Categorization of PAP

Disease Causes of PAPManifestation Reported in Neonates, ChildrenaGenetically CausedbExposure CausedHistologically Intact Lung Interstitial Tissue, Primarily Alveolar Filling
Surfactant-dysfunction syndromes
 SFTPB mutationsYYNN
 SFTPC mutationsYYNN
 ABCA3 mutationsYYNN
 TTF1 mutationsYYNN
Impaired GM-CSF signaling
 GM-CSF receptor α chain of mutationsYYNY
 Turner syndrome with heterozygous GM-CSF receptor α chain mutationsYYNY
 GM-CSF receptor β chain mutationsYYNY
 Autoimmune GM-CSF antibodiesYNNY
Hematologic disorders and other malignancies
 GATA2 deficiencyYYNY
 MDS (most common)YYNY
 Chronic myelomonocytic leukemiaYYNn.k.
 Acute lymphatic leukemiaYYNYc
 Congenital dyserythropoietic anemiaYYNY
 Fanconi’s anemiaYYNY
 Hemophagocytic lymphohistiocytosisYNN
 Sideroblastic anemiaYNcNYc
 Primary myelofibrosis, chronic lymphocytic leukemia, cutaneous T-cell lymphoma, thymic alymphoplasia, adult T-cell leukemia and/or lymphoma, idiopathic thrombocytopenic purpura, aplastic anemia, chronic myeloid leukemia, overlap myeloproliferative neoplasm, acute myeloid leukemia, hairy-cell leukemia, multiple myeloma and/or plasmocytoma, polycythemia vera, essential thrombocythemia, amyloidosis, Hodgkin disease, non-Hodgkin lymphoma, adenocarcinoma, glioblastoma, melanoma, small-cell lung carcinoma, clear-cell renal cell carcinoma, mesotheliomaNY or n.k.NcYc or n.k.
Systemic diseases
 Lysinuric protein intolerance (SLC7A7 mutation)YYNY (50%), N (50%)
 MARS mutationsYYNN
 Niemann Pick type C2YYNN
 Niemann Pick type BYYNn.d.
 Bone marrow, stem cell transplantYNNYc
 Systemic lupus erythematosus, granulomatosis with polyangiitis, microscopic polyangiitis, membranous nephropathy, dermatomyositis with interstitial lung disease, coincident in many other rheumatologic diseases and interstitial lung diseases, lung transplantNNNYc or N
Immunologic diseases
 Adenosine deaminase deficiencyYYNY
 DiGeorge syndrome type 2YYNn.d.
 Monoclonal gammopathyNNNY
 Selective immunoglobulin A deficiencyNNNY
 Severe combined immunodeficiencyYYNY
 X-linked hyper–immunoglobulin M syndromeYYNn.d.
 CytomegalovirusYNYN or Nc
 Epstein-Barr virusYNYN or Nc
M tuberculosisYNYN or Nc
 Atypical mycobacteriaYNYN or Nc
NocardiaNNYN or Nc
P jiroveciYNYN or Nc
 Chemotherapy, antineoplasticYNYY
 Busulfan, sirolimus, everolimus, tyrosine kinase inhibitors (including imatinib, nilotinib, and dasatinib), mycophenolate and cyclosporine combination, smoked fentanyl patches, leflunomide, hydrofluoric acid (inhaled)NNYY
Types of dust exposure, inorganic
 Aluminum, cement, marble, indium, iron, silica and silica-leaking breast implants, tin, titanium (and varnish)NNYN (except aluminum, silica)
Types of dust exposure, organic
 Bakery flour, chlorine, cleaning products, cotton, fertilizer, agricultural dust, fumes, gasoline, hydrofluoric acid, parrots, pigeons, petroleum, sawdustNNYN or Nc
Miscellaneous conditions
 Osteopetrosis caused by TCIRG1 gene mutationYYNYc
 Total anomalous pulmonary venous return with coarctation of the aorta (single case)YN, YcNY, pulmonary hypoplasia
  • Y or N indicates highest likelihood and/or firm knowledge from publications; frequently extensive data are lacking and these indications are based on estimation. n.d., not done; n.k., not known.

  • a Manifestation of PAP is proven in this age group (not of disease).

  • b May be germline or clonal in monocytes.

  • c Indicates uncertainty.