Phenotypic variations of macrostomia - 4 distinct variations: complete lateral facial cleft, simple macrostomia, macrostomia with diastasis of the facial musculature, and isolated facial musculature diastasis - Different physical appearances and varying levels of severity for each variation - Abnormalities involve skin, subcutaneous tissue, facial muscles, and mucous membrane - Severity of abnormalities can range from minor to severe

Complete lateral facial cleft - Cleft runs from corner of the mouth towards the bottom of the ear - Outside of the ear on affected side appears normal - Region of soft tissue connects the cleft to the right lateral posterior hard palate - No soft palate internally - Severe form of macrostomia

Simple macrostomia - Less severe form of macrostomia - Does not affect facial muscles - Not associated with soft tissue or bone deformities - Small cleft(s) extend from the mouth and can be surgically repaired - Relatively milder physical appearance

Diastasis of the facial musculature - Clefts slightly more severe than in simple macrostomia - No bone deformities, but minor soft tissue deformities present - Muscle diastasis, particularly separation of the masseter, is the defining feature - Partial correction possible through surgery - Moderate physical appearance

Isolated facial musculature diastasis - More severe muscle separation, but no true open cleft - Bones in the region remain unaffected - Phenotype appears as indentation of the cheek - External ear can also be deformed - Relatively severe form of macrostomia

Mechanism and Genetic factors - No definitive mechanism to explain macrostomia's development - Likely interactions between genes and the environment - Improper development of the first and sometimes second brachial arch - Complex nature of macrostomia leads to various theories - Environmental contaminants may play a role in causing macrostomia - Macrostomia classified as a heritable autosomal dominant disease - Responsible mutation found on the short arm of chromosome 1 (1p32-1p34) - Heterozygous mutation in the gene PTCH2 (Val147Ile) - PTCH2 encodes a transmembrane protein involved in inhibiting the sonic hedgehog signaling pathway - Loss of function mutation leads to a lack of control of cell growth during development