Achondroplastic dwarfism

Help for Slow-Growing Children

"I guess it was may motherly instinct that told me somethingwas wrong,' Chicago homemaker Mary Andrews says of her son Deno's growth problem. "Up until 2 1/2 he grew normally. But after that my sisters and in-laws would give me hand-me-downs [from their same-age children] and they would still fit him. I noticed that all the other kids were much taller.'

When Deno was 4 1/2 and still not growing as fast as his playmates, his mother decided to see if the problem might be due to some medical condition.

The diagnosis on Deno was not encouraging. Doctors toldAndrews that her child had a deficiency of human growth hormone (hGH)--his pituitary gland did not release enough of the protein that made him grow. They predicted that he would never reach more than 4 feet high.

"I was totally depressed,' says Andrews of that diagnosis10 years ago. "I had never heard of anything like this.' At the time, the treatment for Deno and thousands of other growth-deficient children in this country was thrice-weekly injections of human growth hormone (somatropin) taken from the pituitary (a small gland at the base of the brain) of cadavers. The yearly treatment for one child required hormone from 25 to 50 pituitary glands. Because of severely limited and expensive supplies, children with hGH deficiency received the hormone only until they had reached certain heights-- 5 feet 6 inches for boys and 5 feet 4 inches for girls.

Then, in April of 1985, three cases of an extremely rare,invariably fatal infection, Creutzfeldt-Jakob disease, were diagnosed in patients who had been using the hormone for five to 12 years. Experts theorized that some batches of the cadaver-derived hormone had contained the virus that causes the disease. (The virus is known to be harbored in the brain tissues of diseased patients.) Since there was no way to guarantee that the virus would be totally removed during the purification process of growth hormone from pituitaries, distribution of the hormone was suspended.

But in October 1985, after three and a half years of clinicaltesting at 13 U.S. medical centers, the Food and Drug Administration approved a genetically engineered form of human growth hormone providing virtually limitless supplies to the 10,000 to 15,000 American children in need of the growth stimulant.

"There is nothing but enthusiasm,' says Denise Orenstein,executive director of the Human Growth Foundation, a Bethesda, Md.-based nonprofit organization made up mainly of parents of children deficient in growth hormone. "This is the first time there has been an unlimited supply.'

The biosynthetic hormone was developed by the San Franciscocompany Genentech. Marketed under the trade name Protropin, it was only the second genetically engineered pharmaceutical, after insulin, to be approved in the United States.

(Genetic engineering, also known as recombinant DNAtechnology, is the process of introducing into a microorganism or other cell, DNA that contains genes for producing a specific protein. The DNA is inserted into the "host' cell in such a way that the cell treats it as its own, following the instructions coded in the gene to make the desired protein, in this case human growth hormone.)

Just what causes hGH deficiency remains a mystery. Occasionallya tumor destroys the pituitary gland, or there is an abnormality of the chromosome that contains the gene for growth hormone. Environmental and untritional influences play some kind of role; during protein deficiency and exercise, growth hormone production increases. Recent research indicates that the problem, in many cases, lies in a part of the brain called the hypothalamus, which releases a substance known as growth hormone-releasing factor. This substance stimulates the release of growth hormone from the pituitary gland.

How well the hypothalamus carries out its task may be affectedby stress, brought on by a variety of conditions--nutritional deficiencies and psychological or physical disturbances, for example. This would explain why abused and poorly fed children sometimes stop growing, even though their pituitaries are producing--but not releasing--sufficient hGH.

Growth hormone deficiency should not be confused withdwarfism. (Achondroplasia, the most common type of dwarfism, is a hereditary disorder of bone formation. The achondroplastic dwarf has a relatively large head, deformed vertebrae, and short extremities, in contrast to the well-proportioned but short body of the growth hormone deficient person.)

Diagnosis of growth hormone deficiency may be difficult.Because the hormone is produced in "spurts' by the pituitary gland, a normal blood test is unlikely to measure it accurately. The job of the diagnostician is to force the pituitary to release a substantial amount at one time. Since growth hormone increases when the blood sugar level is low, blood is sometimes drawn from children with a suspected deficiency after they have gone to sleep, after exercising, or after an injection of certain drugs. About 90 percent to 95 percent of the children who show low levels of growth hormone after such stimulation will benefit from hGH therapy.

According to Dr. Gilbert August, vice chairman of endocrinologyand metabolism at Children's Hospital in Washington, D.C., the best candidates for hGH therapy are children who show a "slowdown in the growth rate.' Unlike normal children who grow about 2 inches a year between ages 3 and 12, hGH-deficient children grow only an inch or an inch and a quarter a year.

"It's hard for the pediatrician to diagnose it because upto 2 [years of age], children are in constantly with all the shots and their height is checked,' notes Andrews, who is now active in the Chicago chapter of the Human Growth Foundation. "But after that age, they [pediatricians] don't see the kids as much. It's kind of up to the parent to spot it early enough.'

