© 2005 American Thoracic Society doi: 10.1164/rccm.2507004
Surfactant Dysfunction Mutations in Children's Interstitial Lung Disease and Beyond
a University of Colorado and Denver Children's Hospital, Denver, Colorado Surfactant has been an important focus in pediatrics since the recognition of surfactant deficiency in premature infants (1). It seemed logical that derangements in this system could contribute to other types of pediatric lung disease, and this hypothesis has been substantiated over the last 15 years. Mutations in the surfactant protein B (SPB) and C (SPC) genes result in significant morbidity and mortality for newborns and young children (2–4). Mutations in the ABCA3 gene, an ATP-binding cassette transporter of lipid found in alveolar type II cell lamellar bodies, have recently been recognized as a cause of fatal neonatal interstitial lung disease (ILD) (5). Children with ILD (chILD) have a range of rare and diverse diagnoses (6). They initially present with a constellation of findings called chILD syndrome. The chILD research network has defined chILD syndrome as a lung condition in children with at least three of the following criteria in the absence of any identified etiology as the primary cause: (1) symptoms of impaired respiratory function, (2) hypoxemia, (3) diffuse infiltrates, (4) presence of adventitious sounds, and (5) abnormal lung function. Primary causes to be excluded include cystic fibrosis, cardiac disease, asthma, acute infection, immunodeficiency, neuromuscular disease, scoliosis, typical bronchopulmonary dysplasia or premature respiratory distress syndrome, and confirmed significant aspiration. To determine a more specific diagnosis, chILD syndrome prompts an extensive evaluation, usually including a lung biopsy. Until recently, children were retrofitted into an adult histologic classification system for ILD (7). As young children with ILD have distinct diagnostic entities not seen in adults (8, 9), and conversely, no documented evidence for usual interstitial pneumonitis, it is not surprising that this adult classification system was limiting (10). A new chILD classification system developed by the chILD imaging and pathology cooperative is based on a retrospective multidisciplinary review of 187 lung biopsies from children younger than 2 years who underwent lung biopsy during a 5-year period at 11 pediatric centers in North America (11). Characteristic histologic features of surfactant dysfunction mutations were documented in 10% of this population, with a 100% mortality noted for ABCA3 patients (12). A category for surfactant dysfunction disorders in infancy is included in the new chILD classification. The work of Bullard and colleagues in this issue of AJRRCM (pp. 1026–1031), examining the role of ABCA3 mutations in older surviving children with ILD, now extends the importance of the ABCA3 mutations beyond infancy (13). DNA samples from 195 children with chronic lung disease of unknown etiology were analyzed. First, ABCA3 was sequenced from DNA samples of children with desquamative interstitial pneumonitis who were older than 10 years at the time of enrollment. Three of four patients had a common missense ABCA3 mutation (E292V) on one allele and a second unique mutation identified on the other, consistent with an autosomal recessive disorder. Second, the remaining DNA samples, not positive for other SPB or SPC mutations, were screened for the E292V mutation, with seven more children identified. Interestingly, a second mutation was not found in two patients, possibly due to missed mutations, other genetic or environmental influences, or decreased rather than absent ABCA3 function causing disease. Clarifying these issues could have major implications for E292V as a genetic modifier for other pediatric and adult lung diseases. In this population of children with chronic lung disease, 5% had the common ABCA3 mutation (E292V) in contrast to 14% who had an SPC mutation and 1% who had an SPB mutation. This likely recognizes only a small fraction of ABCA3 mutations, as only the E292V mutation was screened for and only SPC and SPB genes fully sequenced. If the CFTR in cystic fibrosis, another large gene in the ATP-binding cassette family, is analogous to ABCA3, there will likely be an extensive number of additional mutations capable of causing diverse disease in children and adults (14). In contrast to the significant mortality in young children with ABCA3, there were only two deaths (6 mo and 11 yr) in this series, suggesting a milder phenotype. The current age of survival for the E292V group was reported as 6 to 32 years. Many patients had symptoms in infancy, but two patients reportedly became symptomatic only later in childhood. Histologic findings of bronchiolitis obliterans and minimal change, not currently considered suggestive of a surfactant dysfunction mutation, were also found in two patients (11). A major obstacle involves identifying patients with ABCA3 mutations. Complete genetic identification of all ABCA3 mutations in all candidate patients is currently not possible. However, the identification of a common mutation (E292V) and pathology techniques, such as surfactant protein staining patterns, as reported by Bullard, and electron microscopy to look for abnormal lamellar bodies (5), could provide a starting point. Electron microscopy should be obtained on all lung biopsies for chILD. Clinical, imaging, and histologic correlations will also be critical to better define and recognize these patients. Bullard and colleagues have provided intriguing data that may represent the proverbial "tip of the iceberg" for pediatric and perhaps adult lung disease related to ABCA3 mutations. Even with limited patient numbers and incomplete clinical information, we suggest the following clinical conclusions. Surfactant dysfunction mutations should be considered in any patient with ILD. In older patients, the presentation may differ from younger children, requiring a higher index of suspicion. A family history is helpful, but cannot be relied on to recognize all patients, as only 50% of the patients had a family history of lung disease. Although perhaps underappreciated in adult ILD (15), now that both ABCA3 and SPC mutations have been reported in adults, surfactant dysfunction mutations should also be considered in the differential of adult ILD. FOOTNOTES Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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