Alternative titles; symbols
SNOMEDCT: 703523004; ORPHA: 1855, 50816;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.2 | Spondyloenchondrodysplasia with immune dysregulation | 607944 | Autosomal recessive | 3 | ACP5 | 171640 |
A number sign (#) is used with this entry because of evidence that spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is caused by homozygous or compound heterozygous mutation in the ACP5 gene (171640) on chromosome 19p13.
Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is an immunoosseous dysplasia combining the typical metaphyseal and vertebral bone lesions of spondyloenchondrodysplasia (SPENCD) 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. The vertebral bodies show dorsally accentuated platyspondyly with disturbance of ossification. Clinical abnormalities such as short stature, rhizomelic micromelia, increased lumbar lordosis, barrel chest, facial anomalies, and clumsy movements may be present (Menger et al., 1989). Central nervous system involvement includes spasticity, mental retardation, and cerebral calcifications, and immune dysregulation ranges from autoimmunity to immunodeficiency. Neurologic and autoimmune manifestations have been observed in different combinations within a single family, suggesting that this disorder may be defined by specific radiographic features but has remarkably pleiotropic manifestations (Renella et al., 2006). Briggs et al. (2016) also noted variability in skeletal, neurologic, and immune phenotypes, which was sometimes marked between members of the same family.
Classification of the Enchondromatoses
In their classification of the enchondromatoses, Spranger et al. (1978) called Ollier disease and Maffucci syndrome types I and II enchondromatosis, respectively; metachondromatosis (156250), type III; and spondyloenchondrodysplasia (SPENCD), also called spondyloenchondromatosis, type IV; enchondromatosis with irregular vertebral lesions, type V; and generalized enchondromatosis, type VI. Halal and Azouz (1991) added 3 tentative categories to the 6 in the classification of Spranger et al. (1978).
Pansuriya et al. (2010) suggested a new classification of enchondromatosis (multiple enchondromas).
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 (616651), 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, one of whom was 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.
Girschick et al. (2015) studied a 9-year-old girl who presented with spasticity, multisystem inflammation, autoimmunity, and immunodeficiency with only minimal metaphyseal changes. The clinical picture was characterized by neurologic impairment due to cerebrovascular disease as well as severe immune dysregulation resulting in autoimmunity and immunodeficiency. In addition to autoimmune hemolytic anemia, thrombocytopenia, polyarthritis, hepatitis, and nephritis, the patient had life-threatening hyperreactivity to viral infections as well as recurrent bacterial infections. In contrast, she exhibited mild signs of skeletal dysplasia, involving only short stature and discrete metaphyseal changes at the wrist.
Bilginer et al. (2016) reported a Turkish sister and brother, aged 16 and 6 years, and an unrelated 16-year-old Turkish girl, with SPENCDI and SLE, and tabulated the features of the 12 reported cases of SPENCDI-associated SLE. All 3 Turkish patients had short stature, arthralgia/arthritis, lupus nephritis, hypocomplementemia, and positive autoantibodies, including antinuclear and anti-dsDNA antibodies. The authors noted that the sibs were homozygous for a previously reported mutation in the ACP5 gene, and that the other family declined genetic testing. Bilginer et al. (2016) stated that early recognition of SPENCDI is imperative and that the condition should be considered in patients with SLE, particularly those who also exhibit short stature and skeletal abnormalities.
Clinical Variability
Schorr et al. (1976) described enchondromatosis, similar to that of Ollier disease (166000), in association with platyspondyly in 2 sons of first-cousin parents of Iraqi Jewish background. Both boys had short stature and normal intelligence.
Sauvegrain et al. (1980) described 2 patients with enchondromatosis with spinal involvement.
Frydman et al. (1986) studied 4 cases that they stated were similar to those of Schorr et al. (1976) and Sauvegrain et al. (1980). The height of the patients was more than 3 SDs below the mean. Kyphoscoliosis with flat vertebrae and with 'cystic' radiolucencies in the posterior part of the bodies was observed. The metaphyses of long bones showed symmetric radiolucencies that extended into the shafts with sclerotic changes in the diaphyses. The proximal fibula and distal ulna were more severely affected than the corresponding areas of the tibia and radius.
Menger et al. (1989) reported 4 patients, 3 of whom were members of 1 family containing complex consanguinity. They pointed to the 2 cases reported by Gustavson et al. (1978) as 'autosomal recessive spondylometaphyseal dysplasia,' as well as to the case of Chagnon et al. (1985). They documented considerable clinical and radiologic variability. One of the patients in the consanguineous family had normal physical appearance and a height at the 10th centile, yet the x-rays showed marked structural irregularities in the dorsal third of the vertebral bodies. Their unrelated patient was the product of an incestuous (father-daughter) union.
