Baraitser-Winter Cerebrofrontofacial Syndrome

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2021-01-18

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Summary

Clinical characteristics.

Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability (ID) that ranges from mild (usually in those with normal brain structure) to profound (typically in those with a neuronal migration defect). Many (but not all) affected individuals have iris or retinal coloboma, sensorineural deafness, and muscle wasting resulting in a peculiar stance with kyphosis, anteverted shoulders, and slightly flexed elbows and knees. Seizures, congenital heart defects, and renal malformations also are common.

Diagnosis/testing.

The diagnosis of BWCFF syndrome is established in a proband with a compatible clinical phenotype and a heterozygous gain-of-function variant in either ACTB or ACTG1.

Management.

Treatment of manifestations: Treatment is symptomatic. Developmental delay requires specific support (speech therapy, physical therapy) adapted to the severity of the handicap.

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

Genetic counseling.

BWCFF syndrome is inherited in an autosomal dominant manner. To date, all affected individuals have had a de novo pathogenic variant. The risk to sibs is low but presumed to be greater than that of the general population because of the possibility of germline mosaicism. If the ACTB or ACTG1 pathogenic variant is known, prenatal testing for subsequent pregnancies of the parents of an affected child is possible.

Diagnosis

Suggestive Findings

Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome should be suspected in individuals with:

Typical craniofacial features (widely spaced eyes, bulbous nose with broad nasal tip and prominent nasal bridge, congenital non-myopathic ptosis, prominent metopic ridge, and highly arched eyebrows)
Intellectual disability

Many (but not all) may have:

Ocular coloboma
Predominantly frontal pachygyria
Wasting of the muscles of the shoulder girdle
Sensorineural hearing loss (SNHL)

Establishing the Diagnosis

The diagnosis of BWCFF syndrome is established in a proband with a compatible clinical phenotype and a gain-of-function heterozygous pathogenic variant in either ACTB or ACTG1 (see Table 1).

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and genomic testing:

Serial single-gene testing (i.e., sequence analysis of ACTB followed by sequence analysis of ACTG1 if no pathogenic variant is identified) can be considered. Note: Deletion/duplication analysis is not indicated since all pathogenic alleles reported to date are gain-of-function missense variants.
A multigene panel that includes ACTB and ACTG1 and other genes of interest (see Differential Diagnosis) may also be considered. 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.
More comprehensive genomic testing including exome sequencing and (when available) genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes ACTB and ACTG1) fails to confirm a diagnosis in an individual with features of Baraitser-Winter cerebrofrontofacial syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation).
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 (BWCFF) Syndrome

Gene ¹	Proportion of BWCFF Syndrome Attributed to Pathogenic Variants in This Gene	Proportion of Pathogenic Variants ² Detected by Test Method
Gene ¹		Sequence analysis ³	Gene-targeted deletion/duplication analysis ⁴
ACTB	34/43 molecularly confirmed ⁵ (>60% clinically diagnosed ⁶)	All pathogenic variants reported to date	Not applicable ⁷
ACTG1	9/43 molecularly confirmed ⁵ (>20% clinically diagnosed ⁶)	All pathogenic variants reported to date	Not applicable ⁷
Unknown ⁶	<20%	NA

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.
4.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.: Verloes et al [2015]
6.: Author, personal observation
7.: 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.

Clinical Characteristics

Differential Diagnosis

Disorders to consider in the differential diagnosis of Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome include the following:

Hypertelorism, Teebi type (or brachycephalofrontonasal dysplasia) (OMIM 145420). This syndrome, of unknown etiology, is characterized by significantly widely spaced eyes. Some affected individuals may have undiagnosed BWCFF.
Noonan syndrome. In BWCFF syndrome without brain anomalies, the facial appearance in infancy (when the metopic ridge is absent), in association with a chest deformity and nuchal skinfolds or pterygium colli may falsely lead to a diagnosis of Noonan syndrome. Coloboma has been reported in some individuals with Noonan syndrome.
Kabuki syndrome. Individuals with Kabuki syndrome have long palpebral fissures reminiscent of BWCFF syndrome.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome, the following evaluations are recommended:

Ophthalmologic examination including fundoscopy
Hearing assessment
Brain MRI
EEG (if brain MRI is abnormal)
Neurology (adult or child) consultation in case of brain MRI anomaly and/or seizures
Neurocognitive evaluation
Echocardiogram for evidence of congenital heart defects
Abdominal ultrasound examination for evidence of malformation of the kidneys and/or ureters
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

There is no specific treatment of BWCFF syndrome. Symptomatic management involves the following.

Ptosis may require surgical treatment.
Coloboma and/or microphthalmia may lead to poor vision and require routine care for these findings.
Hearing loss may require routine care including hearing aids.
Epilepsy is treated using standard protocols.
Developmental delay requires specific support (speech therapy, physical therapy) adapted to the severity of the disability.
Malformations of the heart, urinary tract, and oral clefts are treated using standard procedures.

Surveillance

Appropriate surveillance includes the following:

Neurodevelopmental follow up by a multidisciplinary team involved in cognitive impairment and appropriate support
Coloboma or microphthalmia: ophthalmologic follow-up (at least yearly) with systematic screening for intraocular hypertension and glaucoma. Although glaucoma has not been reported to date, it is a known complication of colobomatous microphthalmia. Early detection allows specific treatment of intraocular hypertension.
Routine follow up of deafness for any evidence of progression
Cardiac defect: cardiology follow up (adapted to the type of congenital heart disease identified)
Renal tract anomaly: nephrology follow up adapted to the anomaly and the risk of renal insufficiency
Screening for malignancies. The risk of malignancies is not established for BWCFF syndrome; 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 www.ClinicalTrialsRegister.eu 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.