Baraitser-Winter Syndrome 1

A number sign (#) is used with this entry because Baraitser-Winter syndrome-1 (BRWS1) is caused by heterozygous mutation in the ACTB gene (102630) on chromosome 7p22.

A subset of patients have a larger deletion of chromosome 7p22 including the ACTB gene and additional variable genes, consistent with a contiguous gene deletion syndrome.

Description

BRWS is a rare developmental phenotype characterized by the combination of hypertelorism, broad nose with 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, and pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Intellectual disability and epilepsy are variable in severity and largely correlate with central nervous system anomalies (summary by Verloes et al., 2015). Di Donato et al. (2014) and Verloes et al. (2015) suggested that BRWS, Fryns-Aftimos syndrome, and cerebrofrontofacial syndrome represent the same clinical entity. The phenotype is highly variable (summary by Cuvertino et al., 2017).

Genetic Heterogeneity of Baraitser-Winter Syndrome

Baraitser-Winter syndrome-2 (BRWS2; 614583) is caused by heterozygous mutation in the ACTG1 gene (102560) on chromosome 17q25.

Clinical Features

In a girl with unrelated parents, Baraitser and Winter (1988) described a seemingly distinct syndrome of iris coloboma, bilateral ptosis, hypertelorism, broad nasal bridge, prominent epicanthal folds, short stature, and mental retardation. This report also contained the description of sibs with similar features who, based on a comparison of phenotypic features and inheritance patterns, Riviere et al. (2012) suggested did not have Baraitser-Winter syndrome.

Fryns and Aftimos (2000) presented the clinical histories and physical findings in 2 unrelated, severely retarded males. Craniofacial dysmorphism in both was distinct, with edema, narrowing of the frontal part of the skull, arched eyebrows, bilateral ptosis, trigonocephaly, hypertelorism with a broad root and bridge of the nose, a large mouth with a fine upper lip and everted lower lip, prominent upper central incisors, posteriorly rotated hypoplastic ears, and a high-arched palate. The neck was short, broad, and webbed, with a low posterior hairline. The upper thorax was narrow with widely spaced hypoplastic inverted nipples. The patients presented in the neonatal period with edema followed by significant weight loss. Both developed complex epilepsy in early childhood with deterioration of mental development, and were profoundly mentally retarded. Seizures were impossible to control, despite maximal pharmacotherapy. Cranial imaging showed pachygyria, most pronounced in the frontal lobes. The patients were able to walk independently but lacked 20 to 30 degrees extension at both knees and elbows. Metabolic investigations and karyotypes were normal. Both boys had unrelated parents and unaffected sibs.

Der Kaloustian et al. (2001) reported a male with multiple craniofacial and skeletal dysmorphic features, mental retardation, and bilateral frontal pachygyria, reminiscent of the cases reported by Fryns and Aftimos (2000). Milunsky and Capin (2003) and Forzano et al. (2004) also reported males with clinical features remarkably similar to the patients reported by Fryns and Aftimos (2000).

Guion-Almeida and Richieri-Costa (2001) described a Brazilian boy, born to normal nonconsanguineous parents, with brachycephaly, a wide forehead, a widow's peak, hypertelorism, wide palpebral fissures with multiple eyelid colobomas, a broad nasal root, a long philtrum, macrostomia, prominent lips, a high-arched palate, a midline alveolar cleft, a small and grooved chin, ear anomalies, structural anomaly of the corpus callosum, and mental retardation. They cited 3 previous reports of a similar syndrome, 2 of which were described by them. One case, which they (Guion-Almeida and Richieri-Costa, 1992) had originally reported as acrocallosal syndrome, was in a Brazilian girl, born to nonconsanguineous parents, who had diffuse cortical atrophy associated with agenesis of the corpus callosum, as well as frontonasal dysostosis, abnormal upper lids, cleft lip/palate, redundant skin in the neck, grooved chin, and bifid thumbs. Another case (Guion-Almeida and Richieri-Costa, 1999) was in a Brazilian girl, born to normal nonconsanguineous parents, with brachyacrocephaly , a wide forehead, hypertelorism, wide palpebral fissures with multiple eyelid colobomas, a broad and high nasal root, an absent nasal tip, a wide columella, a long and smooth philtrum, a carp-like mouth, macrostomia, a thin upper lip with midline notching, submucous cleft of the soft palate, a small and grooved chin, ear anomalies, Dandy-Walker anomaly, a structural anomaly of the corpus callosum, gray matter heterotopia, and mental retardation. The third case, reported by Masuno et al. (2000), was in a Japanese girl with brachycephaly, a wide forehead, hypertelorism, macroblepharon with eyelid colobomas, ectropion, a broad nasal root, a depressed nasal tip, macrostomia, a small and grooved chin, ear anomalies, a structural anomaly of the corpus callosum, dilatation of the fourth ventricle, a urogenital sinus, and mental retardation.

