Abnormal Development - Cleft Lip and Palate: Difference between revisions

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* '''A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4'''<ref name="PMID20436469"><pubmed>20436469</pubmed></ref> "Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance."
* '''A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4'''<ref name="PMID20436469"><pubmed>20436469</pubmed></ref> "Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance."
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Revision as of 20:38, 16 December 2014

Embryology - 28 Mar 2024    Facebook link Pinterest link Twitter link  Expand to Translate  
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Educational Use Only - Embryology is an educational resource for learning concepts in embryological development, no clinical information is provided and content should not be used for any other purpose.

Introduction

Human Embryo Face (Week 7, Carnegie stage 18, 44 - 48 days, CRL 13 - 17 mm)
Human Embryo clefting. (Week 6, GA week 8, Stage 16, ventral view)
Bilateral cleft lip and cleft palate.
Ultrasound - Cleft Lip
Surgical repair of the lip (cheiloplasty).

International Classification of Diseases (ICD-10)

  • Q36 Cleft lip Incl.: cheiloschisis congenital fissure of lip harelip labium leporinum Excl.: cleft lip with cleft palate (Q37.-)
  • Q37.0 Cleft hard palate with bilateral cleft lip


The way in which the upper jaw (maxillae) forms from fusion of the smaller upper prominence of the first pharyngeal arch leads to a common congenital defect in this region called "clefting", which may involve either the upper lip, the palate or both structures.


The palate anatomically separates the nasal cavity from the oral cavity and structurally has a bony (hard) anterior component and a muscular (soft) posterior component ending with the uvula. The oral side of the palate is covered with a squamous stratified (pluristratified) epithelium. The surface of the hard palate of most mammalian species is further thrown into a series of transversal palatal ridges or rugae palatinae. Both the palatal ridge number and arrangement are also species specific.


Neural crest has a major contribution to the palate development and there are a number of molecular, mechanical and morphological steps in involving the fusion of contributing structures including a key epithelial to mesenchymal transition. In palate formation there are two main and separate times and events of development, during embryonic (primary palate) and an early fetal (secondary palate). This separation of events into embryonic and fetal period corresponds closely to the classification of associated palate abnormalities.


The primary palate is formed by two parts:

  1. maxillary components of the first pharyngeal arch (lateral)
  2. frontonasal prominence (midline)


The secondary palate can also be divided in two anatomical parts:

  1. anterior hard palate - ossified (contributions from the maxilla and palatine bones).
  2. posterior soft palate - muscular.


Palate Links: palate | cleft lip and palate | cleft palate | head | Category:Palate

Some Recent Findings

  • Functional Significance of MMP3 and TIMP2 Polymorphisms in Cleft Lip/Palate[1] "Evidence from biological and human studies strongly supports a role for MMP and TIMP genes as candidate genes for non-syndromic cleft lip with or without cleft palate (NSCL/P). We previously showed the association of promoter polymorphisms in MMP3 (rs3025058 and rs522616) and TIMP2 (rs8179096) with NSCL/P. In this study, we examined the functional significance of these polymorphisms. A specific DNA-protein complex for MMP3 rs522616 A was detected, and this allele by itself showed greater promoter activity than the G allele. However, the effect of rs522616 was ultimately regulated by the rs3025058 allele on the background. For TIMP2 rs8179096, the T allele showed a 2.5-fold increase in promoter activity when compared with allele C, whereas both C and T alleles were found to bind to nuclear factor kappa B. Our results provide new evidence that promoter polymorphisms in MMP3 and TIMP2 are functional and may affect gene transcription with possible effects on craniofacial development."
  • A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4[2] "Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance."
More recent papers
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More? References | Discussion Page | Journal Searches | 2019 References | 2020 References

Search term: Cleft Lip and Palate

<pubmed limit=5>Cleft Lip and Palate</pubmed>

Textbooks
Pharyngeal arch cartilages.jpg
  • The Developing Human: Clinically Oriented Embryology (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
  • Larsen’s Human Embryology by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

