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Cleft Palate and Cleft Lip Palate

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									Cleft Palate and Cleft Lip/ Palate
        Embryology, Epidemiology
             and Genetics
      Dr Janna Kenny, specialist trainee in clinical genetics
• Affects 1.7 per 1000 live births
• Cleft lip =/- palate 1/700-1/1000
  – 80% unilateral
  – Left side more commonly affected
• Syndromic or non syndromic (isolated)
• Cleft palate 4/10,000- spectrum from bifid
  uvula to wide u-shaped central cleft
• Complex
• Occurs early in embryological development-
  lips and palate fully formed by week 12
• Requires cell migration and fusion
• Clefts formed at sites of fusion
• Susceptible to teratogens
• Many genes involved including SHH, FGF10
Day 22                    Day 27                Day 29

First pharyngeal          First & second        Maxillary (a) &
arch & frontonasal        pharyngeal arches     Mandibular (b)
region                                          prominences

                                 Embryology continued

                               medial nasal prominence
frontonasal prominence                                                              maxillary prominence
                                                       lateral nasal prominence

           5 weeks                    5 weeks                      6 weeks              6 weeks

•medial nasal prominences form middle of nose, upper lip, part of maxilla and primary
•maxillary prominences grow medially compressing medial nasal prominences
•mandibular prominences fuse to form lower jaw

Slide Courtesy of Dr Smithson. Pictures from
                           cut between maxillary and mandibular prominences
                               allows visualization of the developing palate

                                                                                9 weeks
                                                                        palatal shelves change
                   medial nasal prominences                          contours to meet in midpoint
                 form anterior or primary palate                       then fuse anteriorly and

        6 weeks                                    7.5 weeks                                     10 weeks
  secondary palatal                             palatal shelves                          fusion of palatal shelves
   shelves (part of                          ascend above tongue                         nasal septum separates
maxillary prominences)                         to allow fusion in                         nasal cavities from oral
                                                     midline                                       cavity
    Slide Courtesy of Dr Smithson. Pictures from
                      Timing of cleft formation

              weeks 5-6                                                       weeks 7-8
maxillary processes grow medially                                      elevation and fusion
  fuse with frontonasal process                                         of palatal shelves
             failure here                                                    failure here
    cleft lip +/- primary palate                                      cleft secondary palate

 Slide Courtesy of Dr Smithson. Pictures from & Dr Smithson
             Epidemiology of clefting
• Orofacial clefts seen in 1 in 70 live births 1

• Marked geographic variability
     – Overall Asian and American Indian highest- 1
       in 500,
     – African lowest- 1 in 2500
     – Caucasian intermediate

Image from
    Epidemiology continued

• Isolated cleft palate more frequent in
• Cleft lip +/- palate more frequent in males
• Cleft palate- 55% isolated, 18% other
  anomalies, 27% syndromic 3
• Cleft lip- 71% isolated, 29% other
    Maternal and environmental factors
• Pregnancy planning confers protection
• Maternal smoking increases risk4
• Maternal alcohol use – studies variable
• Exposure to organic solvents and agricultural
  chemicals- inconsistent evidence
• Drugs especially anticonvulsants
• ??Viral infection
• Folate and zinc deficiency cause clefts in
  animals. Contradictory studies in humans
• Maternal multivitamin use- reduction5
“There is no strong evidence for an association
between oral clefts and folic acid intake alone.
Multivitamin use in early pregnancy, however, may
protect against oral clefts, especially CL/P although
this association may be confounded by other
lifestyle factors associated with multivitamin use.”5

Current recommendation from UK cleft genetics
group is for women at increased risk who are
planning a pregnancy to take a multivitamin
preparation with folic acid for 2 months pre-
conception, continued until 12 weeks
                                  Genetic Factors

• Cleft lip +/- palate listed as a feature of more
  than 200 syndromes eg van der Woude

      Pictures courtesy of Dr M Lees
• Isolated cleft palate a feature of more than
  400 syndromes eg Smith Lemli Opiz

Pictures from LMD dysmorphology database

CHROMOSOMAL                      SINGLE GENE                         UNCLASSIFIED
 ABNORMALITY                      DISORDER

  Anomalies                                        Phenytoin                  Limb
                                   Over 400
   multiple                       syndromes                                 Cardiac
  Trisomy 13                                                               Vertebral
  Trisomy 18
  Midline cleft
                                         Anomalies multiple in 15%
                                         More likely in CPO/CLP than cleft lip alone
  Slide courtesy of Dr M. Lees
        Genetic and Family studies

• family history 26%

• recurrence risk to siblings 30-40 times
  general population risk

• monozygotic twins greater concordance
  than dizygotic
   Overall genetic risks for clefts in families
Relationship to index case              Cleft lip + palate (%)    Isolated cleft palate (%)

sibs - overall risk                              4.0                          1.8

sib - no one else in family                      2.2

sib - 2 affected sibs                            10                            8

sib and parent                                   10

children of affected                             4.3                           3

second° relative                                 0.6

third° relative                                  0.3

general population                               0.1                          0.04

           large studies of small families suggests 3-14 gene model
                      effects of sex, bilateral involvement
                           environmental interactions

                      Jugessur and Murray Curr Opin Gen Devel 2005 15:270-8
• Segregation analysis studies identified
  small number of loci
• Linkage studies implicate several genes
• But population based association studies
  often inconclusive
• Important gene- environment interactions.
  Studies inconclusive
Key gene families in craniofacial morphogenesis
Polarizing signals   Shh
                     Bmp2, Bmp4
                     Smad2, Smad3, Smad4

Growth factors       Egf, Egfr
                     Tgfß1, Tgfß2, Tgfß3
and receptors
                     Fgf1, Fgf2, Fgf8
                     Fgfr1, Fgfr2

Transcription        Dlx1, Dlx2, Dlx3, Dlx4, Dlx5,
factors              Gli2, Gli3
                     Tbx1, Tbx22

Cell adhesion        Pvrl1

Extracellular        Col2A1                          Stanier and Moore
                     Col11A1, Col11A2,               Hum Mol Genet
                     Mmp2, Mmp3, Mmp9, Mmp13         2004
• facial development is complex- many
  genes involved
• CLP most cases aetiology unknown –
  genes, environment & maternal factors
• Some genes have strong effect-
  syndromes but if non-syndromic no tests
• Identification of associated features
  important for counselling
• Much still to learn

1. Mossey et al, Global registry and database
   of craniofacial anomalies, WHO 2003
2. Mossey et al, Lancet 2009 374; 1773
3. Calzolari et al, Am J Med Gen 2007; 143:
4. Little at al, Bull World Health Org 2004; 82:
5. Johnson et al, Int J Epidemiol 2008;

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