Abstract 1851 Poster Session IV, Tuesday, 5/4 (poster 346)

Surfactant Protein-B (SP-B) deficiency as a cause of Congenital Alveolar Proteinosis is a rare (1:1,000,000 births), lethal disorder that occurs due to the autosomal recessive inheritance of mutations in SP-B genes. The most common mutation detected is 121ins2. Carrier frequency is estimated at 1/100. It has been questionned whether the HMD which occurs in more mature infants (≥ 34 weeks) might develop due to factors other than surfactant system immaturity. Approximately 40 such infants are born at our institution each year. We hypothesized a two-hit model in which mild developmental immaturity of the surfactant system, in combination with a genetic predisposition toward partially diminished functional levels of a surfactant protein (e.g. heterozygosity for a mutation in SP-B), might result in HMD; either hit alone might not suffice to cause disease. Objective: We sought to determine whether carrier state for SP-B mutation 121ins2 might provide a genetic predisposition, toward HMD in infants ≥ 34 weeks that would account for more than 10% of such cases. Design: We obtained IRB approval to prospectively serially identify a cohort of infants ≥ 34 weeks with HMD for anonymous genotyping at the SP-B 121ins2 locus. A sample size of 22 allowed a comparison of the presumed 12lins2 allele frequency of 0.007 to an hypothesized allele frequency not greater than .10 in this population, with [alpha]=.05 and β=0.2. Enrollment occurred during a 6 month period in 1998. Criteria for inclusion were clinical and CXR diagnosis of HMD. DNA was extracted from discarded cord blood. A PCR based Amplification Refractory Mutation System assay was developed to detect the SP-B 12lins2 mutation. Population: There were more males(16) than females(6) identified (P=0.2), with a median gestational age of 35 weeks (range 34 - 39). Nine of 22 were born from multiple gestation pregnancies. Three infants received antenatal steroids. Fourteen infants required mechanical ventilation, while 5 received only CPAP and 3 received hood oxygen only. Twelve of fourteen endotracheally intubated infants received surfactant therapy. Results: We detected no infants carrying the SP-B 121ins2 mutation. Conclusions: Our data suggest that heterozygosity for this mutation does not explain the majority of cases of "big kid" HMD. We cannot exclude the possibility that SP-B 121ins2 heterozygotes might be at increased risk for HMD. It is also possible that other surfactant protein gene sequence variants or mutations may predispose to the development of HMD in this population.