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Baraitser-Winter Cerebrofrontofacial Syndrome

, MD, PhD, , PharmD, PhD, , MD, PhD, and , MD, PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: March 24, 2022.

Estimated reading time: 24 minutes

Summary

Clinical characteristics.

Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations. Seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction are also common.

Diagnosis/testing.

The diagnosis of BWCFF syndrome is established in a proband with suggestive findings and a heterozygous missense pathogenic variant in either ACTB or ACTG1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatment for medical concerns in conjunction with the associated specialist; management of developmental delay and intellectual disability is tailored to the individual.

Surveillance: Routine follow up recommended for neurodevelopmental assessment in all; follow up as needed for those with seizures (neurologic evaluation), coloboma or microphthalmia (ophthalmologic evaluation), hearing loss (audiologic evaluation), cardiac defects, renal tract anomalies, and gastrointestinal dysfunction.

Genetic counseling.

BWCFF syndrome is an autosomal dominant disorder. Most individuals with BWCFF syndrome reported to date have the disorder as the result of a de novo ACTB or ACTG1 pathogenic variant. If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once the ACTB or ACTG1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for BWCFF syndrome are possible.

Diagnosis

No consensus clinical diagnostic criteria for Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome have been published.

Suggestive Findings

BWCFF syndrome should be suspected in individuals with the following clinical and imaging findings.

Clinical findings

  • Typical craniofacial features (widely spaced eyes, bulbous nose with broad nasal tip and prominent nasal bridge, congenital nonmyopathic ptosis, prominent metopic ridge, and highly arched eyebrows)
  • Developmental delay / intellectual disability

Variably present findings:

  • Ocular coloboma
  • Wasting of the muscles of the shoulder girdle
  • Sensorineural hearing loss

Imaging findings. Frontal-predominant pachygyria especially in combination with posterior-band heterotopia and enlarged perivascular spaces on brain imaging

Establishing the Diagnosis

The diagnosis of BWCFF syndrome is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) missense variant in either ACTB or ACTG1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with intellectual disability are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

An intellectual disability multigene panel that includes some or all of the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Baraitser-Winter Cerebrofrontofacial Syndrome

Gene 1, 2Proportion of BWCFF Syndrome Attributed to Pathogenic Variants in GeneProportion of Probands with a Pathogenic Variant 3 Detectable by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
ACTB >55%100% 6NA 7, 8
ACTG1 >35%100% 6NA 7, 8
Unknown 9<10%NA

BWCFF = Baraitser-Winter cerebrofrontofacial; NA = not applicable

1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on variants detected in these genes.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

7.

Deletions and duplications of either ACTB or ACTG1 do not result in the BWCFF syndrome phenotype.

8.

All pathogenic variants reported to date are gain-of-function missense variants in ACTB or ACTG1; thus, testing for deletion (haploinsufficiency) or duplication (overexpression) is not indicated.

9.

Estimate based on authors' experience

Clinical Characteristics

Clinical Description

Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations [Verloes et al 2015, Yates et al 2017]. BWCFF syndrome has been reported in fewer than 100 individuals.

Significant variation in clinical features is observed, and some individuals whose diagnosis was made through identification of a pathogenic variant on gene panel or exome analyses (rather than on clinical suspicion) are expected to show milder or incomplete phenotypes (formes frustes) that would not have led unambiguously to a clinical diagnosis of BWCFF syndrome.

Table 2.

