New Form Of Inherited Dwarfism In Large Pakistani Family Caused By Genetic Mutation In A Pituitary Receptor

November 03, 1998

CHICAGO --- In 1994, after reading an article in a Karachi, Pakistan, newspaper describing a cluster of dwarfs living in a remote area in the province of Sindh, Pakistan, two Northwestern University Medical School researchers traveled there to investigate the disorder. That scientific journey led to the identification of a new, genetically inherited form of dwarfism.

Gerhard Baumann, M.D., professor of medicine, and Hiralal G. Maheshwari, M.D., research fellow at the Medical School, describe results of their study in an article in the November issue of the Journal of Clinical Endocrinology and Metabolism.

Baumann and Maheshwari set up a field laboratory in a district hospital 30 kilometers from where the dwarfs lived. There they compiled a full range of ecological, nutritional, clinical, biochemical and genetic data on the dwarfs and conducted extensive interviews to establish family relationships and medical histories.

All 18 dwarfs (aged newborn to 28 years old came from a single inbred family living in two neighboring villages in an area where marriages between first-degree relatives are common. One, affected, dwarf couple had a son (also affected), demonstrating fertility in both sexes.

The height, weight, head circumference, bone maturation and blood pressure of the group were significantly below normal. The mean height of adult males was 130 centimeters, or a little over 4 feet. Females had a mean height of 114 centimeters, or were about 3.5 feet tall. However, their bodies were normally proportioned and showed no deformities. Their intelligence was normal.

Baumann and Maheshwari became aware of reports of four similar, pediatric-age dwarfs in two other families (of Indian origin). Males experienced late-onset puberty, at about age 16, and as adults had a distinctive, raspy, high-pitched voice.

Biochemical findings in all the participants were consistent with growth hormone deficiency, with abnormal levels of insulin-like growth factors. Subsequent genetic analysis linked the unique form of dwarfism to an inactivating mutation in the gene for the growth hormone-releasing hormone receptor (GHRH-R), which triggers pituitary growth hormone secretion and growth in humans. The mutated GHRH-R causes growth hormone deficiency due to GHRH resistance.

Molecular genetic testing showed that inheritance of the dwarfism trait is transmitted in an autosomal recessive manner; i.e., the mutated gene, located on chromosome 7, must be carried by both parents for the disorder to manifest. Those who had only one copy of the gene (heterozygous) had mild biochemical GHRH-R abnormalities but only minimal or no growth retardation.

Four of the affected males in the group were later brought to the Medical School for further evaluation, which included magnetic resonance imaging of the pituitary, bone density testing and additional hormone level assessments. Results of the tests are forthcoming.

Dwarfism of Sindh, as this syndrome is now called, is the human genetic counterpart to the little (lit/lit) mouse. This mouse also has a mutation in the GHRH-R, causing GHRH resistance, an underdeveloped pituitary, growth hormone deficiency and a dwarfed body. The mouse also has decreased brain weight, a finding consistent with the small head circumference in the human dwarfs.

Baumann said these findings may facilitate studies of milder mutations in the GHRH-R or related genes as a potential cause of some growth disorders, as well as a better understanding of the genetic regulation of growth.
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