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Greig Cephalopolysyndactyly Syndrome

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Copyright 1989, 1996, 1999, 2005

Synonyms of Greig Cephalopolysyndactyly Syndrome

Disorder Subdivisions

General Discussion

Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. Characteristic digital features may include extra (supernumerary) fingers and/or toes (polydactyly), webbing and/or fusion of the fingers and/or toes (syndactyly), and/or additional abnormalities. Craniofacial malformations associated with this disorder may include a large and/or unusually shaped skull; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical abnormalities. The range and severity of symptoms may vary greatly from case to case. In most cases, GCPS is inherited as an autosomal dominant trait.

Symptoms

Greig cephalopolysyndactyly syndrome, a rare genetic disorder that is present at birth (congenital), is characterized by abnormalities of the fingers and toes (digits) and the head and facial (craniofacial) area. The range and severity of symptoms vary from individual to individual, with the facial characteristics, in particular, being quite subtle in some cases.

Infants with this disorder exhibit various digital malformations, including extra (supernumerary) fingers and/or toes (polydactyly); webbing or fusion of the fingers and/or toes (syndactyly); abnormally wide thumbs and/or great toes (halluces); and/or split (bifid) end bones of the thumbs and/or halluces (terminal phalanges). Affected infants with supernumerary digits will usually display the additional digit(s) toward the "pinky finger" side of the hand (postaxial polydactyly) and the "big toe" side of the foot (preaxial polydactyly).

Affected infants also exhibit several craniofacial malformations including an abnormally large head (macrocephaly); a high, prominent or protruding forehead (frontal bossing); a broad nasal bridge; and/or widely spaced eyes (ocular hypertelorism). In some cases, the fibrous joints (sutures) between certain bones in the skull may be abnormally wide and may close unusually late in development; on the other hand, in rare cases, certain cranial sutures may close prematurely (craniosynostosis). Such irregular closure of the sutures may cause the head to appear unusually shaped (scaphocephaly or plagiocephaly).

In many individuals with GCPS, additional abnormalities may be present. These may include permanently flexed fingers (camptodactyly), dislocation of the hip, protrusion of a portion of the large intestine through an abnormal opening in the muscular wall that lines the lower abdominal cavity (inguinal hernia), and/or other physical abnormalities. In rare cases, developmental delays and abnormalities affecting the nerve fibers (corpus callosum) that connect the two cerebral hemispheres of the brain may be present.

Causes

In most cases, Greig cephalopolysyndactyly syndrome is inherited as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

In a small number of cases, the disorder may be due to spontaneous (de novo) genetic changes (mutations) early in embryonic development that occur for unknown reasons (sporadic). In such cases, the disorder is not inherited from the parents.

The gene responsible for Greig cephalopolysyndactyly syndrome, the GLI3 gene, is located on the short arm (p) of chromosome 7 (7p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 7p13" refers to band 13 on the short arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Mutations disrupting the normal function (expression) of the GLI3 gene are responsible for the disorder. For example, some cases where Greig cephalopolysyndactyly syndrome was inherited as a dominant trait, the disorder was shown to result from a balanced chromosomal translocation in one of the parents involving chromosome 7p13. A translocation is balanced if pieces of two or more chromosomes break off and trade places, creating an altered but balanced set of chromosomes. If a chromosomal rearrangement is balanced, it is usually harmless to the carrier. However, balanced rearrangements are sometimes associated with a higher risk of abnormal chromosomal development in the carrier's offspring. In addition, in some sporadic cases of GCPS, affected individuals have exhibited missing chromosomal material (deletion) involving 7p13. Therefore, according to the medical literature, deletion and/or reduced expression of the GLI3 gene at chromosome 7p13 is thought to lead to GCPS.

Affected Populations

Greig cephalopolysyndactyly syndrome (GCPS) is an extremely rare genetic disorder that is present at birth (congenital) and affects males and females in equal numbers. There have been over 50 cases of this disorder reported in the medical literature. However, because some affected individuals may exhibit few and/or mild symptoms, they may never be diagnosed with the disorder. Therefore, it is difficult to determine the true frequency of GCPS in the general population.

Related Disorders

Symptoms of the following disorders can be similar to those of Greig cephalopolysyndactyly syndrome. Comparisons may be useful for a differential diagnosis:

GLI3 morphopathies are a group of related disorders characterized by mutations in the GLI3 gene located on the short arm of chromosome 7. This group of disorders includes GCPS, Pallister-Hall syndrome, postaxial polydactyly type A, and preaxial polydactyly type IV. These disorders occur due to different mutations of the GLI3 gene (allelic disorders) and share some similar characteristics. Despite similarities, these disorders are considered distinct clinical entities. (For more information on Pallister-Hall syndrome, choose "Pallister Hall" as your search term in the Rare Disease Database).

Acrocallosal syndrome (ACLS) is a rare genetic disorder characterized by multiple craniofacial abnormalities, including an enlarged head (macrocephaly), a protruding forehead (frontal bossing), and/or widely spaced eyes (ocular hypertelorism). Some cases of acrocallosal syndrome occur due to mutations of the GLI3 gene. In other cases, mutations of the GLI3 gene has been ruled out as a cause for the disorder. Additional symptoms associated with ACLS include absence (agenesis) of the nerve fibers that connects the two halves of the brain (corpus callosum), mental retardation, and digital abnormalities including extra fingers and toes on the hands and/or feet (polydactyly). In the past, many researchers suspected that ACLS and GCPS may have represented variable expressions of the same disorder. ACLS is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Acrocallosal" as your search term in the Rare Disease Database.)

