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Last updated:
December 12, 2022
Years published: 1989, 1996, 1999, 2005, 2015, 2018, 2022
NORD gratefully acknowledges Elaine Lee, NORD Editorial Intern from the University of Notre Dame, and Leslie G Biesecker, MD, Director, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.
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 (cutaneous or osseous syndactyly), and/or additional abnormalities. Craniofacial malformations associated with this disorder may include a large and/or unusually shaped skull; metopic synostosis; 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 among affected individuals. In most individuals, GCPS is inherited in an autosomal dominant pattern.
GCPS, 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 individuals.
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 (cutaneous or osseous 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 have the additional digit(s) toward the “pinky finger” side of the hand (postaxial polydactyly) and the “big toe” side of the foot (preaxial polydactyly). The extra digit can be a complete digit or a non-functional incomplete digit. The degree of digital fusion may also vary from the skin only joining part of the distance to the fingertip to the skin being joined all the way to the tip of the finger. In some cases, only the soft tissue is fused, but in others, the bone or boney cartilage may be fused.
Affected infants can also have craniofacial malformations including an abnormally large head (macrocephaly); a high, prominent or protruding forehead (frontal bossing); high anterior hairline; 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 individuals, certain cranial sutures may close prematurely (craniosynostosis). Such irregular closure of the sutures may cause the head to appear unusually shaped (scaphocephaly, trigonencephaly, 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. Rarely (less than 10% of affected individuals), it can include developmental delays, intellectual disability, seizure, build-up of fluid inside the skull (hydrocephalus), and abnormalities affecting the nerve fibers (corpus callosum) that connect the two cerebral hemispheres of the brain may be present. In most individuals with the severe form of the disorder, it is caused by a deletion of the entire GLI3 gene. The larger the deletion, the more likely the individual will show these uncommon symptoms, because larger deletions can affect other genes in addition to GLI3.
GCPS is caused by abnormal variants in the GLI3 gene. Most of the variants in GLI3 that cause the disorder are single nucleotide changes, deletions or insertions. Less commonly, affected individuals have larger insertions or deletions of the gene. Patients who have very large deletions that include GLI3, and neighboring genes are diagnosed with the “Greig cephalopolysyndactyly contiguous gene syndrome.” A few patients have the disorder because of a balanced chromosomal translocation. Regardless of the specific variant type, it is deletion and/or reduced expression of the GLI3 gene that leads to GCPS.
GCPS is inherited in an autosomal dominant pattern. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Disorders inherited in a dominant pattern 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 an affected parent to an offspring is 50% for each pregnancy regardless of the gender of the child.
GCPS affects males and females in equal numbers. There have been over 200 patients with 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.
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 pregnancies at 50% risk, GCPS may be detected before birth by observing extra fingers or toes (polydactyly) and an enlarged skull (macrocephaly) during ultrasound imaging. During ultrasonography, reflected sound waves create images of the developing fetus. There are other prenatal testing methods available, such as analyzing the fetal cells.
X-rays and CT scanning may be used to detect and reveal the extent of bone fusion in severe occurrences of osseous syndactyly. In some individuals with GCPS, X-ray studies may also reveal advanced bone age.
Macrocephaly is defined as a head circumference greater than the 97th centile compared to appropriate age and sex standards. In addition, if the distance between the pupils is greater than the 97th centile compared to appropriate age and sex standards, then the individual has widely spaced eyes that can be considered as GCPS feature.
Two conditions must be considered prior to diagnostic testing: the presence of developmental delay or intellectual disability and history of recurrent pregnancy losses in the parent of the individual. Once the clinical features consistent with GCPS are confirmed (through X-rays and CT scans), individuals without significant developmental delay or intellectual disability should have genetic testing through sequence analysis. If the individual does have developmental delay or intellectual disability, he or she should have either comparative genomic hybridization or SNP-array to detect possible copy number changes in the GLI3 gene. If the individual has a history of recurrent pregnancy losses, consideration should be given to chromosome (cytogenetic) testing. A balanced chromosome translocation that interrupts the GLI3 gene can cause pregnancy losses due to an unbalanced chromosome translocation in offspring
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.
