Cerebellar-Facial-Dental Syndrome
A rare, autosomal recessive, multiple congenital anomalies/dysmorphic syndrome characterized mainly by developmental delay, variable intellectual disability, microcephaly, cerebellar hypoplasia, dysmorphic features (central incisors macrodontia and slender fingers), short stature and variable congenital anomalies.
Epidemiology
To date, ten patients carrying biallelic BRF1 variants have been reported in the literature.
Clinical description
The clinical features of the syndrome include developmental delay and intellectual disability. Congenital microcephaly is present in all patients with [occipital frontal circumference recorded and with progressive deceleration. Postnatal growth retardation occurred in all patients with height last evaluation between -2.5 and -5 SD. The most constant dysmorphic features include central incisors macrodontia and slender fingers. Laryngomalacia, tracheomalacia, congenital heart defect, sensorineural hearing impairment and inner ear malformation have been reported. Brain malformations, as detected on magnetic resonance imaging, may include cerebellar hypoplasia, corpus callosum hypoplasia and, more variably, enlarged cisterna magna and enlarged lateral ventricles.
Etiology
The disorder is due to biallelic variants in the BRF1 (14q32.33) gene; the pathogenic variants reported are missense variants, with only one frameshift mutation identified. All variants affect protein residues located within the cyclin 2 protein domain.
Diagnostic methods
All patients reported had been diagnosed by next generation sequencing.
Differential diagnosis
The disorder is distinguished from other intellectual disability syndromes mainly by short stature and progressive microcephaly. Prominent upper incisors is a remarkable sign.
Antenatal diagnosis
Where the mutations has been identified previously in a proband, prenatal molecular genetic testing could be offered.
Genetic counseling
The pattern of inheritance is autosomal recessive. Families with an affected child should be counselled that there is a recurrence risk of 25% for each pregnancy.
Management and treatment
Standard management is indicated for intellectual disability and postnatal growth retardation. Echocardiography, abdominal ultrasound and hearing evaluation is recommended at birth. Surveillance should include frequent monitoring of growth and development. Regular ophthalmological follow up is recommended.
Prognosis
Patients reported with poor prognosis are related to complex heart defects.