Mild Nasal Clefting May be Predictive for ALX4 Heterozygotes

Heterozygous loss-of-function mutations in ALX4 are responsible for enlarged parietal foramina, whereas patients with biallelic ALX4 mutations display a phenotypic spectrum of clinical findings, from mild to severe alopecia, cranium bifidum, hypertelorism, microphthalmia, with alar clefting being the pivotal sign in all affecteds. We report on four affected individuals in a three-generation family, displaying a phenotypic spectrum ranging from mild nasal clefting and broad columella to subtle changes in nasal configuration in addition to parietal foramina, caused by a novel ALX4 mutation(c.646C>G, p.Arg216Gly). This is the second report of a family showing vertical transmission of a dominant ALX4 mutation with facial involvement in addition to parietal foramina, mimicking mild recessive ALX4 phenotype. We discuss possible pathological mechanisms that may have lead to phenotypic variation in the family and challenges in genetic counseling. (C) 2014 Wiley Periodicals, Inc.