Cerebellofaciodental syndrome in an adult patient: Expanding the phenotypic and natural history characteristics

Abstract

Cerebellofaciodental syndrome is characterized by facial dysmorphisms, intellectual disability, cerebellar hypoplasia, and dental anomalies. It is an autosomal‐recessive condition described in 2015 caused by pathogenic variants in BRF1. Here, we report a Brazilian patient who faced a diagnostic challenge beginning at 11 months of age. Fortunately, whole‐exome sequencing (WES) was performed, detecting the BRF1 variants NM_001519.3:c.1649delG:p.(Gly550Alafs*36) and c.421C>T:p.(Arg141Cys) in compound heterozygosity, thus finally achieving a diagnosis of cerebellofaciodental syndrome. The patient is currently 25 years old and is the oldest patient yet reported. The clinical report and a review of published cases are presented. Atlanto‐occipital fusion, a reduced foramen magnum and basilar invagination leading to compression of the medulla‐spinal cord transition are skeletal findings not reported in previous cases. The description of syndromes with dental findings shows that such anomalies can be an important clue to relevant differential diagnoses. The cooperation of groups from different international centers made possible the resolution of this and other cases and is one of the strategies to bring medical advances to developing countries, where many patients with rare diseases are difficult to diagnose definitively.

Maf1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass

“…Additionally, BRF1 mutations have been shown to be causative for cerebellofaciadental syndrome (34,35,61). Some patients with RNA pol III-related mutations, but not all, show bone-related phenotypes (34)(35)(36)(37)(38). The considerable heterogeneity of these syndromes has been suggested to be related to differential changes in RNA pol III-dependent transcription (55).…”

“…This includes POLR3related hypomyelinating leukodystrophies (54-56), Wiedemann-Rautenstrauch syndrome, a neonatal progeroid syndrome (57-60) and Cerebellar hypoplasia with endosteal sclerosis (37,38). Additionally, BRF1 mutations have been shown to be causative for cerebellofaciadental syndrome (34,35,61). Some patients with RNA pol III-related mutations, but not all, show bone-related phenotypes (34)(35)(36)(37)(38).…”

“…Furthermore, RNA pol III-dependent transcription may play a role in Cerebellofaciodental syndrome which is associated with mutations in the RNA pol III-specific transcription factor, BRF1. This syndrome is characterized by a neurodevelopmental phenotype as well as changes in the facial and dental structure and delayed bone age (34)(35)(36) . Additionally, bone phenotypes have been described in a subgroup of patients with mutations in RNA pol III subunits (34)(35)(36)(37)(38).…”

“…This syndrome is characterized by a neurodevelopmental phenotype as well as changes in the facial and dental structure and delayed bone age (34)(35)(36) . Additionally, bone phenotypes have been described in a subgroup of patients with mutations in RNA pol III subunits (34)(35)(36)(37)(38).…”

A case of atlanto-occipital fusion with other multiple anatomic variations

“…The studies suggest a fusion between AOF and the dimensions of the foramen magnum that the sagittal dimensions and area of the foramen magnum were significantly smaller in skulls with occipitalization [13].Foramen magnum is an important landmark, which is closely associated with the brainstem and spinal cord [14]. AOF, reduced foramen magnum and basilar invagination which may compress the medulla-spinal cord transition and the spinal cord or brain stem [15].…”