Hypothyroidism Caused by Chronic Autoimmune Thyroiditis in Very Young Infants

Table 1. Table 1. Laboratory-Test Results in Four Children with Acquired Primary Hypothyroidism.

We studied four infants who were referred to four medical centers with symptoms and signs of hypothyroidism. The infants' clinical and laboratory data are summarized in Table 1. Serum thyroxine and thyrotropin concentrations were measured at each center by standard immunoassay procedures. Tests for antithyroid peroxidase and antithyroglobulin antibodies were performed by hemagglutination or immunoassay,¹² and tests for thyrotropin-receptor antibodies by measuring the ability of unextracted serum to inhibit the binding of radiolabeled bovine thyrotropin to porcine thyroid membranes¹³.

Patient 1

Figure 1. Figure 1. Growth Charts of Four Children with Acquired Primary Hypothyroidism.

The arrows show the times of diagnosis and the initiation of therapy. The curves indicate the 5th, 50th, and 95th percentiles. The weight of each child was consistently at the same percentile as the height or at a higher percentile (data not shown).

Patient 1 was a girl born before statewide screening was introduced. Her health was normal until 1.1 years of age, when she was noted to have a placid, sallow appearance, coarse facial features, a hoarse cry, a moderately enlarged tongue, and an umbilical hernia. Her growth and development had been normal, but some deceleration in growth was evident at diagnosis (Figure 1). The thyroid was not palpable. Her serum thyroxine concentration was less than 1.0 μg per deciliter (12.8 nmol per liter), and her serum thyrotropin concentration was 533 mU per liter. Thyroid radioiodine uptake was 2 percent at 24 hours (normal, 12 to 30 percent). There was no family history of autoimmune thyroid disease. Treatment with thyroxine resulted in the disappearance of all signs of hypothyroidism. At a chronologic age of 3.5 years her mental age was 4.1 years and her intelligence quotient was 102 (Stanford-Binet test). In fourth grade she was an honor-roll student, and her intellectual achievement at the age of 14 years is normal.

Patient 2

Patient 2 was a boy who was found to have hypothyroidism at the age of 2.0 years. As a newborn he had meconium aspiration and seizures and was hospitalized for eight days in the neonatal intensive care unit. The results of neonatal screening for hypothyroidism were normal. His growth and development were normal for 1 year but then slowed, and linear growth stopped after the age of 1.5 years (Figure 1). When he was 2.0 years old his parents reported regression in his speech and his ability to walk and follow commands. He was constipated and slept excessively. Physical examination revealed dry, coarse hair and skin, an umbilical hernia, carotenemia, and a closed anterior fontanel. The thyroid gland was not palpable, but the results of technetium imaging were normal. His serum thyroxine concentration was less than 2.5 μg per deciliter (32 nmol per liter), and his serum thyrotropin concentration was more than 42 mU per liter. There was no family history of autoimmune thyroid disease. The boy's symptoms and signs of hypothyroidism resolved with thyroxine therapy. Although an audiologic examination at 8 months of age had been normal, audiometry and testing of brain-stem auditory responses at 2.5 years revealed a mild-to-moderate, primarily high-frequency neurosensory hearing loss that has persisted. The boy was fitted with hearing aids. When he was 4.5 years old his growth and development were normal, except for a substantial delay in speech.

Patient 3

Patient 3 was a boy who was evaluated at nine months of age because of poor weight gain, a deceleration in linear growth (Figure 1), and a slight delay in attaining developmental milestones for three months. The results of neonatal screening for hypothyroidism were normal. At the age of 1.2 years he was given a diagnosis of hypothyroidism on the basis of delayed motor and language development; a hoarse cry; dry, coarse hair; coarse facial features with macroglossia and a dull appearance; an enlarged anterior fontanel; dry, cool, mottled skin with carotenemia; a protuberant abdomen; pseudohypertrophy of the calf muscles; and absent deep-tendon reflexes. His thyroid gland was not palpable. His serum thyroxine and thyrotropin concentrations were less than 1.0 μg per deciliter and 129 mU per liter, respectively. A technetium thyroid scan was normal. Neither parent had elevated levels of thyroid antibodies, and there was no known autoimmune thyroid disease in the family. Thyrotropin-receptor antibodies were not detected in the patient or either parent. Within two months after the initiation of thyroxine therapy the symptoms and signs of hypothyroidism disappeared, and the boy had some improvement in reaching developmental milestones. A developmental assessment at that time revealed only slight gross- and fine-motor delay, normal receptive language, a six-month delay in expressive language, and a few recognizable words.