Baraitser-Winter Cerebrofrontofacial Syndrome: Frequency of Select Features

Feature (% of Persons w/Feature)Comment
Dysmorphic craniofacial features (100%) incl:
  • Prominent metopic ridging or trigonocephaly (65%)
  • Widely spaced eyes (95%)
  • Bilateral ptosis (90%)
  • Highly arched eyebrows (90%)
  • Ocular coloboma (30%); may be assoc w/microphthalmia (<10%)
  • Small ears w/↑ posterior angulation, anteverted pinnae, overfolded, thick helix, & underdeveloped antihelix (73%)
  • Wide, short, thick, & upturned nose, w/large, flat tip (85%)
  • Long, smooth philtrum (84%)
  • Wide mouth w/downturned corners & everted vermilion of lower lip (45%)
  • Cleft lip & palate (10%)
Some persons may have rather mild craniofacial features & be considered nondysmorphic.
Developmental delay / intellectual disability (>95%)
  • Mild-to-moderate developmental delay w/mild intellectual disability
  • Delays profound if severe lissencephaly present
  • Rare individuals w/normal intelligence
Microcephaly (~50%)Microcephaly may be of prenatal onset, usually mild, but may be severe w/lissencephaly (≥ -5 SD).
Brain malformation (83%) incl:
  • Pachygyria (frontal or predominantly central) &/or subcortical band heterotopia (61%)
  • Periventricular heterotopias (2%)
  • Corpus callosum abnormality (20%)
Epilepsy (50%)
  • Typically assoc w/structural brain anomalies
  • Age dependent
  • Manifests from 1st mos of life to 24 yrs
Neuromuscular abnormality (20%)
  • Peculiar stance, joint contractures, & pterygia observed in some persons
  • Contractures & muscle wasting may progress w/time.
Vision abnormality (30%)Assoc w/coloboma & microphthalmia
Sensorineural &/or conductive hearing loss (35%)
  • Can be progressive
  • May be assoc w/inner ear malformation
Moderate short stature (44%)
Cardiovascular abnormality (38%)
Genitourinary abnormality (41%)Incl:
  • Hydronephrosis (23%)
  • Structural renal malformation (10%)
  • Micropenis, cryptorchidism, & hypospadias (rare)
Skeletal features (20%)Incl pectus deformity & broad thumbs & hallux
Gastrointestinal dysfunction (41%)
  • Frequent chronic constipation (requiring daily medication) & reflux disease
  • Occasional vomiting, diarrhea, feeding difficulties, failure to thrive
  • Several persons required tube feeding & PEG.
  • Rare anomalies incl intestinal malrotation, duodenal atresia, & bowel pseudo-obstruction
Abdominal anomaly (rare 1)Omphalocele
Malignancy (<5%)Lymphoma & leukemia have been reported.

PEG = percutaneous endoscopic gastrostomy

1.

Dysmorphic craniofacial features vary from mild to severe and evolve considerably over time. With age the facial features become significantly coarser. The face is round and flat in infancy. In those with more severe facial involvement, the widely spaced eyes are reminiscent of frontonasal dysplasia due to the degree of increased spacing and wide nose.

General craniofacial shape is characterized a flat malar region and retrognathia with a pointed chin, and often by prominent metopic ridging or trigonocephaly.

Eyes are widely spaced with bilateral ptosis, which may require surgery. Other findings:

  • Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus), lagophthalmos, and euryblepharon; appearance may resemble the ocular findings in Kabuki syndrome although the gestalt is different.
  • Highly arched eyebrows in continuity of the lateral edges of the nose
  • Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia

Ears are often small with increased posterior angulation, sometimes anteverted pinnae, with an overfolded, thick helix and an underdeveloped antihelix.

Nose and mouth

  • Wide, short, thick, and upturned nose, with a large, flat tip, a thick columella, anteverted, thick nares, and a median grove (in the most severe cases)
  • Prominent nasal bridge, flat in its middle part
  • Long and smooth philtrum and thin vermilion border of the upper lip
  • Wide mouth with downturned corners, everted vermilion of the lower lip
  • Cleft lip and palate

Developmental delay (DD) / intellectual disability (ID) is highly variable:

  • In children with normal brain structure, motor delay is common, but otherwise development is only mildly to moderately delayed. ID is usually mild. Rare individuals with normal intelligence have also been reported.
  • Among those with a cortical malformation, development is always delayed. ID varied from profound in those with severe and diffuse lissencephaly to mild ID in some with anterior pachygyria or periventricular heterotopia.

Brain malformations are present in more than 80% of individuals. Findings may include:

  • Frontal or predominantly central pachygyria; more rarely, severe lissencephaly or microlissencephaly [Poirier et al 2015];
  • Subcortical band and/or periventricular heterotopias;
  • Short, thick, or absent corpus callosum [Rossi et al 2003];
  • Chiari malformation [Sandestig et al 2019].

