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A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the triad of patent ductus arteriosus (PDA), facial dysmorphism (wide-set eyes, downslanting palpebral fissures, mild ptosis, flat midface, flat nasal bridge and upturned nasal tip, short philtrum with a triangular mouth, and thickened, everted lips) and hand anomalies (aplasia or hypoplasia of the middle phalanges of the fifth fingers).
ORPHA:46627Classification level: Disorder
Approximately 100 individuals from 13 families have been reported in the medical and scientific literature.
Typical facial features include wide-set eyes, downslanting palpebral fissures, mild ptosis, flat midface, flat nasal bridge, upturned nasal tip, a short philtrum, a triangular mouth, and thickened (patulous) everted lips. Hand abnormalities include aplasia or hypoplasia of the middle phalanges of the fifth fingers but can also be as minimal as fifth finger clinodactyly, which can be a normal finding and overlaps with numerous other syndromes. Less common features associated with Char syndrome include additional heart defects (such as interventricular communication or complex congenital defects), additional hand abnormalities (such as interstitial polydactyly, distal symphalangism of the fifth fingers, fusion of the distal interphalangeal joints), polythelia, foot anomalies (interphalangeal joint fusion, clinodactyly, interstitial polydactyly, or syndactyly), strabismus, mild to moderate developmental delay, prominent occiput, persistence of the deciduous teeth in the absence of permanent dentition, and somnambulism.
Causal mutations have been identified in the TFAP2B gene (chromosome 6p12.3), encoding a member of the AP-2 family of transcription factors. TFAP2B sequence analysis detects pathogenic variants in approximately 50% of affected individuals. The pathogenic variant p.Pro63Arg is associated with a less severe phenotype with mild facial dysmorphism, PDA and absence of hand anomalies. TFAP2B mutations have also been reported in familial patent arterial duct.
The diagnosis is established by the presence of the key clinical features. Differential diagnosis The associated facial features associated are not often confused with those observed in other disorders. The primary differential diagnosis includes other heart-hand syndromes (including Holt-Oram syndrome, Tabatznik syndrome, and heart-hand type III).
Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the pathogenic variant in the family. In at-risk pregnancies, prenatal ultrasound examination may identify abnormal hands or feet, as well as complex congenital heart defects. PDA is a normal fetal feature and cannot be used as a diagnostic marker in utero.
The pattern of inheritance is autosomal dominant but may arise de novo. Where the parent is affected, the sibling recurrence risk is 50%. In sporadic cases, the sibling recurrence risk is very low (<1%) due to the theoretical possibility of gonadal mosaicism in a parent.
Management and treatment
The major focus for management and treatment is the cardiovascular involvement. Management of PDA after the immediate newborn period is determined by the degree of shunting from the aorta to the pulmonary artery. Surgical ligation or ductal occlusion with catheterization are treatment options. Early special care for the dysmorphia and hand anomalies is not required but plastic surgery may be considered later in life. The outcomes of plastic surgery for the facial features are unknown. Preventive pediatric care should be offered for the associated anomalies (including visual problems and developmental delay).
The prognosis depends on the potential presence of associated heart malformations. Early intervention of the additional anomalies can improve outcomes.
- Clinical genetics review
- English (2013)