Spondyloenchondrodysplasia with immune dysregulation combines the typical metaphyseal and vertebral bone lesions in spondyloenchondrodysplasia (SPENCD; 271550) with immune dysfunction and neurologic involvement. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands ... Spondyloenchondrodysplasia with immune dysregulation combines the typical metaphyseal and vertebral bone lesions in spondyloenchondrodysplasia (SPENCD; 271550) with immune dysfunction and neurologic involvement. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands of chondroid tissue within bone. It has been suggested by some that the various clinical manifestations observed in association with SPENCD may be pleiotropic manifestations of a single nosologic entity defined by the presence of typical spondylar and metaphyseal changes (summary by Renella et al., 2006).
Roifman and Melamed (2003) described a syndrome of combined immunodeficiency, autoimmunity, and spondylometaphyseal dysplasia in 4 patients, 2 of whom were brother and sister. The parents of the affected sibs were first cousins of Portuguese descent. The 18-year-old ... Roifman and Melamed (2003) described a syndrome of combined immunodeficiency, autoimmunity, and spondylometaphyseal dysplasia in 4 patients, 2 of whom were brother and sister. The parents of the affected sibs were first cousins of Portuguese descent. The 18-year-old sister had repeated infections including pneumonia and multiple upper respiratory infections. At 12 years of age, she developed chronic restrictive lung disease caused by interstitial fibrosis. At the age of 3 years, she had a prolonged episode of idiopathic thrombocytopenic purpura (ITP), which responded poorly to prednisone or intravenous immunoglobulin, but resolved after splenectomy. At 3.5 years of age, she was found to have thyroid enlargement and hypothyroidism. Linear growth was observed to be delayed at 4 years of age. Radiologic findings were those of spondylometaphyseal dysplasia. Her younger brother contracted Campylobacter enteritis at 3 months of age and experienced multiple upper respiratory infections. At 3.5 years of age, 3 weeks after experiencing a short upper respiratory infection, he developed ITP and fatal encephalitis. Review of chest x-ray revealed metaphyseal sclerosis of both proximal humeri. The other 2 patients of Roifman and Melamed (2003) had skeletal changes consistent with spondylometaphyseal dysplasia. One, a 5-year-old male, had fulminant hemorrhagic chickenpox at the age of 3 years, which required treatment with acyclovir. He had multiple episodes of upper respiratory infections. At 4 years of age he was found to have ITP. The other patient, a 10-year-old male, had susceptibility to infection from infancy. He was diagnosed with Crohn disease at 5 years of age after a lengthy history of diarrhea. At 8 years of age, he was found to have hypothyroidism. Roifman and Melamed (2003) compared the findings in their patients with those in patients with Roifman syndrome (300258), Schimke immunoosseous dysplasia (242900), ADA deficiency (102700), and cartilage-hair hypoplasia (250250). Renella et al. (2006) reported the clinical and radiographic findings in 10 individuals from 6 families with spondyloenchondrodysplasia, one of whom was the female patient previously reported by Roifman and Melamed (2003) as a 'novel' form of skeletal dysplasia with immune deficiency; Renella et al. (2006) stated that her clinical findings and radiographs were compatible with spondyloenchondrodysplasia. Seven individuals had central nervous system manifestations including spasticity, developmental delay, and late-onset cerebral calcifications. Six had clinical manifestations of autoimmunity, and 1 had been diagnosed with immune deficiency. Neurologic and autoimmune manifestations were seen in different combinations within 1 single family. Renella et al. (2006) suggested that spondyloenchondrodysplasia may be a single entity defined by specific radiographic features but with remarkably pleiotropic manifestations that include CNS disease as well as immune dysregulation. Kulkarni et al. (2007) reported a 5-year-old Indian boy with short stature and a history of recurrent respiratory infections, tuberculosis, and severe varicella infection, in whom radiologic and immunologic evaluation revealed spondylometaphyseal dysplasia, compromised cellular immunity, and evidence of various autoimmune disorders such as systemic lupus erythematosus (see SLE, 152700), juvenile rheumatoid arthritis (604302), and autoimmune thrombocytopenia. The authors noted that the radiologic findings in this case exactly matched those reported by Roifman and Melamed (2003), with splayed, sclerotic irregular long bone metaphyses and platyspondyly. Renella and Superti-Furga (2007) stated that the history, clinical findings, and radiographic features of the patient described by Kulkarni et al. (2007) were typical of spondyloenchondrodysplasia, and attributed the immune dysregulation with signs of immune deficiency and autoimmunity to the pleiotropism of the disorder. Navarro et al. (2008) reported 2 unrelated patients, 1 born of consanguineous parents, whose manifestations of spondyloenchondrodysplasia included short stature, metaphyseal changes, and platyspondyly; both had intracranial calcifications, although they were discordant for the presence of mental retardation, spasticity, and white matter abnormalities. In addition, 1 patient had features consistent with diagnoses of Sjogren syndrome (270150), polymyositis, hypothyroidism, and severe scleroderma (see 181750), whereas the other had clinical manifestations and an autoantibody profile of SLE, further illustrating the association of SPENCD with immune dysregulation.
In a 27-year-old French woman with spondyloenchondrodysplasia mapping to chromosome 19p13, who was originally reported by Navarro et al. (2008), Briggs et al. (2011) performed genotyping that indicated a possible homozygous deletion within the ACP5 gene (171640); quantitative ... In a 27-year-old French woman with spondyloenchondrodysplasia mapping to chromosome 19p13, who was originally reported by Navarro et al. (2008), Briggs et al. (2011) performed genotyping that indicated a possible homozygous deletion within the ACP5 gene (171640); quantitative multiplex PCR of short fluorescent fragments of DNA from the patient and her mother and reverse transcription PCR analysis provided further evidence of a homozygous deletion, although the breakpoints could not be precisely defined. Analysis of ACP5 in an additional 9 patients from 7 families, including families previously studied by Roifman and Melamed (2003), Renella et al. (2006), and Navarro et al. (2008), revealed homozygous or compound heterozygous mutations in all of them (see, e.g., 171640.0001-171640.0004). An Indian boy with spondyloenchondrodysplasia, previously reported by Kulkarni et al. (2007), was also found to have an approximately 5-kb homozygous deletion encompassing the APC5 gene. Briggs et al. (2011) noted that these patients presented a diverse spectrum of autoimmune phenotypes, including systemic lupus erythematosus (152700), Sjogren syndrome (270150), hemolytic anemia (see 205700), thrombocytopenia, hypothyroidism (140300), inflammatory myositis (160750), Raynaud disease (179600), and vitiligo (see 606579). In 5 families with spondyloenchondrodysplasia and immune dysregulation mapping to chromosome 19p13, Lausch et al. (2011) sequenced the candidate gene ACP5 and identified homozygous or compound heterozygous mutations that segregated with disease in each of the families; analysis of DNA from an additional 6 SPENCDI families revealed ACP5 mutations in all of them (see, e.g., 171640.0004-171640.0007). None of the 10 mutations was detected in 228 control alleles.