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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

1
1] Department of Genetics, APHP-Robert DEBRE University Hospital, and Paris-Diderot University, Paris, France [2] INSERM UMR 1141, Hôspital Robert DEBRE, Paris, France.
2
Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Dresden, Germany.
3
Department of Genetics, APHP-Robert DEBRE University Hospital, and Paris-Diderot University, Paris, France.
4
Radboud University Medical Centre, Nijmegen, The Netherlands.
5
Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA.
6
Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
7
Children's Hospital of Eastern Ontario, Ottawa, Canada.
8
Hospital das Clínicas da Faculdade de Medicina da Universidade and Instituto de Biociênicas da Universidade, São Paulo, Brazil.
9
Service de Génétique Médicale, Purpan University Hospital, Toulouse, France.
10
Service de Génétique Médicale, University Hospital, Nantes, France.
11
Department of Genetics, University Hospital Gasthuisberg, Leuven, Belgium.
12
Department of Hematology, APHP Lariboisière Hospital, Paris, France.
13
Service de Génétique Médicale, University Hospital, Rouen, France.
14
Dipartimento di Genetica Medica, Ospedale Galliera, Genova, Italy.
15
Service de Génétique Médicale, University Hospital, Dijon, France.
16
Service de Génétique Médicale, University Hospital, Nice, France.
17
Department of Clinical Genetics, Hospital of Rehabilitation of Craniofacial Anomalies (HRAC), University of São Paulo, Bauru, Brazil.
18
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
19
Department of Medical Genetics, Dr Faruk Sükan Maternity and Children's Hospital, Konya, Turkey.
20
Service de Génétique Médicale, University Hospital, Bordeaux, France.
21
Medical Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
22
Erasmus Medical Center, Rotterdam, The Netherlands.
23
Dipartimento di Pediatria, Università Federico II, Naples, Italy.
24
Clinics Hospital of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
25
Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
26
Service de Génétique Médicale, University Hospital, Amiens, France.
27
North York General Hospital, Toronto, Ontario, Canada.
28
McMaster University, Hamilton, Ontario, Canada.
29
Department of Pediatrics, Pennsylvania State University, Hershey, PA, USA.
30
Service de Génétique Médicale, La Timone University Hospital, Marseille, France.
31
Department of Pediatrics and Ophthalmology, University of Minnesota Medical Center, Minneapolis, MN, USA.
32
Genetic Department, University Hospital, Angers, France.
33
Service de Génétique Médicale, University Hospital, Lyon, France.
34
Department of Genetics, University Hospital, Iasi, Romania.
35
Service de Génétique Médicale, St Luc University Hospital, Brussels, Belgium.
36
Mitteldeutscher Praxisverbund Humangenetik, Dresden, Germany.
37
Department of Genetics, University Hospital, Groningen, The Netherlands.
38
Office of the Chief Medical Examiner, City and County of San Francisco, CA, USA.
39
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
40
1] Dipartimento di Genetica Medica, Ospedale Galliera, Genova, Italy [2] Seattle Children's Hospital, Seattle, WA, USA.
41
Seattle 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
PMCID:
PMC4326722
DOI:
10.1038/ejhg.2014.95
[Indexed for MEDLINE]
Free PMC Article
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