Printer Friendly

Syndrome associated with cleft palate and cleft lip.


A syndrome is a pattern of multiple anomalies that are pathogenically related and therefore have a common known or suspected.

Cleft palate (CP) has a prevalence of 6.39 per 10,000 live births . In contrast to cleft lip/ palate, CP is much more likely to be associated with an underlying syndrome or other congenital anomalies. (1,2,3)

Since it can be difficult to distinguish between the malformation of cleft palate and cleft palate as a disruption of normal development, all cases of cleft palate, including those caused by Pierre Robin sequence, will be discussed in this review.

Syndromes associated with cleft lip & palate:

I. Pierre Robin Sequence:

Pierre Robin sequence is a common cause of cleft palate. This sequence can occur in isolation, but is associated with an underlying syndrome in over 50% of cases. This condition is not a diagnosis unto itself, but rather encompasses the pathogenesis of the cleft palate.

Infants born with Pierre Robin sequence are born with their tongue positioned posteriorly, often causing blockage of the pharynx and airway, a process called gloosoptosis. This affects both breathing and feeding. (1,2)

II. Stickler Syndrome:

Stickler syndrome is by far the most common identifiable cause of cleft palate. It was first studied and characterized by Gunnar B. Stickler in 1965. Stickler syndrome is a subtype of collagenopathy, types II and XI. This is an autosomal dominant disorder with variable expressivity; in other words, there is a great deal of variablitiy in the clinical presentation of patients with this disorder. Individual with this condition may have just a few or all of the clinical features associated with this disorder. Stickler syndrome is characterized by distinctive facial abnormalities, ocular problems, hearing loss, and joint problems

Mutations in the COL11A1, COL11A2 and COL2A1 genes cause Stickler syndrome. These genes are involved in the production of type II and type XI collagen. Mutations in any of these genes disrupt the production, processing, or assembly of type II or type XI collagen. Defective collagen molecules or reduced amounts of collagen affect the development of bones and other connective tissues, leading to the characteristic features of Stickler syndrome.

The classic presentation of Stickler syndrome is Pierre Robin sequence, including cleft palate; early onset osteoarthritis, often in early adulthood but sometimes in later; and myopia .In addition, sensorineural hearing loss is very common in Stickler syndrome. Many individual with stickler syndrome also have characteristic facial features including micrognathia in infancy, a flat facial profile, epicanthal folds and midface hypoplasia. The nasal bridge is often flat, even in adulthood.

Development is usually normal in Stickler syndrome. These individuals do not appear to be increased risk for any particular learning disabilities. Speech and language problems are usually related to the cleft palate and hearing loss. (3-11)

III. Velocardiofacial Syndrome (Deletion 22q11.2 syndrome)

Velocardiofacial syndrome is a relatively common condition with an incidence of approximately 1 in 4000 live births. This disorder is caused by intersitial deletion of chromosome 22q11.2. this is highly variable condition with many names, including Digeorge syndrome and Conotruncal face syndrome. The most common anomalies are palate anomalies (cleft palate and / or velopharyngeal insufficiency), congenital heart defects, hypocalcemia, immunodefeciency and dysmorphic facial features.

The facial characteristics associated with velocardiofacial syndrome include microcephaly, narrow palpebral fissures, a wide nasal root, a bulbous nose, vertical maxillary excess, a thin upper lip, a long face, micrognathia, and minor auricular anomalies.

Individuals with deletion 22q11.2 syndrome can have myriad medical problems, and these can include kidney or urinary tract anomalies. There is a close association between VCFS and DiGeorge syndrome which includes small or absent thymus, tonsils, adenoids and hypocalcaemia. These children may have medial displacement of the carotid artery over the cervical vertebrae and this should be borne in mind while planning any pharyngeal surgery like pharyngeal flap for Velo pharyngeal incompetence (VPI) correction. The majority of these patients will need support for their learning problems. (12-15)

IV. OSMED Syndrome:

Otospondylomegaepiphyseal dysplasia (OSMED) is a skeletal disorder characterized by skeletal abnormalities, distinctive facial features, and severe hearing loss. The condition involves the ears (oto-), affects the bones of the spine (spondylo-), and enlarges the ends (epiphyses) of long bones in the arms and legs. The features of OSMED are similar to those of another skeletal disorder, Weissenbacher-Zweymuller syndrome.

