Pulmonary Alveolar Microlithiasis

A number sign (#) is used with this entry because of evidence that pulmonary alveolar microlithiasis is caused by homozygous mutation in the gene encoding type IIb sodium-phosphate cotransporter (SLC34A2; 604217), which is involved in phosphate homeostasis in several organs, on chromosome 4p15.

Description

Pulmonary alveolar microlithiasis is a rare disease characterized by the deposition of calcium phosphate microliths throughout the lungs. Most patients are asymptomatic for several years or even for decades, and, generally, the diagnosis is incidental to clinical investigations unrelated to the specific disorder. Cases with early onset or rapid progression are rare. A 'sandstorm-appearing' chest roentgenogram is a typical diagnostic finding. The onset of this potentially lethal disease varies from the neonatal period to old age, and the disease follows a long-term progressive course, resulting in a slow deterioration of lung functions. About one-third of the reported cases are said to be familial (summary by Corut et al., 2006).

Clinical Features

Pulmonary alveolar microlithiasis is characterized by multiple minute calcifications located in the alveoli that produce a typical radiographic appearance. Castellana et al. (2002) reviewed the over 300 individuals reported with pulmonary alveolar microlithiasis. The age at clinical onset was highly variable (5-41 years), and there was a great discrepancy between radiologic features and clinical symptoms. The age range at diagnosis was wide, but usually occurred between the ages of 20 and 30 years. The condition usually evolved over 10 to 20 years and was sometimes very indolent.

Brandenburg and Schubert (2003) presented the radiographic features of a 28-year-old patient with the disorder. Despite the striking radiographic changes with nodular ('sandstorm-like') calcifications in the lungs, the patient had only mild pleuritic chest pain. A hallmark of the disorder is a striking dissociation between the radiologic findings and the mild clinical signs and symptoms.

Ritchie et al. (1992) found pulmonary alveolar microlithiasis in a 5-year-old boy being investigated for multiple exostoses (133700). Neither disorder was identified in other members of the immediate family.

Senyigit et al. (2001) described this disorder in 6 males in 1 family. Five of the patients were cousins, and the other patient was their uncle. The diagnosis was based on the demonstration of microliths by bronchoalveolar lavage in 5 patients and transbronchial biopsy in 1.

Inheritance

Family studies are consistent with autosomal recessive inheritance (Castellana et al., 2002).

Caffrey and Altman (1965) described the disorder in premature twins who died at age 12 hours and reviewed 66 reported cases. Thirty-four cases, including theirs, were familial, occurring in 13 families.

In Spain, Lopez-Areal et al. (1965) described 2 affected sisters in 1 family, and a boy and his 2 sisters in another. O'Neill et al. (1967) observed 3 affected sibs. Affected brother and sister with first-cousin parents were reported by Burguet and Reginster (1967). In Beirut, Balikian et al. (1968) described the disorder in 2 pairs of brothers and an unrelated girl.

Population Genetics

Ucan et al. (1993) stated that only 173 cases of this disorder had been reported worldwide, and that the condition is unusually common in Turkey. They reported 52 Turkish cases, 49 of which had previously been described only in Turkish publications. A positive family history was noted in 19 of 39 patients. All the familial cases were sibs except for 3 who had a maternal aunt/nephew relationship. Of the 52 cases, 10 were free of symptoms. Ucan et al. (1993) found that the cases reported in the Turkish literature between 1962 and 1993 constituted 23% of all 225 cases published world wide up to that time. In addition, some of the patients reported from other countries in the following years were of Turkish descent.

Senyigit et al. (2001) pointed out that a considerable percentage of cases of this disorder have been reported from Turkey.

Molecular Genetics

Using homozygosity mapping in the family reported by Senyigit et al. (2001), Corut et al. (2006) mapped a locus for pulmonary alveolar microlithiasis to 4p15.31-p15.2. By a candidate gene approach they chose to investigate SLC34A2, which encodes the type IIb sodium-phosphate cotransporter (604217). They identified 6 homozygous exonic mutations in the SLC34A2 gene in 7 unrelated patients with the disorder. Absence of functional protein product of the gene was considered compatible with calcium phosphate deposition in alveolar airspaces. Thus, Corut et al. (2006) demonstrated that impaired activity of the phosphate transporter is presumably responsible for the microliths, and pulmonary alveolar microlithiasis is a recessive monogenic disease with full penetrance.

History

Castellana et al. (2002) stated that pulmonary alveolar microlithiasis was first described by Puhr (1933).