Clinical characteristics.

Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by macrocephaly, widely spaced eyes associated with increased interpupillary distance, preaxial polydactyly with or without postaxial polydactyly, and cutaneous syndactyly. Developmental delay, intellectual disability, or seizures appear to be uncommon manifestations (~<10%) of GCPS and may be more common in individuals with large (>300-kb) deletions that encompass GLI3. Approximately 20% of individuals with GCPS have hypoplasia or agenesis of the corpus callosum.

Diagnosis/testing.

The diagnosis of GCPS is established in a proband who has typical clinical findings and either a heterozygous pathogenic variant of GLI3 or a deletion of chromosome 7p14.1 involving GLI3.

Management.

Treatment of manifestations: Elective surgical repair of polydactyly with greatest priority given to correction of preaxial polydactyly of the hands; for polydactyly of the feet, the cosmetic benefits and easier fitting of shoes can be outweighed by potential orthopedic complications. Syndactyly which is more than minimal is typically repaired surgically.

Surveillance: Monitoring for evidence of increased rate of head growth or neurologic concerns and the need of brain MRI.

Genetic counseling.

GCPS is inherited in an autosomal dominant manner and is caused by either a pathogenic variant involving GLI3 or a deletion of chromosome 7p14.1 involving GLI3. The proportion of individuals with GCPS caused by de novo genetic alteration is unknown. If the causative genetic alteration in the proband is a deletion of chromosome 7p14.1, the parents of the proband are at risk of having a balanced chromosome rearrangement; if a parent has a balanced structural chromosome rearrangement, the risk to sibs of a proband depends on the specific chromosome rearrangement and the possibility of other variables. Each child of an individual with GCPS has a 50% chance of inheriting the GCPS-causing genetic alteration. Prenatal testing for pregnancies at increased risk is possible if the GCPS-causing genetic alteration has been identified in an affected family member or a parent is known to have a balanced structural chromosome rearrangement involving 7p14.1. The reliability of ultrasound examination for prenatal diagnosis is unknown.

Suggestive Findings

Greig cephalopolysyndactyly syndrome (GCPS) should be suspected in individuals with the following features:

• Macrocephaly
• Widely spaced eyes associated with increased interpupillary distance (>97th centile)
• Preaxial polydactyly with or without postaxial polydactyly
• Cutaneous syndactyly

Establishing the Diagnosis

The diagnosis of GCPS is established in a proband who has typical clinical findings and one of the following on molecular genetic testing (see Table 1):

• A heterozygous pathogenic (or likely pathogenic) variant of GLI3 (~80% of affected individuals) [Wild et al 1997, Debeer et al 2007, Johnston et al 2010, Jamsheer et al 2012, Démurger et al 2015]
• A heterozygous deletion of chromosome 7p14.1 involving GLI3 (~20% of affected individuals) [Debeer et al 2007, Johnston et al 2010, Jamsheer et al 2012, Démurger et al 2015]

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous GLI3 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis [CMA], exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings of GCPS described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with polydactyly and/or macrocephaly are more likely to be diagnosed using genomic testing (see Option 2).

Note: If the affected individual has significant developmental delay or intellectual disability or if there is a history of recurrent pregnancy losses for the parents of the proband, CMA should be considered first, followed by sequence analysis of GLI3.

Clinical Description

To date, more than 200 individuals with Greig cephalopolysyndactyly syndrome (GCPS) have been reported with a pathogenic variant in GLI3 [Williams et al 1997, Kalff-Suske et al 1999, Debeer et al 2003, Johnston et al 2005, Debeer et al 2007, Schulz et al 2008, Johnston et al 2010, Hurst et al 2011, Jamsheer et al 2012, Patel et al 2014, Démurger et al 2015, Abdullah et al 2019, Siavrienė et al 2019, Khan et al 2021, Polivka et al 2021, Sczakiel et al 2021, Garcia-Rodriguez et al 2022]. The following description of the phenotypic features associated with GCPS is based on these reports.

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 153470).

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

Widely spaced eyes defined as interpupillary distance >2 SD above the mean (newborns 27-41 weeks' gestational age), interpupillary distance >97th centile (individuals 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 radiograph. This is difficult to assess when diagnosing a proband.
• Cutaneous syndactyly. The cutaneous syndactyly may be partial or complete; in occasional severely affected individuals, parts of the distal phalanges may be fused.

Cognitive/neurologic concerns. Developmental delay, intellectual disability, or seizures appear to be uncommon manifestations (~<10%) of GCPS. These complications are more likely if the child has central nervous system 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].

