MOLECULAR AND PHENOTYPIC VARIABILITY IN THE CONGENITAL ALVEOLAR PROTEINOSIS SYNDROME-ASSOCIATED WITH INHERITED SURFACTANT PROTEIN-B DEFICIENCY

Congenital alveolar proteinosis (CAP) is an often fatal cause of respi ratory failure in term newborn infants; which has been associated with a genetic deficiency of surfactant protein B (SP-B) as a result of a frameshift mutation (121ins2) in a family with three affected siblings . In the index cases the deficiency of SP-B was associated with qualit ative and quantitative abnormalities of the surfactant proteins A and C. Immunostaining for lung surfactant proteins and a search for the 12 1ins2 mutation by restriction enzyme analysis of DNA extracted from pa raffin-embedded lung tissue was performed for 7 additional affected in fants from 6 families, bringing to 10 the total number of patients wit h CAP who have been studied, In six infants, the surfactant protein im munostaining pattern was similar to that of the index cases. Of these, three patients were homozygous for the 121ins2 mutation; one was a co mpound heterozygote with the 121ins2 in one allele and a different mut ation in the other; and three patients lacked the mutation in both all eles. One infant had an abundance of SP-B, suggesting phenotypic heter ogeneity in CAP. Lung ultrastructural abnormalities, such as a reduced number of lamellar bodies, absent tubular myelin, and basal secretion of surfactant lipids and proteins, suggest a significant derangement of surfactant metabolism. The phenotypic heterogeneity in infants with CAP raises the possibility that variable degrees of SP-B deficiency m ay be more common than previously suspected.