Early enough means that children with hGH deficiencyshould be diagnosed before puberty, and the sooner, the better. HGH can be administered, says August, "as long as the growth centers of the bone are still open, usually until about mid-puberty [about age 15].' However, he adds that "there is a limit to the amount of catch-up growth you can expect.'

Patients receive injections three times a week until theyare at a bone age of 14 to 16. Children with growth hormone deficiency often have a bone age that lags behind their chronological age. This allows for continued growth for a longer time. Deno, for example, now 15 1/2 and 5 feet 3 inches tall, will continue to receive the injections until the bone growth centers (epiphyses) close, probably in another year and a half. By then, he is expected to reach 5 feet 6 inches.

There has been concern that administering the hormonemight produce the ill effects seen in people who naturally have too much of it--acromegaly (an abnormal enlargement of the hands, feet and face) and diabetes. But so far the only side effect of Protropin has been the production of antibodies to the biosynthetic hormone in about 40 percent of the children who participated in the clinical trials. At least one patient stopped growing due to the antibodies, but resumed growth when given natural hGH before its distribution was halted. Yet, for the most part, the antibodies do not appear to have an inhibitory effect on the hormone.

The antibody-producing side effect is "similar to insulin,'says August. "A certain percentage--over 50 percent--will develop antibodies with the old [animal-derived] insulin. But with the new [genetically engineered] human insulin, the number is very low.'

An extra amino acid in the biosynthetic version of hGHmay be responsible for the antibody formation. So researchers are trying to produce an exact copy of the natural hormone by removing the extra amino acid.

The record for first-year growth with the hormone is 7inches, but realistic expectations are 3 to 5 inches the first year, somewhat less the second year, and after that, a normal growth rate.

Physicians warn that often parents and children, enthusedby promises of height in a society that values it so highly, may expect far too much. In a study of 11 children who received hGH, Diane Rotnem, assistant professor of sociel work at The Yale Child Center in New Haven, Conn., found that when children didn't grow as much as they had hoped, they became angry, pessimistic, guilty, and generally negative.

Deno has averaged 2 to 4 inches per year, but his motheradmits to impatience "if it looked like he wasn't growing' according to the wall marks at home that chart his progress.

Brian Stabler, associate professor of psychology at the Universityof North Carolina School of Medicine, reported in a study of children getting hGH that 45 percent of the patients and their parents overestimated the child's height in relation to peers, and nearly 80 percent had unrealistic expectations of the beneficial effects of hGH on the child.

"We are dealing with something that affects the body image,'Stabler notes. "And there will be some families who will hope and expect that changing the height will change everything else. Some are bound to be disappointed because its actual effect is very limited. All parents want their children to be as handsome as possible. These things are perfectly understandable in the context of the society. The unreasonableness comes when they think that hGH will affect intelligence, physical attractiveness, athletics and social skills.' Stabler urges counseling for the child and the parents. "If we work with them, we should expect that they will have less psychological trauma,' he says.

Psychologists stress the importance of a counseling programalong with the hormone injections to explain treatment limitations and realistic expectations.

"We meet regularly with the family,' Stabler says. "Parentsbegin to think about terminal height and they need to think about rate of growth. They tend to think in inches, and endocrinologists think in centimeters. We clarify their hopes and expectations.'

[Endocrinologists are specialists in the hormone-producingglands, such as the pituitary.]

Stabler is investigating how tempermanent might be a partof hGH deficiency. Past research has suggested that children with hGH deficiency are more passive, shy and retiring.

Other research is examining whether biosynthetic growthhormone therapy is safe and effective treatment for Turner's syndrome, a chromosomal irregularity that may affect up to 8,000 girls in the United States. Not only are these girls short, but they also may have other physical abnormalities, including heart defects. Genetech plans to study the effects of hGH on 150 children with Turner's syndrome at six or seven medical centers, looking at both the physical and psychosocial effects of the disease and its treatment.

With increased understanding of growth hormone, and withmore companies poised to spring into production, broader applications are in sight, particularly in the area of what is called "cosmetic endocrinology.' Some researchers believe that the true function of growth hormone is not to stimulate growth, but to conserve muscle tissue while reducing fat during periods of stress. Growth hormone apparently stimulates the release of fat from cells and, during fasting, prevents the body from burning up muscle for fuel. So, hGH is being scrutinized as a possible aid in weight reduction. In addition, since the production of hGH decreases with age, some researchers believe that it may eventually be used to retard wrinkling and the fat distribution associated with aging. FDA has not approved hGH for either use because studies to prove its safety and efficacy have not been completed.

COPYRIGHT 1987 U.S. Government Printing Office
COPYRIGHT 2004 Gale Group