Greig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disorder caused by functional haploinsufficiency of GLI3, a zinc-finger transcription factor in the Hedgehog signaling pathway. GCPS is characterized by preaxial polydactyly, cutaneous syndactyly, macrocephaly, and hypertelorism. GLI3 normally functions as both a transcriptional activator and repressor in Hedgehog signaling; GCPS results from loss of total GLI3 protein through large deletions, translocations, or various intragenic mutations, in contrast to the allelic disorder Pallister-Hall syndrome which results from truncating mutations that produce a constitutive repressor.
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name: Greig Cephalopolysyndactyly Syndrome
creation_date: '2026-02-13T00:31:42Z'
updated_date: '2026-05-09T03:15:56Z'
category: Mendelian
description: >
Greig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disorder
caused by functional haploinsufficiency of GLI3, a zinc-finger transcription
factor in the Hedgehog signaling pathway. GCPS is characterized by preaxial
polydactyly, cutaneous syndactyly, macrocephaly, and hypertelorism. GLI3
normally functions as both a transcriptional activator and repressor in
Hedgehog signaling; GCPS results from loss of total GLI3 protein through
large deletions, translocations, or various intragenic mutations, in contrast
to the allelic disorder Pallister-Hall syndrome which results from truncating
mutations that produce a constitutive repressor.
disease_term:
preferred_term: Greig cephalopolysyndactyly syndrome
term:
id: MONDO:0008287
label: Greig cephalopolysyndactyly syndrome
parents:
- Limb Development Disorders
inheritance:
- name: Autosomal Dominant
description: >
Autosomal dominant with variable expressivity. Caused by functional
haploinsufficiency of GLI3. Large deletions, translocations, and
various intragenic mutations all cause GCPS, consistent with loss
of function as the pathogenic mechanism.
evidence:
- reference: PMID:15739154
reference_title: "Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations."
supports: PARTIAL
snippet: "functional haploinsufficiency of GLI3 causes GCPS"
explanation: "Demonstrates that GLI3 haploinsufficiency is the mechanism underlying GCPS."
prevalence:
- population: Published GCPS cases
percentage: Unknown
notes: >-
Population prevalence has not been established; recent literature reviews
still describe only about 200 reported cases, indicating that GCPS remains
exceptionally rare.
evidence:
- reference: PMID:34828280
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder (about 200 cases reported), characterized by macrocephaly, hypertelorism, and polysyndactyly."
explanation: Contemporary review abstract documents the limited reported case count and supports unknown but extremely low prevalence.
pathophysiology:
- name: GLI3 Haploinsufficiency
description: >
GLI3 is a bifunctional zinc-finger transcription factor that mediates
Hedgehog (Hh) signaling. In the absence of Hh signal, GLI3 is
proteolytically processed into a truncated repressor form (GLI3R);
when Hh is present, full-length GLI3 acts as a transcriptional
activator (GLI3A). GCPS results from reduced total GLI3 protein
through diverse mutation types (deletions, translocations, missense,
frameshift), consistent with haploinsufficiency.
biological_processes:
- preferred_term: Hedgehog Signaling Pathway
term:
id: GO:0007224
label: smoothened signaling pathway
evidence:
- reference: PMID:15739154
reference_title: "Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations."
supports: SUPPORT
snippet: "GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations"
explanation: "Diverse mutation types all cause GCPS, consistent with haploinsufficiency rather than gain-of-function."
- name: Disrupted Anterior-Posterior Limb Patterning
description: >
Reduced GLI3 protein disrupts the GLI3A/GLI3R ratio, perturbing
the anterior-posterior repressor gradient in the developing limb.
This gradient normally restricts digit number and specifies digit
identity. Disruption leads to preaxial polydactyly, syndactyly,
and craniofacial features including macrocephaly and hypertelorism.
biological_processes:
- preferred_term: Embryonic Limb Morphogenesis
term:
id: GO:0030326
label: embryonic limb morphogenesis
evidence:
- reference: PMID:10693759
reference_title: "Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb."
supports: PARTIAL
snippet: "PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein"
explanation: "Establishes the GLI3 processing mechanism that generates repressor gradient in limb development."
- reference: PMID:10693759
reference_title: "Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb."
supports: PARTIAL
snippet: "The resulting anterior/posterior Gli3 repressor gradient can be perturbed by mutations of Gli3 in human genetic syndromes"
explanation: "Links GLI3 mutations to disruption of the anterior-posterior limb patterning gradient."
phenotypes:
- name: Preaxial Polydactyly
description: >
Extra digits on the preaxial (thumb/radial) side of the hand. May
range from subtle thumb broadening to fully formed extra digits.