Neurologic

  • Epilepsy, of no specific type and of variable severity, is present in 50% of individuals, often in conjunction with structural cerebral anomalies.
  • Variable muscular hypotonia, particularly of the upper body, is frequent and may result in progressive scoliosis beginning from age eight to 10 years.
  • Many affected individuals, especially teenagers and adults, have a peculiar stance with kyphosis, anteverted shoulders, and slightly flexed elbows and knees, which may be associated with limited joint movement. Axillary and popliteal pterygia may be present at birth. A few have congenital arthrogryposis multiplex congenita.
  • Increasingly difficult ambulation is seen in some adults, which may indicate a slowly progressive myopathic process with slowly progressive, generalized muscle weakness. Some adults may become dependent on a wheelchair for mobility and develop late-onset spinal deformity (kyphosis, scoliosis).

Vision abnormality. Iris and retinal coloboma and microphthalmia may severely impair vision. Ptosis may require surgical correction. An individual has been reported with congenital fibrosis of oculomotor muscles [Chacon-Camacho et al 2020]. Esotropia and refractive errors were noted.

Hearing loss. Sensorineural hearing loss of variable degree may be present and can be progressive and require hearing aids. The inner ear and auditory nerve may be malformed and hypoplastic. Several individuals have frequent otitis media resulting in conductive hearing loss especially in early childhood.

Growth

  • Normal or low intrauterine growth; moderate short stature is observed in 50% of teenagers and adults.
  • Head circumference is typically low normal at birth, although several individuals with severe prenatal microcephaly have been reported [Vontell et al 2019]; mild postnatal microcephaly develops in about half of individuals.

Gastrointestinal dysfunction [Authors, unpublished observations]

  • Constipation (either chronic or occasional) is the most frequently observed GI finding. Rarely, bowel pseudo-obstruction occurs.
  • Frequent vomiting and gastroesophageal reflux disease have been reported occasionally in newborns and small children.
  • Severe feeding difficulties requiring nasogastric tube feeding with subsequent feeding tube have been reported in several children.
  • Structural malformations include duodenal atresia and intestinal malrotation; one individual developed liver cirrhosis.

Other malformations

  • Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects, abnormal aortic valve, aortic stenosis, mitral valve regurgitation, and tricuspid regurgitation have been identified.
  • Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication, and hypospadias.
  • Musculoskeletal features include broad thumbs and hallux (rarely, duplication of the hallux and/or thumbs).

Malignancy. Three individuals with different hematologic malignancies have been reported; causal relationship has not been demonstrated, but also cannot be reliably excluded (see Cancer and Benign Tumors).

Prognosis. Limited data have been published in adults with BWCFF syndrome; only six individuals older than age 40 years are reported in the literature [Hampshire et al 2020]. From the authors' experience, the neuromuscular involvement tends to worsen with time, with progressive muscle wasting and weakness, progressive scoliosis, osteoporosis, and loss of ambulation in the fifth decade of life. Cognitive decline was reported [Di Donato et al 2014]. Life span may be reduced; two adult individuals died in the third decade of life as a result of acute ileus, neurologic decline with feeding difficulties, and recurrent pneumonias [Authors, unpublished observations]. The oldest known individual was 62 years old at the last follow up.

Genotype-Phenotype Correlations

Although phenotypic expression of BWCFF syndrome is remarkably variable, even among unrelated individuals harboring an identical pathogenic variant, two pathogenic variants have been found in those with the most severe presentation of the BWCFF syndrome clinical spectrum, including microcephaly and pachygyria, profound intellectual disability, and epilepsy along with variable anomalies of other systems. These variants are p.Thr120Ile in ACTB and p.Thr203Met in ACTG1.

Penetrance

The penetrance of BWCFF syndrome appears to be complete, but no single clinical manifestation is constant.

Nomenclature

Cerebrofrontofacial syndrome type 1 and type 3 and Fryns-Aftimos syndrome represent the severe end of the BWCFF syndrome spectrum. As the same pathogenic variant can lead to any of those three phenotypes, those entities are not considered allelic disorders, but rather part of the phenotypic spectrum of BWCFF syndrome.

Prevalence

BWCFF syndrome is rare. Slightly fewer than 100 individuals with a molecularly confirmed diagnosis have been documented to date. However, considering the phenotypic variability, it may be underdiagnosed.

Differential Diagnosis

Disorders to consider in the differential diagnosis of Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome are summarized in Table 4.

Table 4.

