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

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 b-and c-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 cancerpredisposing 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.

Genetic Basis of Brain Malformations

“…Many patients with ACTB and ACTG1 mutations have pachygyria with an anteriorto-posterior severity gradient, similar to that observed in males with DCX mutations [Rivière et al, 2012a;Verloes et al, 2015].…”

“…Mutations in the ACTB and ACTG1 genes are associated with Baraitser-Winter cerebrofrontofacial syndrome which is characterized by the combination of hypertelorism, a broad nose with a large tip and prominent root, congenital nonmyopathic ptosis, ridged metopic suture, arched eyebrows, iris or retinal coloboma, sensorineural deafness, shoulder girdle muscle bulk, and progressive joint stiffness [Rivière et al, 2012a;Di Donato et al, 2014;Verloes et al, 2015]. Many patients with ACTB and ACTG1 mutations have pachygyria with an anteriorto-posterior severity gradient, similar to that observed in males with DCX mutations [Rivière et al, 2012a;Verloes et al, 2015].…”

Could Dissimilar Phenotypic Effects of ACTB Missense Mutations Reflect the Actin Conformational Change Two Novel Mutations and Literature Review

“…Additionally, patient 2 showed features that are not typically found in persons with ACTB mutations, such as ventricular arrhythmia with prenatal debut and thrombocytopenia. Individuals with ACTB mutations have been reported with a broad phenotypic variability [Verloes et al, 2015] and, in some cases, described as distinct clinical entities [Johnston et al, 2013]. Verloes et al [2015] studied 36 patients with a molecularly proven actinopathy and described 6 additional cases from the literature (33 ACTB and 9 ACTG1).…”

“…Individuals with ACTB mutations have been reported with a broad phenotypic variability [Verloes et al, 2015] and, in some cases, described as distinct clinical entities [Johnston et al, 2013]. Verloes et al [2015] studied 36 patients with a molecularly proven actinopathy and described 6 additional cases from the literature (33 ACTB and 9 ACTG1). They suggested that there could be an important mutation-specific variability in the phenotype of actinopathies.…”

“…Mutation clustering suggested a gain-of-function effect. Verloes et al [2015] presented detailed phenotypic descriptions and neuroimaging of 36 patients and reviewed 6 cases from the literature with a molecularly proven actinopathy. Recently, Yates et al [2017] provided an overview of the clinical characteristics (including some novel findings), diagnosis, management, mutation spectrum, and genetic counseling.…”