Macrostomia, Isolated
Description
Macrostomia is a congenital defect resulting from persistent lateral facial clefts, caused by failure of the maxillary and mandibular portions of the first branchial arch to unite normally. Macrostomia is a rare anomaly, with an estimated incidence of 1 in 150,000 to 300,000 births and is most often associated with other anomalies. Unilateral macrostomia is more common than bilateral (summary by Hawkins et al., 1973).
Clinical FeaturesHawkins et al. (1973) reported a 9-month-old girl with isolated bilateral macrostomia who underwent successful repair at 5 months of age. There was no history of medication, illness, or nutritional deficiency during early pregnancy, and no family history of congenital anomalies.
Gleizal et al. (2007) reviewed 90 reported cases of congenital macrostomia over the previous 50 years. Unilateral macrostomia was seen in 70 (80%) of the cases, and 62 (89%) of those were associated with other facial deformities such as ear anomalies, preauricular tags, and mandibular dysplasia. Analysis of the 20 reported cases of bilateral macrostomia, 14 of which had been previously published (see, e.g., McCarthy and West, 1977 and 200110), revealed that 12 (60%) were isolated and 4 (20%) were associated with bilateral microsomia. Only 3 cases presented with ear deformities and preauricular skin tags. Gleizal et al. (2007) concluded that bilateral macrostomia represents a distinct entity from unilateral macrostomia and provided details of surgical repair techniques.
MappingFan et al. (2009) performed linkage analysis in a large 4-generation Han Chinese family segregating autosomal dominant macrostomia and obtained a maximum lod score of 4.18 (theta = 0.0) at marker D1S2797. Haplotype analysis identified an interval between markers D1S193 and D1S2652 on chromosome 1p34-p32.
Molecular GeneticsIn 6 affected and 2 unaffected members of a large 4-generation Han Chinese family segregating autosomal dominant macrostomia mapping to chromosome 1p34-p32, Fan et al. (2009) identified heterozygosity for a 1423G-A transition in exon 11 of the PTCH2 gene (603673), resulting in a val471-to-ile (V471I) substitution in the fourth transmembrane domain. The mutation was not found in 520 unrelated controls. Functional studies in mouse mesenchymal stem cells demonstrated that wildtype but not mutant PTCH2 inhibited SMO-induced luciferase activity, and overexpression of wildtype PTCH2 significantly inhibited cell proliferation, but overexpression of the V471I mutant did not appear to have a major effect on cell growth rate. Fan et al. (2009) suggested that the PTCH2 V471I mutation may be associated with macrostomia.