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Greig Cephalopolysyndactyly Syndrome

Synonym: Cephalopolysyndactyly Syndrome
, MD
Medical Genomics and Metabolic Genetics Branch
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: June 19, 2014.

Summary

Clinical characteristics.

Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- 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 of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.

Diagnosis/testing.

The diagnosis of GCPS is based on clinical findings and family history. GLI3 is the only gene known to be associated with GCPS; GLI3 alterations (i.e., cytogenetic abnormalities involving GLI3 or pathogenic variants of GLI3) can be identified in more than 75% of typically affected individuals.

Management.

Treatment of manifestations: Elective surgical repair of polydactyly with greatest priority given to correction of preaxial polydactyly of the hands; evaluation and treatment as needed for hydrocephalus or other CNS abnormalities in individuals showing signs of increased intracranial pressure, developmental delay, loss of milestones, and/or seizures.

Surveillance: Monitoring for evidence of occipitofrontal circumference (OFC) increasing faster than normal.

Genetic counseling.

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 proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with a GLI3 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the underlying genetic cause in the family (i.e., deletion of 7p13, balanced chromosome rearrangement, or GLI3 pathogenic variant) has been identified. The reliability of ultrasound examination for prenatal diagnosis is unknown.

Diagnosis

Major findings of Greig cephalopolysyndactyly syndrome (GCPS) are the following.

Macrocephaly. Occipitofrontal (head) circumference (OFC) is greater than 97th centile compared to appropriate age- and sex-matched normal standards [Allanson et al 2009]. Note: An enlarged OFC must be interpreted with caution in families in which a parent (or parents) of the proband has benign familial macrocephaly (OMIM).

Some individuals with GCPS have a high anterior hairline, and a prominent (or bossed) forehead.

Widely spaced eyes. Interpupillary distance is more than 2 SD above the mean (newborns 27-41 weeks’ gestational age or interpupillary distance above the 97th centile (age 0-15 years) or a subjectively increased interpupillary distance [Hall et al 2009]. Increased inner canthal distance (i.e., telecanthus, or apparent widely spaced eyes) may be present as well but is not as distinctive a finding as increased interpupillary distance. Increased interpupillary distance is often associated with a wide nasal bridge.

Limb anomalies

  • Preaxial polydactyly. At least one limb should manifest one of the following [Biesecker et al 2009]:
    • Preaxial polydactyly (duplication of all or part of the first ray)
    • A markedly broad hallux (visible increase in width of the hallux without an increase in the dorso-ventral dimension)
    • A markedly broad thumb (increased thumb width without increased dorso-ventral dimension)
  • Other limbs may manifest preaxial or postaxial polydactyly and some limbs may have five normal digits. The postaxial polydactyly may be type A, type B, or intermediate forms.
    • Postaxial polydactyly type A (PAP-A) is the presence of a well-formed digit on the ulnar or fibular aspect of the limb.
    • Postaxial polydactyly type B (PAP-B) is the presence of a rudimentary digit or nubbin in the same location. The finding of postaxial polydactyly type B must be evaluated critically when present in an individual of west-central African descent as that feature is a common variant (1% prevalence).
  • Some individuals have widening of the first digit apparent only on x-ray. This is difficult to assess when diagnosing a proband.
  • Cutaneous syndactyly. The cutaneous syndactyly may be partial or complete; in occasional severe cases, parts of the distal phalanges may be fused.

Establishing the Diagnosis

A presumptive diagnosis* is established in a proband with preaxial polydactyly, cutaneous syndactyly of toes 1-3 or fingers 3-4, widely spaced eyes, and macrocephaly.

Note: The diagnosis should be made with caution in infants with multiple other malformations, especially in the absence of a positive family history.

A firm diagnosis* is established in:

  • A first-degree relative of a proband for whom the diagnosis has been independently established. The first-degree relative of a proband may be diagnosed as affected if he/she has pre- or postaxial polydactyly with or without syndactyly or the craniofacial features.
    Note: Postaxial polydactyly type B should not be used as a diagnostic criterion for first-degree relatives of persons who are of west-central African descent.
  • A proband who has features of GCPS and a pathogenic variant in GLI3.

*The distinction of presumptive and firm diagnoses is based on data of Johnston et al [2005], who suggested that the clinical criteria were useful but may not be sufficiently specific to warrant a "firm" diagnosis on clinical grounds alone. A small but significant fraction of individuals with features of GCPS do not have a pathogenic variant in GLI3. 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.