Winter (2001) reviewed several reports that are listed in this entry and in entry 606156. He noted considerable overlap between the cases and suggested that they represent a syndrome, which he called cerebrofrontofacial syndrome, that is comprised of 3 types based on brain MRI findings. The brain scans in type 1 are characterized by periventricular nodular heterotopia. In type 2, there are multiple cystic areas in the white matter radiating at right angles to the ventricles. These are interpreted as being dilated Virchow-Robin spaces. In type 3, there is no periventricular nodular heterotopia or cystic areas of the brain. Verloes et al. (2015) considered types 1 and 3 to be the same as Baraitser-Winter syndrome; type 2 corresponds with Sener syndrome (606156).

Valente et al. (2005) reported an 18-year-old boy with what they termed 'Fryns-Aftimos syndrome.' The distinct facial phenotype included facial edema, ptosis, hypertelorism, and temporal flattening. Other features included webbed neck, hypoplastic thorax with inverted nipples, limited extension of the elbows and knees, epilepsy, and severe mental retardation. MRI showed diffuse pachygyria and an unusual skull base presentation with a small posterior fossa and narrowed foramen magnum. Notably, the unaffected mother had subsequent spontaneous abortion of an anencephalic male fetus with limb abnormalities, suggesting X-linked inheritance.

Riviere et al. (2012) reported on 10 children with Baraitser-Winter syndrome and mutations in the ACTB gene. Six of the 10 had short stature; 6 of 9 evaluated had postnatal microcephaly; all 9 evaluated had intellectual disability and seizures, and 4 of 8 had hearing loss; 8 of 10 had trigonocephaly; all 10 had hypertelorism and congenital ptosis, and 9 had high-arched eyebrows. Colobomata of the iris or retina were present in 6 of 10 and all 8 for whom data were available had anterior-to-posterior gradient lissencephaly of the pachygyria or pachygyria-band type. Neither familial recurrence nor consanguinity had been observed in any families, including the 18 reported by them, and no pathogenic copy-number variants had been detected using chromosome microarrays.

Riviere et al. (2012) reported substantial phenotypic overlap between Baraitser-Winter syndrome and those reported to have Fryns-Aftimos syndrome, including trigonocephaly, hypertelorism, congenital ptosis, high-arched eyebrows, broad nose, and low-set posteriorly rotated malformed ears; both have predominantly proximal contractures and a cortical malformation. Riviere et al. (2012) noted that most Fryns-Aftimos patients were described at an older age than those with Baraitser-Winter syndrome, and suggested that part of the clinical distinction between both phenotypes may be the result of aging, leading to more coarse facial features and joint limitation.

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. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma. Verloes et al. (2015) suggested that the phenotype in the twins described by Gearing et al. (2002) and Procaccio et al. (2006) with juvenile-onset dystonia (607371) was compatible with BRWS.

Clinical Variability

Cuvertino et al. (2017) reported 3 unrelated patients (XXIV, XXV, and XXVI) with a pleiotropic developmental disorder associated with de novo heterozygous loss-of-function frameshift or nonsense mutations in the ACTB gene (102630.0008-102630.0010). The patients were 12, 14, and 18 years of age. Two had feeding difficulties in infancy, 1 had postnatal growth retardation, and 2 had microcephaly. They had mild to moderate intellectual disability with variable speech and/or motor delay and variable behavioral abnormalities, such as hyperactivity. One patient had dystonia and 2 had pectus deformities. Additional features, found in 1 patient each, included tracheoesophageal fistula, esophageal atresia, distal skeletal anomalies, and hypertrichosis (patient XXIV); excess skin and lytic lesions of the skull (patient XXV); and atrial septal defect, sensorineural hearing loss, and mild joint contractures (patient XXVI). Dysmorphic features were also variable, and included hypertelorism, wavy eyebrows, dense eyelashes, wide nose, wide mouth, and prominent chin. Cuvertino et al. (2017) commented that, in their opinion, the phenotype in these patients was distinct from those observed in BRWS, although there were some overlapping features.

