Children's Interstitial Lung Disease Network:
A Cooperative Approach to the Classification of Pediatric Diffuse Lung Diseases
Moderator: Dr. Claire Langston
Section 2 -
Surfactant Disorders: Clinical and Pathologic Spectrum
(Surfactant Metabolism and Deficiencies in Surfactant Proteins)
Susan E. Wert
Cincinnati Children's Hospital Medical Center
Cincinnati , OH
Genetic disorders of
surfactant metabolism have been recognized as underlying causes of acute respiratory distress and failure
in full term neonates, as well as of interstitial lung disease (ILD) in older infants, children, and
adults. The genes involved in these disorders are the surfactant protein B gene (SFTPB), the surfactant protein C gene (SFTPC) and the
ABCA3 gene. Surfactant protein B (SP-B) and C (SP-C) are small hydrophobic
proteins that are synthesized in alveolar type 2 cells and secreted into the alveolar lumen, where they
function to stabilize and enhance spreading of surfactant phospholipids along the alveolar surface. This
mixture of proteins and lipids reduces surface tension at the air-liquid interface, preventing collapse
of the lung at the end of expiration. ABCA3 is an integral membrane protein that has been localized to
the limiting (outer) membrane of the lamellar body, which is the intracellular storage organelle for
surfactant lipids and proteins in alveolar type 2 cells. ABCA3 is a member of a large family of
ATP-binding cassette proteins that transport a variety of substances across
biological membranes, including lipids.
Surfactant lipids are
composed primarily of phosphatidylcholine (PC or lecithin) and, in particular, disaturated or
dipalmitoylated phosphatidylcholine (DSPC or DPPC), with lesser amounts of phosphatidylglycerol,
phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, and cholesterol. SP-B
is encoded by a single gene on human chromosome 2, while SP-C is located on human chromosome 8. Both
proteins are synthesized as large precursor proteins (proSP-B and proSP-C), which are then processed by
several proteolytic enzymes (Napsin A, Cathepsin H and Pepsinogen C) to yield the smaller, hydrophobic,
active airway peptides. The final processing steps for both SP-B and SP-C take place in the lamellar
body, where these proteins associate with surfactant phospholipids and are then secreted together with
the lipids into the airway. Both surfactant phospholipids and proteins are recycled by the type 2 cell
or catabolized by alveolar macrophages.
SFTPB Mutations :
Hereditary SP-B deficiency
has been reported in over 75 individual children from unrelated families and is inherited as an autosomal
recessive disease. Over 40 distinct mutations in the SFTPB gene have been
identified and characterized to date by Dr. Lawrence Nogee, Johns Hopkins University , Baltimore , MD.
Two-thirds of the mutant alleles are accounted for by a common mutation, 121ins2, in exon 4. The gene
frequency is one mutation per 1000-3000 individuals. Mutations in SFTPB
cause acute respiratory distress at birth, which is progressive and usually
fatal by 3 months of age. Lung disease is caused by the complete absence of SP-B (loss-of function), and
clinical findings are consistent with those seen in preterm infants with RDS due to insufficient
surfactant stores. In general, SP-B deficiency is associated with histopathologic diagnoses of
congenital pulmonary alveolar proteinosis (PAP) and desquamative interstitial pneumonits (DIP).
Histopathologic features of genetic SP-B deficiency include: 1) a severe alveolar proteinosis admixed
with desquamated type II cells and alveolar macrophages, 2) intact, hyperplastic, alveolar epithelia with
prominent alveolar Type II cells, and 3) interstitial thickening. Immunohistochemical features include
1) absence of immunostaining for proSP-B and the mature SP-B peptide and (2) increased amounts of SP-A
and proSP-C immunopositive material in the airspaces. The presence of increased amounts of partially
processed proSP-C in the airspace suggests that SP-B is required for normal processing or trafficking of
SP-C. Aberrant or incompletely processed forms of proSP-B may or may not be detected depending on the
location of the mutation in the gene. Phospholipid profiles may be abnormal, resembling that of an
immature lung; and lamellar body formation is perturbed. No mature lamellar bodies are found, although
many large multivesicular bodies are detected by electron microscopy.
