Case report: Primary familial brain calcification associated with a rare PDGFRB variant, coexisting with nontraumatic osteonecrosis of the femoral head

Abstract

Primary familial brain calcification (PFBC) is a rare genetic neurodegenerative disorder characterized by bilateral calcifications in the brain. PFBC may manifest with a broad spectrum of motor, cognitive, and neuropsychiatric symptoms. Several causal genes have been identified in PFBC, which are inherited as both autosomal dominant and autosomal recessive traits. Herein, we present the case of a Chinese family diagnosed with PFBC. The family members carry a rare heterozygous variant (p. R334Q) in exon 7 of platelet-derived growth factor receptor β (PDGFRB) gene. The platelet-derived growth factor-B/PDGF receptor β (PDGF-B/PDGFRβ) signaling pathway plays a crucial role in pericyte development in various organs and tissues. Notably, this variant uniquely coexists with nontraumatic osteonecrosis of the femoral head. Additionally, we reviewed previous studies on PFBC-causing variants in PDGFRB.

Keywords: PDGFRB; case report; osteonecrosis of the femoral head; primary familial brain calcification; whole-exome sequencing.

Figure 1

Timeline, brain imaging, MRI of femoral head, pedigrees, and sequencing results of the family with PFBC and ONFH. (A) A timeline of historical and current information of the care. (B) Brain imaging of the patient and her father. White arrows indicate calcification regions in the bilateral basal ganglia. (C) Osteonecrosis of the femoral head. Coronal T1-weighted magnetic resonance imaging displayed slightly hypointense lesions in both femoral heads, with a more pronounced pattern on the right side (white arrow). (D) Pedigrees of the family with PFBC with PDGFRB mutation R334Q. A black arrow marks the proband. Males and females are indicated by squares and circles, respectively. Symbols with slashes indicate deceased individuals. Black symbols indicate individuals with PFBC and confirmed PDGFRB R334Q mutation; gray symbols indicate individuals with similar clinical manifestations without genetic analysis; symbols with question marks indicate individuals with unknown status. (E) Sequencing chromatogram of the mutation R334Q in PDGFRB. (F) Multiple sequence alignment in the PDGFRB gene. Amino acids surrounding the mutation position (marked with a red box) are listed.

Figure 2

Schematic diagram of the PDGFRB gene and localization of variants. SP, signal peptide; TM, transmembrane domain; JM, juxtamembrane domain. Variants in red indicate a confirmed detrimental effect to induce PFBC, variants in blue indicate an unclear relationship with PFBC, and the variant in black indicates the mutation (R334Q) found in this family.