Acrocallosal syndrome

Overview

Acrocallosal syndrome is a rare genetic disorder characterized by a combination of corpus callosum agenesis or hypoplasia (partial or complete absence of the structure that connects the two brain hemispheres), craniofacial anomalies, digital malformations, and intellectual disability. The syndrome typically presents in infancy or early childhood and may also include neurological abnormalities such as seizures and hypotonia. First described in the 1970s, acrocallosal syndrome is now known to result from mutations in specific genes affecting early brain and skeletal development.

Causes

Acrocallosal syndrome is most commonly caused by mutations in the KIF7 or GLI3 gene. These genes are involved in the sonic hedgehog (SHH) signaling pathway, which is critical for the development of the brain, limbs, and face during embryogenesis.

The syndrome is inherited in an autosomal recessive pattern, meaning that a child must inherit two copies of the mutated gene, one from each parent, to be affected. Consanguinity (parents being related by blood) is often reported in affected families.

Symptoms

Acrocallosal syndrome presents with a wide range of clinical features that can vary in severity. Common signs and symptoms include:

Neurological Features:

• Partial or complete agenesis of the corpus callosum

• Intellectual disability or developmental delay

• Hypotonia (low muscle tone)

• Seizures (in some cases)

Craniofacial Abnormalities:

• Macrocephaly (large head circumference)

• Prominent forehead

• Hypertelorism (widely spaced eyes)

• Depressed nasal bridge

Limb and Digital Anomalies:

• Polydactyly (extra fingers or toes), typically postaxial

• Syndactyly (fusion of digits)

• Clubfoot or other foot deformities

Additional findings may include feeding difficulties, delayed milestones, and in rare cases, structural heart or kidney anomalies.

Diagnosis

Diagnosis of acrocallosal syndrome is based on clinical evaluation and confirmed by imaging and genetic testing. Diagnostic steps include:

• Brain imaging (MRI or CT): To detect agenesis or hypoplasia of the corpus callosum

• Physical examination: To identify craniofacial and limb anomalies

• Developmental assessments: To evaluate cognitive and motor delays

• Genetic testing: Identification of pathogenic variants in KIF7 or GLI3

• Family history review: Especially important in consanguineous families

Treatment

There is no cure for acrocallosal syndrome, but treatment is supportive and focuses on managing the specific symptoms and improving the child’s developmental outcomes. A multidisciplinary team is often required. Key aspects of management include:

• Early intervention therapies: Including physical, occupational, and speech therapy

• Management of seizures: With antiepileptic drugs if present

• Surgical correction: For polydactyly, syndactyly, or other limb deformities

• Special education services: Tailored learning plans for intellectual disability

• Ongoing developmental monitoring: By neurology, orthopedics, and genetics specialists

Prognosis

The prognosis for individuals with acrocallosal syndrome varies depending on the severity of brain malformations and the degree of developmental delay. While many children will have significant intellectual and motor impairments, early supportive therapies can enhance function and quality of life. Seizures and other complications can often be controlled with medical care. Lifespan is not well documented but may be shortened in cases with severe organ anomalies or profound neurological deficits. With proper support, some individuals may achieve limited independence in adulthood.