Oro-facial-digital syndrome is a rare genetic disorder in which there have been four types identified. Symptoms common to all types include episodes of neuromuscular disturbances, split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue, a broad based nose, vertical folds of the skin covering the inner angle where the eyelids meet (epicanthic folds), more than the normal number of fingers and/or toes, shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose "Oro-Facial-Digital" as your search term in the Rare Disease Database.)

Pfeiffer syndrome (acrocephalosyndactyly type V) is generally accepted to be the same condition as Noack syndrome (acrocephalopolysyndactyly type I). It is a rare genetic disorder characterized by craniofacial abnormalities, digital malformations, and/or additional physical abnormalities. Affected individuals may exhibit several bone abnormalities of the face and head (craniofacial dysostosis), including a short, pointed head (acrobrachycephaly) and widely spaced eyes (ocular hypertelorism). Several abnormalities of the jaws and teeth may also be present, including an underdeveloped upper jawbone (maxillary hypoplasia), highly arched palate, prominent lower jaw (prognathism), and improper alignment of the teeth (malocclusion) when the jaws close. Individuals with Pfeiffer syndrome may also have webbed fingers and/or toes (syndactyly); abnormally short, broad thumbs and big toes; and/or malformed, misshapen, and/or absent bones (i.e., proximal and terminal phalanges) within the thumbs and/or great toes. Additional physical abnormalities may be present in some cases. Pfeiffer syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose "Pfeiffer" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
Greig cephalopolysyndactyly syndrome (GCPS) is usually diagnosed at birth based upon a thorough clinical evaluation; identification of characteristic physical findings; and specialized imaging procedures, including X-rays and computed tomography (CT) scanning. In some cases, GCPS may be detected before birth (prenatally) by observing the presence of extra digits (polydactyly) and an enlarged skull (macrocephaly) during ultrasound imaging. During ultrasonography, reflected sound waves create images of the developing fetus.

X-rays and CT scanning may be used to detect and reveal the extent of bone fusion in severe cases of syndactyly. In many cases of GCPS, X-ray studies may also reveal abnormally advanced bone age.

Treatment
The treatment of GCPS is directed toward the specific symptoms apparent in each individual. Treatment may require the efforts of a team of specialists who may need to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), orthopedic and plastic surgeons, physical and occupational therapists, and/or other health care professionals.

Specific therapies for the treatment of this disorder are symptomatic and supportive. In some cases, surgery may be performed to correct digital and/or craniofacial abnormalities. Genetic counseling will be of benefit for affected individuals and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Greig Cephalopolysyndactyly Syndrome Resources

(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., digital abnormalities, craniofacial abnormalities, etc.].)

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
Grzeschik KH. Greig Cephalopolysyndactyly Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:201.

Jones KL., ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co: 1997:426.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:799-800.

Buyce ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1402.

JOURNAL ARTICLES
Johnston JJ, et al. Molecular and clinical aspects of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype predication from the type and position of GLI3 mutations. Am J Med Genet. 2005;76:609-22.

Johnston JJ, et al. Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome. Am J Med Genet. 2003;123:236-42.

Debeer P, et al. Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations. Am J Med Genet. 2003;120:49.58.

Ausems MG, et al. Greig cephalopolysyndactyly syndrome in a large family: a comparison of the clinical signs with those described in the literature. Clin Dysmorphol. 1994;3:21-30.

Vortkamp A, et al. Isolation of a yeast artificial chromosome contig spanning the Greig cephalopolysyndactyly syndrome (GCPS) gene region. Genomics. 1994;22:563-58.

Fryns JP, et al. Apparent Greig cephalopolysyndactyly and sinus node disease. Am J Med Genet. 1993;45:38-40.

Vortkamp A, et al. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature. 1991;352:539-40.

Gemmill RM, et al. A 2.5-mb physical map within 3p21.1 spans the breakpoint associated with Greig cephalopolysyndactyly syndrome. Genomics. 1991;11:93-102.

Drabkin H, et al. Regional and physical mapping studies characterizing the Greig polysyndactyly 3;7 chromosome translocation, t(3;7)(p21.1;p13). Genomics. 1989;4:518-29.

Pliskin ME, et al. The occurrence of a fibro-osseous lesion and multiple dental anomalies in a patient with the Greig cephalopolysyndactyly syndrome. Oral Surg Oral Med Oral Pathol. 1988;66:475-9.

Gollop TR, et al. The Greig cephalopolysyndactyly syndrome: report of a family and review of the literature. Am J Med Genet. 1985;22:59-68.

Kunze J, et al. Greig cephalopolysyndactyly syndrome. Report of a sporadic case. Helv Paediatr Acta. 1985;40:489-495.

Merlob P, et al. Greig's syndrome. Neonatal radiologic manifestations. J Radiol. 1984;65:187-9.

Baraitser M, et al. Greig cephalopolysyndactyly: report of 13 affected individuals in three families. Clin Genet. 1983;24:257-65.

Merlob P, et al. A newborn infant with craniofacial dysmorphism and polysyndactyly (Greig's syndrome). Acta Paediatr Scand. 1981;70:275-7.

Fryns JP, et al. The Greig polysyndactyly craniofacial dysmorphism syndrome: variable expression in a family. Eur J Pediatr. 1981;136:217-20.

Duncan PA, et al. Greig cephalopolysyndactyly syndrome. Am J Dis Child. 1979;133:818-21.

Fryns JP, et al. The Greig polysyndactyly-craniofacial dysmorphism syndrome. Eur J Pediatr. 1977;126:283-7.

FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:175700; Last Update:3/18/2005. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175700 Accessed On: April 29, 2005.

Biesecker LE. Updated: Oct. 7, 2004. Greig Cephalopolysyndactyly Syndrome. In.: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2004. Available at http://www.genetests.org. Accessed: April 29, 2005.

Report last updated: 2008/04/11 00:00:00 GMT+0