A defining feature distinguishing GCPS from Pallister-Hall syndrome
(which typically shows postaxial polydactyly).
phenotype_term:
preferred_term: Preaxial polydactyly
term:
id: HP:0100258
label: Preaxial polydactyly
evidence:
- reference: PMID:24736735
reference_title: "New insights into genotype-phenotype correlation for GLI3 mutations."
supports: PARTIAL
snippet: "Typical GCPS combines polysyndactyly of hands and feet and craniofacial features"
explanation: "Polysyndactyly including preaxial polydactyly is a defining feature of GCPS."
- reference: PMID:28224613
reference_title: "GLI3-related polydactyly: a review."
supports: SUPPORT
snippet: "the preaxial polydactyly type IV-Greig-acrocallosal spectrum"
explanation: "Preaxial polydactyly is the characteristic limb pattern in the GCPS spectrum."
- name: Cutaneous Syndactyly
description: >
Soft tissue syndactyly (webbing) between fingers and/or toes.
Combined with polydactyly as polysyndactyly, a hallmark of GCPS.
phenotype_term:
preferred_term: Syndactyly
term:
id: HP:0001159
label: Syndactyly
evidence:
- reference: PMID:24736735
reference_title: "New insights into genotype-phenotype correlation for GLI3 mutations."
supports: SUPPORT
snippet: "Typical GCPS combines polysyndactyly of hands and feet and craniofacial features"
explanation: "Syndactyly combined with polydactyly is characteristic of GCPS."
- name: Macrocephaly
description: >
Increased head circumference, often with frontal bossing. A
craniofacial hallmark of GCPS, reflecting the role of GLI3 in
cranial development.
phenotype_term:
preferred_term: Macrocephaly
term:
id: HP:0000256
label: Macrocephaly
evidence:
- reference: PMID:15739154
reference_title: "Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations."
supports: NO_EVIDENCE
snippet: "The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS"
explanation: "Large cohort study establishing macrocephaly as a clinical criterion for GCPS diagnosis."
- name: Hypertelorism
description: >
Widely spaced eyes, another craniofacial feature characteristic
of GCPS.
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
- name: Abnormal Corpus Callosum
description: >
Structural abnormalities of the corpus callosum, including agenesis
or hypoplasia. More commonly associated with contiguous gene
deletions or specific mutation locations.
phenotype_term:
preferred_term: Abnormal corpus callosum morphology
term:
id: HP:0001273
label: Abnormal corpus callosum morphology
evidence:
- reference: PMID:24736735
reference_title: "New insights into genotype-phenotype correlation for GLI3 mutations."
supports: SUPPORT
snippet: "a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS"
explanation: "Corpus callosum abnormalities correlate with specific GLI3 mutation locations in GCPS."
genetic:
- name: GLI3 Mutations (Haploinsufficiency)
association: Causative
notes: >
Functional haploinsufficiency of GLI3 on chromosome 7p14.1.
Multiple mutation types cause GCPS: translocations, large
deletions, exonic deletions/duplications, small in-frame
deletions, missense, frameshift/nonsense, and splicing mutations.
Among truncating mutations, those in the first third or last third
of the gene cause GCPS, while mutations in the middle third cause
Pallister-Hall syndrome.
evidence:
- reference: PMID:15739154
reference_title: "Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations."
supports: SUPPORT
snippet: "among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation"
explanation: "Clear positional genotype-phenotype correlation within GLI3 distinguishes GCPS from PHS."
- reference: PMID:15739154
reference_title: "Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations."
supports: SUPPORT
snippet: "These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis"
explanation: "Robust genotype-phenotype correlation confirms GCPS and PHS as distinct allelic disorders."
- reference: PMID:20672375
reference_title: "Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations."
supports: SUPPORT
snippet: "the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists"
explanation: "Expanded cohort of 174 probands confirms robust genotype-phenotype correlation despite broader phenotypic spectrum."
treatments:
- name: Surgical Correction of Polydactyly
description: >
Surgical removal of extra digits, typically performed in early
childhood. Syndactyly release may also be performed for
functional improvement.
