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. 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

Alain Verloes  1 , Nataliya Di Donato  2 , Julien Masliah-Planchon  3 , Marjolijn Jongmans  4 , Omar A Abdul-Raman  5 , Beate Albrecht  6 , Judith Allanson  7 , Han Brunner  4 , Debora Bertola  8 , Nicolas Chassaing  9 , Albert David  10 , Koen Devriendt  11 , Pirayeh Eftekhari  12 , Valérie Drouin-Garraud  13 , Francesca Faravelli  14 , Laurence Faivre  15 , Fabienne Giuliano  16 , Leina Guion Almeida  17 , Jorge Juncos  18 , Marlies Kempers  4 , Hatice Koçak Eker  19 , Didier Lacombe  20 , Angela Lin  21 , Grazia Mancini  22 , Daniela Melis  23 , Charles Marques Lourenço  24 , Victoria Mok Siu  25 , Gilles Morin  26 , Marjan Nezarati  27 , Malgorzata J M Nowaczyk  28 , Jeanette C Ramer  29 , Sara Osimani  3 , Nicole Philip  30 , Mary Ella Pierpont  31 , Vincent Procaccio  32 , Zeichi-Seide Roseli  17 , Massimiliano Rossi  33 , Cristina Rusu  34 , Yves Sznajer  35 , Ludivine Templin  30 , Vera Uliana  14 , Mirjam Klaus  36 , Bregje Van Bon  4 , Conny Van Ravenswaaij  37 , Bruce Wainer  38 , Andrew E Fry  39 , Andreas Rump  2 , Alexander Hoischen  4 , Séverine Drunat  3 , Jean-Baptiste Rivière  40 , William B Dobyns  41 , Daniela T Pilz  39
Affiliations

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

Alain Verloes et al. Eur J Hum Genet. 2015 Mar.

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.

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Figures

Figure 1
Figure 1
Mutation spectrum of BWCFF syndrome. The scheme takes advantage of the similarity of exon organization and protein sequence. Non-coding exon sequences are narrower and lighter. Functional domains are coded in color (apparent dispersion of each domain explained by 3D configuration). The number of the first aminoacid of each exon, and of the last aminoacid of exon 5 are mentioned. The full colour version of this figure is available at European Journal of Human Genetics online.
Figure 2
Figure 2
The spectrum of facial dysmorphology of BWCFF. Facial appearance of 15 patients with ACTG1 (An) or ACTB (Bn) mutations, subjectively sorted by gradient of severity. Picture of Patient B32 was previously published.
Figure 3
Figure 3
Evolution of the phenotype with time. Evolution of the facial appearance of five patients with ACTG1 (An) or ACTB (Bn) mutations.
Figure 4
Figure 4
Non-facial anomalies in BWCFF. Patient B34: preaxial polydactyly of feet – Patient B6: pectus excavatum – Patient B19: brachydactyly and nail hypoplasia – Patient B11: Noonan-like appearance of mild BWCFF syndrome – Patient B32: severe CFF appearance: note bifid nose, narrow shoulder girdle with hypoplastic muscles webbed neck and severe scoliosis – Patient A1: note typical stance of older BWCFF patients, with anteverted shoulders and semiflexed knees.
Figure 5
Figure 5
MRI aspects of BWCFF – ACTB and ACTG1. T1 and T2-weighted axial and T1-weighted sagittal MR images ordered by extent of the cortical malformation. ACTG1: focal (central) pachygyria (A6), pachygyria and posterior subcortical band heterotopia (A2: white arrow) and diffuse pachygyria (A8, A3). Patient B22 also had a number of periventricular nodular heterotopia (see). ACTB: normal cortex (B12), focal (central) pachygyria (B2 B22; white arrows), predominantly frontoparietal pachygyria (B9, B5), diffuse pachygyria (B8, B14), lissencephaly (B3). Note the shortened and thick corpus callosum (B2, B5, B14 and A8).
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References

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