Aetiopathogenesis+of+Facial+Clefts

7/27/2019 Aetiopathogenesis+of+Facial+Clefts

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D R . W . L . A D E Y E M O ,

B D S , F M C D S , F W A C S , P H D , F I C S

A S S O C I A T E P R O F E S S O R / C O N S U L T A N T

O R A L A N D M A X I L L O F A C I A L S U R G E O N

U N I V E R S I T Y O F L A G O S / L U T H

Aetiopathogenesis of facial

clefts


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Cleft lip and palate is one of the most common

abnormalities found in live births

May account for up to 65% of all cogenitalanomalies in some series


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Pathogenesis

The embryologic basis of cleft palate is failure of themesenchymal masses derived either from thee maxillaryprominences (i.e., the lateral palatine processes) or fromthe 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 maxillaryprominence on the affected side to unite withmedial nasal prominence (unilateral)


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www.icareunit.com


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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


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There have been numerous reports on the possiblecauses of cleft lip and palate in the literature.

These reports have been derived from

epidemiological studies, animal studies, and humangenetic in vitro studies.

Early studies suggested a multifactorial thresholdmodel for the aetiology of nonsyndromic cleft lip and

palate.


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The possible mechanism of the interaction betweenenvironmental and genetic factors has beensuggested as follows: that genetic factors createsusceptibility for cleft, clefts develops whenenvironmental factors trigger the geneticallysusceptible phenotype.


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Genetic influences

Reports have suggested that the proportion ofenvironmental and genetic factors varies with the sexof the affected individual, the severity of the cleft, thetype of cleft (whether Syndromic or no-Syndromic,cleft lip with or without palate or isolated cleftpalate, and unilateral and bilateral cleft.

The duration and timing of the teratogens on the

foetus also affects the severity of the anomaly


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Genes had been shown to play an important role infacial development that includes genes identified asgrowth factors, cytokines, self-signaling molecules,and structural proteins.

Gene linkage and association studies have confirmedrole for a number of these genes.


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The application of increasing complex analyses suchas molecular markers; that incorporate the severityof the phenotype and the addition of environmental

variables facilitate the detection of even small geneeffects and provide an increasing powerful platformfor the collection of genetic data


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Genetic influences

Studies in genetic influences have beencontroversial on account of discrepancies insamples and models

Small pedigree

Low penetrance

Genetic heterogenicity

Varying influence of environmental factors All leading to different conclusions


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BIXEL CLASSIFICATION

Syndromic variety; monogenic ,chromosomic orenvironmental( 1% of CL, 8% of CP)

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

Sporadic or isolated; 75% of CLP and 80% 0fisolated CP


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Threshold concept of multifactorial inheritance


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CLEFT LIP AND PALATE LOCI

CL/P loci Chromosomic

location

Year of

identification

OFC1 6p24-p23 1990

OFC2 2p13 1989

OFC3 19q13 1995

OFC4 4q21-q31 1994

OFC5/MSX1 4q16 1997

OFC6/IRF6 1q32.3-q41 1992

OFC7/PVRL1 1123.3 1998

OFC8/TP73L 3q28 1999


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CL/P LOCI Chromosomic

location

Year of

identification

OFC9 13q33.1-q34 2002

OFC10/SUMO1 2q33 2006

MTHFR 1q36 1995

TGFB3 14q24 1998

RAR 17q21.1 1992


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Isolated Cleft palate loci

2q32

X49.0

Concordance rate in monozygotic twins is 40%-60%, while for dizygotic twins is 5%


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Environmental influences

Drugs (modified by genetics, timing and dosage )Phenytoin

Thalidomide

Vaproic acid

BenzodiazepinesSteroids

Amphetamines

Maternal

AgeAlcohol intake


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Dioxin

Smoking

Altitude

Socioeconomic class Vitamin B deficiencies


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Table 4. Geneenvironment interactions in cleft lip andpalate

TGFA/Smoking TGFA/Alcohol TGFA/Vitamins MSX1/Smoking

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


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The timing of these interactions are crucial,occurring between the 5-7 weeks in utero

By the 12th week the processes are completed


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About 1/2 of children with some form of cleftinghave 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


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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


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Implications

Gene therapy

Vitamin B supplements for at risk groups

Prenatal counselling

Folic acid supplements (?)


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summary

Orofacial clefts are a group of disorders of geneticorigin often unmasked by environmental influences.

Environmental interactions in the aetiology of cleft

is well documented.

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