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Eur J Hum Genet. 2015 Mar;23(3):292-301. doi: 10.1038/ejhg.2014.95. Epub 2014 Jul 23.

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.

Author information

  • 11] Department of Genetics, APHP-Robert DEBRE University Hospital, and Paris-Diderot University, Paris, France [2] INSERM UMR 1141, Hôspital Robert DEBRE, Paris, France.
  • 2Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Dresden, Germany.
  • 3Department of Genetics, APHP-Robert DEBRE University Hospital, and Paris-Diderot University, Paris, France.
  • 4Radboud University Medical Centre, Nijmegen, The Netherlands.
  • 5Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA.
  • 6Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
  • 7Children's Hospital of Eastern Ontario, Ottawa, Canada.
  • 8Hospital das Clínicas da Faculdade de Medicina da Universidade and Instituto de Biociênicas da Universidade, São Paulo, Brazil.
  • 9Service de Génétique Médicale, Purpan University Hospital, Toulouse, France.
  • 10Service de Génétique Médicale, University Hospital, Nantes, France.
  • 11Department of Genetics, University Hospital Gasthuisberg, Leuven, Belgium.
  • 12Department of Hematology, APHP Lariboisière Hospital, Paris, France.
  • 13Service de Génétique Médicale, University Hospital, Rouen, France.
  • 14Dipartimento di Genetica Medica, Ospedale Galliera, Genova, Italy.
  • 15Service de Génétique Médicale, University Hospital, Dijon, France.
  • 16Service de Génétique Médicale, University Hospital, Nice, France.
  • 17Department of Clinical Genetics, Hospital of Rehabilitation of Craniofacial Anomalies (HRAC), University of São Paulo, Bauru, Brazil.
  • 18Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
  • 19Department of Medical Genetics, Dr Faruk Sükan Maternity and Children's Hospital, Konya, Turkey.
  • 20Service de Génétique Médicale, University Hospital, Bordeaux, France.
  • 21Medical Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • 22Erasmus Medical Center, Rotterdam, The Netherlands.
  • 23Dipartimento di Pediatria, Università Federico II, Naples, Italy.
  • 24Clinics Hospital of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
  • 25Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
  • 26Service de Génétique Médicale, University Hospital, Amiens, France.
  • 27North York General Hospital, Toronto, Ontario, Canada.
  • 28McMaster University, Hamilton, Ontario, Canada.
  • 29Department of Pediatrics, Pennsylvania State University, Hershey, PA, USA.
  • 30Service de Génétique Médicale, La Timone University Hospital, Marseille, France.
  • 31Department of Pediatrics and Ophthalmology, University of Minnesota Medical Center, Minneapolis, MN, USA.
  • 32Genetic Department, University Hospital, Angers, France.
  • 33Service de Génétique Médicale, University Hospital, Lyon, France.
  • 34Department of Genetics, University Hospital, Iasi, Romania.
  • 35Service de Génétique Médicale, St Luc University Hospital, Brussels, Belgium.
  • 36Mitteldeutscher Praxisverbund Humangenetik, Dresden, Germany.
  • 37Department of Genetics, University Hospital, Groningen, The Netherlands.
  • 38Office of the Chief Medical Examiner, City and County of San Francisco, CA, USA.
  • 39Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
  • 401] Dipartimento di Genetica Medica, Ospedale Galliera, Genova, Italy [2] Seattle Children's Hospital, Seattle, WA, USA.
  • 41Seattle Children's Hospital, Seattle, WA, USA.

Abstract

Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode β- and γ-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.

PMID:
25052316
[PubMed - in process]
PMCID:
PMC4326722
[Available on 2016-03-01]
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