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Cleft Lip and Cleft Palate

Cleft Lip and Cleft Palate

The embryological development of craniofacial structures is an intricate sequential Sequential Computed Tomography (CT) process involving tissue growth and directed cell apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy. As the most common craniofacial malformation of the newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn, the diagnosis of a cleft is clinical and usually apparent at birth. The type and severity of the defect cause various degrees of difficulty with speech development, feeding, swallowing Swallowing The act of taking solids and liquids into the gastrointestinal tract through the mouth and throat. Gastrointestinal Motility, tooth eruption, and cosmetic issues. Ultimate correction is through surgical repair.

Last updated: 31 Jan, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Contents

Overview

Classification

  • Orofacial clefts (OFCs) can be isolated or part of a multi-organ syndrome. 
  • OFCs include:
    • Cleft lip (CL) with or without cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy (CLP)
    • Cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy (CP) 
  • Typical orofacial clefts can be further subdivided based on the anatomy and position of the cleft: 
    • Clefts anterior to the alveolus (unilateral, median Median After arranging the data from loWest to highest, the median is the middle value, separating the lower half from the upper half of the data set. Measures of Central Tendency and Dispersion, or bilateral) 
    • Complete and incomplete clefts
    • Postalveolar clefts
Cleft lip

Cleft lip

Image by Lecturio.
Cleft palate

Cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy

Image by Lecturio.

Epidemiology

The prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of orofacial clefts varies widely around the world. The following data are specific to the United States.

  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: Unilateral presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor is more common than bilateral.
    • CL: 3.1 per 10,000 live births
    • CP: 5.9 per 10,000 live births
    • CLP: 5.6 per 10.000 live births
  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency based on infant gender Gender Gender Dysphoria:
    • CL and CLP are more common in males.
    • CP is more common in females.
  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency based on maternal factors:
    • Age
      • CL, CP, and CLP are more common in infants born to mothers aged 35 and older.
      • May be due to higher prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of trisomy 13 Trisomy 13 Trisomy 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome 13. As the 3rd most common trisomy, Patau syndrome has an incidence of 1 in 10,000 live births. Most cases of Patau syndrome are diagnosed prenatally by maternal screening and ultrasound. More than half of the pregnancies result in spontaneous abortions. Patau Syndrome (Trisomy 13) and 18 in these children
    • Ethnicity
      • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of OFC is similar overall between ethnicities, with 2 exceptions:
        • Infants of non-Hispanic Native Americans/Alaskan Native mothers have a higher-than-average prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of OFC.
        • Infants of non-Hispanic African American mothers have a significantly lower prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of OFC.
    • Health factors: increased prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of OFC is seen in children of mothers who:
      • Smoke
      • Are diabetic
      • Are obese
      • Consume alcohol during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care

Etiology

  • Nonsyndromic clefts have multifactorial etiologies:
    • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics
      • Twin studies show a genetic component to non-syndromic clefting.
      • Multiple genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure are implicated; mutations in interferon regulatory factor 6 (IRF6) are commonly seen with nonsyndromic clefting.
    • Environmental
      • Maternal exposures
        • Alcohol consumption
        • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases
        • Pre-gestational and gestational diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
        • Folate deficiency Folate deficiency A nutritional condition produced by a deficiency of folic acid in the diet. Many plant and animal tissues contain folic acid, abundant in green leafy vegetables, yeast, liver, and mushrooms but destroyed by long-term cooking. Alcohol interferes with its intermediate metabolism and absorption. Folic acid deficiency may develop in long-term anticonvulsant therapy or with use of oral contraceptives. This deficiency causes anemia, macrocytic anemia, and megaloblastic anemia. It is indistinguishable from vitamin B12 deficiency in peripheral blood and bone marrow findings, but the neurologic lesions seen in B12 deficiency do not occur. Megaloblastic Anemia during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
    • Teratogens
      • Anti-seizure medications
        • Phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs
        • Valproate Valproate A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs
        • Topiramate Topiramate A sulfamate-substituted fructose analog that was originally identified as a hypoglycemic agent. It is used for the treatment of epilepsy and migraine disorders, and may also promote weight loss. Second-Generation Anticonvulsant Drugs
      • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 antagonists
        • Methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy
        • Retinoic acid
  • Syndromic clefts: Multiple syndromes feature CL, CP, and CLP as part of the constellation of symptoms. 
    • Pierre Robin sequence Robin sequence Pierre Robin sequence, also known as Pierre Robin syndrome or simply Robin sequence, is a condition in infants that is characterized by a smaller-than-normal mandible, a tongue that retracts back into the throat, and difficulty breathing. Pierre Robin Sequence 
    • Patau syndrome Patau syndrome Trisomy 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome 13. As the 3rd most common trisomy, Patau syndrome has an incidence of 1 in 10,000 live births. Most cases of Patau syndrome are diagnosed prenatally by maternal screening and ultrasound. More than half of the pregnancies result in spontaneous abortions. Patau Syndrome (Trisomy 13) ( trisomy 13 Trisomy 13 Trisomy 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome 13. As the 3rd most common trisomy, Patau syndrome has an incidence of 1 in 10,000 live births. Most cases of Patau syndrome are diagnosed prenatally by maternal screening and ultrasound. More than half of the pregnancies result in spontaneous abortions. Patau Syndrome (Trisomy 13)) 
    • Edwards syndrome Edwards syndrome Edwards syndrome, or trisomy 18, is a genetic syndrome caused by the presence of an extra chromosome 18. The extra chromosome is either from 3 full copies of chromosome 18 or an additional segment of chromosome 18. As the 2nd most common trisomy, Edwards syndrome is seen in 1 out of every 5,500 live births. Edwards Syndrome (Trisomy 18) ( trisomy 18 Trisomy 18 Edwards syndrome, or trisomy 18, is a genetic syndrome caused by the presence of an extra chromosome 18. The extra chromosome is either from 3 full copies of chromosome 18 or an additional segment of chromosome 18. As the 2nd most common trisomy, Edwards syndrome is seen in 1 out of every 5,500 live births. Edwards Syndrome (Trisomy 18)) 
    • DiGeorge syndrome DiGeorge syndrome DiGeorge syndrome (DGS) is a condition caused by a microdeletion at location q11.2 of chromosome 22 (thus also called 22q11.2 syndrome). There is a defective development of the third and fourth pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). DiGeorge Syndrome (partial deletion in chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 22)
  • Pierre robin sequence

