Key points

Introduction

The process of lip and palate morphogenesis depends on complex molecular signaling pathways to enable cellular proliferation, differentiation, and apoptosis. Both genetic and environmental factors may be responsible for dysregulating these pathways, leading to development of cleft lip or palate. Cleft lip with or without cleft palate is a distinct entity from cleft palate only. Palate closure occurs between weeks 8 and 12 in utero, and lip formation is concluded by week 7. During these periods of development, dysregulation of different pathways leads to cleft of the lip, palate, or both ( Figs. 1 and 2 ).

Left unilateral cleft lip and palate.

Bilateral cleft lip and alveolus.

Cleft lip and palate, when it occurs as the only malformation (anomaly), is considered nonsyndromic. Seventy percent of all cases of cleft lip and palate are nonsyndromic. Cases of cleft palate only are different in that they are nonsyndromic 50% of the time.

However, when cleft lip and palate or cleft palate alone is associated with other clinical features (anomalies), it is considered syndromic. Thus, cleft lip and palate occurs as syndromic 30% of the time. Cleft palate only occurs as syndromic 50% of the time. The diagnosis of a syndrome is made from the overall pattern of anomalies present. The more anomalies noted, the easier it is to diagnose. However, sometimes, some of these features may not be fully expressed and are more difficult to diagnose.

More than 500 syndromes are identified with cleft lip and palate as part of the phenotype. The most common mechanisms related to syndromic cleft lip and palate are either single gene mutations or chromosome abnormalities. Of note are the findings in some syndromes of trisomy chromosomes (13, 18, and 21), partial deletions, and duplications. Therefore, several genomic regions containing loci either excessive or insufficient can lead to cleft lip and palate. There are both autosomal dominant inheritance patterns and autosomal-recessive patterns of inheritance of syndromic clefting. A few syndromes also have an X-linked inheritance pattern ( Fig. 3 ).

Chromosome.

Multiple genes have been identified over recent years that are responsible for different aspects of syndromic cleft lip and palate formation:

Genes have also been identified in nonsyndromic cleft lip and palate:

• IRF6

• 8q24 locus

• Vax1

Other genes studied with a likely association with nonsyndromic cleft lip and palate include:

• MSX1

• FOXE1

• MYH9

• MAFB

• ABCA4

• 17q22 locus

• BMP4

• FGFR2

Research is still ongoing to prove the relationships between these genes and clefting disorders.

For a complete listing of all genes/syndromes identified thus far, refer to the National Institutes of Health Web site OMIM (Online Mendelian Inheritance in Man): http://www.ncbi.nlm.nih.gov/omim .

Introduction

The process of lip and palate morphogenesis depends on complex molecular signaling pathways to enable cellular proliferation, differentiation, and apoptosis. Both genetic and environmental factors may be responsible for dysregulating these pathways, leading to development of cleft lip or palate. Cleft lip with or without cleft palate is a distinct entity from cleft palate only. Palate closure occurs between weeks 8 and 12 in utero, and lip formation is concluded by week 7. During these periods of development, dysregulation of different pathways leads to cleft of the lip, palate, or both ( Figs. 1 and 2 ).

Left unilateral cleft lip and palate.

Bilateral cleft lip and alveolus.

Cleft lip and palate, when it occurs as the only malformation (anomaly), is considered nonsyndromic. Seventy percent of all cases of cleft lip and palate are nonsyndromic. Cases of cleft palate only are different in that they are nonsyndromic 50% of the time.

However, when cleft lip and palate or cleft palate alone is associated with other clinical features (anomalies), it is considered syndromic. Thus, cleft lip and palate occurs as syndromic 30% of the time. Cleft palate only occurs as syndromic 50% of the time. The diagnosis of a syndrome is made from the overall pattern of anomalies present. The more anomalies noted, the easier it is to diagnose. However, sometimes, some of these features may not be fully expressed and are more difficult to diagnose.

More than 500 syndromes are identified with cleft lip and palate as part of the phenotype. The most common mechanisms related to syndromic cleft lip and palate are either single gene mutations or chromosome abnormalities. Of note are the findings in some syndromes of trisomy chromosomes (13, 18, and 21), partial deletions, and duplications. Therefore, several genomic regions containing loci either excessive or insufficient can lead to cleft lip and palate. There are both autosomal dominant inheritance patterns and autosomal-recessive patterns of inheritance of syndromic clefting. A few syndromes also have an X-linked inheritance pattern ( Fig. 3 ).

Chromosome.

Multiple genes have been identified over recent years that are responsible for different aspects of syndromic cleft lip and palate formation:

Genes have also been identified in nonsyndromic cleft lip and palate:

• IRF6

• 8q24 locus

• Vax1

Other genes studied with a likely association with nonsyndromic cleft lip and palate include:

• MSX1

• FOXE1

• MYH9

• MAFB

• ABCA4

• 17q22 locus

• BMP4

• FGFR2

Research is still ongoing to prove the relationships between these genes and clefting disorders.

For a complete listing of all genes/syndromes identified thus far, refer to the National Institutes of Health Web site OMIM (Online Mendelian Inheritance in Man): http://www.ncbi.nlm.nih.gov/omim .