Baraitser-Winter Syndrome 2

A number sign (#) is used with this entry because Baraitser-Winter syndrome-2 (BRWS2) is caused by heterozygous mutation in the ACTG1 gene (102560) on chromosome 17q25.

For a phenotypic description and a discussion of genetic heterogeneity of Baraitser-Winter syndrome, see BRWS1 (243310).

Clinical Features

Riviere et al. (2012) reported 8 patients with Baraitser-Winter syndrome-2. Three of 7 of those examined had short stature; 4 of 7 had postnatal microcephaly; all 5 patients evaluated had intellectual disability; 5 of 6 had hearing loss; and 7 of 8 had seizures. Seven of 7 had trigonocephaly; 7 of 8 had hypertelorism; 7 of 7 had high-arched eyebrows; and 8 of 8 had ptosis. Five of 7 had iris or retinal coloboma and 7 of 7 patients evaluated had anterior-to-posterior gradient lissencephaly of the pachygyria or pachygyria-band type.

Verloes et al. (2015) described the phenotype and neuroimaging of 42 patients with a clinical diagnosis of Baraitser-Winter syndrome, Fryns-Aftimos syndrome, or cerebrofrontofacial syndrome, and suggested that the disorder be unified under a single designation. The major clinical anomalies were striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital nonmyopathic ptosis, ridged metopic sutures, and arched eyebrows. Iris or retinal coloboma was present in many cases, as was sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects, and renal tract anomalies were seen in some patients. Microcephaly developed in some patients. Nearly all patients with ACTG1 mutations and around 60% of those with ACTB mutations had some degree of pachygyria with anteroposterior severity gradient, and rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness were common. Early muscular involvement, occasionally with congenital arthrogryposis, was present. Intellectual disability and epilepsy were variable in severity and largely correlated with central nervous system anomalies.

Inheritance

Riviere et al. (2012) reported that, with one exception, all patients with Baraitser-Winter syndrome have been sporadic. The only report of affected sibs involved patients 1 and 2 in the original report (Baraitser and Winter, 1988), and further analysis of phenotypic features led Riviere et al. (2012) to consider these individuals, lost to follow-up, as not having Baraitser-Winter syndrome.

Molecular Genetics

Riviere et al. (2012) reported 8 patients with Baraitser-Winter syndrome carrying heterozygous missense mutations in the ACTG1 gene; in 7 patients the mutation was proven to have occurred de novo. One mutation was recurrent in 3 patients, a ser-to-phe substitution at codon 155 (102560.0009). One of these 3, LP98-096, was originally reported by Baraitser and Winter (1988) as patient 3. All the others had novel missense mutations. Autosomal dominant progressive nonsyndromic hearing loss (DFNA20/26; 604717) is also caused by mutations in ACTG1, and congenital or later-onset progressive hearing loss is a common feature of Baraitser-Winter syndrome, suggesting partially overlapping pathogenic mechanisms for Baraitser-Winter syndrome and DFNA20/26. Riviere et al. (2012) suggested that Baraitser-Winter syndrome represents the severe end of a spectrum of cytoplasmic actin-associated phenotypes that begins with Baraitser-Winter syndrome and extends to nonsyndromic hearing loss.

Verloes et al. (2015) described the molecular findings in 42 patients with a clinical diagnosis of BRWS, Fryns-Aftimos syndrome, or cerebrofrontofacial syndrome. Thirty-three patients had a mutation in ACTB and 9 patients had a mutation in ACTG1. Verloes et al. (2015) suggested that ACTG1 mutations may have a more central role in neuronal migration because 8 of the 9 ACTG1 patients had a migration disorder versus one-third of those carrying ACTB mutations. Verloes et al. (2015) identified several patients with BRWS-like phenotypes in whom the ACTB and ACTG1 gene screening was negative.