51. Cleft lip and palate, embryology and classification
- After a lifetime spent doing autopsies, William Boyd, the eminent pathologist of the last century was left wondering as to how it is that people live rather than die. Since then human affairs have become far more complicated giving birth to an adage also called Murphy’s Law (as applicable to the mechanical world): that if something can go wrong, it will. In very recent times, Atul Gawande has written some very well researched and insightful books which include “Checklist” and “Complications” which show a way to avoid errors in clinical practice.
- In the in vivo scenario the embryological development of a human foetus is so complicated that one is left wondering at the small number of congenital anomalies that occur in live births. The mystery is somewhat explained when we view an interesting statistical detail, that of the incidence of one holo-prosencephaly in two hundred and fifty aborted foetuses. Obviously nature’s sensitive signaling does not allow foetuses with major craniofacial abnormalities to progress to full term. The development of the craniofacial skeleton is hugely complex and consists of formation of cellular masses, their division, their growth, migration and then fusion at a later date. This process is vulnerable to disruption at every stage by a faulty gene (a priori) or because of abnormal mutations due to internal or external factors. The latter are called environmental (teratogenic) (see para 7), the former occur due to a faulty protein metabolism in the basement membrane of the genetic cells. There is little clarity of how this comes about.
- When a sperm fertilizes an ovum in the fallopian tube (Fig. 1) to produce a zygote, the die is cast. Environmental factors cast their shadow only later till about three months of gestation. The zygote as it travels through the uterine cavity has already started multiplying and this group of cells is called a morula. The morula develops a fluid layer within and is then called a blastocyst which has an outer layer of cells called trophoblast which attaches itself to the uterine wall and forms the placental structures. The inner layer is the embryoblast which will form the embryo (Fig. 2). During its very early stages the cells of this structure undergo what is known as gastrulation in which the precursors of the three defining layers of the body, ectoderm, mesoderm and endoderm come to be differentiated (Fig. 3).
- From here onwards the embryo develops into a rostral (head) and a caudal (tail) part which are quite distinct and their junction is where the oral pit is located. The development of the caudal part is simpler. It grows rostral wards, develops somites on either side to develop limbs and the segmental thoracic cage.
- The development of the rostral part is more complicated, the ectoderm in the future neural part which will form the brain leads the way and forms two hillocks on either side of its own median plate (Fig. 6). The hillocks grow one on the other (Fig. 7), turn on themselves medially and subsequently a tube is formed (Fig. 8-9). The failure to form a tube causes deformities such as anencephaly. These cells are called neuroectoderm. The neuroectodermal cells have a pluripotent character and develop also into mesoderm and endoderm, the latter forming the lining of the gut beginning at the gums (where the outer epithelium represents the ectoderm, the muscles the mesoderm and the inner mucosa the endoderm) (Fig. 10). The mesoderm forms the bulk of the bilateral processes which migrate from the central tube; in the beginning centrifugally. The bilateral character of the embryo begins early and allows the two parts of the brain to separate failing which deformities such as micro-cephaly or Cyclops develop (holo-prosencephaly) and usually result in unviable fetuses. It is from the lateral processes on either side made of the pluripotent (referred to earlier as gastrulation) neuroectodermal tissue that the face develops, expanding at first and then moving centripetally to fuse with the descending median part of the neuroectoderm (Fig. 11-12). A craniofacial cleft forms when this fusion is disrupted (please see chapter on Origin of Craniofacial Clefts). Clefts of the lip and palate are only one such malformation of the many that occur along the way and essentially involve only the maxillary and the median nasal process and the disruption involving them. Basically the malformation either results because there is an inherent deficiency of the fusing process of genetic origin or when the process of fusion is interrupted by causes which occur later on.
