Alveolar hemorrhage generally occurs before the age of 5 years and may be life threatening. After the second decade of life, patients develop ILD. Chest CT scans initially show diffuse ground-glass opacities with septal thickening and honeycomb cysts. The number of cysts tend to increase through time as the ground-glass opacities decrease, with an ultimate pattern that is most consistent with NSIP or lymphocytic interstitial pneumonia [93]. Histopathological evaluation shows alveolar hemorrhage and pulmonary capillaritis with vascular in ltration by neutrophils and necrosis of the capillary walls, as well as lymphoid aggregates around airways [94]. Lung biopsies of older patients show NSIP and follicular bronchiolitis or diffuse interstitial pulmonary neuroendocrine cell hyperplasia [94, 95].

Most patients have at least a partial response to immunosuppression particularly in the case of alveolar hemorrhage but death or need for lung transplantation can occur with disease progression and during acute exacerbation of the disease [94].

Pulmonary Alveolar Proteinosis

GMCSF Receptor Mutations

Pulmonary alveolar proteinosis (PAP) is a syndrome that is characterized by alveolar accumulation of surfactant due to autoimmune, hereditary, and environmental etiologies. Autoimmune PAP caused by an autoantibody to GM-CSF is the most frequent form of PAP, representing 90% of cases. PAP may not only result from several heritable genetic mutations, especially in the GM-CSF receptor gene, but also from surfactant gene mutations [77, 96]. The GM-CSF receptor is composed of an α chain, encoded by CSF2RA, and a β chain, encoded by CSF2RB. Homozygous mutations of CSF2RA and heterozygous mutations of CSF2RB have been associated with PAP. Patients with PAP associated with CSF2RA mutation are usually below 5 years, while mean age of patient with autoimmune PAP is 50 years. However, CSF2RA PAP is very similar to autoimmune PAP and may lead to pulmonary brosis. Features of CSF2RA PAP that are unlike autoimmune PAP include that interstitial cell in ltration is generally absent, alveolar and serum concentration of GM-CSF are increased due to compensatory mechanisms, and anti-GM-CSF antibodies are absent. Whole-lung lavage is generally effective, but GM-CSF therapy does not seem to provide bene t [97–99]. Studies are underway to determine if GM-CSF receptor mutations can be corrected by hematopoietic stem cell transplantation or pulmonary macrophage transplantation [100, 101].

GATA2

GATA2 is a transcriptional factor that plays a key role in the functionality of hematopoietic stem cells. GATA2 mutations

were initially associated with MonoMAC syndrome (monocytopenia, lymphopenia, mycobacterial infection) and were further associated with numerous hematological disorders [102]. GATA2 mutation has also been associated with PAP syndrome, but pulmonary brosis has also been reported [103, 104]. Hematopoietic stem cell transplantation may improve lung disease in patients with GATAs de - ciency [102].

MARS

Homozygous mutations of methionyl-tRNA synthetase

(MARS), an enzyme that catalyzes the binding of methionine to tRNA and plays a critical role in protein synthesis, have been described in a cohort of 34 children with ILD from La Réunion Island belonging to the same family [105]. Most of them presented with PAP, and a similar mutation was detected in two independent families (of Comorian and Tunisian origin) [105]. The mean age at diagnosis is almost 9 months. All patients have respiratory failure and failure to thrive, half have hepatomegaly related to steatosis and one-­ third have splenomegaly. CT scanning shows a crazy paving pattern and consolidations (76%). In addition to accumulation of surfactant consistent with a PAP pattern, pulmonary histology shows lipoid pneumonia (42%), brosis (42%), and interstitial infammation (84%). Overall survival at the age of 5 years is 65%. Despite temporary improvement after pulmonary lavage, survival is not different between patients receiving and not receiving therapeutic pulmonary lavage [106]. MARS activity is restored in vitro by methionine supplementation suggesting a possible targeted therapy [105]. The pathophysiology of the lung disease has yet to be understood and the risk of recurrence after pulmonary transplantation has not been evaluated.

Lysinuric Protein Intolerance

Lysinuric protein intolerance (LPI) is an autosomal recessive disease caused by mutations of SLC7A7 that result in defective transport of cationic amino acids across epithelial cell membranes in the intestine and kidney [107]. The disease is usually diagnosed in children who present with failure to thrive and gastrointestinal symptoms. The most frequent chronic manifestations are related to renal and pancreatic insuf ciency. Lysinuric protein intolerance is diagnosed by the presence of excessive amounts of dibasic amino acids (argi`, lysine, ornithine) in the urine, particularly after protein ingestion, and/or mutation of SLC7A7 [107]. Pulmonary manifestations are variable and range from subclinical ILD to respiratory insuf ciency. PAP is frequently present and patients may develop lung brosis out of proportion to the severity of PAP [107]. The treatment is based on a low protein diet and oral supplementation with citrulline. Whole-lung lavage and nebulized GM-CSF therapy seem to be effective. However, recurrent PAP may lead to death and