Greig Cephalopolysyndactyly Syndrome (GCPS)

疾患概要

Summary

Greig Cephalopolysyndactyly Syndrome (GCPS) is a rare genetic condition that affects the development of the head, face, limbs, and, in some cases, the central nervous system. It is most commonly recognized by a combination of three physical characteristics: wide-set eyes, known as hypertelorism; a noticeably large head, or macrocephaly; and the presence of extra fingers or toes, referred to as polydactyly. Although the condition is uncommon, advances in clinical genetics and molecular diagnostics have improved both the understanding of its underlying causes and the accuracy of its diagnosis. This review explains the key clinical features, the genetic mechanisms responsible for GCPS, approaches to diagnosis, and the current outlook for individuals living with this condition.

Overview

Core Characteristics

GCPS affects multiple systems but is most easily identified by its physical manifestations. The facial features include a broader than average distance between the eyes, giving a distinctive appearance from early infancy. Macrocephaly is another consistent finding, with head circumference measuring above typical growth charts for age and sex. Polydactyly is highly characteristic and often presents in a predictable pattern. In the feet, the additional digit frequently appears adjacent to the big toe, while in the hands, it commonly appears near the fifth finger. In some individuals, the extra digits may be fused or partially fused with adjacent fingers, a condition known as syndactyly. These features vary in degree but are usually apparent at birth, aiding early clinical recognition.

Genetic Basis

The genetic foundation of GCPS is well understood and centers on pathogenic changes in the GLI3 gene, located at chromosome region 7p14.1. The GLI3 gene encodes a transcription factor that plays a crucial role in embryonic patterning, particularly during the development of the brain and limbs. When this gene undergoes a mutation, the precise signaling pathways that guide normal limb formation and craniofacial structure are disrupted, leading to the characteristic features of the syndrome.

GCPS follows an autosomal dominant inheritance pattern. This means that a single mutated copy of the GLI3 gene, inherited from either parent or occurring as a new mutation during embryogenesis, is sufficient to produce the condition. Individuals with large deletions or more complex mutations in the GLI3 gene often present with additional complications such as delayed cognitive development, seizures, or structural abnormalities of the central nervous system. This reflects the gene’s broad influence on early neural development.

Prevalence

Epidemiological data indicate that GCPS occurs in approximately one to nine individuals per million worldwide. These numbers are considered estimates rather than precise figures because the condition is frequently underdiagnosed or misdiagnosed, particularly in regions with limited access to advanced genetic testing. Diagnostic uncertainty is further compounded by the overlap of its clinical signs with those of other congenital disorders. As genetic sequencing becomes more widely available and affordable, the identification rate of GCPS is expected to improve, allowing for better data on its true global prevalence.

Diagnosis

Clinical Evaluation

The process of diagnosing GCPS typically begins with a careful physical examination. Physicians look for the classic combination of hypertelorism, macrocephaly, and polydactyly, sometimes accompanied by syndactyly. While these features can raise a strong clinical suspicion, they are not sufficient to confirm the diagnosis on their own because similar patterns can be found in other genetic syndromes. A thorough family history is also important, as the autosomal dominant inheritance pattern means that one parent may show subtle or unrecognized features of the syndrome.

Molecular Genetic Testing

To establish a definitive diagnosis, molecular genetic testing is considered essential. This usually involves direct sequencing of the GLI3 gene to detect point mutations or small deletions and duplications. In cases where more significant genetic rearrangements are suspected, techniques such as comparative genomic hybridization or next-generation sequencing panels can provide more comprehensive insights. A positive test result not only confirms the diagnosis but also assists in prognosis, family counseling, and risk assessment for future pregnancies.

Prenatal Diagnosis

Prenatal testing for GCPS is increasingly possible but remains limited in accuracy depending on the method used. Non-invasive prenatal testing (NIPT) can indicate an elevated probability of chromosomal alterations linked to the condition but does not provide definitive results. Ultrasound imaging during pregnancy can sometimes reveal suggestive physical features such as extra digits or macrocephaly in the developing fetus, but its reliability varies, especially in early gestation. When a family history of GCPS is known, targeted genetic testing through chorionic villus sampling or amniocentesis offers a more definitive prenatal diagnosis.

Prognosis

General Outlook

The overall prognosis for individuals with GCPS is often favorable, particularly in cases where symptoms are limited to the characteristic craniofacial and limb features. Cognitive development in these individuals is typically within the normal range, and life expectancy is not reduced. Most children grow into adulthood with minimal medical intervention beyond routine surgical or orthopedic management of polydactyly, should functional or cosmetic concerns arise.

Complicated Presentations

More complex presentations of GCPS, particularly those associated with large deletions in the GLI3 gene, can lead to additional challenges. These may include significant cranial or skeletal anomalies, seizures, or structural abnormalities in the brain. Such cases often require a multidisciplinary approach involving geneticists, neurologists, orthopedic surgeons, and developmental specialists. Surgical interventions may be needed to correct hand or foot deformities, and supportive therapies can help address neurological or developmental complications when present.

Future Directions

Genetic counseling remains a cornerstone of care for families affected by GCPS, offering critical information about inheritance patterns, recurrence risks, and family planning options. Advances in molecular biology and gene-editing technologies are being explored as potential future treatments, though they remain experimental and are not yet available in clinical practice. Enzyme-based and gene-therapy approaches, while promising, are still in the research phase and require further validation before they can be applied in a therapeutic context.

References

Biesecker LG, Johnston JJ. Greig Cephalopolysyndactyly Syndrome. GeneReviews®.
Biesecker, L. G. (2008). Greig Cephalopolysyndactyly Syndrome. Orphanet Journal of Rare Diseases.
Perez, G., et al. The UCSC Genome Browser Database: 2025 Update. Nucleic Acids Research.
Harrison, P. W., et al. Ensembl 2024. Nucleic Acids Research.

For more information on the role of Non-Invasive Prenatal Testing (NIPT) in genetic screening and risk management during pregnancy, consult clinical genetics resources that provide validated, peer-reviewed guidance.