The Blind Spot of Bone Disease: Adult Hypophosphatasia in a Middle-Aged Man With Prolonged Fracture Healing

Hypophosphatasia (HPP) is a rare inherited disorder caused by pathogenic variants in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase. In adults, it presents with nonspecific musculoskeletal features and is often mistaken for osteoporosis. We describe a 47-year-old man referred to endocrinology with a previous diagnosis of osteoporosis and recurrent femoral fractures with markedly delayed healing, at ages 30 and 39 years. He also had chronic musculoskeletal pain and atraumatic loss of teeth early in childhood, at age four; a bone scan showed multiple metatarsal fractures, and nephrocalcinosis was present. Serum alkaline phosphatase was persistently low and pyridoxal 5'-phosphate was elevated at 494 mcg/L (reference range: 5-50 mcg/L), while thyroid, parathyroid, cortisol, pituitary, renal, hepatic, and vitamin D evaluations were unremarkable. Several relatives had related manifestations. Adult HPP was diagnosed clinically in 2017, and genetic testing later identified an apparently homozygous, likely pathogenic ALPL variant (c.214A>G, p.Ile72Val). Treatment with asfotase alfa was associated with marked improvement, and he regained the ability to walk without a cane. This case shows that persistently low alkaline phosphatase in an adult with recurrent fractures and poor fracture healing should prompt evaluation for HPP before osteoporosis is assumed and that the diagnosis need not wait for genetic confirmation. Greater clinical awareness may shorten diagnostic delay.