NIH
Zebra of the Week: Hypophosphatasia (HPP)
Hypophosphatasia (HPP) is a rare, inherited metabolic bone disease caused by pathogenic variants in the ALPL gene, leading to deficiency of tissue‑nonspecific alkaline phosphatase (TNSALP). Reduced TNSALP activity results in accumulation of substrates that inhibit bone mineralization, producing a spectrum of skeletal and systemic manifestations that vary widely by age of onset and residual enzyme activity.
Clinically, HPP spans a continuum—from perinatal and infantile forms, which may present with severe hypomineralization, respiratory compromise, and hypercalcemia, to childhood and adult-onset disease, characterized by recurrent or poorly healing fractures, bone pain, chondrocalcinosis, muscle weakness, and premature tooth loss with intact roots. The mildest form, odontohypophosphatasia, primarily affects dentition without overt skeletal disease. Inheritance is most often autosomal recessive in severe phenotypes, while milder presentations may be autosomal dominant or recessive.
Because symptoms can mimic more common conditions such as rickets, osteoporosis, or osteomalacia, diagnostic delay is common. A key clinical clue is persistently low serum alkaline phosphatase for age and sex, often accompanied by elevated serum pyridoxal‑5‑phosphate or urinary phosphoethanolamine. Diagnosis is supported by clinical features, biochemical findings, radiographic changes, and confirmatory genetic testing.
Management depends on severity and may include multidisciplinary supportive care, fracture prevention, and avoidance of antiresorptive therapies, which can worsen outcomes. Enzyme replacement therapy has transformed prognosis in severe pediatric disease, underscoring the importance of early recognition.
In March 2026, AstraZeneca announced positive results from its global phase 3 program of efzimfotase alfa, an investigational enzyme replacement therapy, demonstrating clinically meaningful improvements in bone health in pediatric patients with hypophosphatasia.
Source: Genetic and Rare Diseases Information Center (GARD). Hypophophatasia (HPP). National Institutes of Health.