A Case of Early-Onset Osteoporosis Due to a Novel WNT1 Variant

WNT pathways play a fundamental role in bone formation by inducing osteoblast differentiation. WNT1 variants are associated with both autosomal recessive osteogenesis imperfecta and autosomal dominant osteoporosis. Here, we report a case of early-onset osteoporosis (EOOP) with multiple low-impact fractures and identify a novel pathogenic WNT1 variant [c.578delA (p.Asp193Alafs∗6)].

A 67-year-old male with EOOP experienced recurrent pathologic fractures after treatment with bisphosphonates for 10 years and denosumab for 6 years. The patient was treated with romosozumab for 1 year, followed by alendronate. Genetic testing revealed a heterozygous, autosomal dominant variant of the WNT1 gene on exon 3, which codes for a premature stop signal resulting in a deletion of the 178 amino acids at the C-terminus.

Genetic testing is advisable for EOOP patients, where secondary causes are ruled out. Romosozumab was ineffective here as sclerostin inhibition cannot restore osteoblastic WNT/β-catenin activity if the functional WNT ligand concentration is subthreshold.

Our case describes a proband's previously unidentified autosomal dominant WNT1 variant leading to EOOP. Future in vitro studies of this WNT1 variant may evaluate its protein expression patterns and effects on the β-catenin signaling cascade.