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. Char syndrome is known to be associated with mutations in the TFAP2B gene.

Research testing

• Sequence analysis. TFAP2B sequence analysis is available on a research basis only. 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.

Genetically Related (Allelic) Disorders

Char syndrome is the only phenotype known to be associated with TFAP2B mutations.

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

Figure 1. Typical facial features in a woman with Char syndrome

Reprinted with permission from: Satoda et al [1999] Char syndrome, an inherited disorder with patent ductus arteriosus, maps to chromosome 6p12-p21. Circulation 99(23):3036-42 (more...)

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• Hypodontia: lack of second and/or third molars in all four quadrants [Gelb, unpublished observation; Mani et al 2005]

• 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)

• Parasomnia [Mani et al 2005]

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.

Evaluations Following Initial Diagnosis

Infants and children suspected of having Char syndrome need a careful cardiac evaluation, usually including an echocardiogram. Evaluation in the newborn nursery may not be completely informative, as the ductus arteriosus may remain open for several days in any neonate.

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 problems such as 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.

Testing 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Char syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis.— 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 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.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. No laboratories offering molecular genetic testing for prenatal diagnosis of Char syndrome are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

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 might 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). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Literature Cited

1. 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]
2. 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]
3. 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]
4. 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]
5. 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]
6. Satoda M, Gelb BD (2003) 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. Oxford University Press, San Francisco.
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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]
13. 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, Jager R, Schorle H. The AP-2 family of transcription factors. Genome Biol. 2005;6:246. [PMC free article: PMC1414101] [PubMed: 16420676]

Acknowledgments

This work was supported in part by a grant from the National Institutes of Health (HD01294) to BDG.

Revision History

• 19 March 2008 (me) Comprehensive update posted to live Web site

• 17 June 2005 (me) Comprehensive update posted to live Web site

• 15 August 2003 (ca) Review posted to live Web site

• 18 April 2003 (bg) Original submission