Genetic and Environmental Factors in Cortisone Induced Cleft Palate 1

Abstract

Cleft lip and/or palate are the most frequently occurring birth defects in the United States, accounting for 13% of all reported anomalies (1). Genetic hypotheses for the etiology of these malformations have evolved slowly, gaining complexity with time. In the first extensive study in humans it was concluded that isolated cleft palate was inherited as a single dominant trait with greatly reduced penetrance (2). More recently, genetic models based on allelic restriction (3) and multifactorial threshold inheritance involving the effects of genetic and environmental factors (4-6) have been advanced. At the present time no clearcut evidence exists which discriminates in humans between the single locus and multifactorial models (7).

Over 20 years ago an animal model for cleft palate was developed in mice (8). It was shown that clefting of the developing secondary palate could be induced by the administration of glucocorticosteroids to pregnant mice between the 11th and 14th days of gestation. Further, it was found that various inbred strains of mice had different degrees of susceptibility to cortisone induced cleft palate (9, 10). Specifically, over 90% of the progeny of A/J and DBA/1 mice given 2.5 mg of cortisone developed cleft palate (C-P), whereas only 20-25% of the offspring of similarly treated C57BL/6 or CBA/J mice had the defect. More recently, it has been found that one factor determining susceptibility to cortisone induced C-P is associated with the major histocompatibility locus (H-2) of the mouse (11). Using congenic strains it was shown that mice of the H-2^a type were susceptible but mice identical genetically except for the fact that they carried the H-2^b or closely associated alleles were resistant. The H-2 complex is not the sole determinant of C-P sensitivity, however, for C3H/HeJ and CBA mice have the same H-2 genotype (H-2^k) but different susceptibilities to cortisone induced C-P (68% vs 12%, respectively) (12).