Clinical characteristics.

Char syndrome is characterized by the triad of typical facial features, patent ductus arteriosus, and aplasia or hypoplasia of the middle phalanges of the fifth fingers. Typical facial features are depressed nasal bridge and broad flat nasal tip, widely spaced eyes, downslanted palpebral fissures, mild ptosis, short philtrum with prominent philtral ridges with an upward pointing vermilion border resulting in a triangular mouth, and thickened (patulous) everted lips. Less common findings include other types of congenital heart defects, other hand and foot anomalies, hypodontia, hearing loss, myopia and/or strabismus, polythelia, parasomnia, craniosynostosis (involving either the metopic or sagittal suture), and short stature.

Diagnosis/testing.

The diagnosis of Char syndrome is established in a proband with suggestive clinical findings and/or a heterozygous pathogenic variant in TFAP2B identified by molecular genetic testing.

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. Hypodontia/tooth anomalies, vision problems, hearing loss, other hand/foot anomalies, parasomnias, and craniosynostosis are treated in a routine manner.

Surveillance: Assessment for signs and symptoms of sleep problems at each visit; monitoring of head shape and size at each visit during the first year of life; vision and hearing screening annually or as clinically indicated; dental evaluations every six months starting at age three years.

Genetic counseling.

Char syndrome is inherited in an autosomal dominant manner. The proportion of cases caused by a de novo pathogenic variant 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 pathogenic variant and having the disorder. If the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Char syndrome should be suspected in individuals with the following clinical and family history findings.

Clinical features

• Typical facial features with depressed nasal bridge and broad flat nasal tip, widely spaced eyes, downslanted palpebral fissures, mild ptosis, short philtrum with prominent philtral ridges with an upward pointing vermilion border resulting in a triangular mouth, and thickened (patulous) everted lips
• Patent ductus arteriosus
• Aplasia or hypoplasia of the middle phalanges of the fifth fingers

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of Char syndrome is established in a proband with suggestive clinical findings and/or a heterozygous pathogenic variant in TFAP2B identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Char syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Char syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

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.

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:

• Other heart defects (e.g., muscular ventricular septal defects, complex congenital defects)
• Other hand abnormalities including interstitial polydactyly [Slavotinek et al 1997], distal symphalangism of the fifth fingers (fusion of distal interphalangeal joints), and hypoplasia of the third fingers [Babaoğlu et al 2012]
• Foot anomalies including interphalangeal joint fusion or clinodactyly [Sweeney et al 2000], interstitial polydactyly [Slavotinek et al 1997], and syndactyly [Slavotinek et al 1997]
• Hypodontia. Lack of second and/or third molars in all four quadrants [Mani et al 2005; Author, unpublished observation]
• Visual impairment. Myopia [Bertola et al 2000], strabismus [Bertola et al 2000, Sweeney et al 2000]
• Hearing abnormalities including profound bilateral hearing loss in two affected individuals [Edward et al 2019; Author, unpublished observation in a member of the enlarged version of the original family studied by Char]
• Polythelia (supernumerary nipples) [Zannolli et al 2000]
• Parasomnia [Mani et al 2005]
• Craniosynostosis involving either the metopic or sagittal suture reported in four affected individuals [Timberlake et al 2019]
• Short stature (≤3 SD below the mean) reported in two affected individuals [Massaad et al 2019, Timberlake et al 2019]

Genotype-Phenotype Correlations

Among the 16 different pathogenic variants in TFAP2B described in publications, seven are loss-of-function alleles and nine are missense changes. For the latter, eight of the nine alter residues in the DNA binding domain (basic domain; residues 223-301) and one is in the transactivation domain (residues 65-86).

• Individuals harboring basic domain alleles tend to have the classic form of Char syndrome (97% with facial features, 58% with PDA, and 79% with hand anomalies) [Satoda et al 1999, Satoda et al 2000, Zhao et al 2001].
• For individuals in the one family inheriting the transactivation domain-altering variant, the facial features were prevalent (14/14) but mild, PDA was generally present (10/14), but hand anomalies were not observed in any [Zhao et al 2001].
• The phenotypes associated with loss-of-function pathogenic variants often included PDA (32/40; 80%) but facial features of Char syndrome were less prevalent (23/39; 59%); features in these individuals not observed in those with missense variants included craniosynostosis (n = 3) and short stature (n = 2) [Massaad et al 2019, Timberlake et al 2019].

Penetrance

The penetrance of Char syndrome has not been formally determined. Two asymptomatic individuals with TFAP2B pathogenic variants have been described [Mani et al 2005, Timberlake et al 2019].

Prevalence

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

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Char syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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.

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 in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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 a de novo pathogenic variant. The proportion of individuals with Char syndrome caused by a de novo pathogenic variant is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent negative family history include molecular genetic testing (if a TFAP2B pathogenic variant has been identified in the proband), 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.
• If the proband has a known TFAP2B pathogenic variant that cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent.* Though theoretically possible, no instance of a proband inheriting a pathogenic variant from a parent with germline mosaicism has been reported.
  * Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
• The family history of some individuals diagnosed with Char syndrome may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation and/or molecular genetic testing (if the causative variant in the proband is known) to establish that neither parent is heterozygous for the causative pathogenic variant.

Sibs of a proband. The risk to sibs of a proband depends on the clinical/genetic status of the parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known TFAP2B pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but have not undergone molecular genetic testing (and/or a pathogenic variant has not been identified in the proband), the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Char syndrome because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a TFAP2B pathogenic variant has a 50% chance of inheriting the pathogenic variant and having Char syndrome.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or is known to have a TFAP2B pathogenic variant, the parent's family members are at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the TFAP2B pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for Char syndrome are possible.

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 has no diagnostic value 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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TFAP2B encodes a transcription factor belonging to the AP-2 class. AP-2 transcription factors act as dimers, either as homodimers (e.g., AP-2β/AP-2b) or as heterodimers (AP-2α/AP-2β). AP-2 dimers bind DNA sequence targets with their basic domains (also known as the DNA binding domain) and have transactivation domains, which affect the transcriptional effects.

Mechanism of disease causation. Evidence for dominant negative AND loss of function. The pathogenic missense variants associated with Char syndrome predominantly alter the basic domain. The effects of those missense alterations appear to be dominant negative, either through altered DNA binding of AP-2 dimers or altered transactivation [Satoda et al 2000, Zhao et al 2001]. In contrast, loss-of-function alleles are likely to act through haploinsufficiency.

Acknowledgments

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

Revision History

• 21 May 2020 (ma) Comprehensive update posted live
• 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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