Lack of Thyroid Hormone Is Linked to Retardation in Infants

BOSTON —  Subtle clues uncovered as an infant lay dying show how some children can be saved from lives of mental retardation, doctors report.

The surprising discovery--made in the throes of a dire emergency--showed doctors that huge tumor-like growths called hemangiomas sometimes make an enzyme that erases thyroid hormone function. Loss of the hormone seriously hampers the growing brain.

In fact, for each month a tiny infant goes without adequate thyroid hormone, the researchers said, he or she permanently loses about four IQ points. This occurs because at birth the brain is still growing, and loss of thyroid hormone leaves the brain poorly developed.

The new finding, made at Children’s Hospital in Boston, “arouses concern that infants with this tumor may be at risk for permanent neurological damage,” the doctors warned last summer in the New England Journal of Medicine. Indeed, the discovery recently spurred a search for other cases, which produced evidence that brain damage linked to loss of thyroid function has hit other children burdened with hemangiomas.

So it is now suddenly vital that infants who have hemangiomas be tested early and regularly for thyroid function and that they be given doses of thyroid hormone if needed. The doctors believe brain damage can be avoided if extra thyroid hormone is given in time to keep the brain growing normally.

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Hemangiomas are a relatively common type of abnormal growth, sometimes seen in first-year infants. They are almost always benign, causing no problems whatever. The blood-red, tumorlike growths arise in about 10% of live births and can occur in any organ. Fortunately, most disappear on their own and require no treatment.

But in a small percentage of cases, a hemangioma doesn’t shrink on its own. And if it is growing in a vital organ--the heart, lungs or liver--it can be life-threatening. Even then, however, most babies can be saved. Doctors have now learned that interferon-alfa, which the body produces naturally, makes even very difficult hemangiomas gradually go away.

But the thyroid problem--and loss of IQ--is a new and wholly unexpected wrinkle. According to Stephen Huang, an endocrinologist at Children’s Hospital, thyroid problems caused by hemangiomas seem to arise only if the growth gets big enough to overwhelm the thyroid gland’s ability to make hormone.

The danger seems to arise in just a tiny minority of cases, when a hemangioma reaches truly massive size. In the baby boy whose problem led to the discovery, the lumpy growths on his liver became so large--softball size--they were crowding his abdomen, putting pressure on his lungs and making breathing difficult.

A decade ago, babies burdened with such large, unruly growths usually died. But now that many can be saved by giving small, regular doses of interferon for months on end, the thyroid problem has become apparent.

In fact, what doctors first suspected were side effects from interferon are perhaps caused by lack of thyroid function instead. There were hints that interferon shots might somehow be reducing IQ.

What the new evidence suggests, however, is that the hemangioma, not the interferon, is what damages brain development by shutting down thyroid function. Huang and his colleagues discovered that massive hemangiomas can “turn on” production of a special enzyme that specifically blocks thyroid hormone’s action.

Normally, this enzyme--Type 3 iodothyronine deiodinase--is seen only in the placenta and in the brain, sites where it seems to protect against too much thyroid activity. But in newborns fighting huge hemangiomas, the researchers found that the enzyme is made in abnormally large amounts by the hemangioma.

The infant boy in whom they made the discovery had a tumor that was making so much of the anti-thyroid enzyme that he required huge doses of the hormone--eight times normal, and far more than what would be given to an adult male--to restore thyroid function, the doctors said.

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“He was a child with massive hemangiomas on his liver,” Huang said, “and he had respiratory failure from that.” The surprise was that “as his tumor grew, his requirement for thyroid hormone also increased. That had not been seen before.”

The baby had been born at home, and for religious reasons the parents had declined to allow the normal test for thyroid function at birth. Thus, when he arrived, desperately ill, at Children’s Hospital, Huang said, “we assumed that he had congenital hypothyroidism.”

Further tests, however, “suggested that he was hypothyroid not because of a thyroid defect, but because he was somehow using (the hormone) up faster than he should. This had never been described before. But it was the only way we could understand what was happening.”

In other words, the infant’s thyroid gland was functioning, but it wasn’t able to pour out enough thyroid hormone to overcome the power of the enzyme released by the hemangioma. And despite heroic efforts to save him, the infant boy soon succumbed.

After the baby died, Huang said, his parents granted permission for a tissue sample to be taken from the tumor. “If they hadn’t felt it was important and allowed us to do that research,” Huang said, a discovery that will help save other babies might not have been made.

Huang, who was on a fellowship at Children’s Hospital, had contacted endocrinologist Reed Larsen at nearby Brigham and Women’s Hospital. Larsen is an expert on hormone metabolism.

The tissue sample from the infant offered the vital answer. The doctors had already guessed the hemangioma might have been making the Type 3 iodothyronine deiodinase because “that is the main enzyme known to break down thyroid hormone in other situations,” Huang said. And their guess turned out to be on target.

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The tumor tissue sample--compared with normal tissues in the placenta or brain--”had activity that was eight times faster” than normal, Huang said. “So it contained previously undescribed levels of activity. What that taught us was that his tumor tissue was able to deactivate thyroid hormone.”

Although the discovery itself was intriguing, what it said about infants and the causes of mental retardation was even more interesting--and important.

“What was exciting about our follow-up,” Huang explained, “was that we began to ask whether this might be present in other known hemangiomas. So we took stored tumor tissue from the pathology department and got permission to test some of those samples. And out of five stored samples, three of them were making the enzyme at levels that were similar to human placenta, which is high. And that showed us that you could find the enzyme activity in hemangiomas” if one searched for such activity.