Pulmonary alveolar microlithiasis (PAM)

PAM is a slowly progressive lung disorder. It is most often diagnosed between 10 and 30 years of age, although diagnosis is possible at any age. Asymptomatic children and young adults may become symptomatic later in life. Symptomatic individuals commonly report dyspnoea, dry cough, fatigue and chest pain. Pneumothorax, clubbing, haemoptysis, hypoxaemia and cyanosis have also been described. Pulmonary function is often preserved initially but may become progressively restrictive over time. Inflammation, fibrosis and calcification of the lung interstitium are accompanying features. PAM is associated with pulmonary hypertension, primarily group 3 pulmonary hypertension secondary to chronic lung disease. It is often discovered incidentally on chest radiographs or through screening of affected families. The disease generally progresses slowly and may ultimately lead to respiratory failure. Extrapulmonary calcifications have also been reported in some patients.

Due to insufficient data, no reliable statement on prevalence can currently be made. Fewer than 1,200 patients have been described in the literature, most from Asia and Europe. However, this number reflects reported cases rather than true disease prevalence.

PAM is caused by biallelic pathogenic variants in the SLC34A2 gene, which encodes the sodium-dependent phosphate transporter NaPi-IIb. Loss of transporter function results in impaired phosphate clearance from the alveolar space and subsequent formation of calcium phosphate microliths.

PAM is inherited in an autosomal recessive manner. Affected individuals carry pathogenic variants in both copies of SLC34A2, one inherited from each parent. Heterozygous carriers are typically unaffected. Consanguinity has been reported in a substantial proportion of affected families.

Diagnosis is based on the characteristic radiographic appearance and the detection of microliths. Chest radiography typically shows a sand-like pattern of calcifications with bilateral basal and mid-zone predominance, whereas high-resolution CT (HRCT) demonstrates diffuse calcified micronodules throughout the lungs. Calcareous laminated microliths, typically less than 1 mm in diameter, can be identified in bronchoalveolar lavage fluid or lung biopsy specimens. When HRCT findings are characteristic, invasive diagnostic procedures, including lung biopsy, are generally not required to establish the diagnosis.

• Establishing the diagnosis: Identification of biallelic pathogenic variants in SLC34A2 confirms the clinical diagnosis at the molecular level.
• Family risk assessment and reproductive counselling: Identification of the causative variants enables predictive testing of at-risk relatives and provides information relevant to family planning.

• Jönsson ÅLM, Hilberg O, Simonsen U, Christensen JH, Bendstrup E. New insights in the genetic variant spectrum of SLC34A2 in pulmonary alveolar microlithiasis; a systematic review. Orphanet J Rare Dis. 2023;18(1):130. doi:10.1186/s13023-023-02712-7. PMID:; PMCID:PMC10230741.
• Cueto-Robledo G, Cantero-Ceballos MDC, Gonzalez-Hermosillo LM, Navarro-Vergara DI, Garcia-Cesar M, Torres-Rojas MB, et al. Severe pulmonary hypertension in pulmonary alveolar microlithiasis: a comprehensive literature review. Curr Probl Cardiol. 2024;49(5):102453. doi:10.1016/j.cpcardiol.2024.102453. PMID:.
• Zhou CY, Elwing JM, Bendstrup E, McCormack FX. Pulmonary alveolar microlithiasis: a disorder of pulmonary phosphate homeostasis. Clin Chest Med. 2025;46(4):649-65. doi:10.1016/j.ccm.2025.07.006. PMID:.