Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the. A number sign (#) is used with this entry because of evidence that Greig cephalopolysyndactyly syndrome (GCPS) is caused by heterozygous mutation in the. The Greig cephalopolysyndactyly syndrome (GCPS) is a pleiotropic, multiple congenital anomaly syndrome. It is rare, but precise estimates of.

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University of Washington, Seattle; July 9, ; Last Update: Typical Greig cephalopolysyndactyly syndrome GCPS is characterized by preaxial polydactyly or mixed cephalopolysyndactyl and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly preaxial polydactyly of the feet and postaxial polydactyly cephalopo,ysyndactyly the hands plus syndactyly of fingers and toes Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.

The diagnosis of GCPS is based on clinical findings and family history. Monitoring for evidence of occipitofrontal circumference OFC increasing faster than normal.

Orphanet: Greig cephalopolysyndactyly syndrome

GCPS either is inherited in an autosomal dominant manner either as a pathogenic variant in GLI3 or as a deletion of 7p13 involving GLI3 or occurs as the result of a de novo or inherited chromosome rearrangement. Individuals with GCPS as the result of a GLI3 pathogenic variant may have an affected parent or may have the disorder as the result of a de novo pathogenic variant.

The cephalopolysyndactylyy of cases caused by de novo pathogenic variants is unknown. Prenatal testing for pregnancies at increased risk is possible if the underlying genetic cause in the family i. The reliability of ultrasound examination for prenatal diagnosis is unknown.

Occipitofrontal head circumference OFC is greater than 97th centile compared to appropriate age- and sex-matched normal standards [ Allanson et al ].

An enlarged OFC must be interpreted with caution in families in which a parent or parents of the proband has benign familial macrocephaly OMIM. Increased inner canthal distance i. Increased interpupillary distance is often associated with a wide nasal bridge. The diagnosis should be made with caution in infants with multiple other malformations, especially in the absence of a positive family history.

This, coupled with the fact that the features of GCPS may be a component of many other syndromes, warrants caution in applying these diagnostic criteria. GLI3 is the only gene in which pathogenic variants are known to be associated with Greig cephalopolysyndactyly syndrome. Cephalopolysyndaftyly in own window.

Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants. Sequence analysis detects variants that are benign, likely benign, of uncertain significancelikely pathogenic, or pathogenic. For issues to consider in interpretation of sequence analysis results, click here. Included in the variety of methods that may be used are: To date, every person with a deletion or duplication of GLI3 has cephalooplysyndactyly a different breakpoint and the sizes of the deletions have ranged from one exon to more than 10 Mb [ Johnston et al ].

Rare Disease Database

Therefore, no single testing modality can detect all such deletions and translocations, making it difficult to quote a detection rate for any single testing modality. Giemsa-banded karyotypes do not detect all deletions, even those on the order cephalopolysyndactjly 1 Mb [unpublished observations].

Confirmation of the diagnosis in a proband.

Two salient clinical features should be considered prior to diagnostic testing. The first is the presence of developmental delay or intellectual disability in the proband.

The second is a history of recurrent pregnancy losses in the parents of the proband. Several large families have been reported as having a mild form of GCPS with excellent general health and normal longevity. Cephalopolysyneactyly with large deletions appear to have a higher incidence of intellectual disability, seizures, and CNS anomalies.


This phenomenon is presumably caused by haploinsufficiency of multiple genes in the vicinity of GLI3. Two individuals with a cephalopoylsyndactyly GCPS phenotype that overlaps with acrocallosal syndrome ceohalopolysyndactyly Figure 1 have been found to have a pathogenic missense variant in GLI3 [ Elson et alSpeksnijder et al ].

Greig Cephalopolysyndactyly Syndrome – GeneReviews┬« – NCBI Bookshelf

GCPS is caused by pathogenic variants of all types, whereas PHS is only caused by truncating variants and one splice variant that generates a frameshift and a truncation. Within the frameshift more A genotype – phenotype correlation has been demonstrated on two levels:. One case of apparent non- penetrance has been reported [ Debeer et al ]. It is difficult to estimate a rate of non-penetrance from a single instance, but it is probably a small fraction.

There is no evidence for genetic anticipation in GCPS. The term “Greig syndrome” describes the dyad of widely spaced eyes and macrocephaly. Because that dyad of anomalies is nonspecific, the term should not be used as a synonym for GCPS [ Gorlin et al ]. GCPS is rare and pan ethnic; the prevalence is unknown. Approximately cases are known to this author.

It is suspected that many individuals with preaxial polydactyly with syndactyly and mild craniofacial features are misdiagnosed as having isolated preaxial polydactyly instead of GCPS see Genetically Related DisordersPPDIV ; however, the distinction may be semantic [ Biesecker ].

