Case Report: Cortical bone loss, impaired mineralization, and reduced adiposity contributing to chronic bone pain in SFRP4-related skeletal disease with an ALPL variant.

BACKGROUND

Pyle disease is a rare metaphyseal dysplasia caused by loss-of-function variants in SFRP4, leading to abnormal cortical modeling with relative preservation of trabecular bone. The mechanisms involved in severe and persistent bone pain in adult patients remain incompletely understood.

CASE PRESENTATION: We report an adult woman with genetically confirmed homozygous SFRP4 p.Asn53Tyr-related skeletal disease presenting with marked and persistent bone pain. Dual-energy X-ray absorptiometry showed preserved lumbar bone mineral density but markedly reduced femoral neck bone mass, consistent with predominant cortical bone loss. Bone alkaline phosphatase levels were persistently low, whereas vitamin B6 levels were within normal limits, arguing against overt classical hypophosphatasia. Additional genetics analysis identified a heterozygous ALPL p.Val474Ile variant of uncertain significance.

RESULTS AND INTERPRETATION: Pelvic MRI demonstrated diffuse bone marrow edema, suggesting an active stress-related process. Whole-body DXA revealed markedly reduced total fat mass (~2nd percentile), indicating reduced adiposity. Together, these observations are consistent with a conceptual model in which cortical bone loss related to SFRP4 dysfunction, potential alterations in mineralization reserve, and reduced adiposity as a possible systemic manifestation of Wnt dysregulation may contribute to chronic bone pain.

CONCLUSION

This case suggests a structural-metabolic framework in which cortical integrity, mineralization reserve, and systemic metabolic context may interact in the generation of bone pain. The proposed model should be considered exploratory and hypothesis-generating and warrants further genetic, functional, and clinical validation.