DiagnosisClinical DiagnosisThe diagnosis of Char syndrome is established by the presence of the following clinical features:Typical facial features with flat midface, flat nasal bridge and broad flat nasal tip, wide-set eyes, downslanting palpebral fissures, mild ptosis, short philtrum with prominent philtral pillars with an upward pointing vermilion border resulting in a triangular mouth, and thickened (patulous) everted lips [Char 1978]Patent ductus arteriosus (PDA) Aplasia or hypoplasia of the middle phalanges of the fifth fingers Molecular Genetic TestingGene. TFAP2B is the only gene in which mutations are known to cause Char syndrome. Research testing Table 1. Summary of Molecular Genetic Testing Used in Char SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ¹ Test AvailabilityTFAP2BSequence analysis TFAP2B mutations ^{2~50%Research only1. Satoda & Gelb [2003]2. Because the disease-causing mutations identified to date all result in mutant protein with dominant negative effects, it is likely that mutations will be missense defects in the coding region for critical domains, particularly the basic domain. Rare mutations altering splice sites, engendering haploinsufficiency, have also been reported [Mani et al 2005] Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. The diagnosis of Char syndrome is established in a proband by clinical findings. TFAP2B sequence analysis detects mutations in about 50% of affected individuals. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersTFAP2B mutations have been found in individuals with PDA but without other features of Char syndrome (nonsyndromic PDA) [Khetyar et al 2008, Chen et al 2011].}

Natural HistoryChar syndrome is characterized by the triad of typical facial features (see Figure 1), patent ductus arteriosus (PDA), and stereotypic hand anomalies (see Diagnosis). FigureFigure 1. Typical facial features in a woman with Char syndrome
Reprinted with permission from Satoda et al [1999] PDA. The ductus arteriosus, the fetal arterial connection between the aorta and pulmonary artery that shunts blood away from the lungs, constricts shortly after birth. If the ductus arteriosus remains patent, left to right shunting (from the systemic circulation into the pulmonary circulation) occurs, resulting in pulmonary hypertension if not corrected. No information is available concerning the likelihood of spontaneous closure of a PDA after the first weeks of life in individuals with Char syndrome, but it is likely to be rather low. Less common features associated with Char syndrome: Polythelia (supernumerary nipples) [Zannolli et al 2000] Hypodontia: lack of second and/or third molars in all four quadrants [Mani et al 2005; Gelb, unpublished observation] Foot anomalies: interphalangeal joint fusion or clinodactyly [Sweeney et al 2000], interstitial polydactyly [Slavotinek et al 1997], syndactyly [Slavotinek et al 1997] Hearing abnormalities: profound bilateral hearing loss in one affected individual [Gelb, unpublished observation in a member of the enlarged version of the original family studied by Char] Visual impairment: myopia [Bertola et al 2000]; strabismus [Bertola et al 2000, Sweeney et al 2000] Developmental delay: mild to moderate Other heart defects (e.g., muscular ventricular septal defects, complex congenital defects) Other hand abnormalities: interstitial polydactyly [Slavotinek et al 1997]; distal symphalangism of the fifth fingers (fusion of distal interphalangeal joints), hypoplasia of the third fingers [Babaoğlu et al 2012].Parasomnia [Mani et al 2005]

Genotype-Phenotype CorrelationsFive of the eight TFAP2B mutations discussed in Satoda et al [2000], Zhao et al [2001], and Mani et al [2005] affect DNA binding, while one mutation, p.Pro62Arg, affects the transactivation domain; two mutations are intronic and predicted to result in haploinsufficiency. The family bearing the p.Pro62Arg mutation consistently had much milder facial dysmorphism and none of the 14 affected members had hand defects. In contrast, the prevalence of PDA and other cardiovascular defects was high. It remains to be explained why the cardiovascular anomalies were so prevalent, especially in light of the mild facial features and normal hands, while basic domain mutations have resulted in striking facial dysmorphia and hand anomalies but far lower prevalence of PDA.

