(Chest. 2001;119:645-647.)
© 2001
American College of Chest Physicians
Focal Congenital Alveolar Proteinosis Associated With Abnormal Surfactant Protein B Messenger RNA*
Eva Mildenberger, MD;
Daphne E. deMello, MD;
Zhenwu Lin, PhD;
Hans Kössel, MD;
Thomas Hoehn, MD and
Hans T. Versmold, MD
*
From the Department of Pediatrics (Drs. Mildenberger, Kössel, and Versmold), Universitätsklinikum Benjamin Franklin, Freie Universität, Berlin, Germany; Department of Pathology (Dr. deMello), Cardinal Gennon Children’s Hospital, St. Louis, MO; Department of Cellular and Molecular Physiology (Dr. Lin), Pennsylvania State University, College of Medicine, Hershey, PA; and Department of Neonatology (Dr. Hoehn), Charité, Campus Virchow-Klinikum, Humboldt-University, Berlin, Germany.
Correspondence to: Eva Mildenberger, MD, Kinderklinik, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany
 |
Abstract
|
|---|
Two siblings presented with typical clinical features of
congenital pulmonary alveolar proteinosis (PAP). Necropsy of one
sibling revealed scattered foci of the diagnostic histologic changes in
the lung tissue. In contrast to infantile and adult PAP, focal
distribution is uncommon in congenital PAP. Defective expression of the
granulocyte-macrophage colony-stimulating factor receptor was ruled
out. The surfactant protein B (SP-B) content in the lung tissue of the
autopsied patient was low, and a deletion in the SP-B messenger RNA was
detected. We speculate that the PAP in our patients was related to the
reduced quantity and/or to the altered quality of SP-B.
Key Words: granulocyte-macrophage colony-stimulating factor receptor deficiency • pulmonary alveolar proteinosis • surfactant protein B deficiency
|
Introduction
|
|---|
Pulmonary
alveolar proteinosis (PAP) comprises the intra-alveolar accumulation of
lipoproteinaceous material resulting from a defective turnover of
surfactant.1
Alveoli filled with granular, eosinophilic
material seen with periodic acid-Schiff (PAS) staining are
diagnostic.2
3
4
The congenital form of PAP manifests
shortly after term birth as a severe lung failure. It usually
progresses to death despite surfactant replacement or extracorporeal
life support. In contrast to adult patients, pulmonary lavage is
difficult to perform in neonates and is not promising in congenital
PAP.3
4
Congenital PAP has been associated with a genetic
deficiency of surfactant protein-B (SP-B)3
and with a
defect in granulocyte-macrophage colony-stimulating factor
(GM-CSF)/interleukin 3/interleukin 5-receptor common {beta} chain
expression.5
We report two siblings with lethal congenital PAP, revealing two
intriguing aspects: first, an uncommon focal distribution of PAP in the
lung tissue found at necropsy of one sibling; second, low but
detectable levels of SP-B with abnormal SP-B messenger RNA.
|
Case Reports
|
|---|
The two male siblings were born in 1996 and 1998. The term infants
were the first children of healthy Turkish parents who are first
cousins. Three maternal brothers had died of infection and dehydration
during infancy, and one maternal sister had died of an unknown disease
at the age of 11 months.
Both infants developed respiratory distress during the first few hours
of life. Intratracheal exogenous surfactant (Survanta; Abbott
Laboratories; Abbott Park, IL) was administered to both infants
with no response. Bacterial and viral infections were excluded by
negative culture and serologic findings. Patient 1 was treated with
extracorporeal membrane oxygenation over 10 days and died of
progressive lung failure at 4 weeks of age. An autopsy was not done. In
patient 2, at age 12 days, a thoracoscopic lung biopsy was performed,
which demonstrated consolidated lungs with nodular infiltrations (Fig 1
). All specimens, obtained both from infiltrated and from apparently
normal lung tissue, showed interstitial fibrosis. At necropsy 2 days
later, the lungs were heavy (right lung, 75 g; left lung, 50
g) and showed, in addition to features of lung injury and reparative
processes, scattered foci of granular, eosinophilic, PAS-positive
material filling about one third of all alveoli (Fig 2
). The foci of PAP were distributed in a random manner with no
preferential localization.
Surfactant protein B was detected qualitatively by Western blot
analysis (SP-B antibody; Chemicon; Temecula, CA) in tracheal aspirates
from both infants obtained > 7 days after the administration of
exogenous surfactant. DNA analysis from parents and children excluded
the known genetic mutations associated with SP-B deficiency
(ie, 121ins2, Arg236Cys, 122delT3
4
6
).
Immunostaining by a method described previously3
revealed
SP-B in the lung tissue of patient 2, but the type II cells lining the
alveoli and the alveolar lumen contained relatively small amounts of
SP-B. SP-B messenger RNA was detected, which reflects intracellular
transcription. However, analysis of the SP-B messenger RNA showed that
the region between exons 7 and 8 was abnormal. The major form had a
12-nucleotide deletion at the beginning of exon 8, which results
in the loss of four amino acids in the SP-B precursor protein. GM-CSF
receptor was detected on leukocytes of patient 2 (no study was done in
patient 1).
|
Discussion
|
|---|
Focal Alveolar Proteinosis
Usually in congenital PAP, there is uniform accumulation of
PAS-positive material in all alveolar spaces.3
4
5
However,
lung tissue of our second patient showed focal distribution of PAP.
