Endocrine Abstracts

JOINT1045

Osteoporosis primarily affects postmenopausal women and several secondary causes may predispose to osteoporosis in premenopausal women or males < 50 years. If no secondary causes are found, possible genetic causes should be considered despite adult age. WNT1-mutation related osteoporosis, a genetic form of osteoporosis is characterized by early-onset fragility fractures in childhood and a rather mild disease course. We describe a novel family with a different phenotype, that presented at adult age with multiple fractures and severe, progressive disease. Patient 1 A 27-year-old man presented with multiple vertebral fractures and 7. 5 cm height reduction. Dual-energy absorptiometry (DXA) Z-scores in the lumbar spine, femoral neck and total hip were -4. 6, -2. 6 and -2. 9, respectively. Biochemistry including calcium, phosphate and bone turnover markers was normal. After exclusion of secondary causes, we performed a genetic analysis revealing a heterozygous pathogenic WNT1 variant (p. Cys218Gly) in exon 4 of Chromosome 2. This variant is known to result in reduced WNT1 signaling and impaired bone mineralization. Patient 2 At the same time, a 59-year-old woman, mother of patient 1, was referred because of several years of back pain and 7 cm height reduction. At presentation, she had multiple vertebral fractures and severe kyphosis. The first vertebral fractures were diagnosed three years earlier. DXA T-scores in the lumbar spine, femoral neck and total hip were -3. 2, -2. 7 and -2. 1, respectively. Secondary causes were excluded and genetic testing revealed that she carried the same WNT1 mutation as her son. Histomorphometry analysis of transiliac bone biopsy after tetracycline double labeling showed low bone turnover in both patients. Patient 1 was started on denosumab 60 mg twice a year. During 3 years of follow-up, he has not suffered from further fractures. Also in patient 2, denosumab was initiated. A year later, BMD had improved markedly, however, she then suffered low-energy hip and humerus fractures. Sequencing of treatments was as follows; denusomab 18 months, followed by 5 mg of zoledronic acid and, 9 months later, initiation of romosozumab. Romosozumab is an anabolic osteoporosis medication that acts via WNT-signaling. The results of 6 months of treatments are available in March 2025. In conclusion, hereditary WNT1-mutation related osteoporosis can present with an adult-onset, severe and progressive phenotype.