Over 40 distinct
mutations in the SFTPC gene have been identified and characterized to date
(personal communication, Dr. Lawrence Nogee), with almost all mapping to the carboxy-terminal domain of
proSP-C. This causes misfolding of proSP-C, resulting in incomplete processing of the propeptide. A
common mutation, I73T, is found in about 25% of these cases. SFTPC
mutations are associated with chronic interstitial lung disease (ILD) in both children and adults. Lung
disease due to SFTPC mutations is inherited as an autosomal dominant trait
with variable penetrance and severity (45%), or as sporadic disease due to a de
novo mutation (51%). Approximately 44% of patients with a SFTPC
mutation developed respiratory symptoms within the first month of life (as neonates), while another 40%
developed symptoms between 1 and 6 months of life (as infants). Onset of respiratory symptoms has been
reported, however, in both older children and adults; and at least 6 asymptomatic individuals with SP-C
mutations have been identified (personal communication, Dr. Lawrence Nogee). Although the incidence of
lung disease due to SFTPC mutations is currently unknown, recent studies
indicate that SFTPC mutations are a rare cause of adult ILD. The population
frequency of disease causing SFTPC variants is, however, currently unknown.
In general, SP-C deficiency is associated with histopathologic diagnoses of DIP, PAP, chronic pneumonitis
of infancy (CPI), and non-specific interstitial pneumonitis (NSIP), although the most common
histopathologic diagnosis in infants is CPI. Immunohistochemical analysis reveals robust staining for
all of the surfactant proteins including proSP-C, which is restricted to alveolar type 2 cells. Two
different patterns of proSP-C staining have been observed: 1) diffuse staining of the cytoplasm and 2)
accumulation of immunoreactive material in a perinuclear compartment. Accumulation of incompletely
processed proSP-C in alveolar type 2 cells may be toxic, resulting in chronic lung injury and disease,
although decreased levels of mature SP-C are also found in these patients, suggesting that routing and
processing of protein from the normal allele is perturbed.
Over 100 distinct
mutations have been identified in the ABCA3 gene (personal communication,
Dr. Lawrence Nogee), making this the largest class of genetic mutations that cause surfactant
deficiency. Population frequencies for these mutations are, however, currently unknown. Genetic ABCA3
deficiency is inherited as an autosomal recessive disease and is associated with surfactant deficiency
(loss-of-function) and fatal respiratory distress in the neonatal period. In general, ABCA3 deficiency
is associated with histopathologic diagnoses of DPI and PAP, as well as with aberrant lamellar body
formation. Therefore, the clinical presentation, mortality rate, and histopathology for ABCA3 deficiency
are similar to those for genetic SP-B deficiency for the majority of neonates with ABCA3 mutations on
both alleles. Recently, a common mutation, E292V, has been identified in 10 older children who were
diagnosed with chronic ILD. Milder neonatal disease with presentation of non-specific symptoms and
findings, including cough, tachypnea, hypoxemia in room air, clubbing, and failure to thrive, were
reported in some of these children, while other children in the study did not have any respiratory
symptoms or findings until later in childhood. In general, immunostaining for all of the surfactant
proteins, as well as ABCA3, is robust, although a subset of cases exhibits poor immmunostaining for the
mature SP-B peptide. Unlike SP-B deficiency, proSP-C staining is restricted to the cytoplasm of alveolar
type 2 cells and is not found in the airspaces. Multiple, small, lamellar bodies with densely packed
phospholipid membranes and eccentrically placed electron-dense cores are detected in type 2 cells, while
phospholipid analyses in a subset of patients revealed abnormal phospholipid profiles with decreased
proportions of phosphatidylcholine. Funding: NIH HL-57403 and HL-56387.
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