| Macrostomia | |
|---|---|
 | |
| Macrostomia from bilateral mouth fissures | |
| Specialty | Medical genetics |
Macrostomia refers to amouth that is unusually wide.[1] The term is from theGreek prefixmakro- meaning "large" and from Greekστόμα, "mouth".[2]
Macrostomia is characterized as a physical abnormality that causes clefts to form on the face of affected individuals. These clefts can form on either or both sides of the face, but they are most commonly seen on the right cheek and have a higher rate of occurrence in males.[3] Macrostomia is very irregular and on average occurs only once in every 150,000 to 300,000 live births.[4] It's unusual for macrostomia to occur on its own and it is included as a symptom for many diseases includingcraniofacial microsomia.[3] The clefts result from improper development and fusion of themandibular andmaxillary processes.[3] The clefts cause problems with facial muscle development.[3] The origin of macrostomia is not yet fully understood: it could have multiple causes.[4]
There are 4 distinct variations of macrostomia.[3] Classifications are a complete lateral facial cleft, simple macrostomia, macrostomia with diastasis of the facial musculature, and isolated facial musculature diastasis.[3] Each has a different physical appearance with varying levels of severity.[3]
The cleft associated with macrostomia is associated with improper or failed fusion of the mandibular and maxillary processes during embryonic development.[3] This can lead to a variety of abnormalities involvingskin,subcutaneous tissue, facial muscles, and themucous membrane.[5] The severity of each abnormality can vary from minor to severe. Environmental contaminants may play a role in causing macrostomia. Many affected individuals were found in Lagos, an industrial area of Nigeria, where water supplies are known to be contaminated by improper disposal of industrial and domestic waste.[5]
The facial cleft runs from the corner of the mouth towards the bottom of the ear. The outside of the ear on the affected side of the face appears as normal and a region of soft tissue connects the cleft to the right lateral posterior hard palate. Internally there is no soft palate.[3]
This version of macrostomia is less severe because it does not affect the facial muscles and is not associated with any soft tissue or bone deformities. A small cleft(s) extends from the mouth and can be repaired surgically.[3]
Clefts in this variant are slightly more severe than the ones seen in simple macrostomia. It also does not have bone deformities, but it does include minor soft tissue deformities. The defining feature is muscle diastasis which is separation of themasseter. This phenotype can also be partially corrected with surgery.[3]
The facial cleft in this case results in a more severe muscle separation even though there is not a true open cleft. Bones in the region remain unaffected and the phenotype appears as an indentation of the cheek rather than an open cleft. The external ear in this phenotype can also be deformed.[3]
Likely due to the complexity of macrostomia, many theories have been provided over time in an attempt to define its origin. There is no definitive mechanism to explain its development but it is likely that there are interactions between genes and the environment resulting in improper development of the first and sometimes second brachial arch.[3]
Macrostomia can be partially classified as a heritableautosomal dominant disease.[6] The responsible mutation is found on the short arm ofchromosome 1 inlocations 32-34 (1p32-1p34).[6] The mutation isheterozygous meaning that it only occurs in oneallele. Asingle base substitution in the 11thcoding region of the genePTCH2 changes anadenine toguanine.[6] This results in avaline being incorporated instead of anisoleucine at the 147th position duringtranslation of the resultingtransmembrane protein (Val147Ile).[6]
The transmembrane protein encoded by PTCH2 is 1204amino acids long and is involved with inhibiting thesonic hedgehog signalling pathway that is involved with development.[6] PTCH2 inhibits the smooth frizzled class receptor (SMO) which when active is responsible for increasing transcription rates of many genes involved with development and differentiation.[7][8] PTCH2 (Val147Ile) is aloss of function mutation which results in a lack of control ofcell growth during development and links it to macrostomia.[6]