Hypoplasia/agenesis of the corpus callosum. Approximately 20% of individuals with GCPS have hypoplasia or agenesis of the corpus callosum.

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

Genotype-Phenotype Correlations

Individuals who have GCPS associated with a large (>300 kb) deletion have a more severe phenotype than those with 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 central nervous system anomalies. This phenomenon is presumably caused by haploinsufficiency of multiple genes in the vicinity of GLI3.

Hypoplasia/agenesis of the corpus callosum may be more common in individuals with truncating variants in the 3' end of the gene [Démurger et al 2015] or individuals with large deletions that encompass GLI3 [Johnston et al 2003].

Note: GCPS has an allelic disorder, Pallister-Hall syndrome (PHS). Frameshift variants in GLI3 in the first third of the gene are only known to cause GCPS (see Figure 1B). Frameshift variants in the middle third of the gene cause PHS and uncommonly cause GCPS. A single truncating variant in the middle of the PHS region, c.2374C>T (p.Arg792Ter), can cause GCPS and has been observed in nine apparently unrelated families [Johnston et al 2005, Abdullah et al 2019, Sczakiel et al 2021]. 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 phenotype.

Figure 1

A. The spectra of GCPS-associated and PHS-associated pathogenic variants 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. (more...)

Penetrance

Apparent non-penetrance has been reported [Debeer et al 2003, Démurger et al 2015]. However, it is difficult to estimate the rate of non-penetrance because the genetic status of the parents is often unknown in simplex families (i.e., families in which the proband is the only affected individual).

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; the prevalence is unknown. Approximately 200 affected individuals are known to these authors. 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, PPD-IV); however, the distinction may be semantic [Biesecker 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Greig cephalopolysyndactyly syndrome (GCPS), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

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.

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 in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

Greig cephalopolysyndactyly syndrome (GCPS) is inherited in an autosomal dominant manner and is caused by either a pathogenic variant involving GLI3 or a deletion of chromosome 7p14.1 involving GLI3.

Balanced chromosome rearrangement. If the causative genetic alteration in the proband is a deletion of chromosome 7p14.1 [Schulz et al 2008], the parents of the proband are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis. 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.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with GCPS have the disorder as the result of a genetic alteration inherited from a parent.
• Some individuals diagnosed with GCPS have the disorder as the result of a de novo GCPS-causing genetic alteration. The proportion of individuals with GCPS caused by de novo genetic alteration 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 radiographs 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 GCPS-causing genetic alteration has been identified in the proband.
• If the proband has a known genetic alteration that cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo alteration in the proband or germline mosaicism in a parent.* Parental mosaicism has been reported in rare families [Démurger et al 2015].
  * Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
• The family history of some individuals diagnosed with GCPS may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the pathogenic variant and may be mildly/minimally affected; affected offspring of a parent with mosaicism would be nonmosaic and thus could have a more severe phenotype than the parent.

Sibs of a proband. The risk to the sibs of a proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs is 50%. (See Mode of Inheritance for recurrence risk information when a parent is a carrier of a balanced chromosome rearrangement.) The prognosis in a sib who inherits a familial genetic alteration is based on the degree of severity present in the family, as intrafamilial variability in GCPS appears to be low.
• If the parents of a proband are clinically unaffected but their genetic status is unknown (either because the genetic etiology in the proband is unknown or because the parents have not undergone molecular genetic testing), the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for GCPS because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with GCPS has a 50% chance of inheriting the GCPS-causing genetic alteration.

Other family members. The risk to other family members depends on the clinical/genetic status of the proband's parents: if a parent is affected and/or is known to have a genetic alteration associated with GCPS or an increased risk of GCPS (i.e., a balanced structural chromosome rearrangement), the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Genetic testing. If the GCPS-causing genetic alteration has been identified in an affected family member or a parent is known to have a balanced structural chromosome rearrangement involving 7p14.1, prenatal and preimplantation genetic testing are possible.

Ultrasound examination. In pregnancies at 50% risk, prenatal ultrasound examination may detect polydactyly, macrocephaly, or other central nervous system abnormalities such as hydrocephalus. However, a normal ultrasound examination does not eliminate the possibility of GCPS in the fetus.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

GLI3 encodes a zinc finger transcription factor that is downstream of sonic hedgehog in the 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).

Mechanism of disease causation. The most common, if not sole, pathogenic mechanism for Greig cephalopolysyndactyly syndrome (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 nonsense or frameshift 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.