6. While the morpho-genetic centres that form the middle-third of the face have now been identified, there is some confusion about the nomenclature as well as the source of these morpho-genetic centres. In the main the fronto-nasal process from the median part of the pluripotent neuroectoderm as it migrates downwards forms the pre-maxilla, the vomer and parts of the primary nasal cartilage as well as the columella of the nose and the philtrum. The rest i.e. the maxilla, the visible part of the nose and the lateral lip form from the two (bilaterally disposed) maxillary processes. While some source the formation of the nose to the median and lateral nasal processes as a part of one fronto-nasal process, the others include the two nasal processes as part of the maxillary processes. The incisor foramen which comes to lie between the pre-maxilla in front (from the fronto-nasal process) and the two palatine processes of the maxilla (from the maxillary processes) is important because the process of fusion anterior to what will become the incisor foramen occurs before the fusion of structures behind the incisor foramen. This sequence has given birth to the terms primary palate (earlier fusion at 6 weeks) and secondary palate (later fusion at 8 weeks) and is used in classifying clefts (clefts of the primary or secondary or both) (Fig. 13-20).
- To paraphrase the legendary plastic surgeon Millard (Cleft Craft, 1976, Vol. 1, Little Brown and Co.), “embryology is important but the surgeon is left with a hole to treat for which a knowledge of what is distorted and/or missing is important because that is the clay with which the surgeon must deal and create what should have been but did not happen. ACH Watson who studied under Millard mentions rather pithily that although there have been significant advances in the last twenty years in several aspects of management of clefts, overall improvement in the scientific basis has been disappointing. This statement came in the year 2001 (Management of Cleft Lip and Palate, Whurr Publishers) but the situation has not changed very much judging by the number of protocols and variations that one finds in the treatment of cleft lip and palate.
- While classification is important for record keeping and subsequent analysis of the results, on the ground that rationale is very difficult to adhere to because in the past too many surgeons operated on far too few patients and did not really adhere to a fixed protocol. Additionally an anatomical classification is hardly a guide to what is present on either side of the cleft. The quality and quantity of muscle for e.g. in the cleft of the soft palate can never be estimated in real terms. To take another example the obliquity of the cleft in the lip is no guide to the shortage of tissue within it and therefore the results will vary though they belong to the same group in the classification. Lastly the breadth of the cleft is so variable across the spectrum that to judge the results by where the cleft is located appears unreasonable. Anybody who has spent many a year in treating clefts will alternately experience dismay and delight at the results that come to happen even though the clefts appeared almost identical and were operated by the same technique and by the same surgeon. Deductive statistical analysis probably has limitations when a single basket has different types of fruit.
- The failure of fusion that causes the non-syndromic phenotype called Cleft Lip, Cleft Palate or both together is usually attributed to multiple factors. While there is enough evidence of the genetic origin of this deformity, this genetic component does not appear to have a high penetration rate along generations. But a genetic predisposition can come to manifest more frequently if environmental factors influence events in the first eight weeks of the development of the foetus. Alcohol, smoking and maternal illness such as German measles and the anti-convulsant drug phenytoin have all been suspected. On the other hand that adequate intake of folic acid immediately and before conception can reduce the incidence of clefts has been partially proven by K. Sridhar in several districts of the Tamil Nadu state in India where 90% of the deliveries either take place in a primary health centre or in a hospital.
- Some observations are however beyond dispute. The incidence of this deformity is high in children both of whose parents have this deformity and if one child is born with this deformity in unaffected parents the chance that one of the following siblings might have such a deformity is higher than in the general population. On the other hand why clefts of the lip (primary palate) up to the incisor foramen and even beyond occur more often on the left side is not known. The higher incidence of the clefts of the secondary palate in girls has been speculatively attributed to a peculiarity in the female foetus in which the palatine process (a part of the maxillary process) rises to become horizontal a week later than the boys. This is a crucial period during which the face is broadening and it is thought that therefore the processes are unable to meet each other and fuse.
- Please refer to definitions of malformation syndrome and sequence in the first chapter on Craniofacial Clefts.