Re: How do cleft palates form?

Cleft lips and cleft palates are congenital deformities which occur during the second month of pregnancy. Most clefts are due to a genetic predisposition combined with ill-defined environmental factors. In most cases, the cleft is the only craniofacial (head/face) abnormality, and is easily repaired. At the severe end, infants born with trisomy 13, also called Patau's Syndrome, have profound mental retardation and severe developmental malformations including a cleft palate and lip, suggesting that some of the genes controling formation of the face reside on chromosome 13.

During the first few stages of development, the nostrils and mouth open in to a common space called the stomodeal chamber. As the face begins to form, this chamber must be divided into the oral and nasal cavities, to allow independent usage of the nose and mouth (so you can breath and eat at the same time). Dividing the chamber is accomplished be the growth of "shelves" (palatal processes) from either side of the chamber which fuse at the midline to form the palate. Similarly, the external mouth is separated from the nostrils by the growth of maxillary processes from either side of the mouth which fuse at the midline to form the upper lip.

A cleft lip is a separation of the two sides of the lip, often including the maxillary bones of the upper jaw, resulting from lack of fusion of the maxillary processes. A cleft palate is an opening in the roof of the mouth in which the two palatal processes failed to close and fuse. The resulting gap may occur on the soft palate only, or it may extend forward through the hard palate, in which case the nasal cavity opens into the mouth and the nasal septum is often absent. Cleft lip and cleft palate can occur on one side (unilateral cleft lip and/or palate), or on both sides (bilateral cleft lip and/or palate), suggesting that the growth of each side occurs independently. Because the lip and the palate develop separately, it is possible for the child to have a cleft lip, a cleft palate, or both cleft lip and cleft palate.

In infancy, cleft palate limits the child's ability to suck and may lead to malnutrition; later, speech difficulties develop. Surgery to form an airtight separation between nose and mouth is usually performed at about 18 months of age. Even with expert surgical repair, however, speech training is necessary, and nose, ear, and sinus infections may remain a hazard. A child born with a cleft also requires several other types of services, like speech therapy, which need to be provided in a coordinated manner over a period of years.

Recent work (cited below) in mice suggests that Transforming growth factor- beta 3 (TGF-b3: a hormone involved in development) may play a key role in cleft formation. Mice lacking the TGF-b3 gene have unique and consistent phenotypic features including poor lung development and cleft palate. Unlike other null mutants with cleft palate, TGF-b3 deficient mice lack other craniofacial abnormalities. The defect appears to result from impaired adhesion of the apposing medial edge epithelia of the palatal shelves and subsequent elimination of the mid-line epithelial seam, both events requiring epithelial-mesenchymal interactions. Other factors are, no doubt, essential for proper palate formation, but by identifying this one factor, it will be easier to identify the causes of clefting in humans.

Proetzel, G, Pawlowski, SA, Wiles, MV, Yin, M, Boivin, GP, Howles, PN, Ding, J, Ferguson, MW, and Doetschman, T (1995), "Transforming growth factor-beta 3 is required for secondary palate fusion," Nature Genetics 11(4):409-14.

Kaartinen, V, Voncken, JW, Shuler, C, Warburton, D, Bu, D, Heisterkamp, N, and Groffen, J (1995), "Abnormal lung development and cleft palate in mice lacking TGF-b3 indicates defects of epithelial- mesenchymal interaction," Nature Genetics 11(4):415-21.