February 03 Surgeon.indd

Molecular, clinical and political approaches to the problem of cleft lip and palate

J.R. Sandy
Division of Child Dental Health, University of Bristol Dental School, Lower Maudlin Street, Bristol, BS1 2LY, U.K.

Correspondence to: J.R. Sandy, University of Bristol Dental School, Lower Maudlin Street, Bristol, BS1 2LY, U.K. Email: Jonathan.sandy@bristol.ac.uk

Keywords: Cleft lip and palate, clinical outcomes, Health Services Reorganisation
Surg J R Coll Surg Edinb Irel., 1 February 2003, 9-16

The oral facial complex in man appears to be exquisitively sensitive to genetic and environmental influences which is why clefts of the palate are the most common congenital birth anomaly. The development of the palate starts at about the 6th week of inter-uterine life and requires development of the palatal shelves from the maxillary processes of the first arch, shelf elevation, medial edge epithelial breakdown and mesenchyme flow with subsequent establishment of osteogenic and myogenic blastemata. This significant level of matrix turnover is partly regulated by the matrix metalloproteinases and potentially this could be affected by abnormalities in gene function. This may represent a common mechanism for a variety of different genes associated with clefting of the palate. The measurement of outcomes for children born with a cleft requires a wide input from a variety of specialities. The development of these outcome measures requires rigorous testing and validation, but it is now possible to use a variety of outcome measures to establish clinical standards and this has been done nationally. The impact of identifying a need for a change in organisation of service delivery was probably underestimated. It is clear that the current organisations in the National Health Service struggle to implement change, even with a detailed study and hard evidence. Reasons for this are outlined and a potential harder hitting strategy for effecting this change is outlined. The move towards primary care trusts within the latest reorganisation of the Health Service is potentially extremely damaging for specialised services for low incidence anomalies

INTRODUCTION
In man, the craniofacial complex appears to be exquisitively sensitive to environmental and genetic influences during development. This explains why cleft palate can be caused by a number of teratogenic agents and that a large variety of nullizygous mutant mice exhibit this anomaly. No single gene defect has yet been identified but candidate genes include TGFa, TGFß3, Msx-1, PVRL1, RARA and GAD67.^1-3 Not surprisingly, clefts of the palate are the most common developmental anomaly in man and are seen in about 1 in 700 live births. This article outlines the research contributions in this area from the Division of Child Dental Health in Bristol, both in basic sciences and health services research. Finally, the use of clinical research to demonstrate a need for change in clinical service is an obvious step. The implementation of changes within the National Health Service is fraught with difficulty. Some of these are discussed and a potential solution to more effective management of change in the Health Service is outlined.

MOLECULAR MECHANISMS
The normal development of the secondary palate commences with the maxillary processes of the first branchial arch orientated vertically downwards and surrounded by a layer of undifferentiated epithelial cells, two or three layers thick. At a precise developmental stage, the palatal shelves elevate from a vertical to a horizontal position above the dorsum of the tongue.³ This movement is rapid and occurs in a matter of minutes or hours and clearly any delay in elevation may result in failure of fusion.

The medial edge epithelium (MEE) of the palatal shelves is lost when fusion occurs and continued mesenchyme flow is seen across the palate. The fate of these cells, particularly the basal layer of MEE cells is controversial. [The MEE cells either migrate from the midline and become incorporated into the nasal or the oral epitheliumor the MEE cells migrate into the body of the mesenchyme and transform into mesenchymal cells, a process known as epithelial-mesenchymal transformation (EMT).^4,5] The events involved in producing a normal intact palate, therefore, include MEE cell adherence, EMT, cell migration or a combination of all these processes. Cleft palate may result from disturbances at any stage of palate development.⁶ An account of the formation of the palate has been given previously together with potential mechanisms which may result in clefting.² Our recent interest has been in the area of the matrix metalloproteinases (MMPs) which represent a major class of highly conserved proteases responsible for matrix metabolism. They are a family of zinc- and calcium-dependent proteases which are synthesised by endogenous connective tissue cells and some types of haemopoetic cells.⁷

Figure 1: Transverse section through a developing mammalian palate. The palatal shelves are derived from the maxillary process and lie in a vertical position on either side of the tongue (courtesy of Nathan Brown)

