Spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation: Clinical and radiographic delineation of a pleiotropic disorder

Abstract

Enchondromas are a feature of several constitutional disorders of bone, and the classification of different nosologic entities is still provisional. Among these disorders, spondyloenchondrodysplasia (SPENCD), as outlined by Schorr et al. [1976], is defined by the presence of radiolucent spondylar and metaphyseal lesions that represent persistence of islands of chondroid tissue within bone. Careful review of radiographic findings is needed to distinguish SPENCD from the many other disorders combining enchondromas with spinal lesions. Even when strict criteria are applied, it appears that SPENCD is clinically heterogeneous, as some SPENCD patients are neurologically intact while others present with spasticity, mental retardation, and cerebral calcifications in different combinations, and it has been suggested that SPENCD should be divided in two types. We herein report ten individuals from six families with SPENCD and illustrate the radiographic changes. Seven individuals had CNS manifestations including spasticity, developmental delay, and late-onset cerebral calcifications. We also noted that six individuals had clinical manifestations of autoimmunity (auto-immune thrombocytopenic purpura, auto-immune hemolytic anemia, auto-immune thyroiditis, and SLE) and one had been diagnosed with immune deficiency. Neurological and autoimmune manifestations were seen in different combinations within one single family. These observations suggest that SPENCD may be a single entity defined by specific radiographic features, but with remarkably pleiotropic manifestations that include CNS disease (spasticity, mental retardation, and calcifications), as well as immune dysregulation ranging from autoimmunity to immunodeficiency. The notion of recessive inheritance hitherto assumed is challenged by the observation of two apparently dominant pedigrees.

Band‐like intracranial calcification with simplified gyration and polymicrogyria: A distinct “pseudo‐TORCH” phenotype

“…An absence in our patients of specific clinical and biochemical features allows for the exclusion of well characterized disorders in which ICC occurs in combination with PMG [Chitayat et al, 1992;Samson et al, 1994;Sakai et al, 1997] or separately as a major diagnostic sign [Aicardi and Goutières, 1984;Coskun et al, 1990;Aalfs and Hennekam 1995;al-Mane et al, 1998;Rapin et al, 2006;Thomas-Sohl et al, 2004;Renella et al, 2006;Saillour et al, 2007;Briggs et al, 2008].…”

Response of knee fibrocartilage to joint destabilization

“…Rapid loading protocols designed to rupture a ligament can either tear one or more ligaments or avulse the enthesis and underlying bone 17, 18 . Direct impact of the articular cartilage is also likely to stress the supporting ligaments and cause bone bruising 5, 7, 19–21 . When examining the histological consequences of the destabilization model 7 , there needs to be consistency in the positioning of the knee prior to sectioning the injured and control tissues.…”

“…A murine germline TRAP gene (Acp5) knockout resulted in a mild form of osteopetrosis, but also caused immune deficiency and chondrodystrophy 28–30 . Similarly, the autosomal recessive human disease due to an inactivating mutation of the Acp5 gene (http://omim.org/entry/271550) presents as a spondyloenchondrodysplasia that includes combined immunodeficiency with autoimmunity 19–21 . Because the immune deficiency appears to be secondary to impaired lysosomal degradation of bacteria, it is assumed that TRAP plays a role in lysosomal physiology, which would also explain its punctate cytoplasmic distribution.…”

Genetic Syndromes with Evidence of Immune Deficiency

“…Neurologic deficits may include spasticity, developmental delay, and cerebral calcifications. 22 Immune defects include low specific antibody titers, T cell mitogenic response, and CD4 T cell count, as well as recurrent infections. Mutations and deletions of the ACP5 gene, encoding an acid phosphatase, have been detected.…”