Mutation analysis and serum FGF23 level in a patient with pulmonary alveolar microlithiasis
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CASE REPORT
Mutation analysis and serum FGF23 level in a patient with pulmonary alveolar microlithiasis Hannes Olauson • Vincent Brandenburg Tobias E. Larsson
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Received: 28 September 2009 / Accepted: 21 December 2009 / Published online: 5 January 2010 Ó Springer Science+Business Media, LLC 2010
Abstract Pulmonary alveolar microlithiasis (PAM) is a rare, hereditary disorder characterized by ectopic formation of calcium-phosphate microliths in the alveolar space. PAM has been reported to arise from inactivating mutations in SLC34A2, encoding a sodium-dependent phosphate co-transporter essential for phosphate transport in the lungs and small intestine. Serum levels of the phosphaturic hormone fibroblast growth factor-23 (FGF23) in PAM have not been determined. Our objectives were to investigate the genetic etiology and circulating level of FGF23 in a 50-year-old male with clinical characteristics of PAM and extra-pulmonary calcifications. The SLC34A2 and FGF23 genes were sequenced for mutations and serum FGF23 analyzed by ELISA. We found no disease-causing mutations or single nucleotide polymorphisms in the genes investigated. Importantly, repeated measurements revealed undetectable or markedly low serum FGF23 (\3–11 RU/ ml). Surprisingly, in the face of low serum FGF23, 1,25dihydroxy vitamin D3 level was low-normal and parathyroid hormone mildly elevated. Total 24-h urinary excretion of phosphate and calcium were low, as was fractional urinary excretion of calcium. In contrast, fractional excretion of phosphate was above normal, likely due to H. Olauson T. E. Larsson (&) Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 86 Stockholm, Sweden e-mail: [email protected] V. Brandenburg Department of Cardiology, University Hospital Aachen, Aachen, Germany T. E. Larsson Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden
elevated PTH. Collectively, PAM may be a polygenic disorder that arises from mutations other than in SLC34A2. The low FGF23 level in our PAM patient supports an intestinal-bone axis, leading to decreased FGF23 expression when intestinal phosphate absorption is compromised. Keywords PAM SLC34A2 Npt2b NaPi-2b Fibroblast growth factor-23
Introduction Pulmonary alveolar microlithiasis (PAM; OMIM #265100) is a rare, autosomal recessive disorder characterized by deposition of calcium-phosphate microliths throughout the lungs [1–3]. In sporadic cases it is associated with calcifications of extrapulmonary organs, such as gonads [4] and pericardium [5]. Even with extensive radiologic findings (‘‘sandstorm lung’’) the clinical symptoms are often mild. Progression of the disease is usually slow, eventually leading to respiratory failure and pulmonary heart disease in middle age. Diagnosis is achieved through radiographic examination, and confirmed by bronchial lavage or transbronchial biopsy. There is currently no effective treatment other than lung transplantation. Inactivating mutations in th
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