Causes and Risk Factors for Cleft Palate
Genetic Factors
Approximately 50% of cleft palate cases occur as part of known genetic syndromes, while the other half occur as isolated non-syndromic defects with strong genetic predisposition. 1
- The demonstrated increased risk for siblings and substantially higher risk for monozygotic twins confirms a genetic etiopathogenesis for cleft palate only (CPO). 2
- Specific genetic syndromes associated with cleft palate include 22q11.2 deletion syndrome, Pierre Robin sequence, Stickler syndrome, Treacher Collins syndrome, and CHARGE syndrome. 3, 4
- In CHARGE syndrome specifically, 25% of patients have cleft lip and palate, making it an under-recognized genetic cause. 4
- Some cases demonstrate a prevalent mode of inheritance, though oligogenic models with reduced penetrance are also proven. 2
Environmental and Medication Risk Factors
Teratogenic Medications
Mycophenolate mofetil (MMF) exposure during pregnancy causes a high incidence of cleft lip/palate abnormalities along with other structural anomalies. 1
- Glucocorticoid exposure before 10 weeks gestation has been associated with increased incidence of oral clefts, though recent studies question this association with low-dose corticosteroids. 1
- Ondansetron use in early pregnancy has been associated with a marginal but statistically significant increase in orofacial clefts. 1
Maternal Factors
- Maternal obesity increases rates of congenital anomalies including cleft lip or palate, though the mechanism remains incompletely understood. 1
- Smoking and alcohol consumption during pregnancy have been demonstrated as risk factors for CPO. 2
- Insufficient intake of folic acid during pregnancy has been suggested to increase the risk for CPO. 2
- Advanced paternal age has been demonstrated as a risk factor, though conflicting results have also been published. 2
Developmental Mechanism
Cleft palate represents a failure of the palatal shelves to fuse during the critical developmental window between 6-12 weeks of gestation. 1
- The classic multifactorial threshold model postulates that small disruptions accumulate across multiple molecular pathways controlling palate closure until a risk threshold is crossed. 1
- Timing of exposure is critically important: the palate forms before 10 weeks gestation, so teratogenic exposures after this period do not cause cleft palate. 1
Critical Clinical Caveats
- Approximately 50% of cases are syndromic, requiring comprehensive genetic evaluation to identify associated conditions that may complicate management. 1
- Environmental factors interact with genetic predisposition in a complex manner, making individual risk prediction challenging. 5, 2
- Diagnosis can be delayed if the child presents with covert phenotypic features such as chorioretinal colobomas, semicircular canal hypoplasia, or unilateral choanal atresia in syndromic cases. 4