Hypophosphatasia (HPP) is an inborn error of metabolism with highly variable clinical severity caused by loss-of-function mutations in the gene encoding tissue nonspecific alkaline phosphatase (TNSALP). The prevalence of the severe form is estimated to be between 1/100,000 and 1/300,000. The prevalence of the mild forms is likely much more frequent.
HPP has been classified into five categories depending on the age at diagnosis. Peter J. Tebben, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition and the Division of Pediatric Endocrinology and Metabolism in the Department of Pediatric and Adolescent Medicine at Mayo Clinic's campus in Rochester, Minnesota, says: "In general, the younger the age at diagnosis, the more severe the disease. Disease severity can range from death in the perinatal period to dental problems or fractures in adulthood."
- Perinatal HPP presents with clinical features noted at birth or before based on a prenatal ultrasound. Clinical exam will reveal obvious skeletal abnormalities including chest wall deformities, as well as short or bowed long bones. The skeleton is hypomineralized, which is readily identified on X-ray. This form of HPP is almost universally fatal shortly after birth.
- Infantile HPP is diagnosed by 6 months of age. Characteristic changes of rickets are seen on X-ray, and fractures are often present. Infants fail to grow appropriately, and some will experience vitamin B-6 responsive seizures. Hypercalcemia and nephrocalcinosis have also been described. Mortality in the infantile form of HPP is substantial.
- Childhood HPP is diagnosed when disease manifests after 6 months of age. Children often have a delay in gross motor milestones and a static myopathy. A common feature of childhood HPP is premature loss of deciduous teeth (before 5 years of age) with the root intact. Radiographs reveal changes of rickets and often a radiolucent band extending from the growth plate into the metaphysis.
- Adult HPP may manifest with recurrent or slow-to-heal metatarsal fractures or subtrochanteric femoral pseudofractures. A recent review of Mayo Clinic patients diagnosed with HPP in adulthood demonstrated they often present with nonspecific musculoskeletal complaints. Many adults with HPP will report having had symptoms during childhood, but the diagnosis was not made until later in life.
- Odontohypophosphatasia, the least severe form of HPP, is diagnosed when dental abnormalities are present but no other skeletal disease, such as rickets or osteomalacia, is identified.
The hallmark laboratory finding in HPP is a low blood level of alkaline phosphatase activity. Dr. Tebben explains: "Because the abnormal alkaline phosphatase gene located on chromosome 1 encodes the tissue nonspecific form of alkaline phosphatase (bone, liver, kidney), measuring bone-specific alkaline phosphatase is typically not necessary. However, a low total alkaline phosphatase is not pathognomonic, as this finding can be associated with other disorders. In adults, prior treatment with anti-resorptive therapy is a common cause of low alkaline phosphatase. However, in the context of the appropriate clinical setting, a low alkaline phosphatase is strong evidence for a diagnosis of HPP."
Dr. Tebben explains: "When interpreting the result of an alkaline phosphatase measurement, it is crucial to utilize the appropriate age and gender-specific reference ranges. Children have significantly higher alkaline phosphatase concentrations compared with adults, and the diagnosis can therefore be overlooked if an adult reference range is applied.
"Additional laboratory tests that are supportive of the diagnosis include hypercalcemia, hyperphosphatemia and hypercalciuria, particularly in the infantile and childhood forms. Phosphoethanolamine and pyridoxal 5'-phosphate are substrates for alkaline phosphatase and are elevated in patients with HPP. Pyridoxal 5'-phosphate is a product of vitamin B-6, and patients taking supplements containing vitamin B-6 should discontinue them two weeks prior to measurement."
Severely hypomineralized bone is seen in patients with perinatal and infantile forms of the disease. Childhood HPP will exhibit metaphyseal changes of rickets and bands of radiolucency extending from the growth plate into the metaphysis. In adults, metatarsal fractures, pseudofractures in the femur and calcium pyrophosphate deposition disease are commonly identified. Enlarged pulp chambers can be seen on dental X-rays.
Bone histology varies depending on the age of presentation and severity of disease. Robert A. Wermers, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Rochester, explains: "Infantile HPP demonstrates severely defective skeletal mineralization, with osteoid composing the majority of the bone tissue. On the other hand, patients with childhood and adult HPP with less severe manifestations may have no evidence of a mineralization defect.
"Iliac crest bone biopsies from more-severe forms of childhood and adult HPP will generally demonstrate osteomalacia, with areas of unmineralized osteoid and absence of tetracycline label uptake. However, findings of osteomalacia can be patchy, with accumulated osteoid on some surfaces, whereas other bone surfaces show normal mineralization. Cortical and trabecular bone volumes are normal in adult HPP."
There is no Food and Drug Administration-approved treatment for HPP. Dr. Tebben notes: "In the perinatal and infantile forms, therapy has largely been supportive. Vitamin B-6 may be helpful for seizures in patients with infantile HPP. Recently, recombinant tissue nonspecific alkaline phosphatase modified to target and anchor to bone has been developed and tested in infants and children with severe HPP. Improved biochemical, radiographic and clinical parameters were observed. Long-term outcomes are yet to be reported. The utility of treatment in less severely affected individuals is unknown."
HPP can manifest with a broad range of symptoms and severity. During infancy and childhood, the diagnosis can readily be made based on clinical, radiographic and basic laboratory findings. Dr. Wermers summarizes: "Adults often present with more nonspecific symptoms, and a low alkaline phosphatase should prompt consideration of HPP. Recognition of adult HPP is important, as the most commonly utilized medications for osteoporosis (anti-remodeling agents) could further impair skeletal mineralization and should be avoided."