{ "id": "ep3wjfzmp3", "slug": "char-syndrome", "title": "Char syndrome", "updated": "2026-10-20", "topic_path": [ { "id": "life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/topics/life" }, { "id": "life.health", "label": "Human health and medicine", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health" }, { "id": "life.health.conditions", "label": "Diseases and injuries", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.conditions" }, { "id": "life.health.conditions.reproductive", "label": "Urinary, reproductive, and developmental conditions", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.conditions.reproductive" }, { "id": "life.health.conditions.reproductive.congenital-developmental", "label": "Congenital and developmental conditions", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.conditions.reproductive.congenital-developmental" }, { "id": "life.health.conditions.reproductive.congenital-developmental.multisystem-named-malformation-syndromes", "label": "Multisystem named malformation syndromes", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.conditions.reproductive.congenital-developmental.multisystem-named-malformation-syndromes" }, { "id": "life.health.conditions.reproductive.congenital-developmental.multisystem-named-malformation-syndromes.vacterl-spectrum-and-associated-anomalies", "label": "VACTERL-spectrum and associated anomalies", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.conditions.reproductive.congenital-developmental.multisystem-named-malformation-syndromes.vacterl-spectrum-and-associated-anomalies" } ], "geo": [ { "id": "geo.us.t1946.life.health.conditions.reproductive.congenital-developmental", "label": "United States · 1946 to 2000: Congenital and developmental conditions", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life.health.conditions.reproductive.congenital-developmental", "path": [ { "id": "geo.us", "label": "United States", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us" }, { "id": "geo.us.t1946", "label": "United States · 1946 to 2000", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946" }, { "id": "geo.us.t1946.life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life" }, { "id": "geo.us.t1946.life.health", "label": "Human health and medicine", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life.health" }, { "id": "geo.us.t1946.life.health.conditions", "label": "Diseases and injuries", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life.health.conditions" }, { "id": "geo.us.t1946.life.health.conditions.reproductive", "label": "Urinary, reproductive, and developmental conditions", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life.health.conditions.reproductive" }, { "id": "geo.us.t1946.life.health.conditions.reproductive.congenital-developmental", "label": "Congenital and developmental conditions", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life.health.conditions.reproductive.congenital-developmental" } ] } ], "excerpt": "Char syndrome (OMIM 169100) is a rare autosomal dominant disorder from TFAP2B variants, marked by patent ductus arteriosus, distinctive facial dysmorphism, and fifth-finger middle phalanx aplasia or hypoplasia.", "snippet": "Char syndrome (OMIM 169100) is a rare autosomal dominant disorder from TFAP2B variants, marked by patent ductus arteriosus, distinctive facial dysmorphism, and fifth-finger middle phalanx aplasia or hypoplasia.", "node": "life.health.conditions.reproductive.congenital-developmental.multisystem-named-malformation-syndromes.vacterl-spectrum-and-associated-anomalies", "markdown": "# Char syndrome\n\n**Char syndrome** is a rare autosomal dominant genetic disorder characterized by the triad of patent ductus arteriosus (PDA), a distinctive facial appearance, and aplasia or hypoplasia of the middle phalanges of the fifth fingers. It was first described by Florence Char in 1978 in a child with PDA, low-set ears, ptosis, a short philtrum, and \"duck-bill\" lips, and it is caused by pathogenic variants in the *TFAP2B* gene, which encodes the transcription factor AP-2β.