Further Delineation of the ACTG1-Associated Baraitser-Winter Cerebrofontofacial Syndrome Phenotype
Clinical Genetics and Therapeutics
-
Primary Categories:
- Clinical- Pediatric
-
Secondary Categories:
- Clinical- Pediatric
Introduction
Baraitser-Winter Cerebrofrontofacial (BWCFF) syndrome is a rare autosomal dominant multiple congenital anomaly syndrome characterized by distinct craniofacial features, short stature and intellectual disability. The typical craniofacial features include hypertelorism, ptosis, microcephaly and a wide face. Individuals can present with brain malformation including pachygyria, agenesis of the corpus callosum and anterior pre-dominant lissencephaly. Additional features can include wastage of the shoulder-girdle muscles, cleft lip and/or palate, duplicated hallux, congenital heart defects, renal tract anomalies, sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. We present a young female with a likely pathogenic variant in ACTG1 identified through a hearing loss panel.
Case Presentation
A 9-year-old female was referred to genetic clinic by her otolaryngologist due to high frequency hearing loss. She reportedly passed her newborn hearing screen, however had a history of chronic otitis media requiring tube placement. She had delayed speech at 2 years of age requiring speech therapy for two months. Recent audiologic testing indicated essentially normal hearing sensitivity 500-3000 Hz sloping to mild to moderate sensorineural hearing loss 4000-8000 Hz, right and essentially normal hearing sensitivity 500-3000 Hz sloping to mild sensorineural hearing loss 4000-8000 Hz, left. Physical exam at the initial evaluation noted exophthalmos, arched eyebrows with lateral sparseness, anteverted nares, high, narrow palate with slight retrognathia. Her growth was noted to be at the 12th centile which is less than expected mid-parental height. A hearing loss panel was coordinated and noted a likely pathogenic variant in ACTG1, c.1003C>T (p.R335C). She was also noted to have a variant of uncertain significance in TMC1, c.1437G>A (p.G513R).
Diagnostic Workup
A hearing loss panel sequenced and performed deletion/duplication analysis on 154 genes. The mitochondrial genome was also analyzed. She was noted to have a likely pathogenic variant in ACTG1, c.1003C>T (p.R335C). She was also noted to have a variant of uncertain significance in TMC1, c.1437G>A (p.G513R). Variants of uncertain significance in three autosomal recessive genes were also identified.
Treatment and Management
Cardiology and neurology evaluations were recommended. A renal ultrasound was coordinated. Maternal testing of the ACTG1 and TMC1 variants was performed. Paternal testing was not performed due to lack of insurance for the father.
Outcome and Follow-Up
The neurological exam was essentially unremarkable and non-focal. She was noted to have some mild appendicular hypotonia. MRI with IACs was unremarkable other than a left maxillary sinus mucous retention cyst or polyp. Echocardiogram noted mild mitral valve prolapse with mild valve insufficiency which appeared to be hemodynamically insignificant. Also noted was trace aortic valve insufficiency which was also deemed hemodynamically insignificant. Renal and bladder ultrasound was within normal limits. Maternal testing was negative for both the ACTG1 likely pathogenic variant and the variant of uncertain significance in TMC1.
Discussion
The phenotypic spectrum of ACTG1-Associated Baraitser-Winter Cerebrofontofacial Syndrome has been historically associated with typical craniofacial features and intellectual disabilities. We report a patient with this rare condition and symptoms less severe than previously reported in the literature. Our patient was noted to have bilateral mild to moderate sensorineural hearing loss and mild dysmorphism. Additional studies to determine whether she had any other congenital anomalies were essentially negative.
Conclusion
In summary, this case highlights the clinical variability of ACTG1-Associated Baraitser-Winter Cerebrofontofacial syndrome. This condition was previously thought to be associated with intellectual disabilities and varying congenital anomalies. ACTG1-Associated Baraitser-Winter Cerebrofontofacial Syndrome should be considered in children with isolated sensorineural hearing loss. This case highlights how expanded access to genetic testing can add to the phenotype of a previously described syndrome.