GLI3-specific laboratory technical considerations. As large deletions make up a considerable percentage of variants in GCPS, deletion/duplication analysis should be incorporated into any testing strategy.

Author Notes

Leslie G Biesecker's web page

Author History

Leslie H Biesecker, MD (2001-present)
Jennifer J Johnston, PhD (2020-present)

Revision History

• 15 February 2024 (jj) Revision: information regarding GLI3 pathogenic variant p.Arg792Ter added to Genotype-Phenotype Correlations and Molecular Genetics; added references (Siavrienė et al [2019], Khan et al [2021], Polivka et al [2021], Sczakiel et al [2021], Garcia-Rodriguez et al [2022])
• 7 May 2020 (ha) Comprehensive update posted live
• 19 June 2014 (me) Comprehensive update posted live
• 30 April 2009 (me) Comprehensive update posted live
• 20 September 2005 (me) Comprehensive update posted live
• 25 August 2003 (me) Comprehensive update posted live
• 9 July 2001 (me) Review posted live
• 20 February 2001 (lgb) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Greig Cephalopolysyndactyly Syndrome" is in the public domain in the United States of America.

Literature Cited

• Abdullah, Yousaf M, Azeem Z, Bilal M, Liaqat K, Hussain S, Ahmad F, Ghous T, Ullah A, Ahmad W. Variants in GLI3 cause Greig cephalopolysyndactyly syndrome. Genet Test Mol Biomarkers. 2019;23:744–50. [PubMed: 31573334]
• 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. The Greig cephalopolysyndactyly syndrome. Orphanet J Rare Dis. 2008;3:10. [PMC free article: PMC2397380] [PubMed: 18435847]
• 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]
• 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]
• Debeer P, Devriendt K, De Smet L, Deravel T, Gonzalez-Meneses A, Grzeschik KH, Fryns JP. The spectrum of hand and foot malformations in patients with Greig cephalopolysyndactyly. J Child Orthop. 2007;1:143–50. [PMC free article: PMC2656707] [PubMed: 19308487]
• Démurger F, Ichkou A, Mougou-Zerelli S, Le Merrer M, Goudefroye G, Delezoide AL, Quelin C, Manouvrier S, Baujat G, Fradin M, Pasquier L, Megarbane A, Faivre L, Baumann C, Nampoothiri S, Roume J, Isidor B, Lacombe D, Delrue MA, Mercier S, Philip N, Schaefer E, Holder M, Krause A, Laffargue F, Sinico M, Amram D, Andre G, Liquier A, Rossi M, Amiel J, Giuliano F, Boute O, Dieux-Coeslier A, Jacquemont ML, Afenjar A, Van Maldergem L, Lackmy-Port-Lis M, Vincent-Delorme C, Chauvet ML, Cormier-Daire V, Devisme L, Genevieve D, Munnich A, Viot G, Raoul O, Romana S, Gonzales M, Encha-Razavi F, Odent S, Vekemans M, Attie-Bitach T. New insights into genotype-phenotype correlation for GLI3 mutations. Eur J Hum Genet. 2015;23:92–102. [PMC free article: PMC4266745] [PubMed: 24736735]
• 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]
• 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.
• 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;35:2162-5. [PubMed: 32495660]
• Gorlin RJ, Cohen MM Jr, Hennekam RCM. Greig cephalopolysyndactyly syndrome. In: Gorlin RJ, Cohen MM Jr, Hennekam RCM, eds. Syndromes of the Head and Neck. New York: Oxford University Press; 2001:995-6.
• 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]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Hurst JA, Jenkins D, Vasudevan PC, Kirchhoff M, Skovby F, Rieubland C, Gallati S, Rittinger O, Kroisel PM, Johnson D, Biesecker LG, Wilkie AO. Metopic and sagittal synostosis in Greig cephalopolysyndactyly syndrome: five cases with intragenic mutations or complete deletions of GLI3. Eur J Hum Genet. 2011;19:757–62. [PMC free article: PMC3128494] [PubMed: 21326280]
• Jamsheer A, Sowinska A, Trzeciak T, Jamsheer-Bratkowska M, Geppert A, Latos-Bielenska A. Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations. J Appl Genet. 2012;53:415–22. [PMC free article: PMC3477483] [PubMed: 22903559]
