CLINICAL AND MOLECULAR GENETICS STUDY OF ACHONDROPLASIA

Abstract

ACH is the most common skeletal dysplasia in humans. It is characterized by disproportionate short stature and certain radiological abnormalities resulting from defect in maturation of chondrocytes in the growth plate cartilage during endochondral ossification.

ACH is an autosomal dominant trait with complete peneterance. About 80-90% of cases are sporadic, resulting from de novo mutations that are almost exclusively of paternal ongm.

The gene responsible for ACH is the FGFR3 gene, located near the telomeric end of the short arm of chromosome 4 (4p16.3). Two missense mutations in exon 10 of the FGFR3 gene were identified in more than 95% of ACH patients. These two mutations occur in the same nucleotide (G1138A and Gl138C), which was proved to have the highest mutation rate of a single nucleotide in the human genome. Both mutations result in the same amino acid substitution; glycine to arginine at codon 380 (G380R) in the transmembrane domain of FGFR3 receptor. G380R causes gain of function of FGFR3 leading to inhibition of endochondral bone growth.

Molecular and •clinical homogeneity of ACH patients have been reported in several countries and. there were few exceptions.

, To confirm the previous reports and disclose the ACH mutations in Egyptian ACH patients, exon 10 ofFGFR3 gene was examined for the G1138A and G1138C mutations in 20 Egyptian ACH patients, their parents and in normal control group.

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The main clinical, anthropometric and radiological abnormalities were defined in the gehotyped patients. Patients were distributed in 3 age groups which roughly correspond to periods of growth. Frequencies of clinical and radiological findings were compared between these groups. Anthropometric SD scores and radiological ratios were tested for correlation withage.

PCR-RFLP analysis was done to detect the G1138A and G1138C mutations, using Bfml and Mspl restriction enzymes respectively.

SSCP analysis was done to 20 PCR products showed positive for the G1138A mutation by. restriction enzyme analysis, and 20 PCR products that were negative for the mutation.

History and • pedigree analysis revealed that 90% of cases were sporadic and were associated with advanced paternal age. Complications varied between patients, the commonest was the respiratory complications, and in older patients lower limb pain was a common finding.

Clinical examination showed homogeneity in body disproportion, relative macrocephaly, frontal bossing, midface hypoplasia in all patients. Some clinical features predominated in certain age groups, while other features were in variable frequencies in all groups.

Mean adult height for males was 122.8 em and for the two adult female patients it was 113 em and 115 em respectively. One patient (age 4 mo) had normal length.