- name: Developmental Monitoring
description: >
Monitoring for developmental delay and corpus callosum
abnormalities, particularly in patients with large deletions
or contiguous gene involvement.
datasets: []
references:
- reference: DOI:10.1136/jmg-2022-108753
title: Conclusion of diagnostic odysseys due to inversions disrupting <i>GLI3</i> and <i>FBN1</i>
found_in:
- Greig_Cephalopolysyndactyly-deep-research-falcon.md
findings:
- statement: Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number.
supporting_text: Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number.
evidence:
- reference: DOI:10.1136/jmg-2022-108753
reference_title: Conclusion of diagnostic odysseys due to inversions disrupting <i>GLI3</i> and <i>FBN1</i>
supports: SUPPORT
evidence_source: OTHER
snippet: Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number.
explanation: Deep research cited this publication as relevant literature for Greig Cephalopolysyndactyly.
- reference: DOI:10.12996/gmj.2023.4053
title: 'A Rare Prenatal Case: Greig Cephalopolysyndactyly Syndrome'
found_in:
- Greig_Cephalopolysyndactyly-deep-research-falcon.md
findings:
- statement: 'A Rare Prenatal Case: Greig Cephalopolysyndactyly Syndrome'
supporting_text: 'A Rare Prenatal Case: Greig Cephalopolysyndactyly Syndrome'
- reference: DOI:10.3389/fphys.2012.00121
title: Loss-of-function of Gli3 in mice causes abnormal frontal bone morphology and premature synostosis of the interfrontal suture
found_in:
- Greig_Cephalopolysyndactyly-deep-research-falcon.md
findings:
- statement: Loss-of-function of Gli3 in mice causes abnormal frontal bone morphology and premature synostosis of the interfrontal suture
supporting_text: Loss-of-function of Gli3 in mice causes abnormal frontal bone morphology and premature synostosis of the interfrontal suture
Greig cephalopolysyndactyly syndrome (GCPS) is a rare, pleiotropic multiple congenital anomaly syndrome classically defined by macrocephaly, widely spaced eyes (hypertelorism/increased interpupillary distance), and limb malformations dominated by preaxial polydactyly with variable syndactyly. It is primarily caused by GLI3 haploinsufficiency with autosomal dominant inheritance, and shows clinically important genotype–phenotype correlations based on variant type/position and variant class (sequence variants vs copy-number/structural rearrangements). Recent genomic diagnostics (2023–2024) highlight that copy-neutral inversions disrupting GLI3 can end long “diagnostic odysseys,” underscoring the need for whole-genome sequencing (WGS) structural-variant (SV) detection and clinician–analyst review in real-world health systems. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3, pagnamenta2023conclusionofdiagnostic pages 1-1)
| Domain | Summary |
|---|---|
| Core identifiers | Disease: Greig cephalopolysyndactyly syndrome (GCPS); MONDO: MONDO:0008287; OMIM: 175700; Orphanet: ORPHA:380; primary causal gene: GLI3; inheritance: autosomal dominant |
| Common synonyms / related names | Greig syndrome; GLI3-related Greig cephalopolysyndactyly syndrome; GCPS; related/overlapping entities: preaxial polydactyly type IV (PPD-IV), GLI3-related Pallister-Hall syndrome |
| Defining clinical pattern | Classic triad: macrocephaly, widely spaced eyes/increased interpupillary distance, and limb malformations including preaxial polydactyly with or without postaxial polydactyly plus cutaneous syndactyly |
| Key clinical features with reported frequencies | Preaxial polydactyly ~90%; cutaneous syndactyly ~75%; macrocephaly ~50%; widely spaced eyes ~50%; postaxial polydactyly ~50%; broad thumb ~30%; broad hallux ~25%; corpus callosum hypoplasia/agenesis ~20%; developmental delay/intellectual disability/seizures uncommon (<10%) |
| Molecular mechanism / variant spectrum | GLI3 haploinsufficiency; pathogenic variant classes include truncating, missense, splice, exonic deletions/duplications, large deletions, translocations, and inversions; GCPS generally associated with variants 5' of nucleotide 1998 and 3' of 3481, whereas Pallister-Hall syndrome is associated with truncating variants between nucleotides 1998 and 3481 |
| Routine molecular diagnostics | Single-gene GLI3 sequencing with reflex deletion/duplication testing; multigene panels; exome sequencing; genome sequencing; chromosomal microarray (especially if developmental delay or larger deletion suspected); qPCR, long-range PCR, MLPA, targeted microarray, karyotype/FISH in selected structural cases |
| Approximate diagnostic yield by modality class | Sequence analysis identifies ~80% of pathogenic findings; gene-targeted deletion/duplication analysis identifies ~20%; karyotype-detectable rearrangements are rare |
| Notable structural variant findings | Copy-neutral inversions disrupting GLI3 identified by WGS in families with GCPS, including 1.2 Mb inversion chr7:42,051,297-43,254,780 and 14.8 Mb inversion chr7:27,245,456-42,072,394; one distal breakpoint lay ~45 kb from HOXA13; such findings resolved diagnostic odysseys of 9-20 years |
| Epidemiology | Rare disorder; prevalence/incidence generally reported as unknown in recent GeneReviews-based evidence; historical estimate range reported in review literature/definitions: ~1-9 per 1,000,000; approximately 300 affected individuals known to GeneReviews authors |
| Prognosis | Often favorable in typical GLI3-related GCPS, with mild forms, excellent general health, and normal longevity reported in large families; prognosis worsens with large (>300 kb) deletions involving GLI3, which are associated with more severe neurodevelopmental/CNS phenotypes |
Table: This table compacts the main disease-knowledge-base facts for Greig cephalopolysyndactyly syndrome, including identifiers, phenotype frequencies, diagnostic strategy, structural variant findings, epidemiology, and prognosis. It is useful as a quick-reference scaffold for a fuller narrative report.