Movies

Ultrasound

Cleft lip 02.jpg
 ‎‎Cleft Lip 15 Week
Page | Play
Cleft lip 01.jpg
 ‎‎Cleft Lip 18 Week
Page | Play

Developmental Animations

Face 001 icon.jpg
 ‎‎Face Development
Page | Play
Palate 001 icon.jpg
 ‎‎Palate (oral view)
Page | Play
Palate 002 icon.jpg
 ‎‎Palate (front view)
Page | Play
Links: Movies | Ultrasound

Clinical Images

Uniateral Cleft Lip
Cleft lip 001.jpg Cleft lip 002.jpg
Complete Unilateral cleft lip and palate
Cleft lip 003.jpg Cleft lip 004.jpg
Complete bilateral cleft lip and palate
Cleft lip 005.jpg Cleft lip 006.jpg

Cleft lip 007.jpg

Surgical repair of the lip (cheiloplasty).

Image source [3]

Statistics

Cleft Palate - Australia (1981-1992)[4]

Australia

Australian Palate Abnormalities (2002-2003)[5]

Cleft lip with or without cleft palate (9.2 per 10,000 births) ICD-10 Q36.0, Q36.1, Q36.9, Q37.0–Q37.5, Q37.8, Q37.9
A congenital anomaly characterised by a partial or complete clefting of the upper lip, with or without clefting of the alveolar ridge or the hard palate. Excludes a midline cleft of the upper or lower lip and an oblique facial fissure (going towards the eye).
  • 17% of the affected pregnancies were terminated in early pregnancy or resulted in fetal deaths. Most of the fetal deaths or terminations of pregnancy (95%) had multiple abnormalities.
  • more commonly seen in males than in females.
  • babies born before 25 weeks of gestation, 150 per 10,000 births had this anomaly. Most babies (80.0%) were born at term with a birthweight of 2,500 grams or more.
  • Maternal age group was not associated with the anomaly.
  • Rates significantly higher among Indigenous women than non Indigenous women.
Australian Palate Abnormalities (2002-2003)  
Cleft lip with or without cleft palate (9.2 per 10,000 births) ICD-10 Q36.0, Q36.1, Q36.9, Q37.0–Q37.5, Q37.8, Q37.9
A congenital anomaly characterised by a partial or complete clefting of the upper lip, with or without clefting of the alveolar ridge or the hard palate. Excludes a midline cleft of the upper or lower lip and an oblique facial fissure (going towards the eye).
  • 17% of the affected pregnancies were terminated in early pregnancy or resulted in fetal deaths. Most of the fetal deaths or terminations of pregnancy (95%) had multiple abnormalities.
  • more commonly seen in males than in females.
  • babies born before 25 weeks of gestation, 150 per 10,000 births had this anomaly. Most babies (80.0%) were born at term with a birthweight of 2,500 grams or more.
  • Maternal age group was not associated with the anomaly.
  • Rates significantly higher among Indigenous women than non Indigenous women.
Cleft palate without cleft lip (8.1 per 10,000 births) ICD-10 Q35.0–Q35.9
A congenital anomaly characterised by a closure defect of the hard and/or soft palate behind the foramen incisivum without a cleft lip. This anomaly includes sub-mucous cleft palate, but excludes cleft palate with a cleft lip, a functional short palate and high narrow palate.
  • overall rate has increased to 9.1 when the rate was estimated using data from the four states that include TOP data. The reported number of fetal deaths or early terminations of pregnancy with this anomaly was small and these deaths or terminations could be due to other associated anomalies.
  • proportion of females with this anomaly was higher (56.9%) than males.
  • 52.7 per 10,000 babies born before 25 weeks of gestation.
  • 83.0% were born at term and most of the babies (82.7%) had a birthweight of 2,500 grams or more.
  • Women aged 40 years or older and women born in South Central America or the Caribbean region had the highest rates of affected births.
  • Multiple births had a significantly higher rate of affected babies than singleton births.
  • Rates did not differ significantly by Indigenous status or areas of residence.
Links: Palate Development | Head Development | Gastrointestinal Tract - Abnormalities | ICD-10 GIT | Australian Statistics
Reference: Abeywardana S & Sullivan EA 2008. Congenital Anomalies in Australia 2002-2003. Birth anomalies series no. 3 Cat. no. PER 41. Sydney: AIHW National Perinatal Statistics Unit.