Phenotypic Overlap with Dubowitz Syndrome

Johnston et al. (2013) described a 7-year-old girl with microcephaly, dysmorphic facial features, and intellectual disability, who was initially given a clinical diagnosis of Dubowitz syndrome (223370). At birth she was noted to have low-set ears, unilateral ptosis, low anterior hairline, and mild hypertrichosis. MRI of the brain at age 34 months was normal as was renal ultrasound and skeletal survey. Examination at age 4.5 years showed metopic ridging with apparent microcephaly and hoarse voice. Craniofacial findings included asymmetric positioning of the globes with left ptosis, short palpebral fissures, and apparent widely spaced eyes; posteriorly rotated ears with abnormally shaped pinnae; broad nasal root, long columella, and alae nasi flaring; prominent tongue, wide mouth, and bifid uvula. Limb findings included distally placed thumbs, small thenar eminence, camptodactyly of digits 3, 4, and 5, and prominent fingertip pads. At age 7 years age, she was noted to have obsessive-compulsive behaviors and hyperactivity as well as severe myopia in her right eye, optic nerve asymmetry, and mild conductive hearing loss. Left vertical talus had been treated. Upon discovery of a mutation in the ACTB gene (see MOLECULAR GENETICS), her diagnosis was changed to atypical Baraitser-Winter syndrome, given the absence of some of the characteristic findings of BRWS including lissencephaly, seizures, and iris/retinal coloboma.

Inheritance

Riviere et al. (2012) reported that, with one exception, all reported patients with Baraitser-Winter syndrome have been sporadic. They considered it likely that the sibs included in the original report (Baraitser and Winter, 1988) did not have Baraitser-Winter syndrome (see HISTORY).

Cytogenetics

Chromosome 7p22 Deletion

Shimojima et al. (2016) reported 5 patients, including a set of monozygotic twin girls, with overlapping deletions of the 7p22.1 region. The shortest region of overlap included 5 genes, 1 of which was ACTB. The patients had nonspecific developmental delay, short stature, microcephaly, failure to thrive, and variable dysmorphic features, including frontal bossing, sparse eyebrows, long eyelashes, hypertelorism, low-set ears, thin lips, long philtrum, midface hypoplasia, small chin, pectus excavatum, and cryptorchidism. Ptosis was not noted. The deletions occurred de novo in 3 patients, and the twins inherited the deletion from their mother, who had developmental delay and microcephaly. Lymphocytes derived from 1 of the patients showed about a 50% reduction in ACTB expression, consistent with haploinsufficiency, which the authors suggested was responsible for the clinical features.

Cuvertino et al. (2017) reported 30 patients from 23 unrelated families with a pleiotropic developmental disorder associated with heterozygous deletions of 7p22, all of which included or putatively affected the ACTB gene as well as additional genes. The deletions, which had different breakpoints, ranged from 0.08 to 3.64 Mb in size, and ACTB was the only gene deleted within the minimal critical region. All patients had developmental delay and intellectual disability that ranged from mild to severe, and most also had motor and speech delay. Behavioral changes included attention deficit and hyperactivity, but most had a friendly sociable demeanor. Other common features included intrauterine and postnatal growth retardation, microcephaly, distal skeletal abnormalities, cryptorchidism, and inguinal hernia. About half of patients had cardiac abnormalities, such as septal defects, and about 40% had renal abnormalities, including horseshoe kidney, vesicoureteral reflux, and renal agenesis. Common dysmorphic features included wavy interrupted eyebrows, dense eyelashes, a wide nose, a wide mouth, and a prominent chin. Some patients had overlapping toes, small nails, and spinal anomalies such as sacral dimples. Eight of 10 patients with brain imaging studies showed abnormalities, including gray matter heterotopia, cortical atrophy, white matter hyperintensities, thin corpus callosum, and enlarged ventricles. Seizures were rare. Cells from 4 patients with deletions showed reduced ACTB transcript levels compared to controls. Although cytoplasmic levels of beta-actin protein in patient fibroblasts were similar to controls, the ACTB-deficient cells were significantly more circular compared to control cells; ACTB-deficient cells also showed impaired migration in an in vitro wound assay. Similar results were obtained in control fibroblasts using siRNA-mediated ACTB gene silencing. Cuvertino et al. (2017) concluded that the phenotype resulted from haploinsufficiency of the ACTB gene, which plays a role in development, particularly of the brain, heart, and kidney.

Chromosome 2p12-q14 Inversion

Pallotta (1991) reported a 6-year-old male with a phenotype similar to Baraitser-Winter syndrome who had a pericentric inversion of chromosome 2: inv(2)(p12q14) who had a phenotype similar to that in the patients reported by Baraitser and Winter (1988). The chromosomal rearrangement had been inherited from his mother, who was phenotypically normal.

similar phenotype was associated with a similar pericentric inversion. Again, the mother, who was phenotypically normal, had the same chromosomal rearrangement. The possibility that an odd number of crossovers in the 'inversion loops' of chromosome 2 caused a very small duplication or deletion of chromosomal material in the affected offspring was raised by Pallotta (1991).

