Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey

J Clin Immunol. 2016 Apr;36(3):220-34. doi: 10.1007/s10875-016-0252-y. Epub 2016 Mar 8.


Purpose: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases.

Methods: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations.

Results: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.

Conclusions: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.

Keywords: ACP5; SPENCD/SPENCDI; Spondyloenchondrodysplasia; interferon signature; tartrate-resistant acid phosphatase (TRAP); type I interferon.

Publication types

  • Multicenter Study

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Autoantibodies / biosynthesis
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Bone and Bones / immunology
  • Bone and Bones / pathology
  • Brain / immunology
  • Brain / pathology
  • Child
  • Child, Preschool
  • Female
  • Gene Expression
  • Genotype
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / immunology
  • Intellectual Disability / pathology
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / pathology
  • Male
  • Mutation*
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / immunology
  • Osteochondrodysplasias / pathology
  • Pedigree
  • Phenotype
  • Purpura, Thrombocytopenic, Idiopathic / genetics*
  • Purpura, Thrombocytopenic, Idiopathic / immunology
  • Purpura, Thrombocytopenic, Idiopathic / pathology
  • Tartrate-Resistant Acid Phosphatase / deficiency
  • Tartrate-Resistant Acid Phosphatase / genetics*
  • Tartrate-Resistant Acid Phosphatase / immunology


  • Autoantibodies
  • Interferon Type I
  • ACP5 protein, human
  • Tartrate-Resistant Acid Phosphatase

Supplementary concepts

  • Spondyloenchondrodysplasia