Expression of the MMPs and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) in craniofacial development is tissue specific with strong temporal and spatial changes.⁸ This latter group provided good evidence of changes in MMP-2 levels in a variety of craniofacial structures but with no identification of tissue levels, temporal changes or discrimination between pro- and active enzyme in the secondary palate. It is known that the candidate molecules involved in palatogenesis, epidermal growth factor (EGF) and transforming growth factor ß (TGFß) also regulate MMP and TIMP synthesis.⁹ The tissue specificity of MMPs and TIMPs may also have some relation to changes in MEE, be it epithelial migration or transformation.¹⁰ The contiguous cells at the MEE seam are joined by cell-cell adhesion molecules of which the major molecules are E-cadherin, an integral membrane glycoprotein and syndecan-1, a heparan sulphate proteoglycan.^11,12 Collaborative work suggests there is simultaneous loss of expression of syndecan-1 and E-cadherin during EMT at the MEE seam of the palate.¹³ The MMP, stromelysin-1 (SL-1) may be pivotal in this process since induction of its expression results in cleavage of the cadherin, loss of epithelial phenotype and a stable EMT conversion.¹⁴

We believe that MMPs and TIMPs may play a crucial role in the formation of the mammalian palate. This argument has gained support in recent publications.^15-18 Disruption of these molecules may form a common link for the significant range of genetic and environmental conditions which result in clefting of the palate. This concept has been supported with recent work from Blavier et al (2001) who demonstrated in vitro that inhibition of MMPs prevented MEE breakdown.¹⁹ Brown et al (2002) used a similar model but suggested that MMP inhibition may also prevent palatal shelf growth and orientation as well as MEE breakdown.²⁰ This latter group also suggested that MMP-3 may have a significant role in MEE breakdown and fusion.

Figure 2: Following shelf elevation, as well as descent of the tongue, the medial edge epithelium undergoes breakdown and the palatal shelf is formed (courtesy of Nathan Brown)

Other potential avenues to determine molecular and cellular mechanisms in palate development involve the use of high throughput genomics and proteomics. This enables normal development processes to yield, up or down regulation of a wide variety of genes and proteins. This lays open a strategy to identify putative candidate genes for scrutiny in population studies.

CLINICAL APPROACHES
The organisation and delivery of cleft care in the United Kingdom has raised concerns for a number of years. This was highlighted with the Eurocleft study when it became obvious that the UK centres involved, in comparison with other European Centres, had poor clinical outcomes.²¹ It was clear to us that to improve the quality of care for these children a number of strategies and research tools needed to be developed. Our initial concerns were with collection of basic information. For example, how many of these children are born in the UK annually? What are the reporting mechanisms and how accurate are they? Other work in the West of Ireland convinced us of the need for collection of this data.²² We identified serious concerns and a lack of rationalisation for orthodontic services, as well as a problem with low volume operators in the delivery of surgical care.^23,24 This culminated in the production of minimum standards in order to try and close what were essentially audit loops.²⁵

The concerns and worries over the standards of health care for children born with a cleft lip and palate in the UK were not resolved after the Eurocleft Study and were clearly focused in a Clinical Standards Advisory Group (CSAG) study into cleft lip and palate.²⁶ This large national study utilised some of the methodology we had previously established and identified concerns on almost every aspect of care, including the recording of births, the process of care and the standards of outcomes.^27-31 This study has been widely reported with clear direction given as to how cleft services should be reorganised.^32-37 There was also the opportunity to further refine methodology from the data collected in the study.^38-40

The inevitable protests on the design of the study and the interpretation of the outcomes centred around the failure to initially prove a relationship between volume and outcome. Subsequent analysis of the data showed that there was an influence of the surgeon’s experience on speech outcomes for these children.^41,42 In addition, when the most crucial outcomes were examined it was found that in five out of six outcomes, high volume operators performed better than low volume operators. In none of the outcomes did low volume operators achieve better results than high volume operators.³⁶ The final CSAG recommendations were agreed unanimously by the CSAG committee and the main points for implementation were as detailed in Table 1.