    Progression of triad of events that underlies the clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor of Pierre Robin sequence Robin sequence Pierre Robin sequence, also known as Pierre Robin syndrome or simply Robin sequence, is a condition in infants that is characterized by a smaller-than-normal mandible, a tongue that retracts back into the throat, and difficulty breathing. Pierre Robin Sequence

    Image by Lecturio.
  • Pierre robin sequence cleft palate

    Imaging finding of the oral cavity during fiberoptic intubation Intubation Peritonsillar Abscess in cases of Pierre Robin sequence Robin sequence Pierre Robin sequence, also known as Pierre Robin syndrome or simply Robin sequence, is a condition in infants that is characterized by a smaller-than-normal mandible, a tongue that retracts back into the throat, and difficulty breathing. Pierre Robin Sequence. Cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy (triangle): root of the tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy (arrowhead). The tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy protruding into the nasal cavity Nasal cavity The proximal portion of the respiratory passages on either side of the nasal septum. Nasal cavities, extending from the nares to the nasopharynx, are lined with ciliated nasal mucosa. Nose and Nasal Cavity: Anatomy via a cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy results in airway Airway ABCDE Assessment obstruction ( larynx Larynx The larynx, also commonly called the voice box, is a cylindrical space located in the neck at the level of the C3-C6 vertebrae. The major structures forming the framework of the larynx are the thyroid cartilage, cricoid cartilage, and epiglottis. The larynx serves to produce sound (phonation), conducts air to the trachea, and prevents large molecules from reaching the lungs. Larynx: Anatomy is not visible).

    Image: “Pierre Robin sequence Robin sequence Pierre Robin sequence, also known as Pierre Robin syndrome or simply Robin sequence, is a condition in infants that is characterized by a smaller-than-normal mandible, a tongue that retracts back into the throat, and difficulty breathing. Pierre Robin Sequence with upper airway Airway ABCDE Assessment obstruction” by US National Library of Medicine. License: CC BY 4.0
  • 48-year-old woman with the 22q11. 2 deletion

    22q11.2 deletion 22q11.2 deletion DiGeorge Syndrome features in a 48-year-old woman.
    (a): The patient’s cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy had previous surgery.
    (b): Mild dysmorphic facial features, including a low anterior hairline, swollen eyelids Eyelids Each of the upper and lower folds of skin which cover the eye when closed. Blepharitis, malar flatness, nose Nose The nose is the human body’s primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Nose and Nasal Cavity: Anatomy with a bulbous nasal tip, hypoplastic nasal alae, square and flat nasal root, small mouth, and a thin upper lip Upper Lip Melasma.

    Image: “48-year-old woman with the 22q11.2 deletion 22q11.2 deletion DiGeorge Syndrome” by Department of Psychiatry, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan. License: CC BY 2.0, edited by Lecturio.
  • Patau syndrome (trisomy 13)

    Patau syndrome Patau syndrome Trisomy 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome 13. As the 3rd most common trisomy, Patau syndrome has an incidence of 1 in 10,000 live births. Most cases of Patau syndrome are diagnosed prenatally by maternal screening and ultrasound. More than half of the pregnancies result in spontaneous abortions. Patau Syndrome (Trisomy 13) ( trisomy 13 Trisomy 13 Trisomy 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome 13. As the 3rd most common trisomy, Patau syndrome has an incidence of 1 in 10,000 live births. Most cases of Patau syndrome are diagnosed prenatally by maternal screening and ultrasound. More than half of the pregnancies result in spontaneous abortions. Patau Syndrome (Trisomy 13))

