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From Research to Reality

To understand her son’s birth defect, a mother makes an emotional and scientific journey

Katherine E. Willmore

What Makes a Cleft

Understanding facial development reveals why facial clefts vary so widely: Clefts occur where fusion is disrupted. Failure of one of the maxillary prominences to fuse with the intermaxillary segment, for example, causes a unilateral cleft lip; failure of both to fuse results in a bilateral cleft lip. Failure of the palatal shelves to elevate creates a cleft secondary palate, like the one our son had, but has no effect on the primary palate or lips. In other cases, one shelf elevates and the other remains vertical, leading to a unilateral cleft palate. And in others, both shelves elevate but do not grow enough to meet at the midline, causing a somewhat less severe cleft. Even if the shelves do elevate properly, failure of the skin between them to break down can disrupt the fusion process, creating a cleft that might only become noticeable when the child starts to speak.

What remains unknown are the factors that cause fusion failure in the first place. Syndromic clefts arise as part of a syndrome in which other structures are also disrupted. More than 400 syndromes that involve facial clefting have been reported. There is often a clear association between the syndrome and specific genes, but the full role that most genes play is not usually known. And the source of the problem is often not the genes associated with the palate. Rather, the mutated genes encode generic developmental processes that help build a variety of structures, including our lungs, teeth, hair and limbs, along with the palate. The generic nature of these processes is what links the often disparate symptoms associated with craniofacial disorders such as Apert syndrome, Crouzon syndrome, Treacher-Collins syndrome and velocardiofacial syndrome. And the same mutation can affect people differently, depending on the rest of the genome and their environmental circumstances. One mutation could be responsible for a minor divot in the top of the upper lip in one individual and a complete bilateral cleft lip in another. Scientists are working to learn how these genes interact with the rest of the genome and with the environment, but current understanding of such interactions is still poor.

At least with syndromic clefts we have a starting point in the search for causes. But the majority of facial clefts appear on their own, with no other symptoms and no known associated mutations. These isolated clefts make up approximately 70 percent of cleft-lip cases and 50 percent of cleft-palate cases. Although our understanding of the mechanics of face and palate development is strong, the large number of factors that contribute to development, and the even greater number of interactions between these factors, keep the underlying cause of most cleft cases a mystery.

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