Researchers Discover Genetic Mutation For Rare Form Of Dwarfism

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 S o 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