Further evidence from two families that craniofrontonasal dysplasia maps to Xp22

Craniofrontonasal dysplasia (CFND) is a rare X-linked disorder that maps to a 13-cM region on Xp22. Phenotypic features include craniosynostosis, hype rtelorism and a broad nasal root with or without a bifid nasal tip. Multipl e examples have been reported of males having a less severe phenotype than females. We report haplotype analyses in two CFND families over the critica l region to which the gene has been mapped. In pedigree 1, a clinically una ffected male inherited the affected marker haplotype spanning the critical region. We suggest that this individual does have the CFND mutation, but ha s an extremely mild phenotype that is not detectable with clinical examinat ion. Under the assumption that he is an unknown phenotype, a combined two-p oint LOD score of 1.68 at zero recombination was obtained, increasing the p reviously reported total to 5.61 (DXS8022). The data do not narrow down the critical region. This result stresses the importance of subjecting fathers of apparently sporadic cases to a highly critical medical examination and may also explain the unequal ratio of reported female-to-male cases.