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Aetiopathogenesis of facial clefts

DR. W. L. ADEYEMO, BDS, FMCDS, FWACS, PHD, FICS ASSOCIATE PROFESSOR/CONSULTANT ORAL AND MAXILLOFACIAL SURGEON UNIVERSITY OF LAGOS/LUTH

Cleft lip and palate is one of the most common

abnormalities found in live births


May account for up to 65% of all cogenital

anomalies in some series

Pathogenesis
The embryologic basis of cleft palate is failure of the

mesenchymal masses derived either from thee maxillary prominences (i.e., the lateral palatine processes) or from the MNP (i.e., either the median palatine process or the nasal septum) to meet and fuse with each otherr.
Cleft lip results from failure of the maxillary

prominence on the affected side to unite with medial nasal prominence (unilateral)

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Common observations : Race incidence higher in orientals >whites >blacks 20% have a family history

Syndromic clefts in 1% to 8%
First degree relatives are 25 times more likely to have a

deformities than normal population

There have been numerous reports on the possible

causes of cleft lip and palate in the literature. These reports have been derived from epidemiological studies, animal studies, and human genetic in vitro studies. Early studies suggested a multifactorial threshold model for the aetiology of nonsyndromic cleft lip and palate.

The possible mechanism of the interaction between

environmental and genetic factors has been suggested as follows: that genetic factors create susceptibility for cleft, clefts develops when environmental factors trigger the genetically susceptible phenotype.

Genetic influences
Reports have suggested that the proportion of

environmental and genetic factors varies with the sex of the affected individual, the severity of the cleft, the type of cleft (whether Syndromic or no-Syndromic, cleft lip with or without palate or isolated cleft palate, and unilateral and bilateral cleft. The duration and timing of the teratogens on the foetus also affects the severity of the anomaly

Genes had been shown to play an important role in

facial development that includes genes identified as growth factors, cytokines, self-signaling molecules, and structural proteins. Gene linkage and association studies have confirmed role for a number of these genes.

The application of increasing complex analyses such

as molecular markers; that incorporate the severity of the phenotype and the addition of environmental variables facilitate the detection of even small gene effects and provide an increasing powerful platform for the collection of genetic data

Genetic influences
Studies in genetic influences have been

controversial on account of discrepancies in samples and models

Small pedigree Low penetrance Genetic heterogenicity Varying influence of environmental factors All leading to different conclusions

BIXEL CLASSIFICATION
Syndromic variety; monogenic ,chromosomic or

environmental( 1% of CL, 8% of CP)

Familiar variety; 25% of CLP, 12% of isolated CP


Sporadic or isolated; 75% of CLP and 80% 0f

isolated CP

Threshold concept of multifactorial inheritance

CLEFT LIP AND PALATE LOCI

CL/P loci OFC1 OFC2 OFC3 OFC4 OFC5/MSX1 OFC6/IRF6 OFC7/PVRL1 OFC8/TP73L

Chromosomic location 6p24-p23 2p13 19q13 4q21-q31 4q16 1q32.3-q41 1123.3 3q28

Year of identification 1990 1989 1995 1994 1997 1992 1998 1999

CL/P LOCI OFC9 OFC10/SUMO1

Chromosomic location 13q33.1-q34 2q33

Year of identification 2002 2006

MTHFR

1q36

1995

TGFB3

14q24

1998

RAR

17q21.1

1992

Isolated Cleft palate loci 2q32 X49.0

Concordance rate in monozygotic twins is 40%-

60%, while for dizygotic twins is 5%

Environmental influences
Drugs (modified by genetics, timing and dosage )

Phenytoin Thalidomide Vaproic acid Benzodiazepines Steroids Amphetamines Maternal Age Alcohol intake

Dioxin Smoking Altitude

Socioeconomic class
Vitamin B deficiencies

Table 4. Geneenvironment interactions in cleft lip and palate

TGFA/Smoking TGFA/Alcohol TGFA/Vitamins MSX1/Smoking MSX1/Alcohol TGFB3/Smoking TGFB3/Alcohol RARA/Smoking MTHFR/Vitamins P450/Smoking GST/Smoking EPHX1/Smoking

In Nigeria, recent study implicate : Muscle

specific homoebox (MSX1), in aetiology of cleft lip and palate defect (Butali et al. 2011). Other environmental factors have also been implicated.

The timing of these interactions are crucial,

occurring between the 5-7 weeks in utero

By the 12th week the processes are completed

About 1/2 of children with some form of clefting

have one or more associated anomalies Syndrome: A group of symptoms regularly occurring together and appear to have a related cause Over 250 known syndromes are associated with clefting

Syndromic clefts
Clefting is a secondary event(>157 syndromes) Trisomy 13 Turners Downs Cri Du Chat Treacher Collins Pierre Robins

Meckels
Wolf Hirsclorn Van der Woude

Implications
Gene therapy Vitamin B supplements for at risk groups Prenatal counselling

Folic acid supplements (?)

summary

Orofacial clefts are a group of disorders of genetic

origin often unmasked by environmental influences. Environmental interactions in the aetiology of cleft is well documented.

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