CSF2RA – Hereditary Pulmonary Alveolar Proteinosis

Hereditary pulmonary alveolar proteinosis (hPAP) is an autosomal recessive disorder of surfactant clearance caused by dysfunction of the GM-CSF receptor α chain (CSF2RA), leading to hereditary pulmonary alveolar proteinosis. To date, three unrelated early-onset hPAP patients have been reported with biallelic CSF2RA lesions: a 3-year-old girl with homozygous CSF2RA deletion unmasked by a complex X chromosome rearrangement (PMID:23918747), a 3-year-old patient and her homozygous but asymptomatic sister (PMID:23206404), and a 4-year-old girl from a consanguineous family carrying homozygous CSF2RA deficiency (PMID:39621143). One additional affected sibling segregated the identical homozygous deletion, confirming autosomal recessive transmission (PMID:23206404). In all cases, surfactant accumulated in the alveoli, manifesting with respiratory failure and short stature due to concomitant SHOX deletion in the first report (PMID:23918747). Functional assays revealed impaired GM-CSF signalling in alveolar macrophages, and hematopoietic stem cell transplantation successfully restored surfactant clearance in the severe case (PMID:39621143). No studies have disputed the CSF2RA–hPAP association. Overall, the limited number of probands with consistent genetic and functional data supports a Limited clinical validity classification. Key Take-home: Biallelic CSF2RA loss confirms recessive hPAP, informing diagnostic testing and curative HSCT strategies.

References

• American journal of medical genetics. Part A | 2013 | De novo complex X chromosome rearrangement unmasking maternally inherited CSF2RA deletion in a girl with pulmonary alveolar proteinosis. PMID:23918747
• Respiratory medicine | 2013 | Hereditary pulmonary alveolar proteinosis. Could it be triggered by Mycoplasma pneumoniae pneumonia? PMID:23206404
• Journal of clinical immunology | 2024 | Restitutio ad integrum: Rescuing the Alveolar Macrophage Function with HSCT in Pulmonary Alveolar Proteinosis Due to CSF2Rα Deficiency PMID:39621143

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