduced and intra-amniotic T4 may be given. If maternal T4 levels high and TSH low, with fetal goiter and signs of fetal hyperthyroidism, increased doses of ATD are suggested. If the probable metabolic status of the fetus is not clear, fetal blood sampling is feasible although carrying significant risk to the fetus. Plasmapheresis to reduce maternal TSH-RAb has been recommended, but few facts are available. Thyrotoxicosis in pregnancy is discussed in Ch.14.

Thyrotoxicosis is rare in the newborn infant and is usually associated with past or present maternal hyperthyroidism.²¹⁸ Neonatal hypermetabolism usually arises from transplacental passage of TSAb. Frequently the infant is not recognized as thyrotoxic at birth, but develops symptoms of restlessness, tachycardia, poor feeding, occasionally excessive hunger, excessive weight loss, and possibly fever and diarrhea a few days after birth. The fetus converts T₄ to T₃ poorly in utero, but switches to normal T₄ to T₃ deiodination at birth. This phenomenon may normally provide a measure of protection in utero that is lost at birth, allowing the development of thyrotoxicosis in a few days. The syndrome may persist for two to five weeks, until the effects of the maternal antibodies have disappeared. The patient may be treated with propranolol, antithyroid drugs given according to the schedule above, and iodide. The antithyroid drug can be given parenterally if necessary in saline solution after sterilization by filtration through a Millipore filter. Newborn infants with thyrotoxicosis are frequently extremely ill, and ancillary therapy, including sedation, cooling, fluids in large amounts, electrolyte replacement, and oxygen, are probably as important in management as specific therapy for the thyrotoxicosis. Propranolol is used to control the tachycardia(218.1). Because of the increased metabolism of such infants, attention to fluid balance and adequacy of nutrition are important.

The patient usually survives the thyrotoxicosis, and the disease is typically self-limiting, with the euthyroid state being established in one or two months. Antithyroid medication can be gradually withdrawn at this time.

Graves' disease can also occur in the newborn because the same disturbance that is causing the disorder in the mother is also occurring independently in the child. Hollingsworth et al.²¹⁹ have described their experience in such patients. The mothers did not necessarily have active disease during pregnancy. Graves' disease persisted in these patients from birth far beyond the time during which TSH-RSAb of maternal origin could persist. Advanced bone age was one feature of the disorder. Behavioral disturbances were later found in some of these children at a time when they were euthyroid.