Greig cephalopolysyndactyly syndrome

Overview

Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder characterized by a combination of craniofacial abnormalities, extra fingers or toes (polydactyly), and fusion of digits (syndactyly). The term “cephalopolysyndactyly” reflects the key features of the syndrome: head and facial anomalies (cephalo), extra digits (poly), and webbed or fused digits (syn). GCPS is typically present at birth and varies in severity among affected individuals. While some cases are mild, others may be associated with developmental delays and neurological abnormalities.

Causes

GCPS is caused by mutations or deletions in the GLI3 gene located on chromosome 7p14.1. This gene plays a crucial role in regulating embryonic development, particularly the formation of the limbs and head. Mutations in GLI3 can disrupt normal signaling pathways, leading to abnormal growth patterns. GCPS follows an autosomal dominant inheritance pattern, meaning only one copy of the altered gene is sufficient to cause the disorder. However, some cases result from new (de novo) mutations with no family history.

Symptoms

The clinical features of Greig cephalopolysyndactyly syndrome can vary widely but typically include the following:

Craniofacial Abnormalities:

• Macrocephaly (unusually large head)

• Broad forehead

• High, prominent forehead and wide-set eyes (hypertelorism)

• Frontal bossing (prominent forehead)

Limb Abnormalities:

• Polydactyly (extra fingers or toes), often preaxial (on the thumb or big toe side)

• Syndactyly (fusion of fingers or toes), typically involving the skin and sometimes bones

• Broad thumbs or halluces (big toes)

Other Possible Features:

• Developmental delay or intellectual disability (in some cases)

• Seizures or hydrocephalus (rare)

• Inguinal hernia or other structural anomalies

The severity and combination of symptoms can differ significantly between affected individuals, even within the same family.

Diagnosis

Diagnosis of GCPS is based on clinical findings, family history, and genetic testing. Key diagnostic steps include:

• Physical examination: Identification of craniofacial and limb anomalies

• Radiographic imaging: To assess bone structure and degree of polydactyly/syndactyly

• Genetic testing: Detection of pathogenic variants in the GLI3 gene confirms the diagnosis

• Prenatal diagnosis: May be possible through ultrasound and molecular testing if the mutation is known

Other conditions with overlapping features, such as Pallister-Hall syndrome, may need to be ruled out through detailed genetic and clinical evaluation.

Treatment

There is no cure for Greig cephalopolysyndactyly syndrome. Treatment is supportive and tailored to each individual's symptoms:

• Surgical correction: For polydactyly and syndactyly to improve function and appearance of the hands or feet

• Physical and occupational therapy: To assist with mobility and fine motor skills

• Speech and developmental therapies: For children with cognitive or developmental delays

• Neurological monitoring: In cases with seizures or suspected brain anomalies

• Genetic counseling: For families to understand the inheritance pattern and recurrence risk

Prognosis

The prognosis for individuals with GCPS is generally good, especially in cases without significant neurological complications. Most children have normal intelligence and life expectancy, and surgical interventions can significantly improve limb function and cosmetic outcomes. In more severe cases with associated developmental delays or neurological issues, long-term care and supportive services may be needed. With appropriate medical and therapeutic management, many individuals lead full and productive lives.