    Image by Lecturio.
  • Edwards syndrome (trisomy 18)

    Edwards syndrome Edwards syndrome Edwards syndrome, or trisomy 18, is a genetic syndrome caused by the presence of an extra chromosome 18. The extra chromosome is either from 3 full copies of chromosome 18 or an additional segment of chromosome 18. As the 2nd most common trisomy, Edwards syndrome is seen in 1 out of every 5,500 live births. Edwards Syndrome (Trisomy 18) ( trisomy 18 Trisomy 18 Edwards syndrome, or trisomy 18, is a genetic syndrome caused by the presence of an extra chromosome 18. The extra chromosome is either from 3 full copies of chromosome 18 or an additional segment of chromosome 18. As the 2nd most common trisomy, Edwards syndrome is seen in 1 out of every 5,500 live births. Edwards Syndrome (Trisomy 18))

    Image by Lecturio.

Pathophysiology

All clefts arise from errors in the embryological development of the face.

  • CL: failure of medial and lateral nasal processes to merge maxillary process during 1st trimester
    • Can be unilateral or bilateral
    • May extend to the nostril
    • May extend deeper and involve the alveolus
    • If failure of fusion extends to palatal shelves, it results in CLP.
  • CP: partial or lack of fusion only involving the palatal shelves
Development of the lip

Development of the lip

Image by Lecturio.
Formation of the palate

Formation of the palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy

Image by Lecturio.

Clinical Presentation

  • Cleft lip
    • Unilateral or bilateral
    • Cleft primary palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy: Cleft involves the upper lip Upper Lip Melasma and alveolus (i.e., anterior to incisive foramen).
    • CLP: involving the palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy in addition to the upper lip Upper Lip Melasma and alveolus (rarely, alveolus may be intact)
    • Severity may vary: complete (involving the nostril), incomplete, or lesser-form (e.g., micro)  
  • Cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy
    • Soft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy only
    • Soft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy and secondary (i.e., posterior to incisive foramen) hard palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy
    • Submucosal: Cleft is hidden underneath a mucosal layer.
  • Cleft palate illustration

    Illustration of a baby with a cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy

    Image: “Cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy” by Centers for Disease Control and Prevention. License: Public Domain
  • Baby with cleft lip

    Six-month-old girl before going into surgery to have her unilateral complete cleft lip repaired

    Image: “Child born with cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy at 5 months of age” by King97tut. License: Public Domain

Diagnosis and Management

Diagnosis

  • Prenatal 
    • Ultrasound
      • Cannot be done before 13–14 weeks as facial structures have not solidified sufficiently
      • Cleft lip is relatively easy to identify by ultrasound.
      • Cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy may need magnetic resonance imaging (MRI) to be identified.
    • Amniocentesis Amniocentesis Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. Polyhydramnios: Prenatal diagnosis may prompt investigation for other syndromic features.
  • Postnatal
    • Clinical diagnosis: at birth, full evaluation of the infant’s suck/swallow ability to determine how to best assist oral feeding
    • Full head-to-toe evaluation for comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus with particular attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment to:
      • Nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification (33% of associated anomalies)
      • Cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) system (24% of associated anomalies)
    • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics consultation

Management

  • Presurgical management:
    • The goal is to facilitate feeding to allow the infant to grow to age and weight required for surgical correction.
    • A multidisciplinary team of healthcare providers is required. 
    • Feeding bottles with large-bore nipples
    • Nasoalveolar molding (orthodontist)
    • Lip taping or lip adhesions
  • Surgical repair of cleft lip is based on the “rule of 10s”: when infant is at least 10 weeks old and weighs 10 pounds and hemoglobin has reached 10 mg/dL
  • Surgical repair of cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy from 9–12 months followed by long-term speech therapy Speech Therapy Treatment for individuals with speech defects and disorders that involves counseling and use of various exercises and AIDS to help the development of new speech habits. Myotonic Dystrophies
  • Alveolar correction may be performed at 7–9 years followed by other corrective surgeries.

References

  1. Tolarová MM, Cervenka J. Classification and birth prevalence of orofacial clefts. Am J Med Genet. 1998;75(2):126-137. https://pubmed.ncbi.nlm.nih.gov/9450872/ 
  2. Mai CT, Cassell CH, Meyer RE, et al. Birth defects data from population-based birth defects surveillance programs in the United States, 2007 to 2011: highlighting orofacial clefts. Birth Defects Res A Clin Mol Teratol. 2014;100(11):895-904. doi:10.1002/bdra.23329 https://pubmed.ncbi.nlm.nih.gov/25399767/ 
  3. Shkoukani MA, Chen M, Vong A. Cleft lip – a comprehensive review. Front Pediatr. 2013;1:53. Published 2013 Dec 27. doi:10.3389/fped.2013.00053 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873527/
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