• Johnston JJ, Sapp JC, Turner JT, Amor D, Aftimos S, Aleck KA, Bocian M, Bodurtha JN, Cox GF, Curry CJ, Day R, Donnai D, Field M, Fujiwara I, Gabbett M, Gal M, Graham JM, Hedera P, Hennekam RC, Hersh JH, Hopkin RJ, Kayserili H, Kidd AM, Kimonis V, Lin AE, Lynch SA, Maisenbacher M, Mansour S, McGaughran J, Mehta L, Murphy H, Raygada M, Robin NH, Rope AF, Rosenbaum KN, Schaefer GB, Shealy A, Smith W, Soller M, Sommer A, Stalker HJ, Steiner B, Stephan MJ, Tilstra D, Tomkins S, Trapane P, Tsai AC, Van Allen MI, Vasudevan PC, Zabel B, Zunich J, Black GC, Biesecker LG. Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations. Hum Mutat. 2010;31:1142–54. [PMC free article: PMC2947617] [PubMed: 20672375]
• 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]
• 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]
• 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]
• 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]
• Khan H, Abdullah, Ahmed S, Nawaz S, Ahmad W, Rafiq MA. Greig Cephalopolysyndactyly syndrome: phenotypic variability associated with variants in two different domains of GLI3. Klin Padiatr. 2021;233:53-8. [PubMed: 33339065]
• 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]
• Krüger G, Gotz J, Kvist U, Dunker H, Erfurth F, Pelz L, Zech L. Greig syndrome in a large kindred due to reciprocal chromosome translocation t(6;7)(q27;p13). Am J Med Genet. 1989;32:411–6. [PubMed: 2729360]
• Patel R, Tripathi FM, Singh SK, Rani A, Bhattacharya V, Ali A. A novel GLI3c.750delC truncation mutation in a multiplex Greig cephalopolysyndactyly syndrome family with an unusual phenotypic combination in a patient. Meta Gene. 2014;2:880–7. [PMC free article: PMC4297881] [PubMed: 25606469]
• Polivka L, Parietti V, Bruneau J, Soucie E, Madrange M, Bayard E, Rignault R, Canioni D, Fraitag S, Lhermitte L, Feroul M, Tissandier M, Rossignol J, Frenzel L, Cagnard N, Meni C, Bouktit H, Collange AF, Gougoula C, Parisot M, Bader-Meunier B, Livideanu C, Laurent C, Arock M, Hadj-Rabia S, Rüther U, Dubreuil P, Bodemer C, Hermine O, Maouche-Chrétien L. The association of Greig syndrome and mastocytosis reveals the involvement of the hedgehog pathway in advanced mastocytosis. Blood. 2021;138:2396-407. [PubMed: 34424959]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Siavrienė E, Mikštienė V, Radzevičius D, Maldžienė Ž, Rančelis T, Petraitytė G, Tamulytė G, Kavaliauskienė I, Šarkinas L, Utkus A, Kučinskas V, Preikšaitienė E. Novel GLI3 variant causes Greig cephalopolysyndactyly syndrome in three generations of a Lithuanian family. Mol Genet Genomic Med. 2019;7:e878. [PMC free article: PMC6732282] [PubMed: 31325247]
• Schulz S, Volleth M, Muschke P, Wieland I, Wieacker P. Greig cephalopolysyndactyly (GCPS) contiguous gene syndrome in a boy with a 14 Mb deletion in region 7p13-14 caused by a paternal balanced insertion (5; 7). Appl Clin Genet. 2008;1:19–22. [PMC free article: PMC3681123] [PubMed: 23776344]
• Sczakiel HL, Hülsemann W, Holtgrewe M, Abad-Perez AT, Elsner J, Schwartzmann S, Horn D, Spielmann M, Mundlos S, Mensah MA. GLI3 variants causing isolated polysyndactyly are not restricted to the protein’s C-terminal third. Clin Genet. 2021;100:758-65. [PubMed: 34482537]
• 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]
• Tommerup N, Nielsen F. A familial reciprocal translocation t(3;7) (p21.1;p13) associated with the Greig polysyndactyly-craniofacial anomalies syndrome. Am J Med Genet. 1983;16:313–21. [PubMed: 6316787]
• 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]
• 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]
• Williams PG, Hersh JH, Yen FF, Barch MJ, Kleinert HE, Kunz J, Kalff-Suske M. Greig cephalopolysyndactyly syndrome: altered phenotype of a microdeletion syndrome due to the presence of a cytogenetic abnormality. Clin Genet. 1997;52:436–41. [PubMed: 9520255]