Char syndrome is characterized by the triad of typical facial features, patent ductus arteriosus (PDA), and aplasia or hypoplasia of the middle phalanges of the fifth fingers. Typical facial features are flat midface, flat nasal bridge and broad flat nasal tip, wide-set eyes, downslanting palpebral fissures, mild ptosis, short philtrum resulting in a triangular mouth, and thickened (patulous) everted lips.
The diagnosis of Char syndrome is established by clinical findings. TFAP2B is the only gene in which mutations are known to cause Char syndrome. TFAP2B sequence analysis detects mutations in about 50% of affected individuals.
Treatment of manifestations: Management of patent ductus arteriosus after the immediate newborn period is determined by the degree of shunting from the aorta to the pulmonary artery; options are surgical ligation or ductal occlusion at catheterization. Hearing loss, visual problems, and developmental delay are treated in a routine manner.
Char syndrome is inherited in an autosomal dominant manner. The proportion of cases caused by de novo mutation is unknown. If a parent of the proband is affected, the risk to the sibs is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. Each child of an individual with Char syndrome has a 50% chance of inheriting the mutation and having the disorder. If the disease-causing mutation has been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.
The 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 Testing
Gene. TFAP2B is the only gene in which mutation is known to cause Char syndrome.
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.
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]
- 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]
- Developmental delay: mild to moderate
- Other heart defects (e.g., muscular ventricular septal defects, complex congenital defects)
- Parasomnia [Mani et al 2005]
Five of the eight TFAP2B mutations discussed in Satoda et al , Zhao et al , and Mani et al  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.
The penetrance of Char syndrome has not been determined formally. One asymptomatic individual with a TFAP2B disease-causing mutation has been described [Mani et al 2005].
Anticipation has not been described in Char syndrome.
The prevalence of Char syndrome has not been determined but is thought to be quite low.
Genetically Related (Allelic) Disorders
Facial 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].
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:
- Tabatznik syndrome
- Heart-hand type III
- Ulnar-mammary syndrome
- Ellis-van Creveld syndrome
Evaluations Following Initial Diagnosis
To 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 consultation
Treatment of Manifestations
The 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.
Children 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 Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search 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.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
Mode of Inheritance
Char syndrome is inherited in an autosomal dominant manner.
Risk to Family Members
Parents of a proband
- Some individuals diagnosed with Char syndrome have an affected parent.
- A proband with Char syndrome may have the disorder as the result of de novo gene mutation. The proportion of cases caused by de novo mutation is unknown.
- Recommendations for the evaluation of parents of a proband with apparent de novo mutation include a physical examination focusing on the facial appearance, heart, and extremities, radiographs if abnormalities of the hands or feet are detected, and echocardiogram if the cardiac exam is abnormal.
Sibs of a proband
- The risk to sibs of a proband depends on the genetic status of the parents.
- If a parent of the proband is affected, the risk to the sibs is 50%.
- When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
- Although no instances of germline mosaicism have been reported, it remains a possibility.
Offspring of a proband. Each child of an individual with Char syndrome has a 50% chance of inheriting the mutation and having the disorder.
Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.
Related Genetic Counseling Issues
Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (i.e., with assisted reproduction) or undisclosed adoption could also be considered.
- The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
- It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
Molecular genetic testing. If the disease-causing mutation has been identified in an affected family member, prenatal testing for at-risk pregnancies may be available from a clinical laboratory that offers either prenatal testing for the gene of interest or custom testing.
Ultrasound examination. For pregnancies at increased risk, prenatal ultrasound examination may identify abnormal hands or feet as well as complex congenital heart defects. Since patent ductus arteriosus is a normal feature in fetuses, it cannot be used diagnostically in utero.
The prenatal finding of complex congenital heart disease could alter the management of the infant at birth as well as suggest a need to change the delivery site to a center able to provide urgent interventions for complex heart defects.
Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- My46 Trait Profile
- Children's Heart FoundationPO Box 244Lincolnshire IL 60069-0244Phone: 888-248-8140 (toll-free); 847-634-6474Fax: 847-634-4988Email: email@example.com
- Congenital Heart Information Network (CHIN)101 North Washington AvenueSuite 1AMargate City NJ 08402-1195Phone: 609-822-1572Fax: 609-822-1574Email: firstname.lastname@example.org
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Gene structure. The cDNA has a coding region of 1350 bp and an overall size of approximately 2 kb. For a detailed summary of gene and protein information, see Table A, Gene.
Benign allelic variants. Two TFAP2B coding variants are present in the SNP database: c.411C>A (p.Asp137Glu) and c.739T>G (p.Ser247Ala) (see Table 2).
Pathogenic 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.)
Normal 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.
- Babaoğlu K, Oruç M, Günlemez A, Gelb BD. Char syndrome, a familial form of patent ductus arteriosus, with a new finding: hypoplasia of the 3rd finger. Anadolu Kardiyol Derg. 2012;12:523–4. [PubMed: 22728731]
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- Chen YW, Zhao W, Zhang ZF, Fu Q, Shen J, Zhang Z, Ji W, Wang J, Li F. Familial nonsyndromic patent ductus arteriosus caused by mutations in TFAP2B. Pediatr Cardiol. 2011;32:958–65. [PubMed: 21643846]
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This work was supported in part by a grant from the National Institutes of Health (HL098123) to BDG.
- 24 January 2013 (me) Comprehensive update posted live
- 19 March 2008 (me) Comprehensive update posted live
- 17 June 2005 (me) Comprehensive update posted live
- 15 August 2003 (ca) Review posted live
- 18 April 2003 (bg) Original submission
Icahn School of Medicine at Mount Sinai
New York, New York
Initial Posting: August 15, 2003; Last Update: January 24, 2013.
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Gelb BD. Char Syndrome. 2003 Aug 15 [Updated 2013 Jan 24]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.