Hepatosplenomegaly, pneumopathy, bone changes and fronto-temporal dementia: Niemann–Pick type B and SQSTM1-associated Paget’s disease in the same individual
Data from exome sequencing show that a proportion of individuals in whom a genetic disorder is suspected turn out to have not one, but two to four distinct ones. This may require an evolution in our diagnostic attitude towards individuals with complex disorders. We report a patient with splenomegaly, pneumopathy, bone changes and fronto-temporal dementia (FTD). “Sea-blue histiocytes” in his bone marrow pointed to a lysosomal storage disease. Homozygosity for a pathogenic mutation in the SMPD1 gene confirmed Niemann–Pick disease type B (NPD-B). Mild cognitive impairment and abnormal brain FDG PET were consistent with FTD. We initially tried to fit the skeletal and neurologic phenotype into the NPD-B diagnosis. However, additional studies revealed a pathogenic mutation in the SQSTM1 gene. Thus, our patient had two distinct diseases; NPD-B, and Paget’s disease of bone with FTD. The subsequent finding of a mutation in SQSTM1 gene ended our struggle to explain the combination of findings by a singular “unifying” diagnosis and allowed us to make specific therapeutic decisions. SQSTM1 mutations have been reported in association with FTD, possibly because of defective autophagy. Bisphosphonates may be beneficial for PDB, but since they are known to inhibit acid sphingomyelinase activity, we refrained from using them in this patient. While the principle of looking for unifying diagnosis remains valid, physicians should consider the possibility of co-existing multiple diagnoses when clinical features are difficult to explain by a single one. Accurate diagnostic work-up can guide genetic counseling but also lead to better medical management.
KeywordsNiemann–Pick type B Paget’s disease of bone Lysosomal storage disease Acid sphingomyelinase Interstitial pulmonary disease
Transfer capacity of the lung for carbon monoxide
Enzyme replacement therapy
High-resolution computed tomography
Lysosomal storage disease
Niemann–Pick disease type B
Online Mendelian inheritance in man
Paget’s disease of bone
Sphingomyelin phosphodiesterase 1
Trabecular bone score
Technetium 99 isotope
We would like to thank Valentin Basset and Stephane Quarroz from the Service and Central Laboratory of Hematology, University Hospital of Lausanne, Switzerland, for preparing the histology illustrations. This research did not receive any specific Grant from funding agencies in the public, commercial or not-for-profit sectors.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 7.van Diggelen OP, Voznyi YV, Keulemans JL, Schoonderwoerd K, Ledvinova J, Mengel E, Zschiesche M, Santer R, Harzer K (2005) A new fluorimetric enzyme assay for the diagnosis of Niemann–Pick A/B, with specificity of natural sphingomyelinase substrate. J Inherit Metab Dis 28:733–741CrossRefPubMedGoogle Scholar
- 13.McGovern MM, Wasserstein MP, Giugliani R, Bembi B, Vanier MT, Mengel E, Brodie SE, Mendelson D, Skloot G, Desnick RJ, Kuriyama N, Cox GF (2008) A prospective, cross-sectional survey study of the natural history of Niemann–Pick disease type B. Pediatrics 122:e341–e349CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Rubino E, Rainero I, Chio A, Rogaeva E, Galimberti D, Fenoglio P, Grinberg Y, Isaia G, Calvo A, Gentile S, Bruni AC, St George-Hyslop PH, Scarpini E, Gallone S, Pinessi L, T.S. Group (2012) SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 79:1556–1562CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Ishii M, Kikuta J (1831) Sphingosine-1-phosphate signaling controlling osteoclasts and bone homeostasis. Biochim Biophys Acta 2013:223–227Google Scholar