Hereditary pulmonary alveolar proteinosis (ORPHA:264675)
A rare, genetic, interstitial lung disease due to mutations in the CSF2R (colony-stimulating factor 2 receptor) alpha or beta subunits and characterized by alveolar accumulation of pulmonary surfactant, presenting a highly variable clinical presentation, ranging from asymptomatic to severe respiratory failure. Characteristic lung biopsy findings include periodic acid-Schiff-positive, granular eosinophilic material, enlarged foamy alveolar macrophages, and well-preserved alveolar walls. The Granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function is impaired but GM-CSF receptor autoantibodies are absent.
Epidemiology
The disease is very rare; it has been suggested to represent between less than 1-6% of the total cases of pulmonary alveolar proteinosis. Most reported cases have mutations due to CSF2RA  mutations rather than CSF2RB mutations. Females are predominantly affected.
Clinical description
The onset of clinical disease is typically insidious, with a subacute, symptom-free period ranging from months to several years. Age of onset is typically in infancy or childhood but may also occur in adulthood, particularly in patients with CSF2RB  mutations. Presenting symptoms include dyspnea (70%), hypoxemia (55%), and cough (56%) and more variably tachypnea (15%) and global respiratory failure (one third). In children and young adults, comorbidities may include failure to thrive, clubbing, pectus excavatum and hepatomegaly. The clinical course may be complicated by respiratory tract infections. Laboratory findings may include elevated serum GM-CSF level (specificity not known) and absence of GM-CSF autoantibodies.
Etiology
Disease is due to disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which is crucial for clearing of pulmonary surfactant by alveolar macrophages. Causal mutations have been identified in CSF2RA (Xp22.32) and CSF2RB (22q12.2-q13.1), genes encoding for the GM-CSF receptor.
Diagnostic methods
Disease is suspected based on clinical presentation and chest computed tomography findings of diffuse bilateral ground-glass opacifications and a superimposed reticular pattern (crazy paving pattern). Characteristic bronchoalvelolar lavage (BAL) findings indicative of hereditary PAP include a milky fluid with substantial amount of sediment and alveoli filled with numerous foamy, lipid- or surfactant-laden macrophages and secreted functional surfactant debris (staining with periodic acid Schiff). Genetic testing is necessary to establish this diagnosis. Testing of asymptomatic siblings requires genetic counseling.
Differential diagnosis
Differential diagnosis includes Autoimmune PAP, PAP related to the production of surfactant (e.g. due to mutations in SP-B or SP-C,  ABCA3, and NKX2-1), PAP secondary to hematologic disorders and malignancies, toxic dust inhalations, and immune deficiency syndromes, rare infections, mutations affecting functions or numbers of mononuclear phagocytes, and mutations affecting lung development.
Genetic counseling
Autosomal recessive inheritance has been reported for GM-CSF receptor mutations and genetic counseling is recommended for affected families. The disease can also occur from deletion of the GM-CSFR gene in the X chromosome pseudoautosomal region 1. Incomplete penetrance is observed. Due to the insidious nature of hereditary PAP, some vigilance for asymptomatic first-degree relatives for disease is advised.
Management and treatment
Whole lung lavage (WLL) is the only effective therapy, and is indicated when respiratory symptoms impair the quality of life, failure to thrive is observed, or lung function deviates from normal. In cases of severe hypoxemia, patients might be need to be supported by extracorporeal membrane oxygenation, allowing for recovery prior to WLL.
Prognosis
The overall prognosis for hereditary PAP treated by WLL is fair. Sometimes intense WLL treatments are necessary, which may significantly impair quality of life. Patients may be susceptible to opportunistic infections, as GM-CSF receptor has been associated with immune deficiency. Immunosuppressive therapy should be avoided, as it increases the risk of infections. The overall outcome reported so far is favorable, although a significant number will continue to have respiratory symptoms.

                            Last update: 
                            January 2020


                            - Expert reviewer(s): 
                            Pr Matthias GRIESE