People with OSMED are often shorter than average because the bones in their legs are unusually short. Other skeletal features include enlarged joints; short arms, hands, and fingers; and flattened bones of the spine (platyspondyly). People with the disorder often experience back and joint pain, limited joint movement, and arthritis that begins early in life. Severe high-tone hearing loss is common in people with OSMED. Typical facial features include protruding eyes; a flattened bridge of the nose; an upturned nose with a large, rounded tip; and a small lower jaw. Virtually all affected infants are born with cleft palate. The skeletal features of OSMED tend to diminish during childhood, but other signs and symptoms, such as hearing loss and joint pain, persist into adulthood.

Mutations in the COL11A2 gene cause OSMED. Mutations in the COL11A2 gene that cause OSMED disrupt the production or assembly of type XI collagen molecules. The loss of type XI collagen prevents bones and other connective tissues from developing properly. (16-18)

V. Van der Woude Syndrome:

Van der Woude syndrome is a condition that affects the development of the face. Many people with this disorder are born with a cleft lip, a cleft palate (an opening in the roof of the mouth), or both. Affected individuals usually have depressions (pits) near the centre of the lower lip, which may appear moist due to the presence of salivary and mucous glands in the pits. Small mounds of tissue on the lower lip may also occur. In some cases, people with van der Woude syndrome have missing teeth.

People with van der Woude syndrome who have cleft lip and/or palate, like other individuals with these facial conditions, have an increased risk of delayed language development, learning disabilities, or other mild cognitive problems. The average IQ of individuals with van der Woude syndrome is not significantly different from that of the general population. Mutations in the IRF6 gene cause van der Woude syndrome.

Van der Woude syndrome is believed to occur in 1 in 35,000 to 1 in 100,000 people, based on data from Europe and Asia. Van der Woude syndrome is the most common cause of cleft lip and palate resulting from variations in a single gene, and this condition accounts for approximately 1 in 50 such cases. (19-23)

VI. Treacher Collins Syndrome:

Treacher Collins syndrome also known as Mandibulofacial dysostosis or Franceschetti- Zwahlen-Klein Syndrome. Treacher Collins syndrome is a condition that affects the development of bones and other tissues in the face. The signs and symptoms of this disorder vary greatly, ranging from almost unnoticeable to severe. Most affected individuals have underdeveloped facial bones, particularly the cheek bones, and a very small jaw and chin (micrognathia) and cleft palate. In severe cases, underdevelopment of the facial bones may restrict an affected infant's airway, causing potentially life-threatening respiratory problems.

People with Treacher Collins syndrome often have eyes that slant downward, sparse eyelashes, and a notch in the lower eyelids called a coloboma. Some affected individuals have additional eye abnormalities that can lead to vision loss. This condition is also characterized by absent, small, or unusually formed ears. Defects in the middle ear (which contains three small bones that transmit sound) cause hearing loss in about half of cases. People with Treacher Collins syndrome usually have normal intelligence.

Mutations in the TCOF1 gene cause Treacher Collins syndrome. Mutations in the TCOF1 gene reduce the amount of treacle that is produced in cells. Researchers believe that a loss of this protein signals cells that are important for the development of facial bones to self-destruct (undergo apoptosis). This abnormal cell death may lead to the specific problems with facial development found in Treacher Collins syndrome. (24-28)

VII. Shprintzen-Goldberg Syndrome:

Also called as Marfanoid-Craniosynostosis Syndrome, Shprintzen-Goldberg Craniosynostosis Syndrome, Shprintzen-Goldberg Marfanoid Syndrome. Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis (involving the coronal, sagittal, or lambdoid sutures), distinctive craniofacial features, skeletal changes (dolichostenomelia, arachnodactyly, camptodactyly, pes planus, pectus excavatum or carinatum, scoliosis, joint hypermobility, or contractures), neurologic abnormalities, mild-to-moderate intellectual disability, and brain anomalies. Cardiovascular anomalies (mitral valve prolapse, mitral regurgitation, and aortic regurgitation) may occur. Minimal subcutaneous fat, abdominal wall defects, cryptorchidism in males, and myopia are also characteristic findings.

