Early Onset Osteoporosis Associated with Novel Mutation of WNT1 Gene

Introduction:
Canonical WNT signaling plays a significant role in bone development and maintenance of bone mass. WNT1 gene mutations have been associated with osteogenesis imperfecta type XV in homozygotes and early onset osteoporosis in heterozygotes. We present a case of early onset osteoporosis associated with a novel mutation of the WNT1 gene.

Case Description:
A 56-year-old female presented for evaluation of early onset osteoporosis. History was significant for hypothyroidism as well as chronic inflammatory demyelinating polyneuropathy on IVIG infusions. She was diagnosed with low bone density in the setting of a vertebral compression fracture from a diving accident when she was 24. She had mild scoliosis, brittle teeth and 10 fractures as a child and young adult including rib fractures, pelvic fracture and compression fracture of the spine, some of which occurred in the setting of low impact trauma. Her family history was notable for possible osteoporosis in her grandmother. Initial evaluation demonstrated PTH 75 (18 - 80 PG/ML), Calcium 9.5 (8.5 - 10.5 MG/DL ), Albumin 4.1 (3.5 - 5.0 G/DL ), 25-hydroxy vitamin D 44.6 (30.0-100.0 ng/mL), Phosphorus 3.6 (2.4 - 4.8 MG/DL), creatinine 0.59 (0.44 - 1.03 MG/DL), TSH 1.24 (0.350 - 5.500 uIU/ML ), 24-hour urine calcium 133 (50 - 300 MG/24H), late night salivary cortisol 0.066 (less than 0.112 ug/dL), tryptase 6.1 ( <11.0 mcg/L), tissue transglutaminase IgA antibody 2.5 (0-20 units), hemoglobin A1c 4.1 (4.3 - 5.6 %), IGF-1 112 (50 - 317 ng/mL), Alkaline Phosphorus 62 (34 - 104 IU/L). Dual-energy X-ray absorptiometry (DEXA) scan at the age of 50 showed bone mineral density (BMD) 0.828 g/cm2 with T score of -2.0 at lumbar spine, BMD of 0.593 g/cm2 with T score of -2.3 at left femoral neck and BMD of 0.707 g/cm2 with T score of -1.9. She sustained a low trauma spine fracture at L1 at the age of 55. Subsequent DEXA scan at age 55 showed significant decline of BMD with T score of -3.3 at lumbar spine and T score of -3.0 at the left femoral neck.
Due to suspicion for osteogenesis imperfecta, a genetic panel was sent which showed a heterozygous variant in WNT1 gene, c.581T >G (p.L194R). She was treated with oral alendronate 70 mg once weekly for less than one year which was stopped due to gastrointestinal side effects. Follow-up is planned for discussion of additional therapeutic options.

Discussion:
Heterozygous mutations in WNT1 have been described in the literature as a cause of early onset osteoporosis. The currently described variant mutation in the WNT1 gene has not been previously reported in literature. In silico analysis using SIFT and PolyPhen2 predict this variant to be deleterious/possibly damaging. Genetic testing and evaluation of bone density in other family members may help further support the clinical importance of this mutation.