Cleft lip and palate, and syndromes affecting the craniofacial region

13 Cleft lip and palate, and syndromes affecting the craniofacial region

A syndrome is the association of several clinically recognizable signs and symptoms, which can occur together in an affected individual. A large number of syndromic conditions involve the craniofacial region (Gorlin et al, 2001) and these can be broadly subdivided into:

Single gene disorders are the result of specific gene mutations and are inherited according to Mendelian rules, with varying levels of penetrance and expressivity within pedigrees:

Cytogenetics, or the study of chromosomal abnormalities, has also revealed a wide range of physical chromosomal alterations, including variations in both number and structure, which can cause perturbations of gene function and congenital malformations.

Teratogenic agents come in many forms and can include:

Identifying candidate genes for genetic conditions

Elucidating the genetic basis of an inherited condition is not a straightforward task. The human genome contains over 3 billion base pairs within the entire DNA sequence and some genetic disorders can arise from a change in only a single one of these. One of the main obstacles is the location and identification of the causative gene, a process that has become easier with advances in molecular biology and bioinformatics (Box 13.1).

Box 13.1 The human genome project

Publication of the draft human genome sequence (Lander et al, 2001; Venter et al, 2001) has provided an important global resource that will have an effect upon all our lives. Within the human genome there are approximately 30,000 genes distributed across the 23 chromosomes and access to this sequence information has important implications for molecular medicine. In particular, geneticists are now able to identify disease genes and position them within the genome much more easily. A candidate sequence can be entered into sophisticated online browsers and the whole human DNA sequence searched in a matter of minutes. This knowledge is also allowing the development of more rapid and specific tests for the presence of, or susceptibility to certain genetic diseases; which will lead to earlier diagnosis and hopefully treatment of these conditions. In addition, knowledge gained from the human genome will allow progress to be made in therapeutics, with the design of drugs that function at the molecular level and target the specific causes of the disease rather than simply controlling the effects. Finally, the sequence is also an invaluable resource for biologists, providing valuable insight into human evolution and diversity.

For single-gene disorders, positional cloning aims to identify, or at least localize, the chromosomal region where a candidate disease gene may reside. Geneticists use markers within the genome that can be tracked through members of an affected pedigree and provide linkage to the candidate region for a particular condition:

Modern geneticists use DNA polymorphisms as markers. These are identifiable sequence variations situated at specific positions within the genome. By identifying those most closely associated with a disease locus, a region of DNA at a specific point within the genome that might harbor the candidate gene for a particular disease is identified. Once the region has been narrowed down in this way, specific genes within the locus can be investigated.

Unfortunately, many disorders are multifactorial and do not behave in a simple Mendelian manner. These conditions have a more complex aetiological basis, being the combined product of:

A good example of a multifactorial condition that can affect the craniofacial region is nonsyndromic cleft lip and palate. For these conditions, populations rather than family pedigrees usually must be investigated, and more complex methods of genetic mapping are required. For this reason, there has been less success in elucidating the basis of multifactorial conditions than that of single-gene disorders.

Cleft lip and palate

Clefts involving the lip and/or palate (CLP) or isolated clefts of the palate (CP) are the commonest congenital anomaly to affect the craniofacial region in man (Fraser, 1970). They represent a complex phenotype and reflect a failure of the normal mechanisms involved during early embryological development of the face. In human populations CLP and CP can be broadly subdivided into:


Whilst a number of causative genes have been identified for different types of syndromic CLP and CP (Table 13.1), the aetiology and pathogenesis of nonsyndromic forms are poorly understood. This is a reflection of the multifactorial nature of these conditions, being the result of genetic and environmental interactions affecting development of the face at specific time points during embryogenesis. It has been suggested that up to fourteen different genetic loci may be involved in nonsyndromic CLP, which means that very large and genetically pure sample sizes are required to identify specific causative genes (Lidral & Murray, 2004).

At the embryological level, perturbations in a variety of mechanisms during facial development are known to cause clefting (Fig. 13.2). A growing number of mutant mouse strains that exhibit CP (and to a lesser extent, CLP) have now been generated and these continue to provide a host of candidate genes for the human condition (Gritli-Linde, 2007; Jiang et al, 2006).


Figure 13.2 Embryonic causes of cleft palate.

