Char syndrome (CS) comprises patent ductus arteriosus, characteristic facial features and abnormalities of the hand. The rare condition is inherited in an autosomal dominant manner and results from mutations in the TFAP2B gene. Still, due to variable penetrance of TFAP2B mutations, pedigree analyses may not yield unambiguous results. Treatment is symptomatic and is focused on inducing closure of the ductus arteriosus in order to achieve cardiovascular stability. Established methods are applied to this end. CS patients have a very good prognosis.
CS is a hereditary condition and associated anomalies are present at birth. Usually, it's the neonates facial features that first raise suspicion as to a congenital disease. Char initially described affected neonates to have low-set ears, bilateral ptosis, a short philtrum and duckbill lips . In subsequent case reports, less pronounced facial abnormalities were outlined, e.g., slightly low-set ears, mild ptosis, and full lips. Additionally, a broad forehead, flared eyebrows, mild hypertelorism, downslanting palpebral fissures, strabismus, a flat nasal bridge and a broad, flattened nasal tip were mentioned . Of note, the facial appearance of CS patients may vary even within families and is known to attenuate over time .
Upon closer inspection, it will become evident that the neonate suffering from CS also presents anomalies of the fifth finger. In detail, there's only one flexion crease, which is due to the aplasia of one of the phalanx bones. The remaining phalanges of the fifth finger are hypoplastic . Fifth finger clinodactyly has also been described in numerous CS patients  .
A patent ductus arteriosus isn't usually recognized at birth, but may become symptomatic within the first days of life. Other patients remain asymptomatic for several weeks. The persistent shunt between the aorta and the pulmonary artery is associated with reduced arterial blood pressure and a characteristic, long, systolic heart murmur.
Additional malformations have been reported occasionally and comprise other congenital heart defects, further anomalies of the hand as well as deformities of the feet, supernummerary nipples, and visual impairment . Later in life, CS patients may experience mild learning difficulties .
Entire Body System
Introduction Chronic Fatigue Syndrome (CFS) is characterized by severe fatigue with typical post-exertional delay to recover from exhaustion, cognitive dysfunctions and flu-like symptoms , . [journals.plos.org]
[…] difficulty talking, chewing or swallowing • a sore or cracked tongue • dry or burning throat • dry or peeling lips • a change in taste or smell • increased dental decay • joint pain • vaginal and skin dryness • digestive problems • dry nose • debilitating fatigue [sjogrens.org]
A new row has developed over chronic fatigue syndrome (CFS) after scientists at Stanford University said they had developed a test which proved the condition exists, while British experts disputed their findings. [telegraph.co.uk]
Some of the symptoms are the same as those of gradually developing blockages: fatigue, an enlarged and tender liver, and abdominal pain in the upper abdomen. [merckmanuals.com]
Signs and symptoms of severe defects in newborns include Rapid breathing Cyanosis - a bluish tint to the skin, lips, and fingernails Fatigue Poor blood circulation Many congenital heart defects cause few or no signs and symptoms. [medlineplus.gov]
- Heat Intolerance
intolerance - Renal / kidney anomalies - Ureter / calyx / pelvis duplication / bifid / retrocava / retroiliac ureter Very frequent - Depressed nasal bridge - Depressed premaxillary region / midface - Downslanted palpebral fissures / anti-mongoloid slanting [csbg.cnb.csic.es]
Checkout 0.00 0 Search for: Home About US DNA Test List Blog Contact us 0.00 0 Looking for DNA Tests — Save 20% on all DNA Tests Home / Malformation Retardation Syndromes / Malformation Retardation Syndromes / Char Syndrome TFAP2B NGS Genetic Test Central Hypoventilation [dnalabnigeria.com]
- Failure to Thrive
The child presented with progressive abdominal distension, pain abdomen and failure to thrive. Examination revealed moderate ascites, hepatomegaly. [symbiosisonlinepublishing.com]
Additional symptoms are failure to thrive, poor eating, vomiting, and diarrhea. An odd appearance, with pale skin, frontal or occipital bossing, micrognathia and pudgy cheeks may be observed. Patients develop gradual motor dysfunction and seizures. [orpha.net]
For infants with less severe symptoms, many will suffer from a failure to thrive in the first year of life and by the second year of life although the health of most children will start to improve, most will remain underweight and of short stature. [dermnetnz.org]
It is characterized by sparse, kinky hair; failure to gain weight and grow at the expected rate (failure to thrive); and deterioration of the nervous system. [ghr.nlm.nih.gov]
Failure to thrive Growth parameters are typically below the second percentile. [emedicine.medscape.com]
- Hearing Impairment
Other symptoms such as vision problems, hearing impairment and developmental delay are treated using routine methods. [news-medical.net]
impairment Mesoaxial foot polydactyly Myopia No permanent dentition Persistence of primary teeth Prominent occiput Sleep disturbance Supernumerary nipple Symphalangism of the 5th finger Ventricular septal defect (Source: Char Syndrome; Genetic and Rare [dovemed.com]
impairment Deafness Hearing defect [ more ] 0000365 Mesoaxial foot polydactyly Central polydactyly of feet 0010112 Myopia Close sighted Near sighted Near sightedness Nearsightedness [ more ] 0000545 No permanent dentition Absence of adult teeth Missing [rarediseases.info.nih.gov]
Characteristic facial features are easily recognized and if there are doubts as to the skeletal malformations underlying the observed anomalies of the fifth finger, radiographic images can rapidly provide clarity. Even in the absence of clinical signs of a patent ductus arteriosus, those findings should encourage to examine for possible heart defects. Besides auscultation, echocardiography is the most useful technique to demonstrate the persistence of the fetal ductus arteriosus. It is recommended to assess the size of the remaining duct, to evaluate the direction of flow - a left-to-right shunt is to be expected, and to estimate the flow velocity and volume. Of note, because closure of the ductus arteriosus may physiologically occur up to several days after birth, a single examination prior to this point in time may not yield conclusive results .