GCPS is a “pleiotropic, multiple congenital anomaly syndrome.” (biesecker2024greigcephalopolysyndactylysyndrome pages 1-1)
A consolidated clinical definition from a GeneReviews-style synthesis describes a classic triad of macrocephaly, widely spaced eyes/increased interpupillary distance, and preaxial polydactyly (± postaxial polydactyly) with cutaneous syndactyly. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3, biesecker2025gli3relatedgreigcephalopolysyndactyly pages 1-3)
A key expert clarification is that the term “Greig syndrome” has sometimes been used for the nonspecific dyad of macrocephaly + widely spaced eyes, and “should not be used as a synonym” for the full GLI3-related GCPS phenotype. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 6-8)
Not retrieved in the current tool run: ICD-10/ICD-11 codes and MeSH descriptors were not directly retrieved from authoritative sources using the available evidence/tools.
Commonly used names in the retrieved evidence include: * Greig cephalopolysyndactyly syndrome (GCPS) (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3) * GLI3-related Greig cephalopolysyndactyly syndrome (GLI3-GCPS) (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3) * Greig syndrome (as a historical/colloquial term; not recommended as a synonym) (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 6-8)
Related/overlapping entities for differential purposes include: * GLI3-related Pallister–Hall syndrome (GLI3-PHS) (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 6-8) * Preaxial polydactyly type IV (PPD-IV) as part of the GLI3 phenotypic spectrum (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 6-8)
The information synthesized here is derived from: * Aggregated disease-level resources/synthesis (GeneReviews-style clinical genetics synthesis) (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3) * Primary human genomics/diagnostics studies (e.g., WGS SV inversions) (pagnamenta2023conclusionofdiagnostic pages 3-4) * Prenatal clinical case report (human) with cytogenetics + array-CGH confirmation (hakcıl2024arareprenatal pages 1-2) * Model organism evidence (mouse Gli3 loss-of-function) supporting developmental mechanisms (veistinen2012lossoffunctionofgli3 pages 1-2)
Primary cause: pathogenic variation affecting GLI3 leading to haploinsufficiency (loss of one functional allele) in the typical GCPS mechanism. (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 6-8, biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3)
Inheritance: autosomal dominant with a 50% recurrence risk to offspring of an affected individual; apparent non-penetrance has been reported. (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 6-8, biesecker2025gli3relatedgreigcephalopolysyndactylya pages 12-15)
Variant classes causing GCPS: sequence variants (including truncating/frameshift, splice, missense), intragenic deletions/duplications, larger deletions involving 7p14.1, and structural rearrangements including translocations/inversions. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 6-8, biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3)
Genetic risk factor (causal): carrying a heterozygous pathogenic/likely pathogenic GLI3 variant or a heterozygous deletion encompassing 7p14.1/GLI3. In the GeneReviews-style synthesis, ~80% of affected individuals have a heterozygous pathogenic GLI3 variant and ~20% have a heterozygous deletion involving 7p14.1/GLI3. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3, biesecker2025gli3relatedgreigcephalopolysyndactyly pages 1-3)
Structural variant risk (underascertained class): copy-neutral inversions disrupting GLI3 can cause GCPS-consistent skeletal phenotypes and are likely underdetected by CNV-biased pipelines. (pagnamenta2023conclusionofdiagnostic pages 1-1, pagnamenta2023conclusionofdiagnostic pages 4-4)
Environmental risk factors: none were identified in the retrieved evidence; GCPS is predominantly a Mendelian developmental disorder caused by GLI3 disruption. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3)
No protective factors or gene–environment interactions were identified in the retrieved evidence.
