2.  Variations clefting congenital deformity
during gestation.
 Common birth defects---complex etiology
 Immediately recognizable disruptions
 Cleft is a fissure or opening—a gap
 Previously known as harelip

3.  Also affect other parts of the face, such
as the eyes, ears, nose, cheeks, and
forehead.
 In 1976, Paul Tessier described fifteen
lines of cleft.
 Facial clefting is the second most
common congenital deformity (after
clubfoot).

4. Approximately 1 in 700 live births
The frequency of CLP differs by sex
2:1 male to female ratio for cleft lip
alone
1:2 male to female ratio for cleft
palate alone
2:1 ratio of left to right sided clefts
among unilateral cleft lip cases

5.  Prevalence rates varies within different
ethnic groups.
 Highest prevalence rates - Native Americans
and Asians
 Lowest prevalance rates- Africans
 Native Americans: 3.74/1000
 Japanese: 0.82/1000 to 3.36/1000
 Chinese: 1.45/1000 to 4.04/1000
 Caucasians: 1.43/1000 to 1.86/1000
 Latin Americans: 1.04/1000
 Africans: 0.18/1000 to 1.67/1000

6. Rate of occurrence of CPO is similar
for Caucasians, Africans, North
American natives, Japanese and
Chinese.
The trait is dominant.

7.  Involves the vermilion border of the upper
lip and may extend through the lip toward
the nostril
 Affects the shape of the nose
 Can be either unilateral or bilateral
 Unilateral clefts usually occur on the left side
 Bilateral clefts usually involve the palate
 Cleft lip by itself is rare

9. Orbicularis
oris
Orbicularis oris -
closes lips,
compresses lips
against teeth,
protrudes lips,
shapes lips during
speech

10. Orbicularis
oris
The orbicularis oris muscles
run parallel to the edge of
the cleft and inserts into
the alar margin. . There is
no muscle in the prolabium
in bilateral cleft

12.  A condition in which the two plates of the
skull that form the hard palate (roof of the
mouth) are not completely joined.
 Soft palate also involved
 Presence of cleft lip
 Connection of the mouth directly to the
nasal cavity.

15. Note transverse orientation
of levator muscle in
middle portion of
the soft palate
The levator muscles
are
orientated more
longitudinally
and insert on
posterior edge of
palatal bone and
along bony cleft
margins

16. Supernumery Teeth- 20%
Dystrophic Teeth- 30%
Missing Teeth- 50%
Malocclusion- 100%

17.  Development of the face
Formed between the 5th and 8th weeks of
gestation
Coordinated by
 complex morphogenetic events
 rapid proliferative expansion
highly susceptible to environmental and genetic
factors

18.  Results from the fusion of
 Two mandibular processes
 One frontonasal process
 Two maxillary processes
 Cleft lip occurs when the fusion
process between the frontnasal
masses and the maxillary
processes is interrupted

20.  Not a major cause of mortality in developed
countries, CLP does cause considerable
morbidity to affected children and imposes a
substantial financial risk for families with a
concomitant societal burden
 problems with feeding
 speaking
 social integration
 middle ear infections which may eventually
lead to hearing loss
 Velopharyngeal Incompetence (VPI)

21. Components
1. Velum
2. Muscles in the
back of the throat

22.  The velum needs to
be closed and the
oral and nasal
cavities separated
when we swallow
and during the
production of most
English speech
sounds

23.  At the time of birth by physical examination
 Recent advances --- diagnose facial clefts in
utero

26. CHILD & FAMILY
PSYCHOLOGIST
SPEECH
THERAPIST
SPECIALIST NURSE
DENTIST
ORTHODONTIST
GENETICIST
ENT/AUDIOLOGY
SURGEON

29.  CLP can occur:
Syndromic CLP
Non-syndromic CLP

30.  Cleft lip with or without cleft palate --- more
than 200 specific genetic syndromes
 Isolated cleft palate --- more than 400
syndromes
 Proportion of orofacial clefts associated
with specific syndromes --- 5% and 7%.