Baraitser-Winter Cerebrofrontofacial (BWCFF) syndrome is a rare autosomal dominant multiple congenital anomaly syndrome characterized by distinct craniofacial features, short stature and intellectual disability. The typical craniofacial features include hypertelorism, ptosis, microcephaly and a wide face. Individuals can present with brain malformation including pachygyria, agenesis of the corpus callosum and anterior pre-dominant lissencephaly. Additional features can include wastage of the shoulder-girdle muscles, cleft lip and/or palate, duplicated hallux, congenital heart defects, renal tract anomalies, sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. We present a young female with a likely pathogenic variant in ACTG1 identified through a hearing loss panel.
Case Presentation
A 9-year-old female was referred to genetic clinic by her otolaryngologist due to high frequency hearing loss. She reportedly passed her newborn hearing screen, however had a history of chronic otitis media requiring tube placement. She had delayed speech at 2 years of age requiring speech therapy for two months. Recent audiologic testing indicated essentially normal hearing sensitivity 500-3000 Hz sloping to mild to moderate sensorineural hearing loss 4000-8000 Hz, right and essentially normal hearing sensitivity 500-3000 Hz sloping to mild sensorineural hearing loss 4000-8000 Hz, left. Physical exam at the initial evaluation noted exophthalmos, arched eyebrows with lateral sparseness, anteverted nares, high, narrow palate with slight retrognathia. Her growth was noted to be at the 12th centile which is less than expected mid-parental height. A hearing loss panel was coordinated and noted a likely pathogenic variant in ACTG1, c.1003C>T (p.R335C). She was also noted to have a variant of uncertain significance in TMC1, c.1437G>A (p.G513R).
Diagnostic Workup
A hearing loss panel sequenced and performed deletion/duplication analysis on 154 genes. The mitochondrial genome was also analyzed. She was noted to have a likely pathogenic variant in ACTG1, c.1003C>T (p.R335C). She was also noted to have a variant of uncertain significance in TMC1, c.1437G>A (p.G513R). Variants of uncertain significance in three autosomal recessive genes were also identified.
Treatment and Management
Cardiology and neurology evaluations were recommended. A renal ultrasound was coordinated. Maternal testing of the ACTG1 and TMC1 variants was performed. Paternal testing was not performed due to lack of insurance for the father.
Outcome and Follow-Up
The neurological exam was essentially unremarkable and non-focal. She was noted to have some mild appendicular hypotonia. MRI with IACs was unremarkable other than a left maxillary sinus mucous retention cyst or polyp. Echocardiogram noted mild mitral valve prolapse with mild valve insufficiency which appeared to be hemodynamically insignificant. Also noted was trace aortic valve insufficiency which was also deemed hemodynamically insignificant. Renal and bladder ultrasound was within normal limits. Maternal testing was negative for both the ACTG1 likely pathogenic variant and the variant of uncertain significance in TMC1.
Discussion
The phenotypic spectrum of ACTG1-Associated Baraitser-Winter Cerebrofontofacial Syndrome has been historically associated with typical craniofacial features and intellectual disabilities. We report a patient with this rare condition and symptoms less severe than previously reported in the literature. Our patient was noted to have bilateral mild to moderate sensorineural hearing loss and mild dysmorphism. Additional studies to determine whether she had any other congenital anomalies were essentially negative.
Conclusion
In summary, this case highlights the clinical variability of ACTG1-Associated Baraitser-Winter Cerebrofontofacial syndrome. This condition was previously thought to be associated with intellectual disabilities and varying congenital anomalies. ACTG1-Associated Baraitser-Winter Cerebrofontofacial Syndrome should be considered in children with isolated sensorineural hearing loss. This case highlights how expanded access to genetic testing can add to the phenotype of a previously described syndrome.