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Greig cephalopolysyndactyly
This condition primarily affects bone development, leading to distinctive features such as extra fingers or toes, unusually wide thumbs or great toes, and certain skull and facial anomalies. It is present from birth and affects individuals across all ethnic backgrounds.
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Overview
Greig cephalopolysyndactyly (GCPS) is a rare inherited disorder present from birth, which affects development, particularly of the hands, feet, and head. The name 'cephalopolysyndactyly' refers to the key features: 'cephalo' for head, 'poly' for many, and 'syndactyly' for fused digits. Individuals with GCPS often have extra fingers or toes (polydactyly), and sometimes fusion of skin between digits (syndactyly). Characteristic facial features are also common, including a prominent forehead and widely spaced eyes [PMID:18451877]. The condition's severity can vary significantly among affected individuals, even within the same family.
Symptoms & clinical features
The primary symptoms of Greig cephalopolysyndactyly involve anomalies of the hands, feet, and skull. In the hands, common features include extra digits (polydactyly), particularly of the thumb, and sometimes webbing or fusion of the skin between fingers (syndactyly). The thumbs and great toes may also appear unusually wide. On the feet, extra toes are a frequent finding, often affecting the great toe [PMID:19468971].
Beyond the limbs, individuals with GCPS typically exhibit specific craniofacial characteristics. These can include a prominent or high forehead (frontal bossing), widely spaced eyes (hypertelorism), and in some cases, an enlarged head circumference. While intellectual disability is not a consistent feature, some individuals may experience developmental delays, though this is less common than the physical anomalies.
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Affected organs
The main body systems affected in Greig cephalopolysyndactyly are the skeletal system, particularly the bones of the limbs (hands and feet) and the skull. The development of digits on the hands and feet is primarily impacted, leading to features like polydactyly and syndactyly. The structure of the skull and face can also be altered, resulting in characteristic facial features.
Risks & severity
The severity of Greig cephalopolysyndactyly can vary considerably. Some individuals might have mild features that do not significantly impact their daily lives, while others may experience more pronounced limb differences or craniofacial anomalies. The condition is congenital, meaning it is present from birth, and its features are generally stable over time. The exact prevalence of GCPS is not well established, but it is considered a rare condition [PMID:20301479]. The condition does not typically affect life expectancy, though associated developmental delays, if present, may require additional support.
Genetic causes
Greig cephalopolysyndactyly is caused by pathogenic variants in the GLI3 gene. This gene provides instructions for making a protein known as GLI3, which acts as a transcription factor. Transcription factors are essential for regulating the activity of other genes.
The GLI3 protein plays a crucial role in embryonic development, particularly in the formation of limbs, the brain, and the face. It helps control cell growth, specialisation, and patterning during these critical developmental stages. Pathogenic changes in GLI3 can disrupt these precise developmental processes, leading to the characteristic features seen in GCPS.
- GLI3 GLI family zinc finger 3The GLI3 gene provides instructions for making a protein crucial for early foetal development, particularly in forming various tissues and organs.
Inheritance pattern
Greig cephalopolysyndactyly is inherited in an autosomal dominant pattern. This means that only one altered copy of the GLI3 gene in each cell is sufficient to cause the condition. An affected individual has a 50% chance of passing on the altered gene, and therefore the condition, to each of their children, regardless of the child's sex.
In some cases, GCPS can result from a new (de novo) genetic alteration that occurs during the formation of egg or sperm cells, or very early in embryonic development. In these situations, the affected individual's parents typically do not have the condition or the genetic change. When GCPS is caused by a de novo variant, the chance of future children in that family being affected is typically very low, though genetic counselling can provide more specific risk assessments.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
A diagnosis of Greig cephalopolysyndactyly is usually suspected based on the characteristic physical features, such as polydactyly, syndactyly, and craniofacial anomalies. Imaging studies, like X-rays, can help confirm skeletal findings.
Confirmation of GCPS is made through genetic testing, which looks for pathogenic variants in the GLI3 gene. In the UK, genetic testing for suspected skeletal conditions like GCPS is available through the NHS Genomic Medicine Service (GMS). Referral to a clinical genetics service is typically made by a GP or specialist paediatrician to discuss testing options. The relevant NHS National Genomic Test Directory R-code for conditions associated with GLI3 variants is often R122 (Limb malformation, isolated or syndromic), though this can vary.
