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Char Syndrome

, MD
Pediatrics and Genetics and Genomic Sciences
Icahn School of Medicine at Mount Sinai
New York, New York

Initial Posting: ; Last Update: January 24, 2013.

Summary

Disease characteristics. 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.

Diagnosis/testing. 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.

Management. 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.

Genetic counseling. Char syndrome is inherited in an autosomal dominant manner. The proportion of cases caused by de novo mutations 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.

Diagnosis

Clinical Diagnosis

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 mutations are known to cause Char syndrome.

Research testing

Table 1. Summary of Molecular Genetic Testing Used in Char Syndrome

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
TFAP2BSequence analysis TFAP2B mutations 2~50%

1. 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.

Clinical Description

Natural History

Char syndrome is characterized by the triad of typical facial features (see Figure 1), patent ductus arteriosus (PDA), and stereotypic hand anomalies (see Diagnosis).

Figure 1

Figure

Figure 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:

Genotype-Phenotype Correlations

Five 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.

Penetrance

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

Anticipation has not been described in Char syndrome.

Prevalence

The prevalence of Char syndrome has not been determined but is thought to be quite low.

Differential Diagnosis

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].

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:

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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.

Surveillance

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

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

This section is written from the perspective that clinical testing for this disorder is available and results can be used for clinical purposes. However, it is the responsibility of the clinician to ascertain whether such testing is available for a specific patient.— ED.

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 a de novo gene mutation. The proportion of cases caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an 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 an 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 a 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.

Family planning

  • 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. 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.

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.

Resources

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.

  • Children's Heart Foundation
    PO Box 244
    Lincolnshire IL 60069-0244
    Phone: 888-248-8140 (toll-free); 847-634-6474
    Fax: 847-634-4988
    Email: info@childrensheartfoundation.org
  • Congenital Heart Information Network (CHIN)
    101 North Washington Avenue
    Suite 1A
    Margate City NJ 08402-1195
    Phone: 609-822-1572
    Fax: 609-822-1574
    Email: mb@tchin.org

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
TFAP2B6p12​.3Transcription factor AP-2 betaTFAP2B homepage - Mendelian genesTFAP2B

Data 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)

169100CHAR SYNDROME
601601TRANSCRIPTION FACTOR AP2-BETA; TFAP2B

Normal 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

Class of Variant AlleleDNA Nucleotide Change
(Alias 1 )
Protein Amino Acid ChangeReference Sequences
Normal c.411C>Ap.Asp137GluX95694​.1
c.739T>Gp.Ser247Ala
Pathologic c.185C>Gp.Pro62Arg
c.600+5G>A
(IVS3+5G>A)
--
c.673C>Tp.Arg225Cys 2
c.673C>Ap.Arg225Ser 2
c.706C>Tp.Arg236Cys 2
c.791C>Ap.Ala264Asp 2
c.821G>Ap.Arg274Gln 2
c.821-1G>C
(IVS4-1G>C)
--
c.865C>Tp.Arg289Cys 2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Six mutations that affect the basic domain

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.

References

Literature Cited

  1. 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]
  2. Bertola DR, Kim CA, Sugayama SM, Utagawa CY, Albano LM, Gonzalez CH. Further delineation of Char syndrome. Pediatr Int. 2000;42:85–8. [PubMed: 10703243]
  3. Char F. Peculiar facies with short philtrum, duck-bill lips, ptosis and low-set ears--a new syndrome? Birth Defects Orig Artic Ser. 1978;14:303–5. [PubMed: 728571]
  4. 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]
  5. Gelb BD, Zhang J, Sommer RJ, Wasserman JM, Reitman MJ, Willner JP. Familial patent ductus arteriosus and bicuspid aortic valve with hand anomalies: a novel heart-hand syndrome. Am J Med Genet. 1999;87:175–9. [PubMed: 10533032]
  6. Khetyar M, Syrris P, Tinworth L, Abushaban L, Carter N. Novel TFAP2B mutation in nonsyndromic patent ductus arteriosus. Genet Test. 2008;12:457–9. [PubMed: 18752453]
  7. Mani A, Meraji SM, Houshyar R, Radhakrishnan J, Mani A, Ahangar M, Rezaie TM, Taghavinejad MA, Broumand B, Zhao H, Nelson-Williams C, Lifton RP. Finding genetic contributions to sporadic disease: a recessive locus at 12q24 commonly contributes to patent ductus arteriosus. Proc Natl Acad Sci U S A. 2002;99:15054–9. [PMC free article: PMC137543] [PubMed: 12409608]
  8. Mani A, Radhakrishnan J, Farhi A, Carew KS, Warnes CA, Nelson-Williams C, Day RW, Pober B, State MW, Lifton RP. Syndromic patent ductus arteriosus: evidence for haploinsufficient TFAP2B mutations and identification of a linked sleep disorder. Proc Natl Acad Sci U S A. 2005;102:2975–9. [PMC free article: PMC549488] [PubMed: 15684060]
  9. Satoda M, Gelb BD. Char syndrome and TFAP2B. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis. San Francisco, CA: Oxford University Press; 2003:798-803.
  10. Satoda M, Pierpont ME, Diaz GA, Bornemeier RA, Gelb BD. Char syndrome, an inherited disorder with patent ductus arteriosus, maps to chromosome 6p12-p21. Circulation. 1999;99:3036–42. [PubMed: 10368122]
  11. Satoda M, Zhao F, Diaz GA, Burn J, Goodship J, Davidson HR, Pierpont ME, Gelb BD. Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nat Genet. 2000;25:42–6. [PubMed: 10802654]
  12. Slavotinek A, Clayton-Smith J, Super M. Familial patent ductus arteriosus: a further case of CHAR syndrome. Am J Med Genet. 1997;71:229–32. [PubMed: 9217229]
  13. Sweeney E, Fryer A, Walters M. Char syndrome: a new family and review of the literature emphasising the presence of symphalangism and the variable phenotype. Clin Dysmorphol. 2000;9:177–82. [PubMed: 10955477]
  14. Zannolli R, Mostardini R, Matera M, Pucci L, Gelb BD, Morgese G. Char syndrome: an additional family with polythelia, a new finding. Am J Med Genet. 2000;95:201–3. [PubMed: 11102923]
  15. Zhao F, Weismann CG, Satoda M, Pierpont ME, Sweeney E, Thompson EM, Gelb BD. Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation. Am J Hum Genet. 2001;69:695–703. [PMC free article: PMC1226056] [PubMed: 11505339]
  16. Zhu L, Vranckx R, Khau Van Kien P, Lalande A, Boisset N, Mathieu F, Wegman M, Glancy L, Gasc JM, Brunotte F, Bruneval P, Wolf JE, Michel JB, Jeunemaitre X. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006;38:343–9. [PubMed: 16444274]

Suggested Reading

  1. Eckert D, Buhl S, Weber S, Jäger R, Schorle H. The AP-2 family of transcription factors. Genome Biol. 2005;6:246. [PMC free article: PMC1414101] [PubMed: 16420676]

Chapter Notes

Acknowledgments

This work was supported in part by a grant from the National Institutes of Health (HL098123) to BDG.

Revision History

  • 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
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