A GeneReviews-style synthesis provides quantitative frequencies for select features: * Preaxial polydactyly (~90%; more common in feet) (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6) * Cutaneous syndactyly (~75%) (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6) * Macrocephaly (~50%) (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6) * Widely spaced eyes / increased interpupillary distance (~50%) (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6) * Postaxial polydactyly (~50%; more common in hands) (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6) * Broad thumb (~30%) and broad hallux (~25%) (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6) * Corpus callosum hypoplasia/agenesis (~20%) (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 1-3) * Developmental delay / intellectual disability / seizures uncommon (~<10%), but risk increases with large deletions encompassing GLI3. (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 1-3)
Visual evidence: The same synthesis includes (i) a mutational-spectrum schematic dividing GCPS vs Pallister–Hall regions and (ii) a feature-frequency table. (biesecker2025gli3relatedgreigcephalopolysyndactyly media 5cc46968, biesecker2025gli3relatedgreigcephalopolysyndactyly media 55afed63)
A 2024 prenatal GCPS case reported ultrasound findings including polydactyly, polyhydramnios, aortic valve stenosis, and nonvisualization of the vesica biliaris, prompting invasive testing and subsequent confirmation of a large 7p deletion encompassing GLI3. (hakcıl2024arareprenatal pages 2-4)
(ontology suggestions; not all are explicitly enumerated in the cited sources) * Macrocephaly — HP:0000256 * Hypertelorism — HP:0000316 / increased interpupillary distance * Preaxial polydactyly — HP:0100259 (hand/foot subtypes may be used) * Postaxial polydactyly — HP:0100258 * Cutaneous syndactyly — HP:0006101 * Broad thumb — HP:0011304 * Broad hallux — HP:0010055 * Corpus callosum agenesis — HP:0001274 * Developmental delay — HP:0001263 * Seizures — HP:0001250 * Craniosynostosis (metopic) — HP:0005464 (metopic ridge/trigonocephaly terms may apply in subsets)
The retrieved evidence supports that many individuals have mild disease and “excellent general health and normal longevity,” implying limited systemic morbidity in typical cases, but does not provide validated quality-of-life instrument data (e.g., SF-36/EQ-5D) specific to GCPS. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 3-6)
Primary causal gene: GLI3 (GLI family zinc finger 3). (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3)
OpenTargets provides a strong disease–target association of GCPS with GLI3 (association score reported; PubMed IDs listed in evidence). (OpenTargets Search: Greig cephalopolysyndactyly syndrome)
Mechanism: Haploinsufficiency of GLI3 in typical GCPS. (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 6-8)
Genotype–phenotype correlation (variant position/type): * Frameshift/truncating variants in the first third of GLI3 are reported as causing GCPS; truncations in the middle third generally cause Pallister–Hall syndrome (PHS) but can uncommonly produce GCPS; truncations in the final third cause GCPS. (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 6-8) * A summarized regional model: “GCPS is primarily caused by GLI3 pathogenic variants 5′ of nucleotide 1998 and 3′ of 3481, whereas PHS is exclusively caused by truncations between 1998 and 3481.” (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 6-8, biesecker2025gli3relatedgreigcephalopolysyndactyly media 5cc46968)
Copy-number/structural mechanisms: * Large deletions (>300 kb) encompassing GLI3 are associated with a more severe phenotype (higher rates of intellectual disability, seizures, CNS anomalies). (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 3-6) * Copy-neutral inversions disrupting GLI3 can be diagnostic causes in families with GCPS-consistent skeletal phenotypes; examples include a 1.2 Mb inversion (chr7:42,051,297–43,254,780) and a 14.8 Mb inversion (chr7:27,245,456–42,072,394). (pagnamenta2023conclusionofdiagnostic pages 3-4)
GLI3 is a Hedgehog (Hh) pathway transcription factor whose processing and the balance of activator vs repressor forms are critical in development; in a Gli3 loss-of-function mouse model, loss of Gli3 causes ectopic Hedgehog pathway activity in cranial sutural mesenchyme associated with abnormal osteogenic differentiation. (veistinen2012lossoffunctionofgli3 pages 1-2, veistinen2012lossoffunctionofgli3 pages 4-5)
GO term suggestions (mechanism-oriented): * Hedgehog signaling pathway — GO:0007224 * Limb development — GO:0060173 (and related patterning terms) * Osteoblast differentiation — GO:0001649 * Cranial suture morphogenesis / skull development — (multiple GO options depending on curation scope)
No GCPS-specific modifier genes or epigenetic signatures were identified in the retrieved evidence.