31. Cleft Lip + Palate- 50%
 Cleft Palate- 30%
 Cleft Lip- 20%
Cleft Lip + Alveolus- 5%

32.  palate Autosomal dominant
developmental
malformations, deafness,
and dystonia
 Familial gastric cancer and
CLP
 Craniofrontonasal
 Roberts
 Holoprosencephaly
 ―Oro-facial-digital‖
 ACTB 1
 CDH1
 EFNB1
 ESCO2
 GLI2
 GLI3

33.  Hydrolethalus
 Van der Woude/popliteal
pterygium
 X-linked mental retardation
and CL/P
 Gorlin
 CLP – ectodermal dysplasia
 HYLS1
 IRF6
 PHF8
 PTCH1
 PVRL1

34.  Oculofaciocardiodental
 CHARGE
 Lethal and Escobar multiple
pterygium
 Stickler type 1
 Stickler type 2
 Stickler type 3
 Desmosterolosis
 Smith-Lemli-Opitz
 Miller
 Craniofrontonasal
 BCOR
 CHD7
 CHRNG
 COL2A1
 COL11A1
 COL11A2
 DHCR24
 DHCR7
 DHODH
 EFNB1

35.  Approximately 70% of cases of CLP occur as
isolated entities
 Defects arise early in embryological
development, have a complex etiology with
both genetic and environmental
contributions and modest recurrence rates
 Specific etiologic factors----difficult

36.  A combination of:
 epidemiologic
 candidate gene
 genome-wide studies
 analysis of animal models
provided deeper insights into the causes of non-
syndromic CLP.

37.  Advent of the genomics era-- major advances
in identifying the causative genetic mutations
underlying syndromic forms of CLP
(http://www.ncbi.nlm.nih.gov/omim)
 In contrast:
 genetic heterogeneity
 departure from Mendelian inheritance patterns
 lack of (and expense of) genomic tools
 necessity for very large datasets
less progress in advancing of the genetic etiology
of non-syndromic CLP

38.  Recent development of innovative
approaches to
 phenotyping
 powerful genomic tools
has increased our understanding of non-
syndromic CLP.

39.  IRF6
 MAFB
 FGFR2
 SUMO1
 FOXE1
 BMP4

40.  Much of the genetic variation for non-
syndromic CLP -- regulatory elements
 Challenging to identify -- regulate genes
across substantial genomic distances
 Chromatin immunoprecipitation followed by
Next Generation Sequence analysis -- highly
sensitive method to accurately identify
enhancer elements

41.  Smoking
 Alcohol
 Steroids
 Hypertension treatment drugs
 Anticonvulsant drugs
 Nitrate compounds
 parental exposure to lead
 Illegal drugs (cocaine, crack
cocaine, heroin, etc.)
 Folate deficiency
 Zinc deficiency
 Cholestrol deficiency

42.  Estimates of the main effects of genes or
environment could be biased if interaction
is not taken into account
 Understanding of cause and pathogenesis is
enhanced by such studies
 Findings of interaction work can inform
decisions about public health strategies

43.  Markers in the GSTT1 (glutathione S-
transferase theta) or NOS3 (nitric oxide
synthase 3) --- influence risk of CL/P in the
presence of maternal smoking
 Smoking ----IRF6 gene
 Multivitamins and IRF6
 Alcohol consumption--- ADH1C

44.  Hyperthermia
 Stress
 Maternal obesity
 Ionizing radiation
 Infection

45.  These are common congenital deformities
that often affect speech, hearing, and
feeding; and may at times lead to airway
compromise.
 The otolaryngologist is a key member of the
cleft palate team, and is in a unique position
to identify and manage many of these
problems .

46.  Global approaches for the identification and
ranking of candidate genes
 Improved methods for analyzing functional
elements controlling gene expression
 Integration of genetic and environmental risk
using epigenetics, systems biology, gene
expression and epidemiology will both better
characterize etiologies, as well as provide
access to better clinical care and prevention