Hypophosphatasia Workup

Assess the alkaline phosphatase levels. The levels are consistently low. Do not use ethylenediaminetetraacetic acid (EDTA) tubes because these cause erroneous test results. The reference range should be appropriate for the age group undergoing testing, and results vary among laboratories.

Laboratory testing must be performed on fasting individuals for phosphate analysis (alkaline phosphatase activity levels can be measured in nonfasting patients). Laboratory evaluations should include levels of calcium, phosphorus, magnesium, alkaline phosphatase, creatinine, parathyroid hormone (PTH), 25(OH) vitamin D, and 1,25(OH)2 vitamin D. Levels of PLP, PPi in plasma, and PEA in urine determine the diagnosis. Measurement of ALP in amniotic fluid yields variable results, which are of relative value in the prenatal diagnosis of this entity. ALP in cultured amniotic cells may be quantified, but interpretation of the results is difficult. Monoclonal antibodies against TNSALP may serve to reveal a deficiency in chorionic villous tissue. The test for PPi is typically performed only in research laboratories.

PEA levels can be obtained from urine to help support the diagnosis. Elevated levels of PEA may also characterize other forms of bone disease.

An elevation of PLP is also present. This test must be done carefully, as the patient's intake of vitamins (particularly vitamin B-6) may affect results.

Liver function test results tend to be normal.

Whenever possible, measure alkaline phosphatase activity levels in all members of the direct family. De novo mutations are rare. Genetic screening of family members is warranted.

Perform a radiologic skeletal survey on patients in whom the diagnosis of hypophosphatasia is being considered.

In lethal cases, there is frequently a near absence of skeletal mineralization. Fractures and rachitic changes are often present. Skin-covered spurs that extend from the medial and lateral aspects of the knee and elbow joints may also be present. Deficient skeletal mineralization is also evident in surviving infants, although it tends to be less severe than in the lethal perinatal cases. Premature cranial synostosis often occurs despite an open fontanelle.

Rachitic deformities characterize the disease in children. Upon radiologic examination of the metaphysis, evidence of radiolucent projections from the epiphyseal plate into the metaphysis is present. This is not found in other types of rickets.

Pseudofractures are one of the hallmarks of hypophosphatasia in adults, often occurring in the lateral aspect of the proximal femur. An increased incidence of poorly healing stress fractures, especially of the metatarsals, also occurs.

Renal ultrasound may reveal nephrocalcinosis.

Radiography findings are normal for patients with odontohypophosphatasia, except for osteopenic appearance of the maxilla.

Bone biopsy is not the standard of care. It is usually performed for research purposes (see Histologic findings).

Bone biopsy findings include structural parameters (bone volume per tissue volume, trabecular number, trabecular thickness) that are close to the age-specific average of the reference range findings. Osteoid indices (osteoid thickness, osteoid surface per bone surface, osteoid volume per bone volume) are markedly elevated. Among dynamic parameters of bone formation (ie, those that require tetracycline labels to be measurable), mineralizing surface is below the age-specific average of the reference range, whether related to bone surface or osteoid surface. Bone formation rate per bone surface is below average. Mineralization lag time is markedly elevated. The accumulation of osteoid is not distributed evenly, as is seen in osteomalacia, but is patchy. These patches typically consist of a mixture of calcified cartilage.^[6]

Both osteoclasts and osteoblasts appear morphologically normal, but the latter lack membrane-associated ALP activity on histochemical testing. This disrupts incorporation of calcium into the matrix.

Histologic examination of the teeth reveals a decrease in cementum, which varies with the severity of the disease. The pulp chamber also appears to be enlarged. The incisors tend to be the most affected.