Patient 4

Patient 4 was normal until the age of nine months, when he was found on physical examination to have a marked depression of the nasal bridge, macroglossia with a slightly protruding tongue, and no deciduous teeth. There was a slight deceleration in growth in the months before diagnosis (Figure 1). His serum thyroxine concentration at birth was normal. His thyroid gland was not palpable. His serum thyroxine and thyrotropin concentrations at diagnosis were less than 1.0 μg per deciliter and 928 mU per liter, respectively. There was no family history of autoimmune thyroid disease. Treatment with thyroxine was initiated. His tongue became normal in size, but his nasal bridge remained depressed. At the age of 1.6 years his neurologic results, language development, and social behavior were normal. Developmental and cognitive evaluation at the age of 2.8 years revealed mild delay; he was functioning at a 1.7-year-old level.

The four infants we studied had nongoitrous primary hypothyroidism that developed during the first two years of life. We believe that the hypothyroidism was acquired, because the three children tested had normal thyroid function when screened at birth and the symptoms and signs of hypothyroidism first appeared rather abruptly at around six to nine months of age and then worsened rapidly. Each child had overt clinical hypothyroidism and severe biochemical hypothyroidism at the time of diagnosis, as well as positive tests for antithyroid peroxidase and antithyroglobulin antibodies. The diagnosis was made soon after the onset of the disease in two infants (Patients 1 and 4), but was delayed several months in the other two (Patients 2 and 3), as evidenced by their age at the onset of growth deceleration (Figure 1). The interval between the onset of symptoms and the initiation of thyroxine therapy was approximately four months. Patient 1, who is 14 years old at this writing, is normal; the remaining three infants are too young to allow an accurate assessment of developmental and intellectual achievement. There is concern, however, about the developmental progress of Patient 3, in whom the interval between the onset of symptoms and signs of hypothyroidism and diagnosis was the longest. The persistent neurosensory hearing deficit in Patient 2 may be a consequence of hypothyroidism.

We believe that the hypothyroidism in these children was caused by chronic autoimmune thyroiditis, given the presence of antithyroid antibodies (except thyrotropin-receptor antibodies) in all four children. This hypothesis would be strengthened by a family history of autoimmune thyroid disease. There was none when these children were first seen, but the mothers of Patients 1 and 2 had positive tests for antithyroid peroxidase antibodies several years later. Antibodies acquired by transplacental passage disappear within three to four months after delivery⁴ and are not associated with hypothyroidism that occurs when it did in these children. Their hypothyroidism is probably permanent; none had thyrotropin-receptor antibodies (which can disappear, thereby resulting in remission¹¹), and several had slightly elevated serum thyrotropin concentrations during follow-up. The lack of goiter, or a family history of goiter, makes it unlikely that any of these children had an inherited biosynthetic defect in thyroid hormonogenesis.

Acquired infantile hypothyroidism must be distinguished from missed cases of neonatal or late-onset congenital hypothyroidism¹⁴. Missed cases of permanent congenital hypothyroidism are rare in programs that screen once during the first week of life. In programs that routinely test a second specimen during the first two months of life, 5 to 10 percent of infants who were normal on neonatal screening have some evidence of hypothyroidism, raising the possibility that transient hypothyroidism is a rather common perinatal event¹⁵. Breast-feeding may delay the onset of symptoms and signs of congenital hypothyroidism,¹⁶ but it does not interfere with the detection of hypothyroidism by screening¹⁷. A recent report described four children with normal neonatal thyroid function in whom hypothyroidism developed during infancy or childhood because of thyroid dyshormonogenesis¹⁸; why the expression of an inborn error of thyroid hormone metabolism that is usually evident at birth was delayed is not known.

Primary hypothyroidism in infancy is rare, but early recognition, confirmation by serum thyrotropin and thyroxine measurements, and therapy are essential to prevent neurologic damage and possible mental retardation. It is important to realize that acquired primary hypothyroidism in infancy is a pathogenic entity distinct from congenital hypothyroidism, yet similar in clinical presentation and, presumably, in the risk of permanent neurologic sequelae.