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Char Syndrome
Introduction
Char syndrome is a rare autosomal dominant disorder characterized by the triad of atypical facial features, patent ductus arteriosus (PDA), and aplasia or hypoplasia of the middle phalanges of the fifth fingers.[1] Florence Char, who described a child in whom PDA was associated with low-set ears, ptosis, short philtrum, and "duck-bill" lips, first reported the syndrome in 1978.[2]
Typical facial features include a depressed nasal bridge and broad flat nasal tip, widely spaced eyes, down-slanted palpebral fissures, mild ptosis, a short philtrum with prominent philtrum ridges with an upward pointing vermilion border resulting in a triangular mouth and thickened (patulous) everted lips.[3] The most commonly identified cardiac anomaly is PDA.[1] Less common findings include other types of congenital heart defects, other hand and foot anomalies, hypodontia, hearing loss, myopia and/or strabismus, polythelia, parasomnia, craniosynostosis (involving either the metopic or sagittal suture), and short stature.[1][3][4]
Etiology
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Etiology
The exact etiology of Char syndrome is still unknown. Recent research suggests that Char syndrome may be caused by mutations in the transcription factor AP-2 Beta (TFAP2B) gene.[5] The disorder is inherited in an autosomal dominant manner, meaning that a single copy of the mutated gene is sufficient to cause the condition.[1] The condition shows complete penetrance but variable expressivity, meaning the mutated gene will always cause the disorder, but the severity of symptoms may vary.[1] Frequently noted pathogenic variants in the TFAP2B gene are missense mutations in the coding region, which is critical for DNA binding.[6][7] Other reported mutations include intronic point mutations and frameshift deletions.[5][8]
Epidemiology
Char syndrome is an extremely rare disorder, with only a few dozen cases reported worldwide.[2] The prevalence of Char syndrome is difficult to determine due to its rarity and the possibility of under-diagnosis. However, based on the limited available data, it is believed to occur in approximately 1 in every 100,000 to 200,000 births.[9] Char syndrome affects both males and females equally and has been reported in various ethnic groups.[9]
Pathophysiology
Char syndrome arises from a mutation in the TFAP2B gene.[10] This gene acts as a molecular switch controlling other genes during embryonic development. It plays a critical role in embryonic development and acts as a transcription factor that regulates the expression of genes involved in the development of the neural crest, a transient embryonic structure that gives rise to various tissues and organs, including the facial structures, the heart, and the limbs.[10] Mutations in the TFAP2B gene disrupt the normal function of the transcription factor, leading to the characteristic features observed in individuals with Char syndrome, with abnormal development of the eyes, nasal passages, heart, and other affected structures.[6][3][11]
History and Physical
The clinical presentation of Char syndrome exhibits a spectrum of severity. This variability necessitates a tailored approach to diagnosis and management for each patient.
Facial dysmorphism is a prominent feature present in >80% of the patients, often characterized by flattened cheekbones, a depressed nasal bridge, a broad and prominent nose with a short philtrum and prominent philtral ridges, mild ptosis, downward-slanted palpebral fissures with widely spaced eyes, a prominent vermilion border with upward slant forming a triangular-shaped mouth with thick and everted lips.[1][12]
Cardiac malformations are another hallmark, with PDA being the most common defect in 68% of the patients.[1] PDA is a fetal vascular connection between the main pulmonary artery and the systemic aorta that typically closes shortly after birth.[12] In individuals with Char syndrome, it can remain open, leading to left to right shunting (from systemic to pulmonary circulation), disrupting the normal blood flow, leading to increased pulmonary blood flow and pulmonary hypertension if not corrected.[1] Affected infants can present with symptoms like tachypnea, difficulty feeding, and failure to thrive. Untreated PDA, in severe cases, can contribute to cardiac failure.[1] Other potential cardiac anomalies associated with Char syndrome include septal defects and valve malformations in 6% of patients.[1][2]
Hand abnormalities are a variable feature of Char syndrome, present in 57% of the cases.[1] These can range from clinodactyly (the pinky finger may bend inwards towards the ring finger), hypoplasia or aplasia of middle phalanges of the fifth finger (under-development or complete absence of middle bone segments), syndactyly (fused fingers), or brachydactyly.[1]
Less common findings include myopia, strabismus, hearing abnormality (including profound bilateral hearing loss), skeletal anomalies, craniosynostosis (including metopic or sagittal sutures), hypodontia (lack of second or third molars), short stature and intellectual disability.[13]
Evaluation
The evaluation of individuals with suspected Char syndrome typically involves a combination of clinical assessment, imaging studies, and genetic testing. Clinical assessment includes a detailed medical history and thorough physical examination focusing on any congenital anomalies affecting the eyes, ears, heart, and teeth.[14]
Imaging studies, such as computed tomography (CT) or magnetic resonance imaging (MRI), are used to further evaluate the structural abnormalities in the eyes, ears, and other affected organs. Echocardiography is used to diagnose PDA and other associated cardiac anomalies.[15]
Genetic testing plays an important role in confirming the diagnosis of Char syndrome, identifying causative mutations, and for genetic counseling. Genetic testing can identify mutations in the gene (heterogenic pathogenic variant).[16][17] Different modalities of molecular genetic testing can include gene-targeted sequencing and whole-exome sequencing. In individuals presenting with symptoms suggestive of Char syndrome, gene-targeted sequencing such as single gene testing and multi-gene panels are used, while in individuals where Char syndrome is not considered, whole-exome sequencing or gene panel testing is utilized.[1][16] Selecting the most suitable testing requires careful analysis of clinical features, differential diagnosis, and available resources.