Victorian Perinatal Data Collection Unit (2003-2004) Top 10 abnormalities, cleft lip and palate was number 10 on the list and the condition occurred with another defect in 33.7% of cases.

Ten most frequently reported Birth Anomalies

  1. Hypospadias (More? Male movie | Genital Abnormalities - Hypospadia)
  2. Obstructive Defects of the Renal Pelvis (More? Renal System - Abnormalities)
  3. Ventricular Septal Defect (More? Cardiovascular Abnormalities - Ventricular Septal Defect)
  4. Congenital Dislocated Hip (More? Musculoskelal Abnormalities - Congenital Dislocation of the Hip (CDH))
  5. Trisomy 21 or Down syndrome - (More? Trisomy 21)
  6. Hydrocephalus (More? Hydrocephalus)
  7. Cleft Palate (More? Palate_Development)
  8. Trisomy 18 or Edward Syndrome - multiple abnormalities of the heart, diaphragm, lungs, kidneys, ureters and palate 86% discontinued (More? (More? Trisomy 18)
  9. Renal Agenesis/Dysgenesis - reduction in neonatal death and stillbirth since 1993 may be due to the more severe cases being identified in utero and being represented amongst the increased proportion of terminations (approximately 31%). (More? Renal System - Abnormalities)
  10. Cleft Lip and Palate - occur with another defect in 33.7% of cases.(More? Palate Development | Head Development)

(From the Victorian Perinatal Data Collection Unit in the Australian state of Victoria between 2003-2004)

Development Overview

  • week 4 - pharyngeal arch formation, first pharngeal arch contributes mandible and maxilla.
  • week 6 - 7 - primary palate formation maxillary processes and frontonasal prominence.
  • week 9 - secondary palate shelves fuse, separating oral and nasal cavities.

Embryonic Period

  • (week 4) - pharyngeal arch formation in rostrocaudal sequence (1, 2, 3, 4 and 6)
  • First pharyngeal arch - upper maxillary (pair) and lower mandibular prominences
  • Late embryonic period - maxillary prominences fuse with frontonasal prominence forming upper jaw (maxilla and upper lip)

Fetal Period

  • palatal shelves elevation
  • palatal shelves midline fusion
Fetal week 10 palate icon.jpg
 ‎‎Fetal Palate
Page | Play

Neural Crest

  • Mesenchyme invaded by neural crest generating connective tissue components
  • cartilage, bone, ligaments
  • arises from midbrain and hindbrain region

Face Development

Stage16-18 face animation.gif

Begins week 4 centered around stomodeum, external depression at oral membrane

5 initial primordia from neural crest mesenchyme

  • single frontonasal prominence (FNP) - forms forehead, nose dorsum and apex
  • nasal placodes develop later bilateral, pushed medially
  • paired maxillary prominences - form upper cheek and upper lip
  • paired mandibular prominences - lower cheek, chin and lower lip

Frontonasal Process

The frontonasal process (FNP) forms the majority of the superior part of the early face primordia. It later fuses with the maxillary component of the first pharyngeal arch to form the upper jaw. Failure of this fusion event during the embryonic period leads to cleft lip. Under the surface ectoderm the process mesenchyme consists of two cell populations; neural crest cells, forming the connective tissues; and the mesoderm forming the endothelium of the vascular network.