Craniofacial findings includes dolichocephaly, high prominent forehead, ocular proptosis, hypertelorism, telecanthus, downslanting palpebral fissures, maxillary hypoplasia, cleft palate with prominent palatine ridges, micrognathia, and apparently low-set and posteriorly rotated ears.

FBN1. Mutations in FBN1 have been reported in three individuals with a clinical diagnosis of Shprintzen-Goldberg syndrome (SGS). Treatment include surgical repair of abdominal hernias, physiotherapy for joint contractures, and placement in special education programs. (29-31)

VIII. Simpson Dysmorphia Syndrome:

Also called as Bulldog Syndrome, DGSX Golabi- Rosen Syndrome, Dysplasia Gigantism Syndrome, X-Linked SDYS, SGB Syndrome, Simpson-Golabi- Behmel Syndrome Simpson dysmorphia syndrome types 1 and 2 are two forms of a rare, X-linked recessive, inherited disorder characterized by unusually large fetuses (prenatal overgrowth) and unusually large babies (postnatal overgrowth). In addition, affected individuals have characteristic

facial features, more than two nipples (super- numerary nipples), and multisystemic malformations that may vary from child to child. Chief among these are cardiac malformations, mild to moderate mental retardation, cleft palate, and more than the five fingers and/or toes (polydactyly).

Symptoms associated with the more common form, Simpson dysmorphia syndrome type 1 (SDYS1), are less severe than those presented in SDYS2.

Individuals usually reach an above-average height. The general distinguishing features typically become less apparent in adulthood. (31)

IX. Holoprosencephaly, type 3:

Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies.

A spectrum of craniofacial anomalies accompanies HPE in approximately 80% of affected individuals. The spectrum of facial anomalies begins with cyclopia, the most severe presentation, and extends in an unbroken continuum to the normal face as seen in individuals who have, but are not expressing, a mutation for HPE inherited in an autosomal dominant manner. Common clinical features in individuals without obvious findings such as cyclopia, synophthalmia, or a proboscis, include microcephaly (although hydrocephalus can result in macrocephaly), ocular hypotelorism (which can be severe), flat nasal bridge, single maxillary central incisor, and cleft lip and/or palate. (32,33)

X. Nevoid basal cell carcinoma syndrome/ Gorlin syndrome :

Nevoid basal cell carcinoma syndrome (NBCCS), also known as basal cell nevus syndrome, multiple basal cell carcinoma syndrome, Gorlin syndrome, and Gorlin-Goltz syndrome, is an inherited medical condition involving defects within multiple body systems such as the skin, nervous system, eyes, endocrine system, and bones. People with this syndrome are particularly prone to developing a common and usually non-life- threatening form of non-melanoma skin cancers.

First described in 1960, NBCCS is an autosomal dominant condition that can cause unusual facial appearances and a predisposition for basal cell carcinoma, a malignant type of skin cancer. The prevalence is reported to be 1 case per 56,000- 164,000 population. Recent work in molecular genetics has shown NBCCS to be caused by mutations in the PTCH gene found on chromosome arm 9q. If a child inherits the defective gene from either parent, he or she will have the disorder. (34)

Facial abnormalities incude macrocephaly, broad facies, frontal and biparietal bossing, mild mandibular prognathism, odontogenic keratocysts ofjaws, misshapen and/or carious teeth, cleft lip and palate, ectopic calcification of falx cerebri.

Conclusion :

Recognition of the associated syndromes and anomalies with the oral cleft is essential to assess the problem and risk faced by the child and for counselling the parents. Proper knowledge and details of anomalies associated with OFC will help to provide necessary treatment and improve survival of these children. Proper epidemiology, dysmorphology assessment and genetic study may lead researchers to the identification of the causative agent.


(1.) Breugem CC, Mink van der Molen AB. What is 'Pierre Robin sequence?' J Plastic Reconstruct Aesthetic Surg. 2009;62:1555-1558.

(2.) Syndromes with oral manifestations. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 308.

(3.) Annunen S, Korkko J, Czarny M, Warman ML, Brunner HG, Kaariainen H, Mulliken JB, Tranebjaerg L, Brooks DG, Cox GF, Cruysberg JR, Curtis MA, Davenport SL, Friedrich CA. Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes. Am J Hum Genet. 1999 Oct;65(4):974-983.

