We administered high doses of calcitriol (up to 32 micrograms per day) to an infant with malignant osteopetrosis, in an attempt to stimulate bone resorption. The patient was placed on a low-calcium diet to prevent hypercalcemia. Measures of bone turnover increased during calcitriol therapy; hydroxyproline excretion rose from 140 to 1358 micrograms per milligram of creatinine per 24 hours, with parallel increases in the ratio of calcium to creatinine in the urine, urinary gamma-carboxyglutamic acid, serum osteocalcin, and serum alkaline phosphatase. A pretreatment bone-biopsy specimen contained no osteoclasts with ruffled borders, a feature of active osteoclasts. After 11 days of calcitriol, ruffled borders were noted. After three months, numerous osteoclasts with ruffled borders and associated bony disruption were evident. Before therapy, the patient's monocytes were incapable of in vitro bone resorption, but after calcitriol, their resorptive capacity was increased to 3.3 times control levels. These data demonstrate that calcitriol increased bone mineral and matrix turnover in our patient. However, during the three months of calcitriol therapy there was only slight clinical improvement in her severe disease. Early and sustained treatment with calcitriol may be useful in osteopetrosis.
Congenital alveolar proteinosis (CAP), a cause of respiratory failure in fill-term newborns, often leads to death in infancy despite medical therapy. We recently described an inherited deficiency of surfactant protein B (SP-B) (N. Engl. J. Med. 1993; 328:406-410) in two siblings with CAP. The SP-B deficiency was accompanied by marked abnormalities, both quantitative (increase) and qualitative (distribution), of SP-A and SP-C in the lungs of the affected infants. Ultrastructural studies of the lung of one of these infants and of a third affected sibling born in the index family showed abundant alveolar concentric multilamellated structures and membranous vesicles but no typical tubular myelin. In addition, membranous vesicles from type II cells and immunogold labeled SP-A and SP-C were found between type II cells and their basement membrane despite intact interepithelial cell junctions. These findings suggest an important role for SP-B in the directionality of surfactant secretion and in the formation of tubular myelin.
Surfactant protein B (SP-B) deficiency is an inherited disease of full-term newborn infants which leads to lethal respiratory failure within the first year of life. Genetic analysis of affected infants has permitted identification of a mutation in the SP-B gene found in several unrelated kindreds which disrupts pulmonary surfactant composition and function. Lung transplantation has resulted in reconstitution of pulmonary surfactant function and long-term survival. SP-B deficiency represents the first opportunity to link physiologic characteristics of respiratory failure in infancy with specific molecular and cellular defects. This linkage will facilitate development of novel strategies for the treatment of neonatal respiratory diseases.
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