Embryonic Palate

Human primary palate

  • develops between embryonic stages 15 and 18.[6]
  • fusion in the human embryo between stage 17 and 18, from an epithelial seam to the mesenchymal bridge.
Stage17-18 Primary palate.gif


EM Links: Image - stage 16 | Image - stage 17 | Image - stage 18 | Image - stage 19 | Palate Development

Fetal Palate

Secondary palate, fusion in the human embryo in week 9. This requires the early palatal shelves growth, elevation, and fusion. There are many fusion events occurring during this period between each palatal shelf, to the primary palate, and also to the nasal septum.

palatal shelf elevation | secondary palate

Bailey141.jpg

Ventral aspect of hard palate of human embryo of 80 mm

Animal Models

Newborn dog with cleft palate

Mouse Palate

  • E11 - protrude from bilateral maxillary processes
  • E12.5 - secondary palatal development begins
  • E12.5-E14 - grow vertically along the developing tongue
  • E14.5 - they elevate, meet, and fuse at the midline, to form an intact palate shelf, reflex opening and closing movements of the mouth
  • E15.5 - palatal fusion is complete, mesenchymal condensation followed by osteogenic differentiation occurs.
Links: Mouse Development | Bone Morphogenetic Protein | Wnt | Pax

International Classification of Diseases=

Cleft lip and cleft palate (Q35-Q37)

Use additional code (Q30.2), if desired, to identify associated malformations of the nose. Excludes Robin's syndrome ( Q87.0 )

Q37 Cleft palate with cleft lip
Q37.0 Cleft hard palate with bilateral cleft lip
Q37.1 Cleft hard palate with unilateral cleft lip
Cleft hard palate with cleft lip NOS
Q37.2 Cleft soft palate with bilateral cleft lip
Q37.3 Cleft soft palate with unilateral cleft lip
Cleft soft palate with cleft lip NOS
Q37.4 Cleft hard and soft palate with bilateral cleft lip
Q37.5 Cleft hard and soft palate with unilateral cleft lip
Cleft hard and soft palate with cleft lip NOS
Q37.8 Unspecified cleft palate with bilateral cleft lip
Q37.9 Unspecified cleft palate with unilateral cleft lip
Cleft palate with cleft lip NOS

Cleft Lip

Cleft Risk Variants

Two genes were identified from a recent genome-wide study.[2]

  • MAFB is expressed in the mouse palatal shelf.
  • ABCA4 is a member of a superfamily of transmembrane proteins, and mutations in ABCA4 play a major role in the etiology of Stargardt disease and related retinopathies. Gene produces an ATP-binding cassette (ABC) superfamily trans-membrane protein


Links: OMIM - MAFB | OMIM - ABCA4

Folate

A recent study of periconceptional folate supplementation using the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2010) identified no statistically significant evidence of any effects on prevention of cleft palate and cleft lip at birth.[8]

References

  1. <pubmed>24799419</pubmed>
  2. 2.0 2.1 <pubmed>20436469</pubmed>
  3. <pubmed>22437671</pubmed>| PMC3928765 | J Appl Oral Sci.
  4. P. Lancaster and E. Pedisich, Congenital Malformations Australia 1981-1992, ISSN 1321-835.
  5. Abeywardana S & Sullivan EA 2008. Congenital Anomalies in Australia 2002-2003. Birth anomalies series no. 3 Cat. no. PER 41. Sydney: AIHW National Perinatal Statistics Unit.
  6. <pubmed>8227288</pubmed>
  7. <pubmed>21331089</pubmed>
  8. <pubmed>20927767</pubmed>


Journals

Reviews

Indian J Plast Surg. 2009 October; 42(Suppl):Cleft Lip and Palate Issue <pubmed>22186724</pubmed> <pubmed>19131313</pubmed> <pubmed>16962647</pubmed> <pubmed>3074914</pubmed> <pubmed>8714286</pubmed>

