Char Syndrome

A number sign (#) is used with this entry because of evidence that Char syndrome (CHAR) is caused by heterozygous mutation in the TFAP2B (601601) gene on chromosome 6p12.

Clinical Features

Davidson (1993) described a large family in which 9 members in 6 sibships in 3 generations had patent ductus arteriosus (PDA; see 607411) in association with unusual facial features, namely, broad, high forehead, flat profile, and short nose with a broad, flattened tip. The facial features appeared to follow an autosomal dominant pedigree pattern with at least 1 instance of male-to-male transmission; PDA showed incomplete penetrance. PDA was reported by the family to be present in 2 other members, one of whom was said to have the facial features and one not.

Pierpoint and Sletten (1994) used the eponym Char syndrome for familial PDA with unusual facial features, including long philtrum, downslanting palpebral fissures, and thick lips. They reported a new family in which 7 members had PDA. Premature birth was not a factor in any of these individuals. PDA had been the only form of congenital heart anomaly present in family members except for one 8-year-old boy who had a small muscular ventricular septal defect. Three generations were affected in an autosomal dominant pedigree pattern.

Sletten and Pierpont (1995) observed 7 relatives in 5 sibships in 3 generations of a family with patent ductus arteriosus and a slightly unusual facial appearance with prominent midface with nose elongation and flattening of the nasal bridge, wide-set eyes, downturned palpebral fissures, mild ptosis, thick lips, and apparently slightly low-set ears. The pattern was consistent with autosomal dominant inheritance although no male-to-male transmission was observed. Sletten and Pierpont (1995) gave an extensive tabulation of reports of familial PDA. They pointed to the syndrome reported by Char (1978) in which patent ductus arteriosus was associated with a much more unusual facies with short philtrum, 'duck-bill' lips, ptosis, and low-set ears. Temple (1992) also described this syndrome, referring to it as Char syndrome.

Slavotinek et al. (1997) described a family with PDA, a distinctive facial appearance (eyebrow flare, short nose, and 'duck-bill' lips), polydactyly, and fifth finger clinodactyly. The facial features were considered consistent with CHAR syndrome. Seven members of 3 generations were affected, with 2 instances of male-to-male transmission. This was the first report of associated polydactyly that was interstitial in type. The foot of 1 patient with 2 toes attached to the fourth metatarsal was illustrated. Evolution of the phenotype with age was noted; the facial findings in older relatives were less pronounced and the 'duck-bill' lips less prominent.

Satoda et al. (1999) pictured characteristic facial features, including short philtrum, prominent lips, flat nasal bridge with upturned nares, and ptosis. They also illustrated the changes in the hand: absent fifth middle phalanges with hypoplasia of the fifth proximal and distal phalanges.

Zannolli et al. (2000) reported a father and daughter with Char syndrome. Both had the typical facial features as well as strabismus and foot anomalies. The daughter also had patent ductus arteriosus. Both patients had supernumerary nipples (163700), a finding not described before in Char syndrome.

Sweeney et al. (2000) reported a mother, son, and daughter with the typical facial features of Char syndrome. The son had symphalangism of the distal interphalangeal joints of the fifth fingers with loss of overlying skin creases and clinodactyly. The mother had similar digital features, and the daughter was said to have had them but was not personally examined by the authors.

Mani et al. (2005) studied a large 3-generation family with Char syndrome (family K144) in which there were 22 affected individuals, including 9 with PDA, facial dysmorphism, and clinodactyly, and 13 who showed dysmorphology and clinodactyly without PDA. In addition, there was 1 obligate carrier who was nonpenetrant for all features, and 1 infant died in the neonatal period from heart failure, with coarctation of the aorta, bicuspid aortic valve, and a large PDA. All 9 PDA patients, including the deceased infant, were born at term from a normal gestation, and were diagnosed between the neonatal period and age 30 years. Thus, in this family, PDA showed incomplete penetrance, whereas dysmorphic facies and clinodactyly showed evidence of high penetrance. Further evaluation of family members revealed additional features segregating with the disorder, including hypodontia in 14 affected individuals, who retained their primary teeth and either partially or completely lacked secondary teeth, and parasomnia in 13, involving sleepwalking associated with food-seeking behavior. There were also 10 affected family members who exhibited protuberant occipital bone with overlying coarse hair; in each case, the border of the occiput had a sharp ridge, suggestive of craniosynostosis. None of these additional features was observed in any unaffected family member. Mani et al. (2005) also studied an affected father and 2 daughters from an unrelated family with Char syndrome (family K145). All exhibited PDA, dysmorphic facies, and clinodactyly; the father's sister was also reported to be affected. Mani et al. (2005) noted that in addition to finger clinodactyly, affected members of both kindreds had varying degrees of clinodactyly of the fourth and fifth toes, and syndactyly of the fourth and fifth toes was seen in 4 affected individuals.

Mapping

Satoda et al. (1999) performed linkage analysis in 2 previously reported multigenerational kindreds with Char syndrome (Char, 1978; Sletten and Pierpont, 1995). Linkage was found with several polymorphic DNA markers mapping to 6p21-p12. A maximum 2-point lod score of 8.39 was observed with D6S1638 at theta = 0.00. Haplotype analysis identified recombinant events that defined the Char syndrome locus with high probability to a 3.1-cM region.

Molecular Genetics

Satoda et al. (2000) used a positional candidate gene strategy and mapped TFAP2B (601601), encoding a transcription factor expressing neural crest cells, to the Char syndrome critical region and identified heterozygous missense mutations altering conserved residues in 2 affected families (601601.0001-601601.0002). Mutant TFAP2B proteins dimerized properly in vitro but showed abnormal binding to TFAP2 target sequence. Dimerization of both mutants with normal TFAP2B adversely affected transactivation, demonstrating a dominant-negative mechanism. Satoda et al. (2000) concluded that their work shows that TFAP2B has a role in ductal, facial, and limb development and suggests that Char syndrome results from derangement of neural crest cell derivatives.

Zhao et al. (2001) studied 8 patients with Char syndrome and identified 4 novel mutations in the TFAP2B gene; 3 occurred in the basic domain (601601.0003-601601.0005) and the other affected a conserved PY motif in the transactivation domain (601601.0006). Zhao et al. (2001) found that all 4 mutations, as well as 2 previously identified mutations in the basic domain, had dominant-negative effects when expressed in eukaryotic cells. Affected individuals with the PY motif mutation had a high prevalence of patent ductus arteriosus, but only mild facial and hand abnormalities as compared to individuals with basic domain (DNA-binding) mutations. The authors concluded that this correlation supports the existence of TFAP2 coactivators that have tissue specificity and are important for ductal development but less critical for craniofacial and limb development.

In a large 3-generation family segregating autosomal dominant Char syndrome, Mani et al. (2005) identified heterozygosity for a splice site mutation (601601.0007) in the TFAP2B gene that segregated with disease in the family and was not found in 200 unrelated control chromosomes. In addition, heterozygosity for a different splice site mutation in TFAP2B was identified in an unrelated family with Char syndrome. The authors noted that in contrast to previously reported dominant-negative TFAP2B mutations in Char syndrome, the mechanism of disease in these 2 kindreds was likely to be haploinsufficiency.