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.

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).

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.

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).

• Cutaneous lymphoma was diagnosed at age 19 years in an individual with BWCFF syndrome and a germline ACTG1 pathogenic variant [Verloes et al 2015].
• Precursor B-cell acute lymphatic leukemia developed at age eight years in a child with BWCFF syndrome and a germline ACTB pathogenic variant [Verloes et al 2015, Diets et al 2018].
• Acute myeloid leukemia, M5 subtype developed at age 21 years in an individual with BWCFF syndrome and a germline ACTB pathogenic variant [Cianci et al 2017].

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.

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.

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.

Surveillance

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.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• Most individuals with BWCFF syndrome reported to date have the disorder as the result of a de novo ACTB or ACTG1 pathogenic variant.
• In rare families, individuals diagnosed with BWCFF syndrome have the disorder as the result of a pathogenic variant inherited from a parent with germline mosaicism [Hampshire et al 2020] or from a heterozygous, affected parent [Yates et al 2017].
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence-risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for an ACTB or ACTG1 pathogenic variant may be mildly/minimally affected.

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

• 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%.
• If the proband has a known ACTB or ACTG1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Hampshire et al 2020].
• If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of a proband is presumed to be low but greater than that of the general population because of the possibility of parental germline mosaicism.

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.

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.

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.

Revision History

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

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