Abstract
Background: Hypophosphatasia is a rare multisystem disease caused by mutations in genes encoding tissue nonspecific alkaline phosphatase, a key player in promoting bone mineralization1. Here we present a case of hypophosphatasia in a patient with history of recurrent fractures and dental caries since childhood. Case Report: Patient is a 52-year-old woman with history of multiple fractures who initially presented for follow up of osteoporosis following an atraumatic ankle fracture. Further questioning revealed a history of 16 atraumatic fractures since the age of 4, involving ankles, toes, and fingers. Several adult teeth had never developed requiring braces to fill in gaps at age 13, dental caries and tooth fractures involving the majority of her adult teeth. DEXA scan in 2019 revealed T score of -2.4 in the left femoral neck. Suspicion for hypophosphatasia in February 2019 following an ankle fracture and patient’s prior history prompted further workup, revealing low serum alkaline phosphatase levels of 29 and 32 (bone fraction 62 percent, liver fraction 38 percent), and Vitamin B6 levels elevated to 66.2. Remainder of workup, with Vitamin D, PTH, Magnesium, and Calcium was normal. A childhood history of multiple atraumatic fractures, various dental issues, with elevated Vitamin B6 and low serum alkaline phosphatase suggested Hypophosphatasia. As bisphosphonates are contraindicated in these patients due to their potential to reduce ALP, teriparatide was initiated. Discussion: Hypophosphatasia involves mutations in tissue nonspecific alkaline phosphatase, a key player in bone mineralization. In normal individuals, this enzyme dephosphorylates inorganic pyrophosphate (PPi), which otherwise inhibits bone mineralization. The mutated TNSALP leads to accumulation of PPi, and thereby unmineralized osteoid.1 Although individual presentations can vary, developmental abnormalities, such as delayed growth, early loss of primary or secondary teeth, or history of multiple fractures are characteristic. Due to the rarity of the disease, and its potential to be confused for more common bone and rheumatologic diseases, diagnosis is often delayed1. Patients in whom suspicion for hypophosphatasia is present, should undergo further testing with bone specific Alkaline phosphatase and Vitamin B6 which would be low and elevated, respectively and may be candidates for enzyme replacement therapy with bone-targeting recombinant alkaline phosphatase1. Traditional treatments such as bisphosphonates potentially decrease ALP and worsen disease, making accurate diagnosis all the more crucial. References1 Bishop N. Clinical management of hypophosphatasia. Clin Cases Miner Bone Metab. 2015;12(2):170–173.
Molecular effects of the tissue-nonspecific alkaline phosphatase gene polymorphism (787T > C) associated with bone mineral density
