Pulmonary alveolar proteinosis (PAP) is a syndrome characterised by accumulation of surfactant in alveoli resulting in respiratory insufficiency [1]. Surfactant homeostasis is critical for lung function and is tightly regulated, in part, by pulmonary granulocyte-macrophage colony-stimulating factor (GM-CSF), which is required for surfactant clearance by alveolar macrophages [2] and alveolar macrophage maturation [1]. The effects of GM-CSF are mediated by cell-surface receptors composed of GM-CSF-binding a-chains and affinityenhancing b-chains (encoded by CSF2RA and CSF2RB, respectively)[3]. Ligand binding activates signalling via multiple pathways including the signal transducer and activator of phosphorylation (STAT) 5 [4]. Disruption of GMCSF signalling causes PAP by impairing surfactant catabolism in alveolar macrophages [1]. In 90% of patients, PAP is caused by neutralising GM-CSF auto-antibodies [5, 6]. Through the Rare Lung Diseases Network global PAP detection programme, we identified PAP caused by recessive CSF2RA mutations and developed novel diagnostic methods to identify patients with PAP caused by GM-CSF receptor dysfunction [4, 7]. Herein, we report a case of hereditary PAP caused by disruption of GM-CSF receptor b-chain function.

A previously healthy 9-yr-old female presented with bilateral pneumonia, followed 3 months later by progressive dyspnoea of insidious onset. The diagnosis of PAP was suggested by chest radiograph findings, high-resolution computed tomography and bronchoalveolar cytology, and was confirmed by surgical lung biopsy. Pulmonary histopathology was typical of primary PAP (fig. 1) and she was successfully treated by serial whole lung lavage therapy. Details of the case history are included in the online supplement. A GM-CSF auto-antibody test was negative and the serum GM-CSF level was increased (25.9 pg? mL-1) suggesting GM-CSF receptor dysfunction as the molecular basis of PAP [4, 7]. A molecular evaluation was undertaken and included GM-CSF receptor detection, STAT-5 phosphorylation, CSF2RA and CSF2RB nucleotide sequencing, and cloning as reported previously [4, 7]. GM-CSF receptor aand b-chains were detected on blood leukocytes from the patient and all family members by flow cytometry and Western blotting (data not shown)[4, 7]. Nucleotide sequencing of leukocyte mRNA and genomic DNA revealed a normal CSF2RA sequence for the patient and all family members (data not shown). A single CSF2RB point mutation (c. 812C. T) in exon 7 was identified in both mRNA and DNA from the patient (who was homozygous for the mutation) and from