(4.) Huang F, Kuo HK, Hsieh CH, Lai JP, Chen PK. Visual complications of Stickler syndrome in paediatric patients with Robin sequence. J Craniomaxillofac Surg. 2007 Mar;35(2):76-80.

(5.) Liberfarb RM, Levy HP, Rose PS, Wilkin DJ, Davis J, Balog JZ, Griffith AJ, Szymko-Bennett YM, Johnston JJ, Francomano CA, Tsilou E, Rubin BI. The Stickler syndrome: genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genet Med. 2003 Jan- Feb;5(1):21-7. Review. Erratum in: Genet Med. 2003 Nov- Dec;5(6):478.

(6.) Nowak CB. Genetics and hearing loss: a review of Stickler syndrome. J Commun Disord. 1998 Sep-Oct;31(5):437-453; 453-454.

(7.) Poulson AV, Hooymans JM, Richards AJ, Bearcroft P, Murthy R, Baguley DM, Scott JD, Snead MP. Clinical features of type 2 Stickler syndrome. J Med Genet. Aug 2004; 41(8):e107.

(8.) Richards AJ, Baguley DM, Yates JR, Lane C, Nicol M, Harper PS, Scott JD, Snead MP. Variation in the vitreous phenotype of Stickler syndrome can be caused by different amino acid substitutions in the X position of the type II collagen Gly-X-Y triple helix. Am J Hum Genet. Epub 2000 Sep 25. 2000 Nov;67(5):1083-1094.

(9.) Royce, Peter M; Steinmann, Beat U; Connective tissue and its heritable disorders : molecular, genetic, and medical aspects; 2nd ed.; New York : Wiley-Liss, c2002. p901-931.

(10.) Snead MP, Yates JR. Clinical and Molecular genetics of Stickler syndrome. J Med Genet. 1999 May;36(5):353-359.

(11.) Zechi-Ceide RM, Jesus Oliveira NA, Guion-Almeida ML, Antunes LF, Richieri-Costa A, Passos-Bueno MR. Clinical evaluation and COL2A1 gene analysis in 21 Brazilian families with Stickler syndrome: identification of novel mutations, further genotype/phenotype correlation, and its implications for the diagnosis. Eur J Med Genet. 2008 May- Jun;51(3):183-196.

(12.) Thomas JA, Graham JM Jr. Chromosomes 22q11 deletion syndrome: an update for the primary peditrician. Clin Pediatr (Phila) 1997;36:253-266.

(13.) Shprintzen RJ, Goldberg RB, Lewin ML, et al. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J. Jan 1978;15(1):56-62.

(14.) Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. Oct 1997;34(10):798-804.

(15.) Cuneo BF. 22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes. Curr Opin Pediatr. Oct 2001;13(5):465-472.

(16.) Melkoniemi M, Brunner HG, Manouvrier S, Hennekam R, Superti-Furga A, Kaariainen H, Pauli RM, van Essen T, Warman ML, Bonaventure J, Miny P, Ala-Kokko L. Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene. Am J Hum Genet. 2000 Feb;66(2): 368-377.

(17.) Temtamy SA, MannikkS M, Abdel-Salam GM, Hassan NA, Ala-Kokko L, Afifi HH. Oto-spondylo-megaepiphyseal dysplasia (OSMED): clinical and radiological findings in sibs homozygous for premature stop codon mutation in the COL11A2 gene. Am J Med Genet A. 2006 Jun 1;140(11):1189-1195.

(18.) Van Steensel MA, Buma P, de Waal Malefijt MC, van den Hoogen FH, Brunner HG. Oto- spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene. Am J Med Genet. 1997 Jun 13;70(3):315-323.

(19.) Ghassibe M, Revencu N, Bayet B, Gillerot Y, Vanwijck R, Verellen-Dumoulin C, Vikkula M. Six families with van der Woude and/or popliteal pterygium syndrome: all with a mutation in the IRF6 gene. J Med Genet. 2004 Feb;41(2):e15.

(20.) Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, Howard E, de Lima RL, Daack-Hirsch S, Sander A, McDonald-McGinn DM, Zackai EH. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet. 2002 Oct;32(2):285-289.