The triad of patent ductus arteriosus, fifth finger and facial anomalies allows for a clinical diagnosis. Nevertheless, it may be interesting to identify the underlying gene mutation, particularly since such knowledge is of great value in prenatal diagnosis. CS has only ever been related to mutations in the TFAP2B gene, but somewhat surprisingly, such sequence anomalies cannot be demonstrated in all patients. Similarly, familial anamnesis may yield clear evidence for an autosomal dominant mode of inheritance, but irregularities like absent male-to-male transmission and absolute non-penetrance in obligate carriers have repeatedly been described  .
Patent ductus arteriosus is known to undergo spontaneous closure, particularly in preterm infants. Indeed, such has been observed in about 79% of infants who survived the neonatal period . Due to the low incidence of CS, reliable data as to the probability of spontaneous closure in affected neonates are not available. However, it has been speculated to be rather low . Treatment of CS patients for patent ductus arteriosus does not differ from that of non-syndromic cases: In the absence of spontaneous closure, surgical ligation or catheterization and ductal occlusion may be considered  as well as medical therapy with indomethacin or ibuprofen to block prostaglandin synthesis .
Abnormal facial features as observed in CS have no impact on physical health, and neither does the malformation of the fifth finger. If need arises, severe anomalies may be corrected by means of plastic surgery, though .
If left untreated, patent ductus arteriosus may entail life-threatening pulmonary artery hypertension and congestive heart failure . By contrast, the patient's prognosis is very good if adequate treatment is provided.
Facial anomalies may constitute a psychological burden and even though they don't affect the patient's abilities to manage everyday life, they may reduce life quality. Possible countermeasures comprise psychological support and, as mentioned above, plastic surgery.
CS has been related to mutations in the TFAP2B gene, which encodes for transcription factor AP-2β and is located on the short arm of chromosome 6 . Distinct mutations have been identified to date, with most disease-causing mutations being missense mutations . The mutations' penetrance seems to be variable, according to multigenerational studies .
In about 1 in 2,000 neonates, patent ductus arteriosus is diagnosed, but cardiovascular development in utero and postnatal closure of the ductus arteriosus may be disturbed by a variety of factors: Because the recurrence rate among siblings doesn't exceed 5%, genetic causes presumably account for only a minority of cases of patent ductus arteriosus  . Furthermore, this cardiac defect has been related to distinct DNA sequence anomalies and those may trigger syndromic or non-syndromic patent ductus arteriosus . Consequently, the incidence of syndromic forms CS must be much lower than the overall incidence of patent ductus arteriosus. Precise epidemiological data cannot be provided at this moment, though.
Transcription factor AP-2β has been related to neural crest development. In detail, this transcription factor has been found to affect retinoic acid-induced differentiation, especially in cells derived from the neuroectoderm . In order to fulfill its task, it binds to the consensus TFAP2 target DNA sequence and forms a functional protein-DNA-complex. Mutated TFAP2β, however, is generally unable to bind to the target sequence and no functional complex can be formed. The precise function of this protein-DNA-complex remains unknown, but TFAPB has been found to be expressed in neural crest cells, which, in turn, exert an influence on cardiovascular development. Interestingly, cardiac neural crest cells have only been detected in the ductus arteriosus, but not in the descending aorta or pulmonary artery, which may explain why those vessels develop normally in CS patients .
Furthermore, TFAP2B is expressed in the facial mesenchyme and probably, CS-associated, abnormal facial features can be explained this way. Little is known about the relation between TFAP2β and limb development, though. Considering that the vast majority of patients carrying pathogenic TFAP2B mutations presents with the complete triad of CS-related symptoms, it seems likely that the early pathophysiological events leading to abnormal face and hand development are identical to those delaying ductus arteriosus closure. However, TFAP2B mutations have occasionally been identified in patients presenting with a patent ductus arteriosus but without CS-related facial features and no apparent hand anomalies  . This condition is sometimes referred to as Patent ductus arteriosus 2. Here, sequence anomalies did not necessarily affect binding to the target sequence, but possibly binding of coactivators . Such coactivators may enhance the transcriptional efficiency of TFAP2B and may be differentially expressed in cardiac, facial and limb tissues. One of those coactivators is Cpb/p300-interacting transactivator 2 . Mutations of Cpb/p300-interacting transactivator 2 have been proven to cause isolated congenital heart defects, a fact that supports the aforementioned hypothesis.
