Molecular and phenotypic variability in the congenital alveolar proteinosis syndrome associated with inherited surfactant protein B deficiency,☆☆,,★★

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Abstract

Congenital alveolar proteinosis (CAP) is an often fatal cause of respiratory 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 qualitative and quantitative abnormalities of the surfactant proteins A and C. Immunostaining for lung surfactant proteins and a search for the 121ins2 mutation by restriction enzyme analysis of DNA extracted from paraffin-embedded lung tissue was performed for 7 additional affected infants from 6 families, bringing to 10 the total number of patients with CAP who have been studied. In six infants, the surfactant protein immunostaining pattern was similar to that of the index cases. Of these, three patients were homozygous for the 121ins2 mutation; one was a compound heterozygote with the 121ins2 in one allele and a different mutation in the other; and three patients lacked the mutation in both alleles. One infant had an abundance of SP-B, suggesting phenotypic heterogeneity 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 may be more common than previously suspected. (J PEDIATR 1994;125:43-50)

Section snippets

CASE REPORTS

The study population consisted of seven infants from six unrelated families with biopsy- or autopsy-proven alveolar proteinosis. Salient clinical features of the infants are indicated in Table I. Roman numerals indicate infants from different families. The index family, previously described,11, 13 has been designated as family I; patients IIa, IIb, and III were reported previously.7, 8 The remaining patients were referred to us for surfactant protein analysis because of their clinical disorder.

METHODS

In all cases a portion of the lung tissue was fixed in 10% formaldehyde, dehydrated, and embedded in paraffin. Paraffin sections were stained with hematoxylin and eosin. Additional paraffin sections, 5 μm in thickness, were obtained on Fisher brand Super Frost/Plus microscope slides (Erie Scientific Co., Portsmouth, N.H.), and immunostaining for SP-A, SP-B, and SP-C was done as described previously.15 The intensity and distribution of the immunoreactivity was graded on a scale of 0 to 4 as

Histopathologic findings

The lungs of all patients with CAP had an appearance similar to that described previously for patient Ia—the alveoli were filled with eosinophilic granular material admixed with desquamated type II cells and macrophages. Alveolar lining cells were prominent and there was interstitial fibrosis that produced thickened airspace septa11 (Fig. 1). Lungs of control subjects (not shown) lacked the alveolar granular material but several lungs did contain detached alveolar lining cells within airspaces.

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DISCUSSION

Pulmonary surfactant is a lipoprotein complex that reduces surface tension at the air-liquid interface in the alveolus.23, 24 Four surfactant-associated proteins have been characterized to date.25 Surfactant proteins B and C are hydrophobic proteins known to enhance the rate of adsorption of phospholipids to the surface monolayer. Surfactant protein B, along with the hydrophilic protein SP-A, participates in the formation of tubular myelin,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39

ADDENDUM

Since the submission of this article, patient VI died at 12 months of age.

We thank David Phelps, PhD, for providing the antibodies to SP-A and SP-B, and Jeffrey Whitsett, MD, for providing the antibody to SP-C.

References (46)

  • J Vanek et al.

    Interstitial plasma cell pneumonia in infnats

    Ann Pediatr (Paris)

    (1953)
  • G Dauzier et al.

    Pneumocystis carinii pneumonia in an infant

    Am J Clin Pathol

    (1956)
  • HT Russell et al.

    Pneumocystis pneumonitis in American infants: report of two cases with autopsy studies

    Am J Clin Pathol

    (1956)
  • JC Haworth et al.

    Thymic alymphoplasia

    Arch Dis Child

    (1967)
  • K Teja et al.

    Pulmonary alveolar proteinosis in four siblings

    N Engl J Med

    (1981)
  • RE Schumacher et al.

    Pulmonary alveolar proteinosis in a newborn

    Pediatr Pulmonol

    (1989)
  • DP Knight et al.

    Pulmonary alveolar proteinosis in the newborn

    Arch Pathol Lab Med

    (1985)
  • M Coleman et al.

    Pulmonary alveolar proteinosis: an uncommon cause of chronic neonatal respiratory distress

    Am Rev Respir Dis

    (1980)
  • LM Nogee et al.

    Deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis

    N Engl J Med

    (1993)
  • DS Strayer et al.

    Immunogenicity of surfactant II. Porcine and bovine surfactants

    Clin Exp Immunol

    (1991)
  • deMello DE, Heyman S, Phelps D, et al. Ultrastructure of lung in surfactant protein B (SP-B) deficiency. Am J Respir...
  • LM Nogee et al.

    A mutation in the surfactant protein B gene as the basis for a fatal neonatal respiratory disease in multiple kindreds

    J Clin Invest

    (1994)
  • DE deMello et al.

    Expression of the 35 kDa and low molecular weight surfactant associated proteins in the lungs of infants dying with respiratory distress syndrome

    Am J Pathol

    (1989)
  • Cited by (0)

    From the Departments of Pathology and Pediatrics, St. Louis University, St. Louis, Missouri; Johns Hopkins University, Baltimore, Maryland; University of California, San Diego and Children's Hospital—San Diego; University of California, Davis Medical Center; Children's Hospital, Los Angeles; Northwestern University, Chicago, Illinois; University of Washington, Seattle; University of Michigan, Ann Arbor; and Washington University, St. Louis

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    Supported in part by grants from the National Institutes of Health No. HL34748 (Dr. deMello), No. 37591 (Dr. Colten), the American Lung Association, the Fleur de Lis Foundation (Dr. deMello), and the March of Dimes (Dr. Nogee).

    Reprint requests: Daphne E. deMello, MD, Department of Pathology, 1465 S. Grand Blvd., St. Louis, MO 63104.

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