Ramer et al. (1995) reported that 2 of 9 children, most of whom shared the features of shallow orbits, ptosis, coloboma, trigonocephaly, gyral malformations, and mental and growth retardation, had identical pericentric inversions involving 2p12-q14. Ramer et al. (1995) noted that the PAX8 gene (167415) maps to 2q12-q14, a site coincident with the distal breakpoint of the inversions identified in the children reported by Ayme et al. (1979) and Pallotta (1991).

Molecular Genetics

Riviere et al. (2012) performed whole-exome sequencing in 3 proband-parent trios segregating BRWS and identified de novo missense changes in the cytoplasmic actin-coding genes ACTB and ACTG1 (102560) in 1 and 2 probands, respectively. The ACTB mutation in the proband was a missense mutation, arg196-to-his (R196H; 102630.0002), that was also found in 6 of 15 additional affected individuals, including patient 1 (11-11287) in the original report of Fryns and Aftimos (2000). Three additional de novo missense mutations in the ACTB gene (R196C, 102630.0003; L65V, 102630.0004; N12D, 102630.0005) were identified in this cohort. Riviere et al. (2012) suggested that the observations supported a dominant-negative or gain-of-function mechanism for the mutations, since none of the patients had deletions or truncating mutations.

In a 7-year-old girl with microcephaly, dysmorphic facial features including ptosis and low-set ears, and intellectual disability, who was initially given a clinical diagnosis of Dubowitz syndrome (223370), Johnston et al. (2013) identified a de novo missense mutation in the ACTB gene (E117K; 102630.0006) and concluded that the patient had an atypical form of Baraitser-Winter syndrome without lissencephaly, seizures, or iris/retinal coloboma.

In 3 patients with a diagnosis of Fryns-Aftimos syndrome, Di Donato et al. (2014) identified mutations in the ACTB gene; see, e.g., R196C (102630.0003), which was previously found in a patient with BRWS1, and T120I (102630.0007). On the basis of the ACTB mutations and analysis of the clinical findings, the authors reclassified the diagnosis of these patients as severe BRWS.

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. Arg196 in ACTB was found to be a hotspot; 8 patients had the R196H substitution and 6 had the R196C substitution. Verloes et al. (2015) suggested that the clinical heterogeneity among these patients with an identical molecular defect demonstrates intrinsic phenotypic variation of BRWS. Verloes et al. (2015) also 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. In 2 patients with a BRWS phenotype, originally described by Guion-Almeida and Richieri-Costa (1992, 1999), Verloes et al. (2015) identified the T120I mutation that had previously been identified by Di Donato et al. (2014). Verloes et al. (2015) suggested that this mutation is associated with a more severe phenotype. Verloes et al. (2015) also identified several patients with a BRWS phenotype in whom the ACTB and ACTG1 gene screening was negative.

In 3 unrelated patients (XXIV, XXV, and XXVI) with a pleiotropic developmental disorder, Cuvertino et al. (2017) identified de novo heterozygous loss of function frameshift or nonsense mutations in the ACTB gene (102630.0008-102630.0010), consistent with haploinsufficiency. Functional studies of these patient cells were not performed, but cells derived from patients with larger deletions including the ACTB gene showed decreased nuclear ACTB protein levels, abnormal regulation and expression of genes involved in the cell cycle, and decreased cellular proliferation. ACTB-deficient cells were also significantly more circular and larger overall compared to control cell, and showed impaired migration in an in vitro wound assay. Cuvertino et al. (2017) noted that the partial overlap of phenotypes of individuals with BRWS resulting from heterozygous ACTB missense mutations and individuals with ACTB loss-of-function mutations suggests that the disorder may result not only from a postulated gain-of-function mechanism, as suggested by Riviere et al. (2012), but might also include effects resulting from a loss-of-function or dominant-negative mechanism. The findings suggested that the phenotype resulted from haploinsufficiency of the ACTB gene, which plays a role in development, particularly of the brain, heart, and kidney.

History

Two of the children reported by Baraitser and Winter (1988) were sibs, which is consistent with autosomal recessive inheritance but does not exclude a submicroscopic abnormality of chromosome structure. Sib occurrence with apparently normal parents may also represent germinal mosaicism in one parent.

Riviere et al. (2012) reviewed the only report of affected sibs, patients 1 and 2 of Baraitser and Winter (1988), a brother and sister born to unrelated Asian parents. These patients both had iris colobomata, but both had normal head size and normal metopic region with no trigonocephaly, as well as normal ears and hearing. Brain imaging was not performed. Riviere et al. (2012) remarked that this family was lost to follow-up, and a cryptic chromosomal imbalance was not excluded. Considering their findings, Riviere et al. (2012) concluded that these 2 sibs should probably not be considered as having Baraitser-Winter syndrome. Patient 3 of the original report was found to have a mutation in the ACTG1 gene (102560.0009).