Teja et al2
reported scattered foci of PAP in a lung
biopsy specimen obtained from a patient who developed PAP during later
infancy (at age 16 months). Singh et al1
observed a wide
range of involvement of alveoli in lung biopsies from adult patients
with PAP. In these specimens, subpleural regions were the most severely
affected. However, the striking subpleural nodular infiltrations of the
lung observed at thoracoscopy in our second patient (Fig 1)
did not
correspond to areas of PAP, but were due to secondary changes.
Cause of Congenital PAP
A defective expression of the GM-CSF receptor was excluded.
The SP-B content of the lung tissue in patient 2 was low. Therefore,
the PAP in our patients may have been related to a partial SP-B
deficiency as described by Ballard et al.4
However, the
known mutations in the SP-B gene, including the Arg236Cys mutation
identified in their patient, were ruled out in our patients. Moreover,
the lung disease of our patients was much more severe than that in the
infant reported by Ballard et al.4
The abnormal SP-B
messenger RNA in our patient led to an altered SP-B precursor protein.
It is possible that the altered SP-B precursor protein was processed
into defective mature SP-B. Thus, PAP in our patients may have been
related to either the quality of SP-B or to a qualitatively defective
SP-B, ie, altered SP-B function. It is also possible that
the underlying defect is unrelated to either the surfactant proteins or
the GM-CSF receptor.
Inheritance
The development of disease in two siblings of consanguineous
parents suggests an autosomal recessive inheritance of the observed
congenital PAP. Possibly the mother’s male and female siblings,
who died in infancy of infection, dehydration, or of an unknown
disease, respectively, also suffered from PAP. It has been reported
that children with the infantile form of PAP present with a
history of vomiting, diarrhea, or pyogenic infections before
respiratory symptoms are prominent.2
Thus, the disease in
this family may be of autosomal recessive inheritance with phenotypic
diversity or it may be consistent with a dominant inheritance with
variable penetrance.
|
Conclusion
|
|---|
As in infantile and adult PAP, congenital PAP can present as a
focal accumulation of PAS-positive alveolar proteinaceous material, so
that the absence of PAP in a small biopsy does not exclude the
diagnosis. Congenital PAP may be caused by a genetic defect with an
autosomal recessive inheritance pattern that affects either SP-B
quantity or quality.
|
Acknowledgements
|
|---|
We thank Paul Stevens, Department of Neonatology,
Charité, Campus Charité Mitte, Humboldt-University, Berlin,
Germany, for the detection of SP-B in the tracheal aspirate and part of
the DNA analysis for SP-B deficiency. We thank Uta Dirksen, Department
of Pediatrics, Universitätsklinikum Düsseldorf, Germany,
for the detection of the GM-CSF receptor. We thank Jürgen
Waldschmidt, Department of Pediatric Surgery,
Universitätsklinikum Benjamin Franklin, Freie Universität,
Berlin, Germany, for the photograph of the thoracoscopy. We thank
Martin Vogel, Department of Pediatric Pathology, Charité, Campus
Virchow-Klinikum, Humboldt-University, Berlin, Germany, for the
photomicrograph of the lung tissue.
|
Footnotes
|
|---|
Abbreviations: GM-CSF = granulocyte-macrophage
colony-stimulating factor; PAP = pulmonary alveolar proteinosis;
PAS = periodic acid-Schiff; SP-B = surfactant protein B
Supported in part by National Institutes of Health grant HL 56000.
Received for publication November 19, 1999.
Accepted for publication August 10, 2000.
|
References
|
|---|
-
Singh, G, Katyal, SL, Bedrossian, CWM, et al (1983) Pulmonary alveolar proteinosis: staining for surfactant apoprotein in alveolar proteinosis and in conditions simulating it. Chest 83,82-86[Abstract/Free Full Text]
-
Teja, K, Cooper, PH, Squires, JE, et al (1981) Pulmonary alveolar proteinosis in four siblings. N Engl J Med 305,1390-1392[ISI][Medline]
-
DeMello, DE, Nogee, LM, Heyman, S, et al (1994) Molecular and phenotypic variability in the congenital alveolar proteinosis syndrome associated with inherited surfactant protein B deficiency. J Pediatr 125,43-50[CrossRef][ISI][Medline]
-
Ballard, PL, Nogee, LM, Beers, MF, et al (1995) Partial deficiency of surfactant protein B in an infant with chronic lung disease. Pediatrics 96,1046-1052[Abstract/Free Full Text]
-
Dirksen, U, Nishinakamura, R, Groneck, P, et al (1997) Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common {beta} chain expression. J Clin Invest 100,2211-2217[ISI][Medline]
-
Lin, Z, deMello, DE, Wallot, M, et al (1998) An SP-B gene mutation responsible for SP-B deficiency in fatal congenital alveolar proteinosis: evidence for a mutation hotspot in exon 4 Mol Genet Metab 64,25-35[CrossRef][ISI][Medline]
This article has been cited by other articles:
|
|
|
|
 
F. Brasch, S. Schimanski, C. Muhlfeld, S. Barlage, T. Langmann, C. Aslanidis, A. Boettcher, A. Dada, H. Schroten, E. Mildenberger, et al.
Alteration of the Pulmonary Surfactant System in Full-Term Infants with Hereditary ABCA3 Deficiency
Am. J. Respir. Crit. Care Med.,
September 1, 2006;
174(5):
571 - 580.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. F. Seymour and J. J. Presneill
Pulmonary Alveolar Proteinosis: Progress in the First 44 Years
Am. J. Respir. Crit. Care Med.,
July 15, 2002;
166(2):
215 - 235.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
Abstract
Introduction