Testing

Gene. GLI3 is the only gene in which pathogenic variants are known to be associated with Greig cephalopolysyndactyly syndrome.

Table 1.

Summary of Molecular Genetic Testing Used in Greig Cephalopolysyndactyly Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
GLI3Sequence analysis 270% 3
Deletion/duplication analysis 4, 5, 65%-10% 7
Loss of heterozygosity analysis 8~50%-75%
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.
4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

To date, every person with a deletion or duplication of GLI3 has had a different breakpoint and the sizes of the deletions have ranged from one exon to more than 10 Mb [Johnston et al 2007]. Because GLI3 is about 300 kb in size, large deletions may not necessarily alter the signal of any given GLI3 FISH, array CGH, or MLPA probe. 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.

6.

Giemsa-banded karyotypes do not detect all deletions, even those on the order of 1 Mb [unpublished observations].

7.
8.

Detects GLI3 deletions

Testing Strategy

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.

  • For individuals with clinical features consistent with GCPS, and without significant developmental delay or intellectual disability or pregnancy losses in the parents, sequence analysis of GLI3 should be considered first, followed by CGH analysis if no GLI3 pathogenic variant is identified, followed by Giemsa-banded karyotyping if no GLI3 pathogenic variant has been identified by the other two methods.
  • If the patient has significant developmental delay or intellectual disability, CGH analysis should be done first, followed by sequence analysis of GLI3, and then Giemsa-banded karyotyping if no GLI3 pathogenic variant has been identified by the other two methods.
  • If there is a family history of parental pregnancy losses, a Giemsa-banded karyotype should be considered first, followed by sequence analysis of GLI3 and then CGH.

Clinical Characteristics

Clinical Description

Several large families have been reported as having a mild form of GCPS with excellent general health and normal longevity.

Developmental delay, intellectual disability, or seizures appear to be uncommon manifestations (estimated at <10%) of GCPS. These complications are more likely if the child has CNS malformations (rare) or hydrocephalus (uncommon), and they may be more common in individuals with large (>300 kb) deletions that encompass GLI3 [Johnston et al 2007].

Genotype-Phenotype Correlations

Individuals who have GCPS associated with a large (>300 kbp) deletion have a more severe phenotype than those with chromosome translocations or single nucleotide variants in GLI3 [Kroisel et al 2001, Johnston et al 2007]. Individuals 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 severe GCPS phenotype that overlaps with acrocallosal syndrome (see Figure 1) have been found to have a pathogenic missense variant in GLI3 [Elson et al 2002, Speksnijder et al 2013].

Figure 1. A.

Figure 1

A. The mutational spectra of GCPS and PHS are distinct. 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. B. Within the frameshift (more...)

A genotype-phenotype correlation has been demonstrated on two levels:

  • Class of variant. Pathogenic variants of all classes can cause GCPS whereas the only class of pathogenic variants that causes the allelic disorder Pallister-Hall syndrome is frameshifting variants. Haploinsufficiency for GLI3 causes GCPS, whereas truncating variants 3' of the zinc finger domain of GLI3 generally cause PHS [Kang et al 1997] (Figure 1A).
  • Variant position. Among all frameshift variants in GLI3, variants in the first third of the gene are only known to cause GCPS (Figure 1B). Frameshifting variants in the middle third of the gene cause Pallister-Hall syndrome and uncommonly cause GCPS. Frameshift variants in the final third of the gene cause GCPS. There is no apparent correlation of the variant position within each of the three regions and the severity of the respective phenotypes.

Penetrance

One case of apparent non-penetrance has been reported [Debeer et al 2003]. It is difficult to estimate a rate of non-penetrance from a single instance, but it is probably a small fraction.

Anticipation

There is no evidence for genetic anticipation in GCPS.

Nomenclature

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 2001].

Prevalence

GCPS is rare and pan ethnic; the prevalence is unknown. Approximately 100 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 Disorders, PPDIV); however, the distinction may be semantic [Biesecker 2008].

Differential Diagnosis

Acrocallosal syndrome (ACLS) (OMIM) includes pre- or postaxial polydactyly, cutaneous syndactyly, agenesis of the corpus callosum (rare in GCPS), widely 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 2002] and can be caused by biallelic pathogenic variants in KIF7 [Putoux et al 2011]. The milder end of the ACLS phenotype can overlap with the severe end of the GCPS phenotype caused by interstitial deletions of 7p13 that delete GLI3 and additional neighboring genes, as discussed in Genotype-Phenotype Correlations.

Some subtypes of oral-facial-digital syndrome have similar limb malformations [Gorlin et al 2001]. (See, for example, Oral-Facial-Digital Syndrome Type 1.)