Differential DiagnosisFacial features. The typical facial features associated with Char syndrome are usually striking and not often confused with facial features observed in other disorders. The facial profile is similar to that of maxillonasal dysplasia (Binder syndrome). Patent ductus arteriosus (PDA) constitutes about 10% of all congenital heart disease. Isolated PDA (in the absence of other congenital heart defects) occurs in about one in 2000 full-term infants. PDA is considerably more common in premature infants. It is one of the cardiac lesions observed in congenital rubella syndrome. PDA occurs in autosomal dominant and recessive disorders that are nonsyndromic [Mani et al 2002]. Screening of a group of individuals with isolated PDA rarely revealed the presence of TFAP2B mutations [Khetyar et al 2008, Chen et al 2011]. Thoracic aortic aneurysm/dissection with PDA is a related autosomal dominant disorder that includes thoracic aortic aneurysms (which can dissect) and PDA. It is genetically distinct from Char syndrome, being caused by mutations in the gene encoding myosin heavy chain 11 [Zhu et al 2006]. See Thoracic Aortic Aneurysms and Aortic Dissections.Hand anomalies. The hand anomalies associated with Char syndrome can be as minimal as fifth finger clinodactyly, which can be a normal finding and overlaps with numerous other syndromes. Heart-hand syndromes. A related heart-hand syndrome includes PDA, bicuspid aortic valve, and hand anomalies (fifth metacarpal hypoplasia and brachydactyly), but normal facies [Gelb et al 1999]. This disorder is genetically distinct from Char syndrome, documented using linkage exclusion for the TFAP2B locus. Other heart-hand disorders to consider:Holt-Oram syndrome Tabatznik syndrome Heart-hand type III Thrombocytopenia-absent radius syndrome Ulnar-mammary syndrome Rubinstein-Taybi syndrome Simpson-Golabi-Behmel syndrome Robinow syndrome Ellis-van Creveld syndrome Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with Char syndrome, the following evaluations are recommended:In infants and children suspected of having Char syndrome: a careful cardiac evaluation, usually including an echocardiogram
Note: Evaluation in the newborn nursery may not be completely informative, as the ductus arteriosus may remain open for several days in any neonate.Medical genetics consultationTreatment of ManifestationsThe major focus for managing individuals with Char syndrome concerns the cardiovascular involvement. Management of patent ductus arteriosus (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 at catheterization are treatment options.The most striking external aspects of Char syndrome, namely the dysmorphia and hand anomalies, require no special care early in life. The dysmorphic features do become important as affected individuals go through childhood and adolescence because of their stigmatizing effects. No data on the success of plastic surgical intervention for the facial features in Char syndrome are available.SurveillanceChildren with Char syndrome need pediatric attention during infancy and childhood.Although certain medical concerns including hearing loss, visual problems, and developmental delay are relatively rare among affected children, their prevalence is greater than in the general population. Ongoing developmental assessment for affected children by a pediatrician may be beneficial so that early intervention can be provided as needed.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Char Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTFAP2B6p12​.3Transcription factor AP-2 betaTFAP2B homepage - Mendelian genesTFAP2BData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Char Syndrome (View All in OMIM) View in own window 169100CHAR SYNDROME 601601TRANSCRIPTION FACTOR AP2-BETA; TFAP2BNormal allelic variants. The cDNA has a coding region of 1350 bp and an overall size of approximately 2 kb. Two TFAP2B coding variants are present in the SNP database: c.411C>A (p.Asp137Glu) and c.739T>G (p.Ser247Ala) (see Table 2). Pathologic allelic variants. Nine TFAP2B mutations have been reported in seven unrelated individuals and families with Char syndrome [Satoda et al 2000, Zhao et al 2001, Mani et al 2005, Babaoğlu et al 2012] (see Table 2). Six of the mutations affect the basic domain. The seventh missense mutation, p.Pro62Arg, alters the PY motif in the transactivation domain. All of these missense changes affect highly conserved residues. Among the six basic domain mutations, five affect arginine residues. This is attributed to the fact that those residues are generally important for DNA binding by transcription factors and that four of the six codons encoding arginine residues contain a CpG dinucleotide. The remaining two mutations affect introns [Mani et al 2005]. (For more information, see Table A.)Table 2. Selected TFAP2B Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹ )Protein Amino Acid ChangeReference SequencesNormal c.411C>Ap.Asp137GluX95694​.1 c.739T>Gp.Ser247AlaPathologic c.185C>Gp.Pro62Argc.600+5G>A
(IVS3+5G>A)--c.673C>Tp.Arg225Cys ² c.673C>Ap.Arg225Ser ² c.706C>Tp.Arg236Cys ^{2c.791C>Ap.Ala264Asp 2 c.821G>Ap.Arg274Gln 2 c.821-1G>C
(IVS4-1G>C)--c.865C>Tp.Arg289Cys 2 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventions 2. Six mutations that affect the basic domainNormal gene product: Transcription factor AP-2β. Proteins in the family of AP-2β transcription factors have a highly conserved structure. The N-terminal half of the protein comprises a transactivation domain, which is the least well-conserved domain among this family of proteins. With the exception of transcription factor AP-2δ, all of the AP-2 proteins contain a PY motif in the transactivation domain. The C-terminal half of the protein, which is highly conserved, contains a basic domain and the helix-span-helix domain. The former is critical for DNA binding and the latter for dimerization. Abnormal gene product: Among the seven transcription factor AP-2β missense mutations reported to date, six affect the basic domain. Analysis in vitro and in cell culture document varying degrees of impairment in DNA binding, both as homodimers and heterodimers, as well as in transactivation [Satoda et al 2000, Zhao et al 2001]. Dimerization appears to be normal. The effects of these mutations are dominant negative since they interfere with the function of normal AP-2 proteins with which they are co-expressed. The seventh mutant affects the PY motif in the transactivation domain. This mutant protein has preserved DNA binding function, but has dominant-negative effects on transactivation. The intron 3 mutation (c.600+5G>A) causes aberrant splicing of exon 3 with exon skipping, resulting in a frameshift that creates a premature stop codon and likely results in nonsense-mediated decay of the transcript [Mani et al 2005]. Thus, this molecular defect causes haploinsufficiency. The other intronic mutation has not been formally tested but would be expected to have similar adverse effects, resulting in haploinsufficiency.}