Abstract
PurposeSpondyloenchondrodysplasia 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.MethodsWe compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations.ResultsWe 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.ConclusionsOur 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.
Highlights
Spondyloenchondrodysplasia (SPENCD) (OMIM: 271,550) is a skeletal dysplasia, characterised by radiolucent metaphyseal and vertebral lesions [1]
We propose that the Online Mendelian Inheritance in Man (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
An interferon signature is recognised in SLE [9] and in monogenic disease in association with mutations in TMEM173 [10] and ISG15 [11] and any of the phenotypes recognised with mutations in TREX1, RNASEH2A/B/ C, SAMHD1, ADAR1 and IFIH1 - including the monogenic encephalopathy Aicardi-Goutières syndrome (AGS), which can show significant overlap with SPENCD [12, 13]
Summary
Spondyloenchondrodysplasia (SPENCD) (OMIM: 271,550) is a skeletal dysplasia, characterised by radiolucent metaphyseal and vertebral lesions [1]. The first extra-osseous manifestations reported in SPENCD were of neurological dysfunction, including developmental delay and spasticity, which may be associated with intracranial calcification [2,3,4,5]. Affected individuals displayed an absence of TRAP serum expression and, in keeping with autoimmune manifestations, increased levels of serum interferon-alpha (IFNα) and an upregulation of interferon-stimulated genes (ISGs) (an interferon signature) [7]. An interferon signature is recognised in SLE [9] and in monogenic disease in association with mutations in TMEM173 [10] and ISG15 [11] and any of the phenotypes recognised with mutations in TREX1, RNASEH2A/B/ C, SAMHD1, ADAR1 and IFIH1 - including the monogenic encephalopathy Aicardi-Goutières syndrome (AGS), which can show significant overlap with SPENCD [12, 13]
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