Acrocallosal syndrome ACLS OMIM includes pre- or postaxial polydactyly, cutaneous syndactyly, agenesis of the corpus callosum rare in GCPSwidely spaced eyes, macrocephaly, moderate to severe intellectual disability, intracerebral cysts, seizures, and umbilical and inguinal hernias. The disorder appears to be inherited in an autosomal recessive manner [ Koenig et al ] and can be caused by biallelic pathogenic variants in KIF7 [ Putoux et al ].

Some subtypes of oral-facial-digital syndrome have similar limb malformations [ Gorlin et al ]. Craniofrontonasal dysplasia has similar facial features [ Gorlin et al ]. Most individuals diagnosed with Greig cephalopolysyndactyly syndrome GCPS have the craniofacial and limb anomalies only.

As for all individuals with malformations, a dysmorphology examination is appropriate to exclude other anomalies. Sophisticated imaging, especially of the CNS, is not routinely indicated unless the clinician detects findings or symptoms that specifically indicate such an evaluation.

Similarly, as most individuals with GCPS have normal development, screening beyond the standard Denver Developmental Screening test is not recommended. The author is not aware of craniofacial reconstructive surgery being performed on individuals with GCPS as the widely spaced eyes and macrocephaly are generally not sufficiently severe to syndome surgery. Repair of polydactyly should be undertaken on an elective basis. Preaxial polydactyly of the hands is syndome to be a higher priority for surgical correction than postaxial cephalopolysgndactyly of the hand or any type of polydactyly of the foot because of the importance of early and proper development of the dyndrome grasp.

As is true for any malformation of the feet, surgical correction must be carefully considered. Cosmetic benefits and easier fitting of shoes can be outweighed by potential orthopedic complications. The only recognized preventable secondary complication may be developmental delay, which may be preventable or ameliorated by early intervention.

Individuals with an OFC that is increasing faster than normal, cephalopoljsyndactyly of increased intracranial pressure, developmental delay, loss of milestones, or seizures should undergo appropriate CNS imaging studies to exclude hydrocephalus, other CNS abnormalities, or cerebral cavernous malformations seen in some individuals with GCPS and large deletions [ Bilguvar et al ; Author, unpublished observations].

Greig cephalopolysyndactyly syndrome

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. There may not be clinical trials for this disorder.

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional.


Greig cephalopolysyndactyly syndrome either is inherited in an autosomal dominant manner as a pathogenic variant in GLI3 or as a deletion of 7p13 involving GLI3 or occurs as the result of a de novo or inherited chromosome rearrangement.

Offspring of a proband. Since intrafamilial variability is generally low, affected offspring are expected to have clinical findings similar to those of the parent.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband’s parents: Greig cephalopolysyndactyly syndrome can be the result of an inherited or de novo chromosome rearrangement.

Parents of a proband. Parents of a proband with an unbalanced structural chromosome constitution e. Offspring of an individual with a balanced or unbalanced chromosome rearrangement are at risk of having a similar or related rearrangement. If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis. A significant range of severity is associated with the GCPS designation; interfamilial variability is greater than intrafamilial variability: This rule excludes founders who may theoretically be mildly affected because they have somatic mosaicism for a GLI3 pathogenic variant.

If a founder has germ cells with the pathogenic variant, his or her offspring may be affected; the affected offspring would be non-mosaic and thus could have a more severe phenotype than the parent.

The prognosis for an individual who has no known family history of GCPS should be based on the malformations present in that individual. Literature surveys are not useful for this purpose because reported cases tend to show bias of ascertainment to more severe involvement. For individuals with a family history of affected family members, the prognosis is based on the degree of severity present in the family, as intrafamilial variability appears to be low.

Considerations in families with an apparent de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity e. DNA banking is the storage of DNA typically extracted from white blood cells for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

In pregnancies of a parent with a cytogenetically visible deletion of 7p13 or a balanced chromosome rearrangement, prenatal testing is possible by chromosome analysis of fetal cells obtained by chorionic villus sampling CVS at approximately ten to 12 weeks’ gestation or by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation.

Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. If the GLI3 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

However, a normal ultrasound examination does not eliminate the possibility of GCPS in the fetus. Preimplantation genetic diagnosis PGD may be an option for some families in which the GLI3 pathogenic variant has been identified.

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Data are compiled from the following standard references: Alterations that cause Greig cephalopolysyndactyly syndrome GCPS range from gross cytogenetic alterations to nucleic acid substitutions. GLI3 is large, with exons spanning at least kb of genomic DNA on the minus strand of chromosome 7, from 41, to 42, bp and comprising at least 15 exons in the current human genome build genome. The current reference sequence for the cDNA is an 8,nt sequence: