Harish S. Hosalkar MD, MBMS (Orth), FCPS (Orth), DNB (Orth)
Hypophosphatasia is a rare metabolic disorder of bone in which there is a deficiency of alkaline phosphatase in the plasma and tissues, leading to abnormal mineralization of bone. In most classification systems, hypophosphatasia is included as a cause of rickets. Although there are some clinical and radiographic similarities, hypophosphatasia has a different pathophysiology and should be differentiated from rickets. There is a wide variation in the severity of the disease, with the prognosis related to the age at onset.
Several forms of hypophosphatasia exist-perinatal, infantile, childhood, and adult. Severe perinatal, infantile and childhood types of hypophosphatasia are transmitted in an autosomal recessive manner, whereas the mild adult type may be transmitted as a dominant or recessive trait.
Genetics and Metabolic issues
This is a recessive condition. The gene for hypophosphatasia is the tissue-nonspecific alkaline phosphatase gene (TNSALP). Many mutations have been described within TNSALP gene leading to deficient synthesis of alkaline phosphatase in liver, bone, or kidney. This enzyme is necessary for the maturation of the primary spongiosa in the physes, and its deficiency results in normal production of bone (osteoid) but inadequate mineralization, with resultant skeletal deformities that mimic rickets. There is widening of the physis, with persistence of the provisional zone of calcification (which cannot calcify) and islands of cartilage continuing down into the metaphysis. The normal columnar arrangement of the chondrocytes of the growth plate is disturbed.
The clinical features vary with the age at which the disease manifests. In the severe perinatal form, the babies may be stillborn. If they survive, they frequently have severe respiratory infections that are life threatening. The onset of symptoms in the infantile form is later in infancy, usually around 6 months of age. These children are usually hypotonic, experiencing anorexia, vomiting, dehydration, and fever. The characteristic changes occur early in life in patients with hypophosphatasia.
i) Absent calcification of the calvaria (craniotabes), late closure of the fontanelles and sutures, and craniosynostosis are common findings. Dentition may be markedly delayed. ii) Bowing of the long bones and knock-knee deformities are frequently seen.
iii) Fractures following minor trauma may occur.
Children who survive early infancy tend to improve clinically with time. Stature is normal in the infant, but as the child matures, dwarfism due to lack of normal endochondral bone growth becomes noticeable.
Hypophosphatasia can be diagnosed in fetuses; ultrasound may show deficient ossification of the fetal skull.Radiographic changes seen in hypophosphatasia are similar to those with rickets.
- Generalized osteopenia, most marked in the calvarium and metaphyseal regions of the long bones, is seen.
- The cranial sutures are initially wide but close prematurely, leading to increased intracranial pressure.
- Broad metaphyses and central cup- or wedge-shaped ossification defects of the central physes are typical radiographic findings (Fig. 5A-B).
- Bowing of the long bones and angular deformities of the lower extremities may be seen.
There is no satisfactory medical therapy for hypophosphatasia. For severe cases, bone marrow transplant
has been used experimentally with some success.
Pathologic fractures may be a difficult problem because of the poor quality of the bone. Closed treatment methods are usually employed. If closed treatment fails, intramedullary fixation has been found to be superior to plate fixation in abnormal bone. Bowing of the long bones and angular deformities of the lower extremities may require treatment, if they are progressive and exceed the physiologic range. They are managed by bracing or, if indicated, surgical treatment.