No non-genetic environmental contributors, lifestyle factors, or infectious triggers were identified in the retrieved evidence; GCPS is primarily a Mendelian disorder due to GLI3 disruption. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3)
In Gli3Xt-J/Xt-J mice (loss-of-function), ectopic osteogenic markers appear early (e.g., ectopic alkaline phosphatase staining by E13.5), heterotopic ossification is present by E16.5–E18.5, and in severe cases the interfrontal suture fuses prior to birth. (veistinen2012lossoffunctionofgli3 pages 1-2, veistinen2012lossoffunctionofgli3 pages 2-4)
Quantitatively, at E18.5 the mean width at the anterior interfrontal suture was increased in mutants (WT 2.8 ± 0.1 mm vs Gli3Xt-J/Xt-J 3.5 ± 0.2 mm; P < 0.001). (veistinen2012lossoffunctionofgli3 pages 1-2)
Cell Ontology suggestions (typical developmental actors): * Osteoblast — CL:0000062 * Osteoprogenitor cell — CL:0000058 * Chondrocyte — CL:0000138 * Cranial neural crest-derived mesenchymal cell (term selection depends on CL availability)
Primary systems involved include: * Limbs/autopod (polydactyly, syndactyly) (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6) * Craniofacial/skull (macrocephaly; cranial suture pathology in a subset; craniofacial dysmorphism) (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6, veistinen2012lossoffunctionofgli3 pages 1-2) * Central nervous system (corpus callosum hypoplasia/agenesis ~20%; DD/ID/seizures uncommon but present) (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 1-3)
GCPS is congenital with manifestations detectable prenatally (e.g., polydactyly on ultrasound in some cases) and present at birth. (hakcıl2024arareprenatal pages 2-4, biesecker2025gli3relatedgreigcephalopolysyndactylya pages 12-15)
Course is typically non-progressive with respect to the congenital malformations; outcomes depend on severity, presence of CNS anomalies, and whether large deletions involve adjacent genes. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 3-6)
Autosomal dominant inheritance is supported by the GeneReviews-style synthesis, with 50% transmission risk to offspring of an affected individual. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 12-15)
The GeneReviews-style synthesis states that prevalence is unknown and notes that “Approximately 300 affected individuals are known to the authors,” indicating ascertainment limitations and likely underdiagnosis of mild cases. (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 6-8, biesecker2025gli3relatedgreigcephalopolysyndactylya pages 6-8)
Not retrieved in this tool run: robust population-based prevalence/incidence estimates from Orphanet/registry epidemiology fields. (The earlier “incidence range 1–9/1,000,000” is not present in the citeable evidence captured here.)
No consensus clinical diagnostic criteria are stated to exist in the GeneReviews-style synthesis, but typical GCPS is recognized by the triad of macrocephaly, widely spaced eyes, and preaxial polydactyly with syndactyly. (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 1-3)
Testing modalities and approximate yields (from synthesis): * GLI3 sequence analysis identifies ~80% of pathogenic variants; gene-targeted deletion/duplication testing identifies ~20%. (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6) * Comprehensive approaches include multigene panels, exome sequencing (noted as most commonly used), genome sequencing, and chromosomal microarray (CMA). (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3)
Structural rearrangements and “diagnostic odysseys” (2023): A 2023 Journal of Medical Genetics study demonstrated that copy-neutral inversions can disrupt GLI3 and segregate with GCPS-consistent skeletal phenotypes; the authors report two inverted segments (1.2 Mb and 14.8 Mb) disrupting GLI3 and state these findings “resolved lengthy diagnostic odysseys of 9–20 years.” (pagnamenta2023conclusionofdiagnostic pages 1-1, pagnamenta2023conclusionofdiagnostic pages 3-4)
Implementation lesson (quoted): the same study explicitly notes that “copy-neutral rearrangements such as inversions are therefore likely to suffer from underascertainment,” and that a CNV-focused SV pipeline can miss these events. (pagnamenta2023conclusionofdiagnostic pages 1-1, pagnamenta2023conclusionofdiagnostic pages 4-4)
Prenatal diagnostic workflow (2024 case): fetal ultrasound abnormalities led to amniocentesis; initial aneuploidy testing was normal, followed by cytogenetics/FISH and array-CGH that identified a 17.4 Mb 7p12.3–14.3 deletion including GLI3, interpreted as de novo after normal parental karyotypes. (hakcıl2024arareprenatal pages 1-2)
Differential diagnoses listed in the GeneReviews-style synthesis include multiple polydactyly/macrocephaly syndromes and GLI3-allelic disorders, including GLI3-related Pallister–Hall syndrome and PPD-IV as part of the phenotypic spectrum. (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 6-8)
Typical GLI3-related GCPS can be mild: “several large families” are reported with “excellent general health and normal longevity,” while developmental delay/intellectual disability/seizures are uncommon (~<10%). (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 3-6)
Prognosis worsens for individuals with large deletions (>300 kb) encompassing GLI3, associated with increased rates of intellectual disability, seizures, and CNS anomalies. (biesecker2025gli3relatedgreigcephalopolysyndactylya pages 3-6)
No disease-specific pharmacotherapy was identified in the retrieved evidence; management is primarily symptomatic and surgical.
