Abstract

1. Pycnodysostosis, an inborn error of bone matrix degradation, results from the deficient activity of the lysosomal protease, cathepsin K, in the osteoclasts of affected individuals. The enzymatic defect leads to a reduced ability of osteoclasts to remove organic bone matrix, which causes defective bone growth and remodeling. Partially degraded collagen fibrils are found in lysosomes within osteoclasts that are actively resorbing bone.

   
   

2. The disorder is transmitted as an autosomal recessive trait by the gene encoding cathepsin K, localized to chromosomal region 1q21. The human cathepsin K cDNA and genomic sequences have been isolated, characterized, and used to analyze the mutations causing pycnodysostosis. All identified defects have been point mutations in the coding region, which obliterate the collagenolytic activity of the mature enzyme.

   
   

3. Clinical manifestations include short stature, a typical dysmorphic appearance, generalized osteosclerosis, dysplastic bones including hypoplasia of the distal phalanges, clavicles, and various craniofacial bones, as well as pathologic fractures and dental abnormalities. Associated complications include osteomyelitis of the jaw, upper airway obstruction, growth hormone deficiency, and myelophthisis. Life span is normal, although disability secondary to the orthopedic problems may cause premature demise.

   
   

4. Diagnosis is usually made by clinical and radiologic examinations. Demonstration of cathepsin K gene defects confirms the diagnosis. Prenatal diagnosis can be accomplished by demonstration of the specific cathepsin K mutation(s) in chorionic villi or cultured amniotic cells, or by linkage analysis for couples known to be cathepsin K mutation carriers.

   
   

5. Therapy is directed at preventing or ameliorating the orthopedic, dental, and medical complications. Surgical intervention may be necessary for patients with significant upper airway obstruction. Growth hormone repletion may improve linear growth for individuals with growth hormone deficiency.

   
   

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