Articles

<pubmed></pubmed> <pubmed></pubmed> <pubmed></pubmed> <pubmed>20149609</pubmed> <pubmed>19341725</pubmed>

Search PubMed

Search Pubmed: cleft lip and palate development |

Additional Images

Terms

  • cleft - An anatomical gap or space occuring in abnormal development in or between structures. Most commonly associated with cleft lip and cleft palate. Term is also used to describe the external groove that forms between each pharyngeal arch during their formation.
  • cleft lip - An abnormality of face development leading to an opening in the upper lip. Clefting of the lip and or palate occurs with 300+ different abnormalities. Depending on many factors, this cleft may extend further into the oral cavity leading to a cleft palate. In most cases clefting of the lip and palate can be repaired by surgery.
  • cleft palate - An abnormality of face development leading to an opening in the palate, the roof of the oral cavity between the mouth and the nose. Clefting of the lip and or palate occurs with 300+ different abnormalities. In most cases clefting of the lip and palate can be repaired by surgery. Palate formation in the embryo occurs at two distinct times and developmental processes called primary and secondary palate formation. This leads to different forms (classifications) and degrees of clefting.
  • epithelial mesenchymal transition - (EMT, epitheliomesenchymal transformation) conversion of an epithelium into a mesenchymal (connective tissue) cellular organization.
  • epitheliomesenchymal transformation - (epithelial mesenchymal transition) conversion of an epithelium into a mesenchymal (connective tissue) cellular organization.
  • medial edge epithelial - (MEE) opposing palatal shelves adhere to each other to form this epithelial seam.
  • palate - The roof of the mouth (oral cavity) a structure which separates the oral from the nasal cavity. Develops as two lateral palatal shelves which grow and fuse in the midline. Initally a primary palate forms with fusion of the maxillary processes with the nasal processes in early face formation. Later the secondary palate forms the anterior hard palate which will ossify and separate the oral and nasal cavities. The posterior part of the palate is called the soft palate (velum, muscular palate) and contains no bone. Abnormalities of palatal shelf fusion can lead to cleft palate.
  • palatogenesis - The process of palate formation, divided into primary and secondary palate development.
  • pharyngeal arch - (branchial arch, Greek, branchial = gill) These are a series of externally visible anterior tissue bands lying under the early brain that give rise to the structures of the head and neck. In humans, five arches form (1,2,3,4 and 6) but only four are externally visible on the embryo. Each arch has initially identical structures: an internal endodermal pouch, a mesenchymal (mesoderm and neural crest) core, a membrane (endoderm and ectoderm) and external cleft (ectoderm). Each arch mesenchymal core also contains similar components: blood vessel, nerve, muscular, cartilage. Each arch though initially formed from similar components will differentiate to form different head and neck structures.
  • philtrum - (infranasal depression, Greek, philtron = "to love" or "to kiss") Anatomically the surface midline vertical groove in the upper lip. Embryonically formed by the fusion of the frontonasal prominence (FNP) with the two maxillary processes of the first pharyngeal arch. Cleft palate (primary palate) occurs if these three regions fail to fuse during development. Fetal alcohol syndrome is also indicated by flatness and extension of this upper lip region.
  • T-box 22 - (TBX22) a transcription factor that cause X-linked cleft palate and ankyloglossia in humans. Tbx22 is induced by fibroblast growth factor 8 (FGF8) in the early face while bone morphogenic protein 4 (BMP4) represses and therefore restricts its expression. (More? OMIM - TBX22)
  • Transforming Growth Factor-beta - (TGFβ) factors induces both epithelial mesenchymal transition and/or apoptosis during palatal medial edge seam disintegration.

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Cite this page: Hill, M.A. (2024, March 28) Embryology Abnormal Development - Cleft Lip and Palate. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Cleft_Lip_and_Palate

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© Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G