Radiology Resident Case of the Week

X-linked Hypophosphatemic Rickets

October 31, 1996

Etiology/Pathophysiology
X-linked hypophosphatemic rickets represents an uncommon cause of rickets overall, but the most common form of rickets due to renal tubular abnormalities. The causes for rickets can most effectively be divided into three pathophysiologic subsets related to 1,25-dihydroxyvitamin D3. The first would be those causes for inadequate availability of the vitamin. This may be due to inherent dietary deficiency of vitamin D or inadequate exposure to ulraviolet light. An additional cause may be the malabsorption of calcium, phosphorous or fat-soluble vitamins from the GI tract. The second category relates to abnormalities in vitamin D metabolism and includes: hepatobiliary disease not only inhibiting proper absorption from the GI tract but also insufficient 25-hydroxylation of the precusor vitamin D2 by hepatocytes; anticonvulsant medications which inhibit hepatocytes from forming 25-hydroxyvitamin D3; renal insufficiency which leads to poor 1-hydroxylation by the kidneys as well as imbalance in Ca-P metabolism of chronic renal failure; inherited 1alpha-hydroxylase deficiency or inherited unresposiveness to the active form of vitamin D3. Finally, the third category consists of abnormalities in tubular reabsorption of phosphate. This mainly consists of genetic and acquired forms of hypophosphatemic rickets.

The patient presented had a genetic form of hypophosphatemic rickets inherited in an X-linked dominant fashion. It is characterized by life-long hypophosphatemia. Several theories have been postulated for the cause of this syndrome. Original researchers believed that this represented a primary abnormality in calcium absorption from the gut with the depressed serum phosphate levels resulting from secondary hyperparathyroidism induced phosphaturia. However, most patients have normal serum PTH levels and no radiographic changes of secondary hyperPTH. The prevailing theory at present is that there are two mechanisms by which the kidneys resorb phosphate, a PTH sensitive mechanism accounting for two-thirds of the resorption and the other third being sensitive to serum calcium levels. It is believed that the hypophosphatemia in X-linked rickets is due to absence of response of the tubules of the kidney to PTH thus eliminating the PTH sensitive two-thirds of phosphate resorption.

Pathology:
As is common to all forms of rickets, the major abnormality is the lack of calcification of developing cartilage and bone due to insufficient availability of inorganic components of bone. This is primarily manifested in long bones as the lack of formation of the provisional zone of calcification.

Miscellaneous
A word may be said about the treatment of X-linked hypophophatemic rickets. Patients may experience some increase in skeletal growth with a regimen of vitamin D2 and phophate, however, as will be shown in this patient, often leads to nephrocalcinosis. Treatment with calcitrol may improve growth without the renal side-effects.

Imaging
Histochemical changes of rickets may precede the radiographic manifestations by several weeks. The principal abnormality seen is that produced by rarefaction and fraying of the provisional zone of calcification in the metaphyses of long-bones. The gap between the metaphysis and ossified epiphysis will be widened, the margin of the metaphysis will be irregular with the metaphysis often concave or cupped as well as widened. In severe cases the rachitic metaphysis will not be seen giving the shafts of the long-bones the appearance of being significantly shortened. The shafts of the long-bones will appear osteopenic but with coarsened trabeculae as the finer secondary trabeculae do not calcify. Transverse radiolucent bands called Looser zones may be seen in the diaphyses of the long-bones.

With treatment the provisional zone of calcification begins to recalcify producing a dense transverse metaphyseal band. With progressive healing the gap between the metaphysis and epiphysis will rapidly fill in.

In X-linked hypophosphatemic rickets the rachitic changes of the growth plates will most often be mild or moderate in severity. Osteopenia will not be a prominent feature. Bowing of the long-bones of the lower extremity can occur but often is minimal and not much more prominent than physiologic bowing. Premature closure of the sutures may be a prominent feature of this form of rickets. As the patient ages, the trabeculae will coarsen and Looser zones may appear with fractures becoming more common. Enthesopathy may predominate with enough paraspinal new bone to cause spinal stenosis. The radiologic features in the spine may resemble ankylosing spondylitis or DISH.

Image 1: AP view of the lower extremities at 16 months of age shows widening of the distal femoral and proximal tibial physes with irregularity and flaring of the metaphyses. There is associated widening of the distal tibial physes with irregularity and cupping of the metaphyses. The tibias and femurs appear bowed somewhat greater than would be expected for normal physiologic bowing.

Image 2: An AP view of the left lower extremity at 37 months with treatment shows interval healing with normal appearing metaphyses and relationship to the epiphyses. Note in particular the subtle dense bands at the metaphyseal margins in keeping with healing process as well as the marked improvement in the severe cupping which existed in the distal tibial metaphyses. The bowing deformities have resolved.

Images 3 and 4: A renal ultrasound in this patient at approximately 5-years of age demonstrates the multifocal arease of hyperechogenicity in both renal medulla in the locations of the pyramids without associated shadowing. This represents the nephrocalcinosis that these patients develop as a sequela of their treatment.

DDX
As discussed above-

I. Insufficient Vitamin D rickets