The GeneReviews-style synthesis states that treatment is symptomatic, with plastic or orthopedic surgery indicated for significant limb malformations. (biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6)
Supportive care is implied for neurodevelopmental issues when present (e.g., developmental assessment and services), but GCPS-specific rehabilitation outcome statistics were not found in the retrieved evidence.
Primary prevention of de novo variants is not currently available; prevention in GCPS is largely reproductive risk reduction and early detection.
No naturally occurring veterinary GCPS analogs were identified in the retrieved evidence.
A Gli3 loss-of-function mouse allele (Gli3Xt-J/Xt-J) is described as a model that largely phenocopies aspects of human GCPS and is used to study craniofacial suture pathology, including premature interfrontal (metopic-equivalent) synostosis with embryonic onset. (veistinen2012lossoffunctionofgli3 pages 1-2, veistinen2012lossoffunctionofgli3 pages 2-4)
A key limitation is that Gli3Xt-J/Xt-J mice die at birth, limiting postnatal phenotyping and long-term outcome studies. (veistinen2012lossoffunctionofgli3 pages 4-5)
References
(biesecker2025gli3relatedgreigcephalopolysyndactylya pages 1-3): LG Biesecker and JJ Johnston. Gli3-related greig cephalopolysyndactyly syndrome. Unknown journal, 2025.
(pagnamenta2023conclusionofdiagnostic pages 1-1): Alistair T Pagnamenta, Jing Yu, Julie Evans, Philip Twiss, Amaka C Offiah, Mohamed Wafik, Sarju G Mehta, Mohammed K Javaid, Sarah F Smithson, and Jenny C Taylor. Conclusion of diagnostic odysseys due to inversions disrupting gli3 and fbn1. Journal of Medical Genetics, 60:505-510, Nov 2023. URL: https://doi.org/10.1136/jmg-2022-108753, doi:10.1136/jmg-2022-108753. This article has 15 citations and is from a domain leading peer-reviewed journal.
(biesecker2024greigcephalopolysyndactylysyndrome pages 1-1): LG Biesecker and JJ Johnston. Greig cephalopolysyndactyly syndrome. Definitions, Feb 2024. URL: https://doi.org/10.1007/978-1-4614-1037-9_111, doi:10.1007/978-1-4614-1037-9_111. This article has 75 citations.
(biesecker2025gli3relatedgreigcephalopolysyndactyly pages 1-3): LG Biesecker and JJ Johnston. Gli3-related greig cephalopolysyndactyly syndrome. Unknown journal, 2025.
(biesecker2025gli3relatedgreigcephalopolysyndactylya pages 6-8): LG Biesecker and JJ Johnston. Gli3-related greig cephalopolysyndactyly syndrome. Unknown journal, 2025.
(OpenTargets Search: Greig cephalopolysyndactyly syndrome): Open Targets Query (Greig cephalopolysyndactyly syndrome, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(biesecker2025gli3relatedgreigcephalopolysyndactylya pages 3-6): LG Biesecker and JJ Johnston. Gli3-related greig cephalopolysyndactyly syndrome. Unknown journal, 2025.
(biesecker2025gli3relatedgreigcephalopolysyndactyly pages 6-8): LG Biesecker and JJ Johnston. Gli3-related greig cephalopolysyndactyly syndrome. Unknown journal, 2025.
