Char Syndrome: Insights on Diagnosis and Treatment

Char syndrome is a rare genetic disorder affecting multiple systems, notably facial features, limb development, and heart structure. Present from birth, its severity varies among individuals. Early recognition is crucial for proper medical management and support.

The Role Of TFAP2B

Char syndrome stems from mutations in the TFAP2B gene, which encodes the transcription factor AP-2 beta. This protein is essential for embryonic development, influencing craniofacial structures, limb patterning, and cardiovascular tissues. As a transcription factor, AP-2 beta regulates genes involved in cellular differentiation and tissue formation. Disruptions in this network result in the syndrome’s characteristic features.

Research has shown that TFAP2B mutations typically lead to loss of function, impairing the protein’s ability to bind DNA and regulate gene expression. Studies in The American Journal of Human Genetics have identified specific missense and nonsense mutations that alter the protein’s structure, affecting transcriptional activity. These mutations interfere with neural crest cell migration, a process critical for developing facial bones, heart valves, and distal limb structures. As a result, individuals with TFAP2B mutations often exhibit a flat midface, shortened fingers, and patent ductus arteriosus (PDA), a congenital heart defect.

Animal studies reinforce the gene’s role in development. Knockout experiments in mice reveal phenotypes similar to human Char syndrome, including craniofacial abnormalities and persistent ductus arteriosus. AP-2 beta is required for proper ductus arteriosus closure after birth. Without this function, the vessel remains open, leading to abnormal circulation and increased cardiac workload.

Physical And Cardiac Characteristics

Individuals with Char syndrome display distinct physical traits affecting the face, hands, and heart. The facial anomalies are particularly recognizable—flattened midface, broad forehead, and a short nose with a flat nasal bridge. The eyes often have downward-slanting palpebral fissures and hypertelorism, an increased distance between them. The philtrum, the groove between the nose and upper lip, may be underdeveloped or absent. These features stem from disrupted neural crest cell migration during embryonic development.

Hand abnormalities, another key characteristic, primarily involve finger malformations. Brachydactyly, or shortened digits, results from underdeveloped or missing phalangeal bones. The fifth fingers may curve inward (clinodactyly), and some individuals exhibit partial webbing (soft-tissue syndactyly). These limb anomalies vary in severity but typically do not impair function.

Cardiac involvement is marked by PDA, where the ductus arteriosus fails to close after birth. This fetal blood vessel, which connects the pulmonary artery to the aorta, should close shortly after delivery. When it remains open, abnormal blood flow increases pulmonary circulation and left ventricular volume overload. If untreated, complications such as pulmonary hypertension, heart failure, and bacterial endocarditis may arise.

Echocardiography with Doppler imaging consistently identifies PDA in affected individuals. The size of the PDA determines its clinical impact—small defects may close spontaneously, while larger ones require intervention. Prostaglandin inhibitors like indomethacin or ibuprofen are sometimes used in neonates, though structural abnormalities may limit their effectiveness. In such cases, transcatheter closure with a coil or occlusion device, or surgical ligation, is necessary.

Diagnostic Factors

Diagnosing Char syndrome involves clinical examination, imaging, and genetic testing. Physicians assess characteristic physical traits, including craniofacial and hand anomalies. A detailed family history can support clinical suspicion, particularly given the syndrome’s autosomal dominant inheritance pattern. Some individuals present with subtle features, making genetic testing essential for confirmation.

Cardiac evaluation plays a key role, as PDA is nearly universal in Char syndrome. Echocardiography with Doppler imaging assesses blood flow and defect size. Cardiac MRI may provide additional details if other congenital anomalies are suspected. While PDA can occur independently, its presence alongside facial and limb anomalies strongly suggests Char syndrome, warranting further genetic investigation.

Genetic testing confirms the diagnosis by identifying pathogenic TFAP2B variants. Next-generation sequencing (NGS) panels for congenital heart defects or craniofacial syndromes often include TFAP2B, streamlining molecular diagnosis. If NGS is inconclusive, Sanger sequencing can detect known mutations. De novo mutations are common, meaning a lack of family history does not rule out the condition. Genetic counseling is recommended for affected individuals and their families.

Inheritance Patterns

Char syndrome follows an autosomal dominant inheritance pattern, meaning a single mutated TFAP2B gene copy can cause the condition. Affected individuals have a 50% chance of passing the mutation to offspring. However, many cases arise from de novo mutations, occurring spontaneously in individuals with no family history.

Variable expressivity means affected individuals may exhibit different features and severity levels. Some show the full spectrum of symptoms, while others have only mild manifestations, complicating diagnosis. Reduced penetrance further affects inheritance, as some individuals with a TFAP2B mutation may display minimal or no symptoms. This variability suggests additional genetic or environmental factors influence expression.

Differential Diagnoses

Distinguishing Char syndrome from other genetic disorders requires careful evaluation and genetic testing. Several syndromes share overlapping craniofacial, limb, or cardiac features, making differential diagnosis essential.

Holt-Oram syndrome, caused by TBX5 mutations, is a common consideration. Like Char syndrome, it involves congenital heart defects and upper limb malformations. However, Holt-Oram typically presents with more pronounced radial ray abnormalities, such as hypoplastic or absent thumbs, which are uncommon in Char syndrome. Additionally, its heart defects often extend beyond PDA, involving atrial and ventricular septal defects. Genetic testing for TBX5 helps differentiate the conditions.

Noonan syndrome, caused by mutations in the RAS/MAPK signaling pathway, also shares features with Char syndrome. Individuals with Noonan syndrome exhibit hypertelorism, a broad forehead, and a short neck, resembling Char syndrome’s craniofacial traits. However, congenital heart defects in Noonan syndrome, such as pulmonary valve stenosis and hypertrophic cardiomyopathy, differ from the isolated PDA seen in Char syndrome. Additional characteristics like short stature, pectus deformities, and developmental delays further distinguish Noonan syndrome. Molecular testing for PTPN11, SOS1, and RAF1 confirms the diagnosis when clinical presentation overlaps.