Hypophosphatemic Rickets

Hypophosphatemic rickets is a rare disorder characterized by low levels of phosphate in the blood, leading to weakened and softened bones. Phosphate is essential for proper bone mineralization, and its deficiency results in rickets in children and osteomalacia in adults. Unlike nutritional rickets caused by vitamin D deficiency, hypophosphatemic rickets is usually genetic and persists despite adequate vitamin D levels.

Symptoms typically appear in early childhood and may include short stature, bowed legs, delayed walking, bone pain, dental problems such as abscesses, and skeletal deformities. Some children may also develop muscle weakness or difficulty running and jumping. Adults with undiagnosed or untreated hypophosphatemic rickets may present with bone pain, fractures, and muscle fatigue.

Hypophosphatasia is caused by mutations in the ALPL gene, which encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Mutations in this gene lead to reduced enzyme activity and accumulation of pyrophosphate and other substrates that inhibit bone mineralization. The disorder can be inherited in either an autosomal recessive or autosomal dominant manner, and the wide range of mutations accounts for the variability in clinical presentations.