(21.) Nopoulos P, Richman L, Andreasen N, Murray JC, Schutte B. Cognitive dysfunction in adults with Van der Woude syndrome. Genet Med. 2007 Apr;9(4):213-218.

(22.) Nopoulos P, Richman L, Andreasen NC, Murray JC, Schutte B. Abnormal brain structure in adults with Van der Woude syndrome. Clin Genet. 2007 Jun;71(6):511-517.

(23.) Rizos M, Spyropoulos MN. Van der Woude syndrome: a review. Cardinal signs, epidemiology, associated features, differential diagnosis, expressivity, genetic counselling and treatment. Eur J Orthod. 2004 Feb;26(1):17-24.

(24.) Dixon J, Jones NC, Sandell LL, Jayasinghe SM, Crane J, Rey JP, Dixon MJ, Trainor PA. Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities. Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13403-13408.

(25.) Marszalek B, Wojcicki P, Kobus K, Trzeciak WH. Clinical features, treatment and genetic background of Treacher Collins syndrome. J Appl Genet. 2002;43(2):223-233.

(26.) Posnick JC, Ruiz RL. Treacher Collins syndrome: current evaluation, treatment, and future directions. Cleft Palate Craniofac J. 2000 Sep;37(5):434.

(27.) Scriver, Charles R; The metabolic & molecular bases of inherited disease; 8th ed.; New York : McGraw-Hill, c2001. p6147-6152.

(28.) Teber OA, Gillessen-Kaesbach G, Fischer S, Bohringer S, Albrecht B, Albert A, Arslan-Kirchner M, Haan E, Hagedorn-Greiwe M, Hammans C, Henn W, Hinkel GK, Konig R, Kunstmann E, Kunze J, Neumann LM, Prott EC, Rauch A, Rott HD, Seidel H. Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation. Eur J Hum Genet. 2004 Nov;12(11):879-890.

(29.) Kosaki R, Takahashi D, Udaka T, Matsumoto M, Ibe S, Isobe T, Tanaka Y, Kosaki K. Genetic heterogeneity of Shprintzen- Goldberg syndrome. Abstract 617. Salt Lake City: The American Society of Human Genetics 55th Annual Meeting; 2005.

(30.) Sood S, Eldadah ZA, Krause WL, McIntosh I, Dietz HC. Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Nat Genet. 1996;12: 209-211.

(31.) Greally MT, Carey JC, Milewicz DM, Hudgins L, Goldberg RB, Shprintzen RJ, Cousineau AJ, Smith WL, Judisch GF, Hanson JW. Shprintzen-Goldberg syndrome: a clinical analysis. Am J Med Genet. 1998;76:202-212.

(32.) Demeyer W, Zeman W, Palmer CG. The face predicts the brain: diagnosticsignificance of median facial anomalies for holoprosencephaly (arhinencephaly). Pediatrics. 1964;34:256-263.

(33.) Kimonis V, Goldstein A, Pastakia B, Yang M, Kase R, DiGiovanna J, Bale A, Bale S (1997). Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome .Am J Med Genet 69(3): 299-308.

(34.) Gorlin R, Goltz R (1960). "Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome". NEngl J Med; 262(18): 908-912.

doi: 10.5866/4.3.920

Manisha Tijare (1), Samar Khan S (2), Ami Desai (3), Megha Jain (4)

(1) Hod & Prof (2,3,4) PG Student Dept of Oral and Maxillofacial Pathology, People's College of Dental Science & Research Centre, Bhopal (MP)

Received: July 13, 2012; Review Completed: August, 13, 2012;

Accepted: September 13, 2012 Published Online: October, 2012 (www. nacd. in) [c] NAD, 2012--All rights reserved

Email for correspondence:
COPYRIGHT 2012 National Academy of Dentistry
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2012 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Tijare, Manisha; Khan S., Samar; Desai, Ami; Jain, Megha
Publication:Indian Journal of Dental Advancements
Date:Jul 1, 2012
Previous Article:Periodontal diseases and cardiovascular diseases --the established link.
Next Article:Cephalometric norms for hyderabad population in natural head position using extracranial reference lines.

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters