A chest X-ray showed diffuse fine bilateral micronodular opacities without evidence of air space consolidations or marked fibrosis. High resolution computed tomography (HRCT) of the chest revealed the characteristic calcified micronodulations in the lung parenchyma. The micronodules were sharply defined and measured less than 1 mm in diameter. The disease diffusely involved all lung fields.

Pulmonary function tests showed a forced vital capacity (FVC) of 1.73 liters (67% predicted); a forced expiratory volume in 1 s (FEV1) of 1.67 liters (76% predicted) and an FEV1/FVC ratio of 120%. Results of room air arterial blood gas analysis were as follows: PaCO₂ 33.5 mmHg, PO₂ 61 mmHg, O2 saturation 93.2 % and pH 7.48.

The patient subsequently underwent surgical lung biopsy. Grossly, the specimen appeared gritty and firm, requiring a chemical decalcification procedure. Histological sections showed diffuse involvement of the lung parenchyma by calcific concretions filling the alveoli. These concretions had a lamellar appearance with concentric “onionskin” morphology (Figure 1A). The alveolar walls were mostly normal but focally mild interstitial fibrosis was appreciated. Bronchiolar epithelia showed no abnormality. On histochemical studies, calcospherites were highlighted by von-Kossa and periodic acid-Schiff (PAS) stains (Figure 1B).

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Figure 1: (A) Diffuse involvement of the lung parenchyma by calcific concretions filling the alveoli (H&E x5), (B) Calcospherites are highlighted by von-Kossa stain (x40).

Genetic testing for SLC34A2 gene was done PCR and DNA sequencing of the coding regions as described previously⁵. A homozygous c.316G>C (p.G106R) mutation found in exon 4 confirmed the PAM diagnosis (Figure 2).

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Figure 2: Genetic testing for SLC34A2 gene shows homozygous c.316G>C (p.G106R) mutation in exon 4 which confirms the PAM diagnosis.

The genetic studies in the current case showed that there is homozygous c.316G>C (p.G106R) mutation in exon 4 and confirmed the diagnosis because this mutation has previously been shown to be associated with PAM in a Turkish family⁵.

Sporadic cases are more common and several hypotheses have been recommended such as inhalation of specific powders and a possible condensation of alveolar mucus which were thought to be involved in the origin of microliths⁹. A previous study indicated that the lung mucociliary function was impaired in patients with microlithiasis, which may represent a pathogenetic factor capable of favoring the formation of alveolar microliths¹⁰. Furthermore, the possibility either of an alveolar thesaurotic process or an alveolar congenital enzymatic defect have also been also proposed⁹.

The incidence is higher in age brackets between 20 to 50 years. However, a case of neonatal microlithiasis and a case occurring at the age of 80 years were also reported^9,11. The disease has preference for the female sex in familial cases and shows a predilection for the male sex in the sporadic form³. The age and the gender of the present case are also compatible with the literature.

Most of the patients follow a protracted course. As the disease progresses, the patients may complain of dyspnea, nonproductive cough, hemoptysis and symptoms of cor pulmonale. Deaths have occurred from 5 to 41 years after the initial diagnosis^9,12. The lungs worsen over time at different rates, leading to pulmonary fibrosis, respiratory failure and chronic pulmonary heart disease. Although pulmonary function tests may initially show normal results, more severely affected patients demonstrate a restrictive pattern along with impaired diffusion capacity³. The current case presented with exertional dyspnea and nonproductive cough. She did not show pulmonary functional abnormalities despite the decreased breath sounds on physical examination, perhaps because she was discovered at an early stage.

The diagnosis of PAM can be based on transbronchial or surgical lung biopsy, bronchoalveolar lavage (BAL), or radiographic findings of high-density interstitial lung parenchyma changes, notably on chest HRCT. A “sandstorm” picture with diffuse high-density micronodules that scatter symmetrically throughout both lung fields with middle and lower lobe predominance characterizes the chest X-ray. HRCT shows unique and characteristic calcified reticular pattern and thickening of the interlobular septa of the lung parenchyma giving the overall appearance of a “stony lung”, with predominant basal and peripheral lung distribution³. The patient's chest X-ray and HRCT findings were also found to be compatible with PAM.

The centers of microliths seen in PAM are nuclei exhibiting the polysaccharide mucoprotein complexes of cellular origin. It has been supposed that they are initially produced in the interstitial region, and that these nucleoli subsequently migrate to the alveolar spaces¹³. There is gradual lamellar deposition of calcium phosphate mixed with small amounts of magnesium and aluminum around the center. The diameter of microliths is about 0.2 μ and they may fill the pulmonary alveolus, whose wall and septum may appear to be pressed. On histochemical studies, microliths are PAS positive and the von Kossa stain can show the calcium ingredient. In the present case, histology of the lung biopsy revealed typical laminated microliths which were PAS- and von Kossa-positive in keeping with the diagnosis of PAM.

From the clinical and radiological perspective, the differential diagnosis of PAM includes miliary pulmonary tuberculosis, pneumoconiosis, pulmonary hemosiderosis, anthracosis and silicosis. At this point, lung biopsy, although invasive, is confirmatory.

Therapeutic methods include BAL, based on the drainage of the liquid to remove the majority of microliths from alveolus, systemic corticosteroids and oral administration of disodium etidronate. Most patients only benefit from lung transplantation^3, and our case is also pending lung transplantation.

The present report aims to contribute to the literature with a new pathologically and genetically proven case to add insight into the etiology of this rare disease. The Turkish race should particularly be investigated for the genetic inheritance in terms of possessing the greatest number of reported cases in worldwide. This case confirms autosomal recessive inheritance and does not support the role of other, non-genetic, factors in the pathogenesis of pulmonary alveolar microlithiasis. No valid therapy is presently able to check the relentless course toward progressive respiratory failure. The disorder may show rapid progression in some cases, probably due to the severity of the genetic disturbance. Effective treatment modalities might be developed after the etiology of PAM has been fully understood.

1) Harbitz F: Extensive calcification of the lungs as a distinct disease. Arch Intern Med 1918,21:139-146.

2) Castellana G, Gentile M, Castellana R, Fiorente P, Lamorgese V: Pulmonary alveolar microlithiasis: clinical features, evolution of the phenotype, and review of the literature. Am J Med Genet 2002,111:220-224, [ PubMed ]

3) Castellana G, Lamorgese V: Pulmonary alveolar microlithiasis. World cases and review of the literature. Respiration 2003,70:549-555, [ PubMed ]

4) Schmidt H, Lorcher U, Kitz R, Zielen S, Ahrens P, Konig R: Pulmonary alveolar microlithiasis in children. Pediatr Radiol 1996,26:33-36, [ PubMed ]

5) Corut A, Senyigit A, Ugur SA, Altin S, Ozcelik U, Calisir H, Yildirim Z, Gocmen A, Tolun A: Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet 2006,79:650-656, [ PubMed ]

6) Deniz O: Pulmonary alveolar microlithiasis. Tuberk Toraks 2005,53:293-298, [ PubMed ]

7) Senyigit A, Yaramis A, Gurkan F, Kirbas G, Buyukbayram H, Nazaroglu H, Alp MN, Topcu F: Pulmonary alveolar microlithiasis: a rare familial inheritance with report of six cases in a family. Contribution of six new cases to the number of case reports in Turkey. Respiration 2001,68:204-209, [ PubMed ]

8) Ucan ES, Keyf AI, Aydilek R, Yalcin Z, Sebit S, Kudu M, Ok U : Pulmonary alveolar microlithiasis: review of Turkish reports. Thorax 1993,48:171-173, [ PubMed ]

9) Lauta VM: Pulmonary alveolar microlithiasis: an overview of clinical and pathological features together with possible therapies. Respir Med. 2003,97:1081-1085, [ PubMed ]

10) D'Addabbo A, Fratello A, Fanfani G, Mele M, Dammacco F: Lung scanning and clearance of inhaled radiogold (198Au) particles in three patients with microlithiasis. Rofo 1981,135:296-300, [ PubMed ]

11) Sears MR, Chang AR, Taylor AJ: Pulmonary alveolar microlithiasis. Thorax 1971,26:704-711, [ PubMed ]

12) Moran CA, Hochholzer L, Hasleton PS, Johnson FB, Koss MN: Pulmonary alveolar microlithiasis. A clinicopathologic and chemical analysis of seven cases. Arch Pathol Lab Med 1997,121:607-611, [ PubMed ]

13) Kawakami M, Sato S, Takishima T: Electron microscopic studies on pulmonary alveolar microlithiasis. Tohoku J Exp Med 1978,126:343-361, [ PubMed ]