Craniofrontonasal dysplasia has similar facial features [Gorlin et al 2001].

Management

Evaluations Following Initial Diagnosis

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.

Treatment of Manifestations *

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 warrant surgery.

Repair of polydactyly should be undertaken on an elective basis. Preaxial polydactyly of the hands is considered to be a higher priority for surgical correction than postaxial polydactyly of the hand or any type of polydactyly of the foot because of the importance of early and proper development of the prehensile grasp.

Cutaneous syndactyly of the fingers is usually repaired if it is more than minimal.

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.

Seizures are treated symptomatically.

*As with the diagnostic criteria (see Diagnosis), no published data support these recommendations, which are those of the author.

Prevention of Secondary Complications

The only recognized preventable secondary complication may be developmental delay, which may be preventable or ameliorated by early intervention.

Surveillance *

Individuals with an OFC that is increasing faster than normal, signs 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 2007; Author, unpublished observations]).

*As with the diagnostic criteria (see Diagnosis), no published data support these recommendations, which are those of the author.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

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. —ED.

Mode of Inheritance

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.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Some individuals diagnosed with GCPS have an affected parent and some have the disorder as the result of a de novo GLI3 pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown, as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient.
  • Recommendations for the evaluation of parents of a child with GCPS and no known family history of GCPS consist of clinical examination and x-rays of hands and feet unless physical signs suggest the need for other studies (e.g., neuroimaging for possible hydrocephalus in a parent). Molecular genetic testing of the parents is indicated if the GLI3 pathogenic variant in the proband has been identified.

Note: (1) Although some individuals diagnosed with GCPS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members. (2) If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the proband's parents:
    • If a parent of the proband is affected, the risk to the sibs is 50%.
    • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with GCPS has a 50% chance of inheriting the GLI3 pathogenic variant. 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: if a parent is affected, his or her family members are at risk.

Risk to Family Members — Chromosome Rearrangement

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.g., deletion, duplication) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis.

Sibs of a proband

  • The risk to sibs of a proband with an unbalanced structural chromosome constitution depends on the chromosome findings in the parents.
  • If neither parent has a structural chromosome rearrangement, the risk to sibs is negligible.
  • If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.

Offspring of a proband. Offspring of an individual with a balanced or unbalanced chromosome rearrangement are at risk of having a similar or related rearrangement.

Carrier Detection

If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis.

Related Genetic Counseling Issues

Range of severity. A significant range of severity is associated with the GCPS designation; interfamilial variability is greater than intrafamilial variability: it is unlikely that a family with a mild GCPS phenotype will have a child affected with severe GCPS. 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. When neither parent of a proband with GCPS has clinical evidence of the disorder, the GLI3 pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

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.

Prenatal Testing

Cytogenetic testing. 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.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Molecular genetic testing. 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.

Ultrasound examination. In pregnancies at 50% risk, prenatal ultrasound examination may detect polydactyly, macrocephaly, or other CNS abnormalities such as hydrocephalus. 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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
    Email: faces@faces-cranio.org
  • National Foundation for Facial Recontruction (NFFR)
    317 East 34th Street
    Room 901
    New York NY 10016
    Phone: 212-263-6656
    Fax: 212-263-7534
    Email: info@nffr.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Greig Cephalopolysyndactyly Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
GLI37p14​.1Transcriptional activator GLI3GLI3 @ LOVDGLI3

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Greig Cephalopolysyndactyly Syndrome (View All in OMIM)

165240GLI-KRUPPEL FAMILY MEMBER 3; GLI3
175700GREIG CEPHALOPOLYSYNDACTYLY SYNDROME; GCPS

Molecular Genetic Pathogenesis

Alterations that cause Greig cephalopolysyndactyly syndrome (GCPS) range from gross cytogenetic alterations to nucleic acid substitutions.

Gene structure. GLI3 is large, with exons spanning at least 296 kb of genomic DNA on the minus strand of chromosome 7, from 41,967,073 to 42,243,321 bp and comprising at least 15 exons in the current human genome build (genome.ucsc.edu; March 2006 build). The current reference sequence for the cDNA is an 8,228-nt sequence: NM_000168.5. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. A number of putative benign variants exist in GLI3 (see Table 2 [pdf]). Most of the variants have been seen in multiple unrelated persons and are not believed to be associated with any phenotypic effects, although they have not been rigorously analyzed for subtle effects. They are included in Table 2 if they lie within an exon or if they are in an intron within 25 bp of an exon. Readers should refer to dbSNP to confirm these data and for additional data (SNPs are from Human Genome build 126).