(pagnamenta2023conclusionofdiagnostic pages 3-4): Alistair T Pagnamenta, Jing Yu, Julie Evans, Philip Twiss, Amaka C Offiah, Mohamed Wafik, Sarju G Mehta, Mohammed K Javaid, Sarah F Smithson, and Jenny C Taylor. Conclusion of diagnostic odysseys due to inversions disrupting gli3 and fbn1. Journal of Medical Genetics, 60:505-510, Nov 2023. URL: https://doi.org/10.1136/jmg-2022-108753, doi:10.1136/jmg-2022-108753. This article has 15 citations and is from a domain leading peer-reviewed journal.
(hakcıl2024arareprenatal pages 1-2): Tilbe Hakçıl, Gülsüm Kayhan, Tuncay Nas, Pınar Telli Celtemen, and Meral Yirmibeş Karaoğuz. A rare prenatal case: greig cephalopolysyndactyly syndrome. Gazi Medical Journal, 35:208-211, Apr 2024. URL: https://doi.org/10.12996/gmj.2023.4053, doi:10.12996/gmj.2023.4053. This article has 0 citations.
(veistinen2012lossoffunctionofgli3 pages 1-2): Lotta Veistinen, M. Takatalo, Y. Tanimoto, D. Kesper, A. Vortkamp, and D. Rice. Loss-of-function of gli3 in mice causes abnormal frontal bone morphology and premature synostosis of the interfrontal suture. Frontiers in Physiology, Feb 2012. URL: https://doi.org/10.3389/fphys.2012.00121, doi:10.3389/fphys.2012.00121. This article has 46 citations.
(biesecker2025gli3relatedgreigcephalopolysyndactylya pages 12-15): LG Biesecker and JJ Johnston. Gli3-related greig cephalopolysyndactyly syndrome. Unknown journal, 2025.
(pagnamenta2023conclusionofdiagnostic pages 4-4): Alistair T Pagnamenta, Jing Yu, Julie Evans, Philip Twiss, Amaka C Offiah, Mohamed Wafik, Sarju G Mehta, Mohammed K Javaid, Sarah F Smithson, and Jenny C Taylor. Conclusion of diagnostic odysseys due to inversions disrupting gli3 and fbn1. Journal of Medical Genetics, 60:505-510, Nov 2023. URL: https://doi.org/10.1136/jmg-2022-108753, doi:10.1136/jmg-2022-108753. This article has 15 citations and is from a domain leading peer-reviewed journal.
(biesecker2025gli3relatedgreigcephalopolysyndactyly pages 3-6): LG Biesecker and JJ Johnston. Gli3-related greig cephalopolysyndactyly syndrome. Unknown journal, 2025.
(biesecker2025gli3relatedgreigcephalopolysyndactyly media 5cc46968): LG Biesecker and JJ Johnston. Gli3-related greig cephalopolysyndactyly syndrome. Unknown journal, 2025.
(biesecker2025gli3relatedgreigcephalopolysyndactyly media 55afed63): LG Biesecker and JJ Johnston. Gli3-related greig cephalopolysyndactyly syndrome. Unknown journal, 2025.
(hakcıl2024arareprenatal pages 2-4): Tilbe Hakçıl, Gülsüm Kayhan, Tuncay Nas, Pınar Telli Celtemen, and Meral Yirmibeş Karaoğuz. A rare prenatal case: greig cephalopolysyndactyly syndrome. Gazi Medical Journal, 35:208-211, Apr 2024. URL: https://doi.org/10.12996/gmj.2023.4053, doi:10.12996/gmj.2023.4053. This article has 0 citations.
(veistinen2012lossoffunctionofgli3 pages 4-5): Lotta Veistinen, M. Takatalo, Y. Tanimoto, D. Kesper, A. Vortkamp, and D. Rice. Loss-of-function of gli3 in mice causes abnormal frontal bone morphology and premature synostosis of the interfrontal suture. Frontiers in Physiology, Feb 2012. URL: https://doi.org/10.3389/fphys.2012.00121, doi:10.3389/fphys.2012.00121. This article has 46 citations.
(veistinen2012lossoffunctionofgli3 pages 2-4): Lotta Veistinen, M. Takatalo, Y. Tanimoto, D. Kesper, A. Vortkamp, and D. Rice. Loss-of-function of gli3 in mice causes abnormal frontal bone morphology and premature synostosis of the interfrontal suture. Frontiers in Physiology, Feb 2012. URL: https://doi.org/10.3389/fphys.2012.00121, doi:10.3389/fphys.2012.00121. This article has 46 citations.