Abstract
BackgroundClinical presentation, diagnosis, management and outcome of molecularly defined congenital pulmonary alveolar proteinosis (PAP) due to mutations in the GM-CSF receptor are not well known.Case presentationA 2 1/2 years old girl was diagnosed as having alveolar proteinosis. Whole lung lavages were performed with a new catheter balloon technique, feasible in small sized airways. Because of some interstitial inflammation in the lung biopsy and to further improve the condition, empirical therapy with systemic steroids and azathioprin, and inhaled and subcutaneous GMCSF, were used. Based on clinical measures, total protein and lipid recovered by whole lung lavages, all these treatments were without benefit. Conversely, severe respiratory viral infections and an invasive aspergillosis with aspergilloma formation occurred. Recently the novel homozygous stop mutation p.Ser25X of the GMCSF receptor alpha chain was identified in the patient. This mutation leads to a lack of functional GMCSF receptor and a reduced response to GMCSF stimulation of CD11b expression of mononuclear cells of the patient. Subsequently a very intense treatment with monthly lavages was initiated, resulting for the first time in complete resolution of partial respiratory insufficiency and a significant improvement of the overall somato-psychosocial condition of the child.ConclusionsThe long term management from early childhood into young adolescence of severe alveolar proteinosis due to GMCSF receptor deficiency requires a dedicated specialized team to perform technically demanding whole lung lavages and cope with complications.
Highlights
Clinical presentation, diagnosis, management and outcome of molecularly defined congenital pulmonary alveolar proteinosis (PAP) due to mutations in the granulocyte-macrophagecolony stimulating factor (GM-CSF) receptor are not well known.Case presentation: A 2 1/2 years old girl was diagnosed as having alveolar proteinosis
There are several causes of this rare condition; mouse models with deletion of granulocyte-macrophagecolony stimulating factor (GM-CSF) or the GM-CSF receptor (GM-CSFR) beta-chain showed the first evidence for involved molecularly mechanisms [3,4]
Secondary PAP develops in association with conditions involving functional impairment or reduced numbers of alveolar macrophages like inhalation of inorganic dusts, myeloic leukemia, myelodysplastic syndrome, immunosuppression related to organ transplantation, and some infections including Pneumocystis [1]
Summary
We report a patient with molecularly defined severe congenital PAP due to a previously undescribed autosomal recessive mutation in the alpha chain of the GM-CSF receptor This mutation leads to a stop of transcription and to a lack of functional protein. The GM-CSF induced responses are mediated through activation of the transcription factor PU. and include increased surfactant catabolism and CD11b expression [20] Impairment of the latter was shown directly in mononuclear cells of the patient after stimulation with GM-CSF. Subcutaneous injections or inhalations of GM-CSF, which have been successfully utilized in adult patients with autoimmune PAP [22,23], were not helpful in our case to reduce alveolar filling as assessed by CT scanning (not shown) or improvement in gas exchange (Figure 2).
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