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC1226056/) • [2](https://www.ncbi.nlm.nih.gov/books/NBK604201/)\n\n| Key fact | Detail |\n|---|---|\n| Core triad | Patent ductus arteriosus, characteristic facial dysmorphism, and aplasia or hypoplasia of the middle phalanges of the fifth fingers[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC1226056/) |\n| Cause | Heterozygous pathogenic variants in *TFAP2B* (AP-2β), chromosome 6p12-p21.1[3](https://www.nature.com/articles/ng0500_42) |\n| Inheritance | Autosomal dominant; each child of an affected individual has a 50% chance of inheriting the variant; cases can also arise de novo[4](https://www.ncbi.nlm.nih.gov/books/NBK1106/) • [5](https://www.orpha.net/en/disease/detail/46627?mode=name) |\n| Frequency | Prevalence below 1 in 1,000,000; approximately 100 individuals from 13 families reported in the literature[5](https://www.orpha.net/en/disease/detail/46627?mode=name) |\n| Mutation mechanism | Missense variants in the basic domain act dominantly negative; splice-site variants act through haploinsufficiency[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC549488/) |\n| Genotype-phenotype link | The PY-motif variant p.Pro63Arg gives PDA with mild facial changes and no hand anomalies[5](https://www.orpha.net/en/disease/detail/46627?mode=name) |\n| Onset | Antenatal, neonatal, or infancy; ICD-10 Q87.8; OMIM 169100[5](https://www.orpha.net/en/disease/detail/46627?mode=name) |\n\n## Clinical features\n\n**Facial appearance.** The typical face includes a depressed nasal bridge and broad flat nasal tip, widely spaced eyes, downslanting palpebral fissures, mild ptosis, a short philtrum with prominent philtral ridges and an upward-pointing vermilion border forming a triangular mouth, and thickened (patulous) everted lips.[4](https://www.ncbi.nlm.nih.gov/books/NBK1106/) GeneReviews notes that these features are usually striking and not often confused with those of other disorders, although the profile resembles [maxillonasal dysplasia](https://www.edgepedia.org/maxillonasal-dysplasia) (Binder syndrome).[4](https://www.ncbi.nlm.nih.gov/books/NBK1106/)\n\n**Heart.** The most commonly identified cardiac anomaly is patent ductus arteriosus, in which the fetal connection between the aorta and the pulmonary artery fails to close after birth.[2](https://www.ncbi.nlm.nih.gov/books/NBK604201/) • [7](https://rarediseases.info.nih.gov/diseases/1237/char-syndrome) Less common cardiac findings include ventricular septal defect and more complex congenital heart defects.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6555769/) Untreated PDA can cause rapid breathing, poor feeding, slow weight gain, and, in severe cases, heart failure.[7](https://rarediseases.info.nih.gov/diseases/1237/char-syndrome)\n\n**Hands and other findings.** The hand anomaly is shortening or absence of the middle phalanx of the fifth (pinky) finger, which can range from minimal fifth-finger clinodactyly, a finding that also occurs in normal individuals, to aplasia.[4](https://www.ncbi.nlm.nih.gov/books/NBK1106/) • [7](https://rarediseases.info.nih.gov/diseases/1237/char-syndrome) Less common features include additional hand and foot anomalies (such as polydactyly, distal symphalangism, and syndactyly), other heart defects, hypodontia or persistence of [deciduous teeth](https://www.edgepedia.org/deciduous-teeth), hearing loss, myopia, strabismus, polythelia, craniosynostosis, mild to moderate developmental delay, short stature, and sleep disturbance including somnambulism.[5](https://www.orpha.net/en/disease/detail/46627?mode=name) • [2](https://www.ncbi.nlm.nih.gov/books/NBK604201/) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC549488/)\n\n## Genetics and molecular mechanism\n\nChar syndrome is caused by heterozygous pathogenic variants in *TFAP2B*, which encodes transcription factor AP-2β, a member of the AP-2 family of sequence-specific DNA-binding proteins expressed in neural crest cells.[3](https://www.nature.com/articles/ng0500_42) • [9](https://medlineplus.gov/genetics/condition/char-syndrome/) Using a positional candidacy strategy, Satoda and colleagues mapped *TFAP2B* to the Char syndrome critical region on chromosome 6p12-p21.1 and identified missense mutations altering conserved residues in affected families; mutant proteins dimerized normally but bound the TFAP2 target sequence abnormally, and dimerization with normal TFAP2B impaired transactivation, demonstrating a dominant-negative mechanism.[3](https://www.nature.com/articles/ng0500_42)\n\n**Two disease mechanisms.** The missense variants associated with the syndrome predominantly alter the basic (DNA-binding) domain and act dominantly negative, through altered DNA binding or altered transactivation.