Selected Disorders in the Differential Diagnosis of Baraitser-Winter Cerebrofrontofacial Syndrome

Gene(s)DisorderMOIKey Features
PTPN11
SOS1
LZTR1
KRAS
RAF1
RIT1
SOS2
BRAF
MAP2K1
MRAS
NRAS
RRAS2 1
Noonan syndrome (NS)AD
(AR) 2
Overlapping features: In BWCFF syndrome w/o brain anomalies, the facial appearance in infancy (when metopic ridge is absent), in assoc w/chest deformity & nuchal skinfolds or pterygium colli, may falsely lead to diagnosis of NS.
Distinguishing features: Coloboma is rarely observed in NS & NS is not assoc w/pachygyria or muscle involvement.
SPECC1L
CDH11
Hypertelorism, Teebi type (brachycephalofrontonasal dysplasia; OMIM PS145420)ADOverlapping feature: significantly widely spaced eyes
FGD1 Aarskog-Scott syndrome (OMIM 305400)XLOverlapping feature: significantly widely spaced eyes
SERAC1 SERAC1 deficiency ARCauses a combination of ID, hypotonia, early-onset dystonia, & deafness

AD = autosomal dominant; AR = autosomal recessive; BWCFF = Baraitser-Winter cerebrofrontofacial; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

Genes are organized first by frequency of causation of Noonan syndrome and then alphabetically. Recent reports have implicated several additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals each, including RRAS and A2ML1 (see Noonan Syndrome).

2.

Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.

Management

No clinical practice guidelines for Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BWCFF syndrome, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Baraitser-Winter Cerebrofrontofacial Syndrome

System/ConcernEvaluationComment
Development Developmental assessment
  • To incl motor, adaptive, cognitive, & speech/language eval
  • Eval for early intervention / special education
Neurologic Neurologic eval
  • To incl brain MRI
  • Consider EEG if brain MRI anomaly &/or seizures present.
Eyes Ophthalmologic eval incl fundoscopyTo assess for malformation, ↓ vision, abnormal ocular mvmt, strabismus
Hearing Audiologic evalAssess for hearing loss
Gastroenterology
  • Abdominal ultrasound &, if necessary, assess GI motility.
  • Assess for feeding difficulties.
To assess for gastrointestinal disorders & dysfunction & feeding difficulties
Cardiovascular EchocardiogramAssess for congenital heart defects.
Genitourinary Renal ultrasoundEvaluate for malformation of kidneys &/or ureters
Hematology Blood count & platelet countBaseline study given possible ↑ risk for hematologic malignancy 1
Genetic counseling By genetics professionals 2To inform affected persons & their families re nature, MOI, & implications of BWCFF syndrome to facilitate medical & personal decision making
Family support
& resources
Assess need for:

BWCFF = Baraitser-Winter cerebrofrontofacial; MOI = mode of inheritance

1.

Note that individuals diagnosed via molecular genetic testing with a pathogenic ACTB variant who have only a mild BWCFF syndrome phenotype in combination with thrombocytopenia may have an allelic disorder, as BWCFF syndrome is not associated with thrombocytopenia (see Genetically Related Disorders).

2.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

No specific treatment for BWCFF syndrome exists. Management recommendations are detailed in Table 6. Malformations of the heart, urinary tract, and oral clefts are treated using standard procedures.

Table 6.

Treatment of Manifestations in Individuals with Baraitser-Winter Cerebrofrontofacial Syndrome

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay /
Intellectual disability
See Developmental Delay / Intellectual Disability Management Issues.
Muscle wasting & joint limitation PT may be helpful to slow progressive joint ankyloses & scoliosis.Orthopedic monitoring during growth spurts & adolescence for early recognition & mgmt of scoliosis
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Abnormal vision &/or
strabismus
Standard treatment(s) per ophthalmologist if coloboma &/or micropthalmia is present & → poor visionPtosis may require surgery.
Hearing Hearing aids may be helpful; per otolaryngologist.Community hearing services through early intervention or school district
GI dysfunction Osmotic laxatives were reported effective in majority of persons w/constipation.GI eval is necessary to monitor long-term medication.

ASM = anti-seizure medication; GI = gastrointestinal; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Intensive and regular physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

Table 7.