Craniofacial reconstructive surgery for GCPS is not common since the widely spaced eyes and macrocephaly are not sufficiently severe enough to warrant surgery. Surgery for extra digit at the thumb/big toe is normally prioritized over the extra digit near the pinky because of the importance of grasping and balancing.
Specific therapies for the treatment of this disorder are symptomatic and supportive. In some patients, surgery may be performed to correct digital and/or craniofacial abnormalities. Genetic counseling is recommended for affected individuals and their families.
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
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
(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.].)
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.
Buyse ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1402.
JOURNAL ARTICLES
Garcia-Rodriguez R, Rodriguez-Rodriguez R, Garcia-Delgado R, Romero-Requejo A, Medina-Castellano M, Garcia Cruz L, Santana Rodriguez A, Garcia-Hernandez JA. Prenatal diagnosis of Greig Cephalopolysyndactyly Syndrome. When to suspect it. J Matern Fetal Neonatal Med. 2022 Jun;35(11):2162-2165. [PubMed PMID: 32495660]
Speksnijder L, Cohen-Overbeek TE, Knapen MF, et al.A de novo GLI3 mutation in a patient with acrocallosal syndrome. Am J Med Genet A. 2013;161A:1394–400. [PubMed: 23633388]
Putoux A, Thomas S, Coene KL, et al. KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nat Genet. 2011;43:601–6. [PMC free article: PMC3674836] [PubMed: 21552264]
Allanson JE, Cunniff C, Hoyme HE, McGaughran J, Muenke M, Neri G. Elements of morphology: standard terminology for the head and face. Am J Med Genet A.2009;149A:6–28. [PMC free article: PMC2778021] [PubMed: 19125436]
Biesecker LG, Aase JM, Clericuzio C, Gurrieri F, Temple IK, Toriello H. Elements of morphology: standard terminology for the hands and feet. Am J Med Genet A.2009;149A:93–127. [PMC free article: PMC3224990] [PubMed: 19125433]
Biesecker LG. The Greig cephalopolysyndactyly syndrome. Orphanet J Rare Dis. 2008;3:10. [PMC free article: PMC2397380] [PubMed: 18435847]
Bilguvar K, Bydon M, Bayrakli F, Ercan-Sencicek AG, Bayri Y, Mason C, DiLuna ML, Seashore M, Bronen R, Lifton RP, State M, Gunel M. A novel syndrome of cerebral cavernous malformation and Greig cephalopolysyndactyly. Laboratory investigation. J Neurosurg. 2007;107:495–9. [PubMed: 18154020]
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.
Elson E, Perveen R, Donnai D, Wall S, Black GC. De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models. J Med Genet. 2002;39:804–6. [PMC free article: PMC1735022] [PubMed: 12414818]
Koenig R, Bach A, Woelki U, Grzeschik KH, Fuchs S. Spectrum of the acrocallosal syndrome. Am J Med Genet. 2002;108:7–11. [PubMed: 11857542]
Kroisel PM, Petek E, Wagner K. Phenotype of five patients with Greig syndrome and microdeletion of 7p13. Am J Med Genet. 2001;102:243–9. [PubMed: 11484201]
Villavicencio EH, Walterhouse DO, Iannaccone PM. The sonic hedgehog-patched-gli pathway in human development and disease. Am J Hum Genet. 2000;67:1047–54. [PMC free article: PMC1288546] [PubMed: 11001584]
Kalff-Suske M, Wild A, Topp J, et al. Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. Hum Mol Genet. 1999;8:1769–77. [PubMed: 10441342]
Kang S, Graham JM, Olney AH, Biesecker LG. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet. 1997;15:266–8. [PubMed: 9054938]
Wild A, Kalff-Suske M, Vortkamp A, Bornholdt D, König R, Grzeschik KH. Point mutations in human GLI3 cause Greig syndrome. Hum Mol Genet. 1997;6:1979–84.[PubMed: 9302279]
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.
INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:175700; Last Update: 08/26/2016. Available at: https://omim.org/entry/175700 Accessed Nov 22, 2022.
Biesecker LG, Johnston JJ. Greig Cephalopolysyndactyly Syndrome. 2001 Jul 9 [Updated 2020 May 7]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1446/ Accessed Nov 22, 2022.
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