The CSAG study was unique, but are concerns about outcomes restricted only to the UK? Further studies in Western Australia identified similar problems with cleft lip and palate patients and highlighted the need to examine healthcare services for low incidence anomalies.^43-45

Although these types of study have short- and medium-term implications in the delivery of care for children born with a cleft, there needs to be an overview of genetic and environmental influences as part of the total care of these children. For example, folic acid supplementation potentially offers a means to significantly reduce neural tube defects and possibly cleft palate with little difficulty.⁴⁶

Figure 3: Gelatin gel zymogram of MMP2 activity at three stages of palatal shelf formation. As the palatal shelves move from the vertical position on either side of the tongue (stage 1), to an elevated position above the tongue where the medial edge epithelium is still visible (stage 2) and finally to the third stage where the palatal shelf is formed, there is an increase in both the pro and active forms of MMP2 (courtesy of Nathan Brown)

POLITICAL APPROACHES
The recommendations of the CSAG report were accepted by Ministers (HSC1998/002) and the Department of Health set up the Cleft Implementation Group (CIG) to develop a commissioning framework for cleft services (HSC1998/087). No previous CSAG report had been followed by a formal process of implementation and cleft services were very much in the vanguard for reconfiguration of other small specialist services. How then could a report which was compelling and driven by detailed and meticulous research struggle with implementation? The recommendations of the CSAG report, were after all unanimous from the Committee itself, the recommendations were accepted by the Government and by most professional groups. This centralisation of care is not unique, there are good examples from European countries that show this is a sensible way forward. It is also supported by the active patient/parent group, the Cleft Lip and Palate Association (CLAPA). The recommendation on volume for surgeons is in line with current World Health Organisation thinking.

Figure 4: Microarray technology enables monitoring of gene changes at different stages of development. This is a gene chip containing 6500 genes. The different levels of light emission are proportional to the level of gene expression. Potentially this technology would enable the identification of candidate genes (courtesy of Nathan Brown)

Almost immediately, one of the difficulties that arose was devolution. Although the study was UK-based and the recommendations assumed a total UK population, it became clear that Scotland, Wales and Northern Ireland were free to develop their own models of care. The CIG only had jurisdiction then in England, but with regional boundaries with the devolved countries this raised potential problems.

Much of the implementation of the CSAG study was devolved to Regions. There were no guidelines on resource implications of service reconfigurations, lack of formal business plans or clear direction and little formal agreement between trusts within a Region; inevitably there has been a considerable delay. The financial intricacies of any reorganisation within the Health Service are always difficult. In the case of cleft lip and palate services which had been placed in many district general hospitals, it was impossible to recover a single session of speech and language therapy or two sessions of orthodontics. Besides, the new service model intended that these specialties should be provided locally and the bulk of the patients’ appointments would not involve undue disruption. There was no clear plan or direction on financial issues other than there was no “new” money. Fortunately, this has been recognised as impossible and those Regions who were able to proceed have been able to make business cases which have dealt, in part, with financial problems. There are of course revenue and capital issues, these are often difficult to achieve in a co-ordinated sequence.

Figure 5: The Clinical Standards Advisory Group national study was of a specific expression of clefting, the unilateral cleft lip and palate. Clefting of the lip and alveolus is obvious. All cases included in the study comprised this expression, syndromic patients were excluded

A further disruption to implementation has been the latest NHS reforms in England and Wales with the creation of primary care trusts (PCTs). This creates problems for low incidence anomalies where the subtleties of care are often lost. This is potentially disastrous, and that is why, in 1991 with the reforms in the NHS and purchaser-provider model, that CSAG was established. Whilst many recognise the need for centralisation of specialist services, it is difficult to obtain consensus amongst PCTs followed by clear financial agreements. Some Regions have appointed a lead PCT to circumvent these problems. This model was applied to the Regions in England where the North West Region, through a Regional Lead, was meant to vanguard the centralisation process. This clearly failed, the North-West Region appears to have made the least progress in centralising its cleft services. The CIG met with Regional Leads to advise on difficulties with centralisation. The Cleft Implementation Group was formally disbanded once all the Regional Leads had laid out their plans for approval. The Cleft Implementation Group has now been replaced by the Cleft Implementation Monitoring Group (CMIG) which meets less regularly but continues to monitor the process and give advice where it is thought appropriate.