Pathogenic allelic variants. A large variety of published pathogenic variants has been reported including cytogenetically visible translocations, interstitial deletions of 7p13, small insertions or deletions that cause frameshifts and premature truncation, nonsense variants, variants that alter a splice site, and missense variants that change an amino acid [Wild et al 1997, Kalff-Suske et al 1999, Elson et al 2002, Debeer et al 2003, Johnston et al 2005]. (For more information, see Table A.)

Selected pathogenic variants reported in individuals with GCPS are listed in Table 3 (pdf). Multiple new pathogenic variants have been identified by Johnston et al [2005]. See Table 4.

Table 4.

Selected GLI3 Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.540_547delp.Asn181CysfsTer15
(A181_T183delinsCfsTer15)
NM_000168​.5
NP_000159​.3
c.658delCp.Arg220ValfsTer3
c.679+2_679+15del14del14--
c.827-3C>G--
c.868C>Tp.Arg290Ter
c.1048dupT
(1048_1049insT)
p.Tyr350LeufsTer62
c.1074delCp.His358GlnfsTer7
c.1497+1G>C--
c.1617_1633delp.Arg539SerfsTer7
(R539_P545delinsSfsTer7)
c.1789C>Tp.Gln597Ter
c.1880_1881delATp.His627ArgfsTer48
c.2374C>Tp.Arg792Ter
c.4119_4123delinsAGCCTGA
(4119_4123delins7)
p.Pro1374AlafsTer2
(P1374_S1375delinsAfsTer2)
c.4403dupT
(4402_4403insT)
p.Leu1469AlafsTer10
c.4427delAp.Asn1476ThrfsTer12
(S1477LfsTer11)
c.4564delGp.Ala1522ProfsTer2
c.4677dupC
(4677_4678insC)
p.Gly1560ArgfsTer38
c.1446C>Gp.Cys482Trp
c.1874G>Ap.Arg625Gln
c.1873C>Tp.Arg625Trp

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. The gene encodes a protein of 1,580 amino acids.

Note: As the result of a cDNA sequencing error, older citations described a longer open reading frame that predicted a protein of 1,596 amino acids; the error was corrected in the GenBank entry NM_000168.3 and in subsequent versions of this sequence.

GLI3 encodes a zinc finger transcription factor that is downstream of Sonic Hedgehog in SHH pathway (SHH-PTCH1-SMO-GLI1, GLI2, GLI3) [Villavicencio et al 2000]. The various GLI proteins in turn regulate genes further downstream in this pathway, including HNF3β, bone morphogenetic proteins, and other as-yet-unknown targets. The human gene is similar to the mouse paralog Gli3 and the vertebrate GLI gene family is homologous to the Drosophila melanogaster gene cubitus interruptus (ci).

Abnormal gene product. The most common, if not sole, pathogenetic mechanism for GCPS is haploinsufficiency. Deletions that remove the entire gene cause a GCPS phenotype that is not known to be different from that caused by single nucleotide variants. In addition, mouse models support the hypothesis that haploinsufficiency is the mechanism. Although it is clear that haploinsufficiency of GLI3 can cause GCPS, the pathogenic mechanism of 3' frameshift or nonsense variants and missense variants is not clear.

It is important to note that mRNA or protein instability may be caused by some of these pathogenic variants in individuals with GCPS, a finding that would be entirely compatible with the general mechanism of haploinsufficiency.

