Greig Cephalopolysyndactyly Syndrome
Summary
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.
Diagnosis
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 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]
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.
Option 1
When the phenotypic findings suggest the diagnosis of GCPS, molecular genetic testing approaches can include single-gene testing, or use of a multigene panel:
- Single-gene testing. Sequence analysis of GLI3 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.Note: A small number of individuals with translocations involving 7p14.1 have been reported [Tommerup & Nielsen 1983, Krüger et al 1989, Debeer et al 2003]. Karyotype may be considered when single gene testing is negative.
- A multigene panel that includes GLI3 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by polydactyly and/or macrocephaly, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in GCPS
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| GLI3 | Sequence analysis 3 | ~80% 4 |
| Gene-targeted deletion/duplication analysis 5 | ~20% 4 | |
| Karyotype 6 | Rare 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.
- 4.
Johnston et al [2005], Debeer et al [2007], Johnston et al [2010], Démurger et al [2015]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Johnston et al [2010] and Démurger et al [2015]) may not be detected by these methods.
- 6.
A small number of individuals with translocations involving 7p14.1 have been reported [Tommerup & Nielsen 1983, Krüger et al 1989, Debeer et al 2003].
Clinical Characteristics
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]. The following description of the phenotypic features associated with GCPS is based on these reports.
Table 2.
Select Features of GCPS
| Feature | % of Persons with Feature | Comment |
|---|---|---|
| Macrocephaly | 50% | |
| Widely spaced eyes | 50% | |
| Preaxial polydactyly | 90% | More common in the feet |
| Markedly broad hallux | 25% | |
| Markedly broad thumb | 30% | |
| Postaxial polydactyly | 50% | More common in the hands |
| Cutaneous syndactyly | 75% |
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 x-ray. 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. Frameshift variants in GLI3 in the first third of the gene are only known to cause GCPS (Figure 1B). Frameshift 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.
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 and pan ethnic; 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].
Differential Diagnosis
Table 4.
Genes of Interest in the Differential Diagnosis of GCPS
| Gene(s) | Disorder | MOI | Clinical Features | Comment |
|---|---|---|---|---|
| EFNB1 | Craniofrontonasal dysplasia (OMIM 304110) | XL 1 |
| Craniofrontonasal dysplasia facial features in females are similar to those of GCPS. 2 |
| KIF7 | Acrocallosal syndrome (ACLS; OMIM 200990) | AR | Pre- or postaxial polydactyly, cutaneous syndactyly, agenesis of the corpus callosum (rare in GCPS), widely spaced eyes, macrocephaly, moderate-to-severe ID, intracerebral cysts, seizures, & umbilical & inguinal hernias | The milder end of the ACLS phenotype may overlap w/the severe end of the GCPS phenotype (see Genotype-Phenotype Correlations). |
| OFD1 3 | Oral-facial-digital syndrome 1 (OFD1; OMIM 311200) | XL | Preaxial polydactyly, widely spaced eyes, syndactyly, agenesis of the corpus callosum (rare in GCPS), cerebellar agenesis, intracerebral cysts, cleft palate, cleft lip, oral frenula, polycystic kidney disease | The milder end of the OFD1 phenotype may overlap w/the GCPS phenotype (see Genotype-Phenotype Correlations). |
AD = autosomal dominant; AR = autosomal recessive; GCPS = Greig cephalopolysyndactyly syndrome; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
Inheritance of EFNB1 craniofrontonasal dysplasia is unusual for an X-linked disorder: heterozygous females are severely affected and hemizygous males are almost asymptomatic.
- 2.
Gorlin et al [2001]
- 3.
Oral-facial-digital syndrome type 1 is caused by pathogenic variants in OFD1; see Phenotypic Series: Orofaciodigital syndrome for other genes associated with this phenotype in OMIM.
Management
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.
Table 5.
Recommended Evaluations Following Initial Diagnosis in Individuals with GCPS
| System/Concern | Evaluation | Comment |
|---|---|---|
| Limb anomalies | Dysmorphology exam | Evaluate for any other malformations. |
| Orthopedic eval | Incl radiographs to understand extent of limb anomalies. | |
| Occupational therapy / developmental eval | Determine any functional limitations that would benefit from therapy. | |
| Potential for developmental delay | Developmental screening | Consider brain imaging if significant delays noted. |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Table 6.
Treatment of Manifestations in Individuals with GCPS
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Polydactyly | Surgical repair |
|
| Cutaneous syndactyly | Surgical repair | Undertaken if syndactyly is more than minimal |
| Seizures | AED therapy as needed |
AED = antiepileptic drug
Surveillance
Table 7.
Recommended Surveillance for Individuals with GCPS
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Macrocephaly | Review rate of head growth in infant & child; if ↑ faster than normal or if neurologic concerns arise, brain MRI is indicated. | W/each visit or at least annually |
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.