3C syndrome

Overview

3C syndrome, also known as Ritscher–Schinzel syndrome, is a rare autosomal recessive genetic disorder characterized by a triad of major abnormalities: craniofacial defects, cerebellar malformations, and cardiac anomalies, hence the name "3C." First described in the 1980s, the condition has since been recognized as a multisystem disorder with wide clinical variability. Individuals with 3C syndrome typically present during infancy or early childhood with features affecting the brain, heart, and facial structure, though the severity and range of symptoms can vary.

Causes

3C syndrome is caused by mutations in the KIAA0196 gene, which encodes a protein known as strumpellin. This protein plays a role in intracellular signaling, endosomal transport, and actin cytoskeleton dynamics, which are important for cell function and development, particularly in neural and cardiac tissues.

The condition is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the mutated gene - one from each parent-to develop the disorder. Parents of an affected child are typically carriers without symptoms.

Symptoms

3C syndrome is defined by the following core features, though additional symptoms may also be present:

• Craniofacial anomalies: Including a prominent forehead, flat nasal bridge, hypertelorism (wide-set eyes), low-set ears, and cleft palate

• Cerebellar malformations: Often including Dandy–Walker malformation (a structural abnormality of the cerebellum and fourth ventricle), hydrocephalus, or cerebellar hypoplasia

• Cardiac defects: Most commonly atrioventricular septal defects, ventricular septal defects (VSD), or other congenital heart abnormalities

Additional signs and symptoms may include:

• Developmental delay or intellectual disability

• Seizures

• Feeding difficulties in infancy

• Growth retardation

• Hypotonia (low muscle tone)

• Kidney or urogenital anomalies (less commonly)

Diagnosis

Diagnosis of 3C syndrome is based on clinical features, neuroimaging, and genetic testing. Diagnostic steps include:

• Clinical evaluation: Observation of characteristic facial features, growth patterns, and developmental concerns

• Brain imaging (MRI or CT): To detect cerebellar malformations such as Dandy–Walker anomaly

• Echocardiogram: To identify congenital heart defects

• Genetic testing: Identification of mutations in the KIAA0196 gene confirms the diagnosis

• Family history analysis: May be helpful in identifying carrier status in consanguineous families

Treatment

There is no cure for 3C syndrome. Treatment is supportive and tailored to the individual’s specific symptoms. A multidisciplinary care team is often required. Management includes:

• Cardiac surgery or medical management: For congenital heart defects

• Neurosurgical care: For hydrocephalus (may require a ventriculoperitoneal shunt)

• Physical, occupational, and speech therapy: To address developmental and motor delays

• Feeding support: For infants with poor feeding or cleft palate

• Educational support: Special education services as needed

• Seizure management: If epilepsy is present

Prognosis

The prognosis for individuals with 3C syndrome varies depending on the severity of heart and brain malformations. Some children with mild symptoms may live into adulthood with appropriate medical and educational support. However, in more severe cases - particularly those with complex cardiac or neurological defects, life expectancy may be significantly reduced. Early diagnosis, coordinated care, and regular monitoring are crucial to improving quality of life and developmental outcomes.