Treatment / Management
Management of Char syndrome requires a comprehensive, multidisciplinary approach, addressing the specific symptoms and complications associated with the disorder.[4] Understanding its etiology and pathophysiology is important in providing proper care and support. Depending on the manifestations of a particular patient, multidisciplinary teams involving various specialties, such as pediatricians, geneticists, craniofacial surgeons, cardiologists, ophthalmologists, otolaryngologists, and orthopedic surgeons, may be involved.
Treatment may include surgical correction of congenital cardiac defects, repair of choanal atresia, and management of eye and ear anomalies.[12] Therapeutic efforts prioritize the correction of hemodynamic abnormalities. Post-neonatal PDA management is guided by the degree of shunting between the aorta and the pulmonary artery.[2][18] Surgical ligation and catheter-based ductal occlusion are the definitive therapeutic options for the management of PDA.[8][19] Craniofacial surgery can address some aspects of facial dysmorphism, aiming to improve aesthetics and potentially alleviate functional difficulties. However, these procedures are complex and require careful consideration of risks and benefits. In addition, patients with Char syndrome require annual surveillance for vision and hearing, dental checkups every 6 months, assessment of signs and symptoms of sleep disorder every 6 months, and monitoring of head shape and size at every visit in infancy.[1][20] Early diagnosis and intervention are crucial to optimize developmental outcomes and quality of life.[4](B3)
Genetic counseling plays a significant role in the management of Char syndrome, providing families with information about the inheritance pattern of the condition and the potential risk of having affected offspring in future pregnancies.[1] Char syndrome follows an autosomal dominant inheritance pattern.[21] In individuals with Char syndrome who have an affected parent, there is a 50% chance of passing the mutated gene on to their children. However, Char syndrome can also occur in those with no family history of the condition due to a new mutation in the TFAP2B gene. These are known as de novo mutations, and the risk to the siblings of a proband appears to be low. Prenatal diagnosis can be performed through chorionic villus sampling (CVS) or amniocentesis to identify the presence of the mutation in the developing fetus.[5]
Differential Diagnosis
When evaluating a patient for Char syndrome, it is crucial to consider a range of differential diagnoses due to the overlap of clinical features with other genetic disorders. These conditions may share similarities in facial anomalies, congenital heart defects, and limb abnormalities, necessitating thorough genetic and clinical assessments to accurately distinguish Char syndrome from other potential diagnoses. Differential diagnoses for Char syndrome include the following:
Prognosis
The prognosis for individuals with Char syndrome can vary depending on the severity of cardiac defects and associated comorbidities. Early intervention and management of cardiac abnormalities can significantly improve outcomes and quality of life for affected individuals.[1] However, some individuals may experience long-term complications, such as intellectual disability, visual impairment, and heart failure.[4]
Complications
Char syndrome can lead to complications that significantly impact the quality of life and overall health of affected individuals. They may be at risk of various complications, including respiratory distress due to choanal atresia, feeding difficulties, hearing loss, developmental disabilities, and skeletal abnormalities.[25]
Cardiac anomalies, particularly PDA, can result in heart failure and other cardiovascular issues if not properly managed. Facial and limb abnormalities may cause functional impairments and require surgical interventions. Additionally, the psychosocial effects of visible physical anomalies can affect self-esteem and social interactions.
Deterrence and Patient Education
Due to its rarity, preventive measures for Char syndrome are limited. However, genetic counseling and prenatal testing become crucial for families with a history of the condition. Carrier screening and prenatal diagnosis options like CVS or amniocentesis can identify potential carriers and diagnose affected fetuses.
Education empowers patients and families by providing comprehensive knowledge about Char syndrome's genetics, clinical variability, and prognosis. It outlines current treatment options and future advancements and emphasizes the importance of multidisciplinary care, including medication management, complication prevention, and regular follow-up. Additionally, connecting patients and families with support resources fosters active participation in care, ultimately improving their quality of life.
Pearls and Other Issues
Char syndrome is a rare condition, and research efforts are ongoing to gain a deeper understanding of the genetic and developmental processes involved. With a limited number of reported cases, further research is needed to define the full spectrum of clinical features associated with Char syndrome. This may involve collaborative efforts at various institutions to create a large patient registry.
Advanced genetic and neuroimaging techniques can help understand the pathophysiology and identify potential genotype-phenotype correlation. This knowledge is essential for exploring potential therapeutic options, including gene therapy approaches that could offer a more definitive future solution.
Additionally, it is crucial to establish dedicated support networks for individuals and families affected by Char syndrome. These networks can provide much-needed resources, foster a sense of community, and empower individuals to navigate the challenges associated with the condition.
The complex nature of Char syndrome necessitates a comprehensive and interdisciplinary approach to care and management. Advancements in understanding its genetic basis and the development of targeted interventions will continue to improve the quality of life for individuals living with Char syndrome.
Enhancing Healthcare Team Outcomes
Char syndrome's complex presentation necessitates a collaborative approach from a well-coordinated interprofessional healthcare team. Physicians, advanced care practitioners, and nurses need strong communication skills to share observations, interpret diagnostic tests, and develop a comprehensive care plan. Pharmacists play a vital role in ensuring safe and effective medication management, while therapists can address developmental delays and improve quality of life.
Effective care coordination, facilitated by nurses and care coordinators, ensures seamless transitions between specialists and avoids treatment gaps. By working together, the team can prioritize patient-centered care, ensuring treatment decisions reflect individual and family needs and goals. This collaborative approach optimizes patient safety, improves outcomes, and ultimately enhances team performance in delivering exceptional care for individuals with Char syndrome.
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