Figure 6: The five-year-old index represents an outcome measure in relation to dentoalveolar relations. An outcome categorised as 1 would have a positive overjet and overbite whereas the most severe dentoalveolar relationship is represented in category 4. This index provides an indication of outcomes and is thought to relate to the quality of primary surgery

The disappointment for many has been the political issues rather than rapid improvement of patient care. Those professionals who perceive their own units under threat have lobbied patients, politicians the media and the public to serve their own needs. Much of this is fuelled with misinformation, misconceptions and occasionally untruths. Indeed, CIG has had to cope with parliamentary questions and a parliamentary debate.

Serious consideration needs to be given to the political abuse of health services. Most healthcare plans cannot be turned around in the term of a parliament and it is doubtful that any politician could have a firm grasp of the problems and difficulties that now lie in an organisation as complex and large as the NHS. Some form of apolitical executive board with significant powers is now needed if well thought out rational plans for change in direction of care are to be implemented. This board, like the Bank of England, would not be subject to political interference. If properly constructed, with appropriate representation from Universities, the Royal Colleges, the Academy of Medical Sciences, the lay population, other carers and users, such a board would be able to act independently without political interference, whim and change. This board would be accountable but capable of delivering long-term planning and effective reconfiguration if needed and appropriate. The CSAG study and implementation has struggled; it has had to deal with three governments, numerous different ministers and a constant stream of civil servants each unsure of their tenure, previous decisions and future strategy. This does not apportion blame, it highlights an unwieldy and ineffective system to deliver change identified by need. As Sir John Butterfield said, “the medical profession, like the great amoeba it is, absorbs important ideas and changes. It does not despair or die. I believe good professions must breed elements of self criticism, be outraged by the ‘pups’ they spawn, react to them, albeit slowly, sit up, bandage the corporate ego, convalesce, rehabilitate, and move on again, though in a different way.”⁴⁷

We need more efficient systems to deliver change, particularly when driven by hard evidence and clearly identified need. Most importantly, we need these systems to produce appropriate care and standards for patients.

ACKNOWLEDGEMENTS
The work in this lecture was carried out at the University of Bristol since my appointment in January 1991. The two lecturers in Developmental Biology who have worked with me in the basic sciences are Jason Mansell and Laura Andrews. Janet Davies was a BSc Intercalation student and Nathan Brown is currently a PhD student in our laboratory. The MSc students who worked on various projects included, Nikki Atack, Sarah Turner, Peter Thomas, Nicky Johnson, Joe McGill and John Kerrigan. Alison Williams worked on the CSAG Project initially as a Research Associate, then as a MRC Health Services Research Training Fellow and has recently received an R&D Career Researcher Award. The CSAG Research Project was a collaboration between the University of Manchester (Professor W C Shaw) and the University of Bristol.

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36. Bearn D, Mildinhall S, Murphy T, Murray J, Sandy JR, Sell D et al. Cleft lip and palate care in the United Kingdom (UK) - The Clinical Standards Advisory Group (CSAG) Study: Part 4 - Outcome comparisons, training and conclusions. Cleft Palate J 2001; 38: 38-43
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39. Bearn DR, Sandy JR, Shaw WC. Cephalometric soft tissue profile in unilateral cleft lip and palate patients. Eur J Orthod 2002; 24: 277-84
40. Johnson N, Sandy JR. An aesthetic index for evaluation of cleft repair. Eur J Orthod 2003 (in press)
41. Williams AC, Sandy JR, Thomas S, Sell D, Sterne J. Influence of surgeon’s experience on speech outcome in cleft lip and palate. Lancet 1999; 354: 1697-98
42. Williams A, Sandy JR, Sterne J.Surgeon experience. Lancet 2000; 355: 932
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45. Williams AC, Johnson N, Singer S, Southall P, Mildinhall S, Semb G et al. Outcomes of cleft care in Western Australia. Aust Dent J 2000; 46: 32-36
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47. Thomas HF. Some reactions to effectiveness and efficiency Maynard A, Chalmers I (Eds) Non-random reflections on health services research, London; BMJ; 1997; 21-27

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