SMDP4 is an interstitial lung disorder characterized by the accumulation of surfactant protein exudate in the alveoli. This results in tachypnea, dyspnea, hypoxemia, a failure to thrive and eventually acute respiratory distress or respiratory failure. Pulmonary alveolar proteinosis (PAP) can occur in one of three forms: Congenital-PAP caused by certain gene mutations, Acquired-PAP caused by neutralizing autoantibodies to CSF2, or Secondary-PAP that occurs as a secondary complication of other conditions. SMDP4 is a congenital form of PAP that is caused by mutations in the CSF2RA gene. PAP is a rare disorder with an estimated incidence rate of 0.1 per 100,000 individuals. Congenital PAP forms a small subset of these, with CSF2RA-associated-PAP being reported in only a handful of cases. Individuals with SMDP4 may exhibit symptoms in early childhood. The disorder may also be triggered by factors such as respiratory tract infections.
Diagnosis is made based on clinical examinations, chest CT scans showing a characteristic ‘crazy paving’ pattern and bronchoscopy studies revealing milky bronchoalveolar lavage positive for periodic acid–Schiff stain. So far, whole lung lavage treatment has been very effective in improving respiratory function in SMDP4 patients. Other treatment options that are currently being researched include pulmonary macrophage transplantation and gene therapy.
SMDP4 follows an autosomal recessive pattern of inheritance and is caused by mutations in the CSF2RA gene. The gene encodes the ligand-binding alpha chain of the Colony Stimulating Factor 2 Receptor. Upon activation of this receptor by Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), it transduces signals that stimulate the production of granulocytes and monocytes. CSF2RA gene variants that have been implicated in SMDP4 include a G174R missense mutation that causes a truncated CSF2RA protein and a large deletion of exons 5 through 13 that results in a complete absence of the protein.
Al-Haidary et al. (2017) described a 5-year-old Saudi boy from a consanguineous family with PAP. He first presented with dyspnea, weight loss and respiratory distress. Investigations revealed ground-glass opacification and interlobular septal thickening in his chest (crazy paving pattern) with milky bronchoalveolar lavage positive for periodic acid–Schiff stain. His serum GM-CSF levels were high and GM-CSF autoantibodies were negative. He was found to be homozygous for a novel c.533G>A (p.Cys178Tyr) variant in the CSF2RA gene. His parents were both heterozygous while his 3.5-year-old sister was found to be homozygous for the mutation. She was asymptomatic and an examination found no abnormal findings. The patient was diagnosed with congenital PAP due to a CSF2RA gene mutation and responded well to therapeutic whole lung lavage treatment.
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