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:

• The closer a marker is to a disease gene, the less often it will be separated during meiotic recombination, and therefore, the marker and the disease gene will tend to be inherited together through generations.

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:

• Numerous susceptibility genes that each makes a minor contribution to the condition; and

• Environmental influences.

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:

• Nonsyndromic, which occur in isolation; and

• Syndromic, which occur in combination with other physical and developmental anomalies.

Classification

A number of formal classifications have been described for CLP and CP; however, the clinical presentation of these conditions is so variable that a specific description of each individual case is more useful (Fig. 13.1).

Figure 13.1 Orofacial clefting.

Unilateral cleft lip (top row), unilateral cleft lip and palate (second row), bilateral cleft lip and palate (third row), isolated cleft palate (bottom row).

• CLP can range from simple notching or isolated clefting of the upper lip with or without involvement of the alveolus, to complete unilateral or bilateral clefts of the lip, alveolus and hard/soft palate; and

• CP can range from a simple submucous cleft (a lack of continuity of the muscles across the palate) or bifid uvula to a complete cleft involving the primary and secondary palate.

Epidemiology

• In Caucasian populations, CLP is seen in approximately 1 : 1,000 live births, but racial differences occur, Asian races being affected most commonly (1 : 500) and African races least (1 : 2,500).

• Males are more commonly affected than females (approximately 2 : 1).

• Unilateral CLP represents around 80% of all facial clefts, with the left side being most commonly affected.

• In 70% of cases CLP is nonsyndromic, whilst the remaining 30% are syndromic.

• In Caucasian populations, CP is seen in around 1 : 2,000 live births (around half that of CLP), with no significant racial differences.

• Females are more commonly affected than males (approximately 4 : 1).

• In 50% of cases CP is nonsyndromic.

Aetiology

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).

Table 13.1 Causative genes in syndromic CLP and CP

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.

Treatment

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:

• Good facial appearance;

• Good orofacial function during speech, eating and swallowing;

• An aesthetic, functional and stable occlusion; and

• Good hearing.

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:

• The GOSLON (Great Ormond Street, London and Oslo) Yardstick was developed as a clinical tool that categorized dental arch relationships into five discrete categories. Using this yardstick, comparison between UK and Norwegian cleft centres demonstrated significant shortcomings in outcome associated with the UK centre (Mars et al, 1987).

• A European, multicentre clinical audit of treatment outcome for complete unilateral CLP (Eurocleft) found the two UK centres that participated to be weakest on almost every aspect of care (Shaw et al, 1992).

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:

• Cleft care should be centralized, with expertise and resources concentrated in 8 to 15 national centres (instead of the 57 identified in the study).

• A common nationwide database should be established for all cleft patients.

• Training for specialist cleft clinicians should only be provided in cleft centres where high-volume and high-quality clinical experience was available.

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

Birth

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.

Figure 13.3 Lip development can be monitored using ultrasound scanning. The external nares of the nose (outlined arrow) and both lips (white arrows) can be seen on this 16 week scan. The baby is on its side and development of these structures is normal.

• The clinical nurse specialist from the regional cleft team provides initial support, help and advice as soon as possible after diagnosis.

• Patient support groups such as the Cleft Lip and Palate Association (CLAPA) also play an important role in providing continued help and advice.

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:

• Feeding is generally successful using an assisted feeding bottle with a standard orthodontic teat, which can be squeezed to generate the necessary pressure; and

• Breastfeeding is occasionally possible, but may need supplementary feeding from a bottle.

Presurgical orthopedics

A period of active presurgical orthopedic alignment of the cleft alveolar segments is occasionally carried out in the neonate to reduce the size of the cleft defect and facilitate surgical repair. Specialized facial strapping or orthodontic plates (Fig. 13.4) are used, which can be passive or active and help mould or reposition the divided facial and maxillary segments. In particular, these plates have been used for:

• Reducing protrusion of the premaxillary segment in bilateral CLP cases;

• Reducing the size of an alveolar cleft and approximating the lip margins in unilateral CLP; and

• Reducing the width of an isolated palatal cleft.

Figure 13.4 Orthopedic cleft appliance to approximate the lip segments prior to repair (left panel) and intraoral orthopedic appliance to approximate the palatal shelves.

Courtesy of Christoph Huppa.

Presurgical orthopedic treatment is usually carried out at the discretion of the operating surgeon. There is currently little substantive evidence to suggest that any of these techniques provide long-term benefit for the dental arch relationship or facial appearance and their use remains controversial.

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:

• Midline scar tissue can prevent transverse growth and produce crossbites; and

• Scar tissue within the tuberosity region can tether the maxilla to the sphenoid bone, preventing downward and forward growth and producing a class III skeletal pattern (Fig. 13.5).

Figure 13.5 Maxillary hypoplasia in a patient with repaired cleft palate.

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).