Hepatosplenomegaly, pneumopathy, bone changes and fronto-temporal dementia: Niemann–Pick type B and SQSTM1-associated Paget’s disease in the same individual

  • Camelia Voinea
  • Elena Gonzalez Rodriguez
  • Catherine Beigelman-Aubry
  • Victor Leroy
  • Bérengère Aubry-Rozier
  • Belinda Campos-Xavier
  • Diana Ballhausen
  • Romain Lazor
  • Frédéric Barbey
  • Luisa Bonafé
  • Andrea Superti-Furga
  • Christel Tran
Letter to the Editor


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.


Niemann–Pick type B Paget’s disease of bone Lysosomal storage disease Acid sphingomyelinase Interstitial pulmonary disease 



Alkaline phosphatase


Acid sphingomyelinase


Transfer capacity of the lung for carbon monoxide


Enzyme replacement therapy


Fronto-temporal dementia


High-resolution computed tomography


Lysosomal storage disease


Next-generation sequencing


Niemann–Pick disease type B


Normal value


Online Mendelian inheritance in man


Paget’s disease of bone


Sphingomyelin phosphodiesterase 1




Sequestosome 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.


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Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Camelia Voinea
    • 1
  • Elena Gonzalez Rodriguez
    • 2
  • Catherine Beigelman-Aubry
    • 3
  • Victor Leroy
    • 4
  • Bérengère Aubry-Rozier
    • 2
  • Belinda Campos-Xavier
    • 5
  • Diana Ballhausen
    • 5
  • Romain Lazor
    • 1
  • Frédéric Barbey
    • 5
  • Luisa Bonafé
    • 5
  • Andrea Superti-Furga
    • 5
  • Christel Tran
    • 5
  1. 1.Respiratory Medicine DepartmentLausanne University HospitalLausanneSwitzerland
  2. 2.Service of Endocrinology, Diabetes and Metabolism, Internal Medicine DepartmentLausanne University HospitalLausanneSwitzerland
  3. 3.Department of Radiodiagnostic and Interventional RadiologyLausanne University HospitalLausanneSwitzerland
  4. 4.Leenaards Memory Centre, Clinical Neuroscience Department, Lausanne University HospitalLausanneSwitzerland
  5. 5.Division of Genetic MedicineLausanne University Hospital, Center for Molecular DiseasesLausanneSwitzerland

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