[4](https://www.ncbi.nlm.nih.gov/books/NBK1106/) In contrast, splice-site mutations in two kindreds altered highly conserved intronic bases required for normal splicing, producing frameshifted mRNAs expected to be degraded by nonsense-mediated mRNA decay; the disease mechanism in those families is haploinsufficiency, where loss-of-function alleles leave one functional copy whose output is insufficient.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC549488/) • [13](https://www.ncbi.nlm.nih.gov/sites/books/NBK1106/) A functional study of *TFAP2B* variants found in isolated PDA showed mutants that could not stimulate transcription and, for one variant, produced no protein, again indicating a haploinsufficient effect.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC4594773/)\n\n**Genotype-phenotype correlation.** Among eight patients studied, four novel mutations were found: three in the basic domain and one, P62R, affecting the conserved PY motif in the transactivation domain. The family with the PY-motif mutation had a high prevalence of PDA but only mild facial abnormalities and no apparent hand anomalies, a phenotype distinct from that of the basic-domain mutations. This correlation supports the existence of tissue-specific TFAP2 coactivators that are important for ductal development but less critical for craniofacial and limb development.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC1226056/) Orphanet records the corresponding variant p.Pro63Arg as associated with a less severe phenotype.[5](https://www.orpha.net/en/disease/detail/46627?mode=name)\n\n**Allelic disorder.** *TFAP2B* pathogenic variants have also been found in individuals with patent ductus arteriosus but no other features of Char syndrome (nonsyndromic PDA, OMIM 617035), although screening of a group of individuals with isolated PDA rarely revealed *TFAP2B* variants.[4](https://www.ncbi.nlm.nih.gov/books/NBK1106/)\n\n## Epidemiology\n\nChar syndrome is rare. Orphanet lists a prevalence below 1 in 1,000,000 and reports approximately 100 affected individuals from 13 families in the medical and scientific literature.[5](https://www.orpha.net/en/disease/detail/46627?mode=name) The American Heart Association's scientific statement on the genetic basis of congenital heart disease notes that approximately half of families with the full diagnostic triad have a detectable heterozygous *TFAP2B* pathogenic variant, indicating that other genes or mechanisms account for the remainder.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6555769/) For context, PDA in general constitutes about 10% of all congenital heart disease, and isolated PDA occurs in about one in 2,000 full-term infants, considerably more often in premature infants.[4](https://www.ncbi.nlm.nih.gov/books/NBK1106/)\n\n## Diagnosis and differential diagnosis\n\nThe diagnosis is established in a proband with suggestive clinical findings, the triad of typical facial features, PDA, and fifth-finger middle phalanx aplasia or hypoplasia, and/or a heterozygous pathogenic *TFAP2B* variant identified by molecular genetic testing; formal clinical diagnostic criteria have not been published.[4](https://www.ncbi.nlm.nih.gov/books/NBK1106/) Testing can include single-gene testing, a multigene panel including *TFAP2B*, or comprehensive genomic testing such as exome sequencing.[4](https://www.ncbi.nlm.nih.gov/books/NBK1106/) A 2024 Chinese case report, for example, identified a de novo heterozygous *TFAP2B* c.944A>C (p.Glu315Ala) variant by whole-exome sequencing in a child with facial dysmorphism, PDA, growth retardation, and curving of the fifth fingers and middle toes, rated likely pathogenic under ACMG guidelines.[11](https://pubmed.ncbi.nlm.nih.gov/39097275/)\n\nThe primary differential diagnosis includes other heart-hand syndromes, among them [Holt-Oram syndrome](https://www.edgepedia.org/holt-oram-syndrome) (*TBX5*), Tabatznik syndrome, and heart-hand syndrome type III, as well as Rubinstein-Taybi syndrome, [Robinow syndrome](https://www.edgepedia.org/robinow-syndrome), Ellis-van Creveld syndrome, and [ulnar-mammary syndrome](https://www.edgepedia.org/ulnar-mammary-syndrome).[5](https://www.orpha.net/en/disease/detail/46627?mode=name) • [4](https://www.ncbi.nlm.nih.gov/books/NBK1106/) PDA is a normal fetal feature and cannot be used as a diagnostic marker in utero; prenatal ultrasound in at-risk pregnancies may identify abnormal hands or feet or complex congenital heart defects.