Affected families and couples may benefit from genetic counseling. Due to the autosomal dominant mode of inheritance, 50% of all children of a known carrier are expected to present with CS. Prenatal diagnosis is feasible and relies on molecular biological analyses. In order to carry out targeted genetic analyses, it is necessary to identify the causal mutation in an affected family member .
Abnormal facial features and minor malformations of the fifth finger can hardly be recognized in early pregnancy and an open ductus arteriosus is a normal finding in prenatal imaging .
CS has first been described by Char in 1978 and although it is currently considered a rare condition, numerous case reports have been published in the meantime   . The original paper has been titled "Peculiar facies with short philtrum, duck-bill lips, ptosis and low-set ears — a new syndrome?" and focused on the facial appearance of affected individuals . Today, CS is more frequently classified as a familial form of patent ductus arteriosus . Besides the cardiac defect and characteristic facial features, CS patients also display certain abnormalities of the hand, namely of the phalanges of the fifth finger.
Several years later, CS has been related to mutations in the TFAPB2 gene . And although such mutations cannot be identified in all patients presenting with the characteristic triad of patent ductus arteriosus, abnormal facial features, and anomalies of the fifth finger, no other gene defect has been associated with this syndrome so far. While the identification of the underlying mutation greatly facilitates both the familial workup of a CS case at hand and the prenatal diagnosis of possible future cases, it is not indispensable to make a diagnosis. The confirmation of the classical symptom triad by means of clinical and cardiac examination is considered sufficient.
There is no causal treatment for this genetic disease. CS patients generally undergo therapy in order to induce closure of the ductus arteriosus, whereby treatment regimens don't differ from those applied in case of an isolated patent ductus arteriosus.
Char syndrome (CS) is a hereditary disorder that comprises patent ductus arteriosus, characteristic facial features and anomalies of the hand. The syndrome is caused by a mutation in the TFAP2B gene. The latter is inherited in an autosomal dominant manner and thus, affected individuals are likely to pass on the disease to half of their children. It is possible to test if an unborn child inherited the defective allele causing CS. In order to do so, it is first of all necessary to analyze samples provided by an affected family member and to identify the precise mutation.
CS is a congenital disease, i.e., symptoms are present at birth. The following may be observed:
- Typical facial features include low-set ears, an increased distance between the eyes, downslanting palpebral fissures, drooping eyelids, a flat midface and short philtrum, and thick, everted lips.
- With regards to the anomalies of the hand, they are usually limited to the little finger, which is generally missing a phalanx bone.
- The aforementioned symptoms are easily recognizable. Because this is not the case for the third hallmark of the disease, the patent ductus arteriosus, those symptoms should encourage to realize a cardiac examination.
The ductus arteriosus connects the aorta and the pulmonary artery. The function of this vessel is to bypass the fetal lung, since the unborn baby is not breathing. However, it should obliterate shortly after birth to allow for an adequate blood oxygenation in the lung and sufficient oxygen supply to peripheral tissues. If it fails to do so and considerable amounts of blood are deviated from the aorta into the pulmonary circulation, an intervention becomes necessary. Depending on the precise results of echocardiography, the treating physician may opt for a medical therapy with indomethacin or ibuprofen, for a surgical ligation or catheterization and ductal occlusion.
The overall prognosis is very good.
- 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(6b):303-305.
- Forsey JT, Elmasry OA, Martin RP. Patent arterial duct. Orphanet J Rare Dis. 2009; 4:17.
- Slavotinek A, Clayton-Smith J, Super M. Familial patent ductus arteriosus: a further case of CHAR syndrome. Am J Med Genet. 1997; 71(2):229-232.
- Mani A, Radhakrishnan J, Farhi A, et al. 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(8):2975-2979.
- Gelb BD. Char Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA): University of Washington, Seattle; 1993-2017.
- Ji W, Benson MA, Bhattacharya S, Chen Y, Hu J, Li F. Characterization of transcription factor AP-2 beta mutations involved in familial isolated patent ductus arteriosus suggests haploinsufficiency. J Surg Res. 2014; 188(2):466-472.
- Satoda M, Zhao F, Diaz GA, et al. Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nat Genet. 2000; 25(1):42-46.
- Khetyar M, Syrris P, Tinworth L, Abushaban L, Carter N. Novel TFAP2B mutation in nonsyndromic patent ductus arteriosus. Genet Test. 2008; 12(3):457-459.
- Patel PM, Momany AM, Schaa KL, et al. Genetic Modifiers of Patent Ductus Arteriosus in Term Infants. J Pediatr. 2016; 176:57-61.e51.
- Zhao F, Weismann CG, Satoda M, et al. Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation. Am J Hum Genet. 2001; 69(4):695-703.
- Davidson HR. A large family with patent ductus arteriosus and unusual face. J Med Genet. 1993; 30(6):503-505.
- Sletten LJ, Pierpont ME. Familial occurrence of patent ductus arteriosus. Am J Med Genet. 1995; 57(1):27-30.