ABSTRACT
Pfeiffer syndrome (PS) is one of the classical craniosynostosis syndromes correlated with specific mutations in the human fibroblast growth factor receptor (FGFR) genes, FGFR1 and FGFR2. In this study, we set out to examine the exons in FGFR2 most commonly associated with mutations in PS, exons IIIa and IIIc, in a panel of 78 unrelated individuals with PS by the most sensitive method (direct DNA sequencing). We have identified a total of 18 different mutations among 40 patients; eight of these mutations have not been previously described. The mutational spectrum displays a non-random character with the frequent involvement of cysteine codons.
Subject(s)
Mutation , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Fibroblast Growth Factor/genetics , Acrocephalosyndactylia/genetics , Alternative Splicing , Amino Acid Sequence , Amino Acid Substitution , Codon , Cysteine , Exons , Humans , Molecular Sequence Data , Mutation, Missense , Point Mutation , Protein Conformation , Receptor Protein-Tyrosine Kinases/chemistry , Receptor, Fibroblast Growth Factor, Type 1 , Receptor, Fibroblast Growth Factor, Type 2 , Receptors, Fibroblast Growth Factor/chemistryABSTRACT
OBJECTIVE: To inform of a new teratogenic syndrome in human beings and its confirmation in rats. MATERIAL AND METHODS: The study comprised three phases: a field study; a case-control study; and a genetic epidemiology study, aiming at identifying the causes of the occurrence of congenital malformations and psychomotor retardation in the city of Matamoros, Tamaulipas. The second-phase clinical multidisciplinary study was carried out at a general hospital, to conduct a comprehensive evaluation of patients identified during the first phase and offer them the necessary treatment. The third-phase experimental study was done in rats in order to confirm the teratogenic effect of the agents detected in the first phase. RESULTS: A total of 44 patients had a peculiar phenotype and mental retardation of varying degrees, all children of ex-workers of the same factory who were in direct contact, without protection, with organic solvents (methyl cellosolve and ethylene glycol). In the clinical study a syndrome was delineated, previously unreported, consisting of a peculiar facies, mental retardation, and musculo-skeletal and sensorial abnormalities. In the experimental study it was demonstrated that both methyl cellosolve and ethylene glycol cause cranio-facial, musculo-skeletal and central nervous system abnormalities, which confirmed the teratogenic effect of these solvents. CONCLUSIONS: The results of this study establish the existence of a new teratogenic syndrome in humans, produced by methyl cellosolve and ethylene glycol, whose teratogenic capacity had not been reported previously.
