Char Syndrome

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 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.