Management & lifestyle
Management of Greig cephalopolysyndactyly focuses on addressing the specific symptoms and supporting development. This typically involves a multidisciplinary team approach. Surgical intervention may be considered to correct polydactyly or syndactyly, especially if the limb differences impact function or appearance. Orthopaedic specialists often guide these decisions.
For any developmental delays, early intervention services, such as physiotherapy, occupational therapy, or speech and language therapy, may be beneficial. Regular monitoring by paediatricians is important to address any emerging health needs. Genetic counsellors play a vital role in providing information about the condition, its inheritance pattern, and family planning options.
UK care pathway
In the UK, individuals suspected of having Greig cephalopolysyndactyly would typically be referred to a Clinical Genetics service. This referral can come from a GP or another specialist, such as a paediatrician. The Clinical Genetics team can offer genetic counselling, discuss diagnostic testing - often through the NHS Genomic Medicine Service (GMS) pathways, using relevant R-codes from the National Genomic Test Directory - and provide information about the condition and its inheritance. Genetic counsellors are key in supporting families through the diagnostic process and explaining implications for relatives.
Frequently asked questions
Is Greig cephalopolysyndactyly always inherited from a parent?
Not always. While Greig cephalopolysyndactyly is typically inherited in an autosomal dominant pattern from an affected parent, it can also arise from a new (de novo) genetic change in an individual where neither parent carries the altered gene. Genetic counselling can help clarify the specific situation for your family.
Do all individuals with Greig cephalopolysyndactyly have the same features?
No, the severity and presentation of features can vary widely among individuals, even within the same family. Some people may have mild limb differences, while others may have more pronounced changes to their hands, feet, and head. This is known as variable expressivity.
Does Greig cephalopolysyndactyly affect intelligence?
While developmental delay can sometimes be associated with Greig cephalopolysyndactyly, it is not a consistent feature, and many individuals have typical intellectual development. If there are concerns about development, appropriate assessments and support can be arranged.
Can Greig cephalopolysyndactyly be detected before birth?
In some cases, characteristic features of Greig cephalopolysyndactyly, such as polydactyly or other limb anomalies, might be observed during prenatal ultrasound scans. If such findings are seen, further investigations, including prenatal genetic testing, can be discussed with a specialist.
What kind of doctors treat Greig cephalopolysyndactyly?
Individuals with Greig cephalopolysyndactyly are typically managed by a team of specialists. This may include paediatricians, clinical geneticists, orthopaedic surgeons (for limb anomalies), and possibly occupational therapists or physiotherapists to support development and function.
References
- Adam MP, Bick S, Mirzaa GM. GLI3-Related Greig Cephalopolysyndactyly Syndrome. 1993. PMID: 20301619
- Biesecker LG. The Greig cephalopolysyndactyly syndrome. Orphanet journal of rare diseases. 2008. PMID: 18435847
- Kozma K, Bembea M, Jurca CM. Greig Cephalopolysyndactyly Contiguous Gene Syndrome: Case Report and Literature Review. Genes. 2021. PMID: 34828280
- Duncan PA, Klein RM, Wilmot PL. Greig cephalopolysyndactyly syndrome. American journal of diseases of children (1960). 1979. PMID: 223435
- Al-Qattan MM, Shamseldin HE, Salih MA. GLI3-related polydactyly: a review. Clinical genetics. 2017. PMID: 28224613
- Gollop TR, Fontes LR. The Greig cephalopolysyndactyly syndrome: report of a family and review of the literature. American journal of medical genetics. 1985. PMID: 3901752
- Garcia-Rodriguez R, Rodriguez-Rodriguez R, Garcia-Delgado R. Prenatal diagnosis of Greig Cephalopolysyndactyly Syndrome. When to suspect it. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2022. PMID: 32495660
- Patel R, Singh SK, Bhattacharya V. Novel GLI3 pathogenic variants in complex pre- and postaxial polysyndactyly and Greig cephalopolysyndactyly syndrome. American journal of medical genetics. Part A. 2021. PMID: 33058447