Redrawn from Chai Y and Maxon RE Jr. (2006) Recent advances in craniofacial morphogenesis. Dev Dyn, 235:2353–75.


A child born with orofacial clefting will require complex long-term treatment, depending upon the severity of the cleft, and there may be lifelong implications for those individuals unfortunate enough to be affected. The principle objectives of treatment are to establish:

If these objectives are achieved, they maximize the chances of an affected child growing up and developing normally within their social environment.

The clinical management of children born with clefting is most effective when carried out by a fully integrated team, in a centralized unit that treats a high number of patients (Box 13.2). The modern cleft team therefore includes a number of key members, in addition to other specialists who may be involved with long-term care (Table 13.2).

Box 13.2 Providing care for patients with orofacial clefting in the United Kingdom

In the late 1980s, some concern was raised amongst healthcare professionals regarding the quality of care being provided for children born with CLP or CP in the UK. This was based principally upon the outcome of two studies:

This concern led to the establishment of a Clinical Standards Advisory Group (CSAG) national investigation into cleft care in the UK. This study reported upon clinical outcome in a total of 457 5- and 12-year-old children affected by nonsyndromic unilateral CLP (Sandy et al, 1998). On the basis of this investigation, the CSAG Cleft Lip and Palate Committee made a number of recommendations regarding the future provision of cleft care in the UK:

These recommendations reflected the findings that high-quality clinical outcome in cleft care was primarily associated with centralization of services; providing clinical operators that treated large numbers of patients the correct environment for high-quality training and the infrastructure to establish effective clinical audit and intercentre comparison. Inevitably, implementation of these recommendations has required a considerable reduction in the number of centres and personnel providing cleft care in the UK, a feat that has not been achieved without some opposition.

Table 13.2 Members of the modern cleft team


Giving birth to a child affected by a cleft can be a distressing experience for the parents, particularly if this condition has not been diagnosed in utero (Fig. 13.3). A multitude of emotions can occur, including shock, anger, guilt, grief and even rejection. It is important that adequate support is given to the parents and that a bond is quickly established between the parents and child.

A baby born with CLP may experience difficulty in feeding at birth. CP produces an open communication between the oral and nasal cavities. Suckling can be slow because the baby will have difficulty generating adequate intraoral pressure and milk can be lost through the nose before it is swallowed. It is important to establish an effective feeding regime as soon as possible:

Surgical repair of cleft lip and palate

A number of individual surgical techniques for repairing the embryonic deficits associated with both the lip and palate have been described. However, evaluating which technique, sequence or timing will provide optimum results is difficult and currently no true consensus for any of these criteria exists (Roberts-Harry & Sandy, 1992; Sandy & Roberts-Harry, 1993).

Early surgery does allow the child to establish good orofacial function as soon as possible and this is particularly important for the development of normal speech. However, surgical repair can be associated with scarring in the maxillary region, which can produce growth deficiencies in all three planes of space:

It is clear from comparative studies that facial growth is compromised in operated cleft subjects when compared with those from unoperated samples, particularly those that have undergone palatal repair (Mars & Houston, 1990). The goal of surgical correction is to minimize any potential growth discrepancy, whilst maximizing the aesthetic and functional outcome.

Lip repair

Surgical repair of cleft lip is usually carried out between 3 and 6 months of age as a single procedure (Fig. 13.6), the exact age being dictated by surgeon preference. Classically, the rule of ‘tens’ has been used, with surgery only taking place once the child is at least 10 weeks old, 10 pounds in weight, and having a haemoglobin level of 10%. However, waiting until these criteria are achieved can delay surgery and it has been argued that this can cause problems with both parent–infant bonding and early growth and development. Indeed, advances in neonatal care and paediatric anaesthesia have made it possible to perform cleft surgery during the neonatal period, although there is currently no clear evidence to suggest that this is particularly advantageous (Schendel, 2000).

Bilateral cleft lip is also repaired with a single procedure, involving simultaneous correction of the lip, nose and alveolus (Mulliken, 2000). The upper lip orbicularis oris muscle must be freed from each lateral cleft element and repaired in the midline anterior to the premaxilla.

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Jan 1, 2015 | Posted by in Orthodontics | Comments Off on Cleft lip and palate, and syndromes affecting the craniofacial region

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