References

Literature Cited

  1. 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]
  2. Biesecker LG. The Greig cephalopolysyndactyly syndrome. Orphanet J Rare Dis. 2008;3:10. [PMC free article: PMC2397380] [PubMed: 18435847]
  3. 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]
  4. 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]
  5. Debeer P, Peeters H, Driess S, De Smet L, Freese K, Matthijs G, Bornholdt D, Devriendt K, Grzeschik KH, Fryns JP, Kalff-Suske M. 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 A. 2003;120A:49–58. [PubMed: 12794692]
  6. 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]
  7. Everman DB. Hands and feet. In: Stevenson RE, Hall JG, eds. Human Malformations and Related Anomalies. 2 ed. New York: Oxford University Press; 2006:935-96.
  8. Gorlin RJ, Cohen MM Jr, Hennekam RCM. Greig cephalopolysyndactyly syndrome. In: Syndromes of the Head and Neck. New York: Oxford University Press; 2001:995-6.
  9. Hall BD, Graham JM Jr, Cassidy SB, Opitz JM. Elements of morphology: standard terminology for the periorbital region. Am J Med Genet A. 2009;149A:29–39. [PubMed: 19125427]
  10. Johnston JJ, Walker RL, Davis S, Facio F, Turner JT, Bick DP, Daentl DL, Ellison JW, Meltzer PS, Biesecker LG. Zoom-in comparative genomic hybridisation arrays for the characterisation of variable breakpoint contiguous gene syndromes. J Med Genet. 2007;44:e59. [PMC free article: PMC2597909] [PubMed: 17098889]
  11. Johnston JJ, Olivos-Glander I, Killoran C, Elson E, Turner JT, Peters KF, Abbott MH, Aughton DJ, Aylsworth AS, Bamshad MJ, Booth C, Curry CJ, David A, Dinulos MB, Flannery DB, Fox MA, Graham JM, Grange DK, Guttmacher AE, Hannibal MC, Henn W, Hennekam RC, Holmes LB, Hoyme HE, Leppig KA, Lin AE, Macleod P, Manchester DK, Marcelis C, Mazzanti L, McCann E, McDonald MT, Mendelsohn NJ, Moeschler JB, Moghaddam B, Neri G, Newbury-Ecob R, Pagon RA, Phillips JA, Sadler LS, Stoler JM, Tilstra D, Walsh Vockley CM, Zackai EH, Zadeh TM, Brueton L, Black GC, Biesecker LG. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet. 2005;76:609–22. [PMC free article: PMC1199298] [PubMed: 15739154]
  12. Johnston JJ, Olivos-Glander I, Turner J, Aleck K, Bird LM, Mehta L, Schimke RN, Heilstedt H, Spence JE, Blancato J, Biesecker LG. Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome. Am J Med Genet A. 2003;123A:236–42. [PubMed: 14608643]
  13. Kalff-Suske M, Wild A, Topp J, Wessling M, Jacobsen EM, Bornholdt D, Engel H, Heuer H, Aalfs CM, Ausems MG, Barone R, Herzog A, Heutink P, Homfray T, Gillessen-Kaesbach G, König R, Kunze J, Meinecke P, Müller D, Rizzo R, Strenge S, Superti-Furga A, Grzeschik KH. Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. Hum Mol Genet. 1999;8:1769–77. [PubMed: 10441342]
  14. Kang S, Graham JM Jr, Olney AH, Biesecker LG. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet. 1997;15:266–8. [PubMed: 9054938]
  15. 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]
  16. 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]
  17. Putoux A, Thomas S, Coene KL, Davis EE, Alanay Y, Ogur G, Uz E, Buzas D, Gomes C, Patrier S, Bennett CL, Elkhartoufi N, Frison MH, Rigonnot L, Joyé N, Pruvost S, Utine GE, Boduroglu K, Nitschke P, Fertitta L, Thauvin-Robinet C, Munnich A, Cormier-Daire V, Hennekam R, Colin E, Akarsu NA, Bole-Feysot C, Cagnard N, Schmitt A, Goudin N, Lyonnet S, Encha-Razavi F, Siffroi JP, Winey M, Katsanis N, Gonzales M, Vekemans M, Beales PL, Attié-Bitach T. KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nat Genet. 2011 Jun;43(6):601–6. [PMC free article: PMC3674836] [PubMed: 21552264]
  18. Speksnijder L, Cohen-Overbeek TE, Knapen MF, Lunshof SM, Hoogeboom AJ, van den Ouwenland AM, de Coo IF, Lequin MH, Bolz HJ, Bergmann C, Biesecker LG, Willems PJ, Wessels MW. A de novo GLI3 mutation in a patient with acrocallosal syndrome. Am J Med Genet A. 2013;161A:1394–400. [PubMed: 23633388]
  19. 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]
  20. 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]

Chapter Notes

Author Notes

Author's web page

Revision History

  • 19 June 2014 (me) Comprehensive update posted live
  • 30 April 2009 (me) Comprehensive update posted live
  • 14 August 2006 (lgb) Revision: deletion/duplication analysis and prenatal diagnosis clinically available
  • 7 February 2006 (lgb) Revision: sequence analysis of GLI3 clinically available
  • 20 September 2005 (me) Comprehensive update posted to live Web site
  • 7 October 2004 (cd) Revision: FISH-metaphase clinically available
  • 25 August 2003 (me) Comprehensive update posted to live Web site
  • 9 July 2001 (me) Review posted to live Web site
  • 20 February 2001 (lgb) Original submission

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Bookshelf ID: NBK1446PMID: 20301619

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