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March 1, 1999

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Researchers Discover Genetic Mutation For Rare Form of Dwarfism

International Team Identifies Defect Among a 23,000-member Brazilian Family

A search for the genetic roots of towering height has led a Johns Hopkins endocrinologist to identify a mutation that causes a rare form of treatable dwarfism. Research results, published in the March issue of the Journal of Clinical Endocrinology and Metabolism, suggest that the mutation could be used as a prenatal screening test for the disorder.

After speaking at a meeting in Washington in 1996, Michael A. Levine, M.D., an authority on acromegaly -- a growth hormone disorder characterized by large hands and feet -- was invited by Brazilian researchers to consult on several families of giants seen at the University of São Paulo Hospital clinic. There, Levine noticed two patients in the waiting area who were unusually small. While he continued to look for the genetic basis for the tall patients, he asked permission to start another study of the shorter ones.

By analyzing DNA samples, Levine, endocrinology instructor Roberto Salvatori, M.D., and an international team of collaborators went on to pinpoint the mutation responsible for dwarfism among at least 105 members of an extended family of Portuguese descent in Sergipe, a remote area in northeastern Brazil. The family comprises 23,000 individuals.

All of the affected family members, whose average height is three and a half feet, inherited defective genes that knock out the receptor for growth hormone releasing hormone (GHRHR). The tiny change in the genetic code for the receptor makes it impossible for chemical signals that stimulate growth of bones to be "heard"; therefore, bone growth is markedly impaired.

The study suggests that defects in the receptor may be a more common cause of growth hormone deficiency than previously suspected, Levine says.

"This family serves as a living laboratory for diagnostic tests and treatment to bypass the broken signaling pathways and restore growth hormone," says Levine, professor of pediatrics, medicine and pathology at Hopkins.

Twenty-two of the affected members studied underwent extensive endocrine evaluation. All had markedly reduced or undetectable blood concentrations of growth hormone. The levels of hormone did not increase in response to different stimuli.

Because the disorder is autosomal recessive for short stature, all affected family members received two copies of the altered gene -- one from each parent. The family has a high frequency of consanguineous marriages, with unions between first-degree cousins and between second-degree cousins relatively common.

In addition to short stature, the affected family members have high-pitched voices and increased amounts of abdominal fat. Except for a somewhat delayed onset of puberty, which did not affect their fertility, they did not manifest any signs or symptoms to suggest deficiency of other pituitary hormones.

In ongoing research since identifying the defective pathway, the researchers have been treating a subset of the population with recombinant human growth hormone. Each patient showed a brisk increase in speed of growth.

Levine and his colleagues are continuing their search for the cause of gigantism.

The work was supported in part by the National Institutes of Health and the Genentech Foundation for Growth and Development. Other institutions involved in the study were the University of São Paulo, Brazil; Federal University of Sergipe, Aracaju, Brazil; Vanderbilt University, Nashville, Tenn.; and Northwestern University, Chicago.

Relevant Web sites:

Little People of America: http://www.lpaonline.org/
Greenberg Center for Skeletal Dysplasia (at Johns Hopkins): http://www.med.jhu.edu/Greenberg.Center/Greenberg.htm
Other research by Dr. Levine: http://www.med.jhu.edu/deptmed/resendo.html

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