[5](https://www.orpha.net/en/disease/detail/46627?mode=name)\n\n## Management\n\nManagement is multidisciplinary, involving pediatricians, geneticists, cardiologists, craniofacial surgeons, ophthalmologists, otolaryngologists, and orthopedic surgeons as manifestations require.[2](https://www.ncbi.nlm.nih.gov/books/NBK604201/) Treatment may include surgical correction of congenital cardiac defects, with post-neonatal PDA management guided by the degree of shunting between the aorta and the pulmonary artery; options include surgical ligation or ductal occlusion at catheterization.[2](https://www.ncbi.nlm.nih.gov/books/NBK604201/) • [4](https://www.ncbi.nlm.nih.gov/books/NBK1106/) The dysmorphic features and hand anomalies themselves require no special care early in life.[12](https://www.ncbi.nlm.nih.gov/books/NBK1106/pdf/Bookshelf_NBK1106.pdf)\n\n## References\n\n1. [Satoda M, et al. Novel TFAP2B Mutations That Cause Char Syndrome Provide a Genotype-Phenotype Correlation. Am J Hum Genet.](https://pmc.ncbi.nlm.nih.gov/articles/PMC1226056/)\n2. [Bongurala AR, Romero-Lopez M. Char Syndrome. StatPearls, NCBI Bookshelf.](https://www.ncbi.nlm.nih.gov/books/NBK604201/)\n3. [Satoda M, et al. Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nat Genet 25:42-46 (2000).](https://www.nature.com/articles/ng0500_42)\n4. [Char Syndrome. GeneReviews, NCBI Bookshelf.](https://www.ncbi.nlm.nih.gov/books/NBK1106/)\n5. [Char syndrome. Orphanet (ORPHA:46627).](https://www.orpha.net/en/disease/detail/46627?mode=name)\n6. [Mani A, et al. Syndromic patent ductus arteriosus: Evidence for haploinsufficient TFAP2B mutations and identification of a linked sleep disorder. PNAS 102:2975-2979 (2005).](https://pmc.ncbi.nlm.nih.gov/articles/PMC549488/)\n7. [Char syndrome. GARD, NIH Genetic and Rare Diseases Information Center.](https://rarediseases.info.nih.gov/diseases/1237/char-syndrome)\n8. [Genetic Basis for Congenital Heart Disease: Revisited. AHA Scientific Statement, Circulation (2018).](https://pmc.ncbi.nlm.nih.gov/articles/PMC6555769/)\n9. [Char syndrome. MedlinePlus Genetics.](https://medlineplus.gov/genetics/condition/char-syndrome/)\n10. [Characterization of transcription factor AP-2 beta mutations involved in familial isolated patent ductus arteriosus suggests haploinsufficiency. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC4594773/)\n11. [Clinical characteristics and genetic analysis of a child with Char syndrome caused by TFAP2B gene variant. PubMed (2024).](https://pubmed.ncbi.nlm.nih.gov/39097275/)\n12. [Char Syndrome. GeneReviews PDF, NCBI Bookshelf.](https://www.ncbi.nlm.nih.gov/books/NBK1106/pdf/Bookshelf_NBK1106.pdf)\n13. [Char Syndrome - GeneReviews® - NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/sites/books/NBK1106/)\n\n---\n*Topic: Encyclopedia › Life and health › Human health and medicine › Diseases and injuries › Urinary, reproductive, and developmental conditions › Congenital and developmental conditions › Multisystem named malformation syndromes › VACTERL-spectrum and associated anomalies*\n\n*Initially written Oct 20, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n", "same_as": [], "url": "https://www.edgepedia.org/char-syndrome", "markdown_url": "https://www.edgepedia.org/char-syndrome.md", "license": { "name": "Edgepedia Community License 1.0", "url": "https://www.edgepedia.org/edgepedia/license", "summary": "Free with credit, commercial use included. AI training is open to everyone. For other uses, organizations over USD 100M in revenue or 100M monthly users license separately.", "spdx": "LicenseRef-Edgepedia-Community-1.0" }, "credit": "\"Char syndrome\", Edgepedia (EdgeChat), https://www.edgepedia.org/char-syndrome. Edgepedia Community License 1.0.", "credit_md": "\"[Char syndrome](https://www.edgepedia.org/char-syndrome)\", Edgepedia (EdgeChat), [https://www.edgepedia.org/char-syndrome](https://www.edgepedia.org/char-syndrome). [Edgepedia Community License 1.0](https://www.edgepedia.org/edgepedia/license).", "credit_html": "\"Char syndrome\", Edgepedia (EdgeChat), https://www.edgepedia.org/char-syndrome. Edgepedia Community License 1.0.", "speakable": "Char syndrome is a rare autosomal dominant disorder from TFAP2B variants, marked by patent ductus arteriosus, distinctive facial dysmorphism, and fifth-finger middle phalanx aplasia or hypoplasia." }