Recommended Surveillance for Individuals with Baraitser-Winter Cerebrofrontofacial Syndrome

System/ConcernEvaluationFrequency
Development Monitor developmental progress & educational needs.At each visit
Neurologic Monitor those w/seizures as clinically indicated.
Eyes If coloboma or microphthalmia present, ophthalmologic follow up w/screening for intraocular hypertension & glaucoma (a known complication of colobomatous microphthalmia)At least annually
Hearing loss Evaluate for progression.Annually
Cardiovascular Monitor for complications if cardiac malformation present.Per cardiologist
Genitourinary Monitor for renal insufficiency if renal anomaly present.Per nephrologist
Gastroenterology Monitor those w/feeding difficulties & GI dysfunction.At least annually
Orthopedic Monitor for scoliosis.At least annually; every 6 mos during growth spurts & adolescence
Family/
Community
Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination.At each visit

Note: The risk of malignancies is not established for BWCFF syndrome, and thus no regular surveillance is recommended. However, screening for hematologic malignancies must be considered in case of physical deterioration or unexplained chronic fever.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is an autosomal dominant disorder.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with BWCFF syndrome has a 50% chance of inheriting the ACTB or ACTG1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the ACTB or ACTG1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals and to young adults who are affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the ACTB or ACTG1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for BWCFF syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Baraitser-Winter Cerebrofrontofacial Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Baraitser-Winter Cerebrofrontofacial Syndrome (View All in OMIM)

102560ACTIN, GAMMA-1; ACTG1
102630ACTIN, BETA; ACTB
243310BARAITSER-WINTER SYNDROME 1; BRWS1
614583BARAITSER-WINTER SYNDROME 2; BRWS2

Molecular Pathogenesis

ACTB encodes the cytoplasmic protein beta-actin (β-actin; actin, cytoplasmic 1), consisting of 375 amino acids. β-actin interacts with multiple cytoplasmic proteins. ACTG1 encodes the cytoplasmic protein gamma-actin (γ-actin; actin, cytoplasmic 2) and is almost identical to β-actin, also consisting of 375 amino acids. Primary sequences of γ-actin and β-actin differ only by four amino acid residues; however, the two proteins have distinct post-translational modifications. Both cytoplasmic actins are essential for cell survival, but they perform various functions in the interphase and cell division, and the actin ratio depends on the cell type. The β- and γ-actins coexist in most cell types as components of the cytoskeleton and as mediators of internal cell motility, and play a role in sarcomere assembly. They have both cooperative interactions and partially nonredundant functions.

ACTB protein plays a role in a wide variety of cellular functions such as cell growth, cell division, cell motility, immune response, maintenance of cell stability, and cytoskeletal formation.

ACTG1 protein functions in non-muscle cells and is abundant in the auditory hair cells. It is responsible for the cellular plasticity and motility and essential for the shape and function of stereocilia of hair cells of the cochlea [Dugina et al 2019, Dugina et al 2021].

Mechanism of disease causation. Pathogenic variants in ACTB and ACTG1 leading to BWCFF syndrome have a gain-of-function effect.

Table 8.

Baraitser-Winter Cerebrofrontofacial Syndrome: Notable Pathogenic Variants by Gene

Gene 1Reference
Sequences
DNA Nucleotide
Change
Predicted
Protein Change
Comment [Reference]
ACTB NM_001101​.5
NP_001092​.1
c.359C>Tp.Thr120IleAssoc w/severe phenotype [Di Donato et al 2014]
ACTG1 NM_001614​.5
NP_001605​.1
c.608C>Tp.Thr203MetAssoc w/severe phenotype [Vontell et al 2019, Chacon-Camacho et al 2020]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Genes from Table 1 in alphabetic order

Cancer and Benign Tumors

Sporadic, isolated tumors (including hepatocellular carcinoma, melanoma, ovarian cancer, leukemia, and B-cell lymphoma) frequently harbor somatic pathogenic variants in ACTB and ACTG1 that are not present in the germline.

A recent study using data available in the cBioPortal database have shown that somatic variants in ACTB and ACTG1 were rare events in 174 cancer studies covering multiple cancer subtypes. However, ACTB and ACTG1 were more frequently mutated in hematologic cancers, specifically in lymphoid and not in myeloid malignancies [Witjes et al 2020]. Whether somatic variants in ACTB and ACTG1 merely represent passenger variants or have a driver effect remains unclear.

Chapter Notes

Revision History

  • 24 March 2022 (ha) Comprehensive update posted live
  • 19 November 2015 (me) Review posted live
  • 9 March 2015 (av) Original submission

References

Literature Cited

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