Key Point:

Researchers have recently identified a genetic mutation that causes life-threatening surfactant deficiency in full-term newborns.

FREDERICK, MD—On rare occasions, full-term newborns develop respiratory failure due to a deficiency in surfactant, the lipid-rich layer that coats the airways and is vital for proper lung function. In an important new discovery, investigators have identified a major contributor to surfactant deficiency in these infants—a mutation in the ATP-binding cassette transporter A3 (ABCA3) gene.

Because the ABCA3 gene appears to be critical for the proper formation of lamellar bodies, the organelles in which surfactant is stored, a mutation could result in the production of abnormal or insufficient amounts of surfactant. “The result is terrible because everything seems fine until the child is born and goes into respiratory distress,” explained Michael Dean, PhD, one of the study’s investigators. “The infant usually dies in a matter of weeks,” added Dr. Dean, who heads the Human Genetics Section in the Laboratory of Genomic Diversity at the National Cancer Institute in Frederick, Maryland.

His group and collaborators from Johns Hopkins Medical School and the University of Cincinnati recently linked ABCA3 mutations to severe neonatal surfactant deficiency in 21 infants who developed the deficiency for unknown reasons.[1] The investigators chose to focus on the ABCA3 gene due to its likely role in lamellar body formation and to associations between other ABC genes and human diseases. The defect they have identified is the third genetic mutation to be linked to the infant respiratory distress syndrome.

OTHER CAUSES ELIMINATED

Dr. Dean’s patients were a subgroup of 337 full-term infants who developed respiratory distress within hours of birth. All had clinical and/or radiographic findings consistent with surfactant deficiency.

In some infants, lung disease was secondary to another disorder, or it was known to result from a mutation in the gene for surfactant proteins B or C. However, in 115 infants, no cause for the respiratory distress could be found. Dr. Dean and his colleagues identified 21 infants in this cohort who had a high likelihood of a genetic basis for their lung disease based on such factors as family history and consanguinity.

Sixteen of the 21 infants studied died (usually within one month of birth), three recovered from their respiratory distress, and one infant developed chronic lung disease. In the remaining case, the outcome was unknown.

Mutations of the ABCA3 gene were found by DNA analysis in 16 of the 21 infants. Of the six infants who had a sibling, five had mutations in at least one allele, and all five were concordant with the sibling for ABCA3 haplotype. The ABCA3 mutations that these sibling pairs shared were limited to their families.

All three of the infants who recovered completely from their respiratory distress lacked the ABCA3 mutation. In contrast, the mutation was present in 14 of the 16 infants who died.

Lung tissue was taken from nine of the infants with the ABCA3 mutation; these samples showed alveolar type II cell hyperplasia and alveolar macrophage accumulations in distal air spaces with varying amounts of proteinaceous material and degrees of interstitial thickening. These findings are consistent with infantile desquamative interstitial pneumonitis and alveolar proteinosis, noted the investigators.

In lung tissue from four infants, light microscopy revealed alveolar type II cells without the typical lamellar bodies. Electron micrographs of lung tissue found lamellar bodies that were smaller, had more densely packed membranes, and were eccentrically placed compared to the lamellar bodies in control lung tissue. (Lamellar bodies typically have a concentric structure.)

The infants in the study were from several major racial or ethnic groups, indicating that ABCA3 mutations are not limited to a single population, stressed Dr. Dean. However, the fact that different families had different mutations suggests that there are no common alleles conferring this condition.

GENETIC SCREENING

It is not yet known what proportion of cases of infant respiratory distress syndrome are caused by the ABCA3 gene mutation, nor have all of the mutations that may underlie the disorder been detected. Nevertheless, identification of this abnormality, coupled with the earlier discoveries of the roles played by mutations in the genes encoding for surfactant proteins B and C, provides hope, said Dr. Dean. At least some cases of respiratory distress syndrome in newborns can now be avoided through genetic screening and counseling, he suggested.

Postnatal Dexamethasone Harms Children’s Development

Key Point: Early postnatal administration of high-dose dexamethasone leads to substantial and persistent reductions in neuromotor and cognitive functioning. In another study of infants with respiratory distress, Tsu F. Yeh, MD, and colleagues have demonstrated that the harmful effects associated with dexamethasone use found at age 2 years persist at least until the children reach school age.[1] “Our findings show quite conclusively that giving an infant dexamethasone shortly after birth can result in psychomotor problems and adversely affect cognitive function,” said Dr. Yeh, the President and a Professor of Pediatrics at China Medical University in Taichung, Taiwan. In this study, Dr. Yeh and colleagues followed up on 262 children who had been enrolled in a 1992–1995 placebo-controlled trial of corticosteroid use for the prevention of chronic lung disease. All of the infants had been born prematurely and had developed severe respiratory distress syndrome requiring mechanical ventilation within six hours of birth. Half were randomized to receive 0.25 mg/kg of dexamethasone every 12 hours during the first week of life; the dosage was then tapered over the next three weeks. The other infants were given saline placebo. The original trial found that dexamethasone use significantly reduced the rate at which the infants developed chronic lung disease but had no impact on mortality. A follow-up analysis performed when the surviving children were age 2 suggested that those who had been treated with the corticosteroid had slower somatic growth and poorer neuromotor function than did the other children. Dr. Yeh’s group sought to determine whether these adverse effects of treatment were transient or persistent. The researchers examined 146 (92%) of the 159 children who had survived to school age—72 in the dexamethasone group and 74 in the control cohort. The mean ages at follow-up in the two groups were 8.3 and 8.1, respectively. Compared with the controls, the children who had been given dexamethasone performed significantly worse on tests of intelligence, distractibility, perceptual organization, and ability to process information. They were also more likely to have borderline or abnormal results on neurologic examination, although the difference between the two groups in this regard did not reach significance. Furthermore, the dexamethasone group had poorer scores on tests of manual dexterity, balance, motor coordination, and visual motor integration. Indeed, that group was more likely than were the controls to score below the fifth percentile for their age on these tests. The dexamethasone group was also more likely to have clinically significant disabilities, such as cerebral palsy or hearing or visual impairment. In addition, they had lower scores on arithmetic, grammar, and phonetic transcription and perception tests than did the controls. Dr. Yeh’s team recommends that early, high-dose dexamethasone therapy not be used to prevent or treat lung disease in premature infants because the harm it causes outweighs its benefits. In an accompanying editorial, Alan H. Jobe, PhD, agreed with this recommendation but cautioned that there still may be a role for lower-dose, later administration—or treatment with a different corticosteroid.[2] Dr. Jobe, who is Director of Perinatal Biology at the Cincinnati Children’s Hospital Medical Center, noted that many clinicians continue to use corticosteroids in premature infants because the drugs do lower the risk of chronic lung disease. However, further research is still needed to determine whether a regimen with an acceptable risk:benefit ratio can be found. “Since clinicians will not stop using corticosteroids, we need to understand how to use them safely, if that is possible,” he said. —Timothy Begany

References 1. Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med. 2004;350:1304-1313. 2. Jobe AH. Postnatal corticosteroids for preterm infants—do what we say, not what we do. N Engl J Med. 2004;350:1349-1351.

—Timothy Begany

Reference
1. Shulenin S, Nogee LM, Annilo T, et al. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004;350:1296-1303.

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