What causes cleft palate in a fetus?

What Causes Cleft Palate in a Fetus

Cleft palate results from a multifactorial etiology involving both genetic susceptibility and environmental exposures during critical periods of palatal development, with the most strongly established modifiable risk factors being maternal smoking, alcohol consumption, lack of folic acid supplementation, and certain medication exposures during the first trimester. 1, 2, 3

Genetic Factors

• Approximately 50% of cleft palate cases occur as part of known genetic syndromes (such as 22q11.2 deletion syndrome, Pierre Robin sequence, Stickler syndrome, and Treacher Collins syndrome), while the other half occur as isolated non-syndromic defects 4, 5, 6, 2
• The demonstrated increased risk for siblings and substantially higher risk for monozygotic twins confirms a strong genetic component, though most cases follow oligogenic inheritance patterns with reduced penetrance rather than simple Mendelian inheritance 6, 7
• Recent genome-wide association studies have identified specific genetic loci contributing to non-syndromic cleft palate, involving disruptions in critical molecular pathways including BMP, TGF-β, and SHH signaling pathways that are essential for proper palatal closure 2, 3

Environmental Risk Factors

Strongly Established Exposures

• Maternal smoking during pregnancy increases risk significantly (OR 2.05,95% CI 1.23-3.41), representing one of the most consistently demonstrated environmental risk factors across multiple populations 1, 2
• Alcohol consumption during pregnancy increases risk (OR 1.90,95% CI 1.17-3.08) 1
• Lack of folic acid supplementation during pregnancy substantially increases risk (OR 3.27,95% CI 1.32-8.09), making this the strongest modifiable risk factor identified 1
• Absence of multivitamin supplementation during pregnancy increases risk (OR 2.6,95% CI 1.19-7.27) 1

Medication Exposures

• Glucocorticoid exposure before 10 weeks gestation has been shown to cause an increase in oral cleft incidence, though more recent studies have questioned the association with low-dose corticosteroids 8, 2
• Mycophenolate mofetil (MMF) exposure during pregnancy causes a high incidence of cleft lip/palate abnormalities (23% structural anomaly rate), along with hypoplastic nails, shortened fifth fingers, and microtia 8
• Ondansetron use in early pregnancy has been associated with a marginal but statistically significant absolute increase of 0.03% in orofacial clefts, though the overall risk remains small 8

Developmental Mechanism

• Cleft palate represents a failure of the palatal shelves to fuse during the critical developmental window between 6-12 weeks of gestation 8, 6
• The classic multifactorial threshold model (MTM) postulates that small disruptions accumulate across multiple molecular pathways controlling palate closure until a risk threshold is crossed, resulting in the defect 8
• Pathway heterogeneity means that disruptions in different molecular pathways can lead to the same phenotypic outcome, and affected individuals may share disrupted pathways but have different specific genetic variants within those pathways 8

Critical Clinical Considerations

• Timing of exposure matters critically: The palate forms before 10 weeks gestation, so teratogenic exposures after this period do not cause cleft palate, though they may affect other developmental processes 8
• Maternal obesity increases rates of congenital anomalies including cleft lip or palate, though the mechanism remains incompletely understood 8
• Advanced paternal age has been demonstrated as a risk factor, though the effect size is smaller than maternal exposures 6
• The etiology differs substantially between isolated cleft palate only (CPO) versus cleft lip with or without cleft palate (CL/P), with CPO having distinct genetic architecture and environmental risk profiles 2, 7