Frydman et al. (1990) reported 6 patients with spondyloenchondrodysplasia, 2 of whom (patients 4 and 5) exhibited progressive spastic quadriplegia. They noted that spastic quadriplegia was also present in the patient of Chagnon et al. (1985) and patient 4 of Menger et al. (1989). In addition, Frydman et al. (1990) suggested that mental retardation, which was found in their patient 5 as well as patient 3 of Sauvegrain et al. (1980) and patient 1 of Menger et al. (1989), might be another variable manifestation of the syndrome. No features of immune dysregulation were reported in the patients of Frydman et al. (1990).
Tuysuz et al. (2004) described 3 Turkish individuals with spondyloenchondrodysplasia, including 2 sibs. One was a 10-year-old boy with short stature, enchondromatous metaphyseal lesions of the long bones, and platyspondyly. His 21-year-old sister had received growth hormone therapy, and she had radiologic findings that were similar but milder than those of her brother. Both sibs had normal intelligence and no calcification of the basal ganglia. The third patient was a 6-year-old boy with short stature, enchondromatous metaphyseal lesions of the long bones, and platyspondyly who also had mental retardation and calcification of the basal ganglia.
Bhargava et al. (2005) reported a mother and son with typical features of spondyloenchondrodysplasia. The father had a normal examination and skeletal survey, and the parents were nonconsanguineous. Bhargava et al. (2005) suggested that autosomal dominant inheritance is possible in this disorder. The radiologic appearance of the spine in the mother changed over time, illustrating the evolving phenotype of the condition: at the age of 42 years, the previously observed lytic enchondromatous lesions of the spine had resolved, leaving mild platyspondyly with endplate scalloping. Bhargava et al. (2005) noted that this resolution of enchondromas as cartilage matures into bone had been reported in other patients as well (Robinson et al., 1991; Uhlmann et al., 1998) and suggested that the disorder might reflect a delay in enchondral bone maturation.
De Bruin et al. (2016) described a Turkish brother and sister, aged 13 and 8 years, who presented for evaluation of severe short stature and were found to be homozygous for a mutation in the ACP5 gene (see MOLECULAR GENETICS). Skeletal survey performed after the molecular diagnosis revealed characteristic findings of spondyloenchondrodysplasia with platyspondyly, widening of the epiphyses of the upper and lower distal extremities, cupping of the ulna, and dense thickening of the radioulnar ligament without Madelung deformity. Brain MRI was normal, and laboratory evaluation showed no evidence of subclinical autoimmune dysfunction.
Spondyloenchondrodysplasia with immune dysregulation was found by Briggs et al. (2011) to be an autosomal recessive disorder.
There is also evidence for autosomal dominant inheritance of the disorder (see, e.g., Bhargava et al., 2005)
In 3 unrelated patients from consanguineous families who had features consistent with spondyloenchondrodysplasia with immune dysregulation, Briggs et al. (2011) performed genomewide genotyping analysis and identified an overlapping region of homozygosity on chromosome 19p13. Linkage analysis yielded a maximum multipoint lod score of 3.6 between basepair positions 10,527,380 and 13,214,722.
Simultaneously and independently, Lausch et al. (2011) performed homozygosity mapping in 5 families with spondyloenchondrodysplasia with immune dysregulation and identified a 3.5-Mb region of homozygosity on chromosome 19p13, obtaining a multipoint lod score of 8.694 (theta = 0) at several SNPs within this interval. Recombination events defined boundaries at SNPs rs1673130 and rs12975915.
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 and 171640.0010). 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.
In a 9-year-old girl who had spasticity, multisystem inflammation, autoimmunity, and immunodeficiency, with only minimal metaphyseal changes, Girschick et al. (2015) sequenced the ACP5 gene and identified compound heterozygosity for a missense mutation (T44M; 171640.0008) and a 1-bp duplication (171640.0009). Tartrate-resistant acid phosphatase (TRAP) activity was biochemically undetectable in the patient. Her unaffected parents were each heterozygous for 1 of the mutations, and both had markedly decreased TRAP levels. The authors concluded that mutation in ACP5 can cause severe immune dysregulation and neurologic impairment even in the absence of metaphyseal dysplasia.
Briggs et al. (2016) compiled clinical, genetic, and serologic data from 26 patients from 18 families with spondyloenchondrodysplasia, including 12 previously reported patients. Autoimmune disease was manifested by 22 of the 26 patients; 4 patients were considered not to demonstrate clinical autoimmune disease, although 2 of those patients were positive for autoantibodies. The other 2 patients were a 36-year-old Iraqi Jewish woman exhibiting apparently isolated skeletal dysplasia and a 35-year-old Arab man, both of whom were originally described by Frydman et al. (1990). The woman had a positive interferon-stimulated genes (ISG) score, and autoantibodies had not been assessed in the man; both were homozygous for a previously reported missense mutation in ACP5 (G109R; 171640.0005). Briggs et al. (2016) noted the marked clinical variability in this disorder, both within and between families, with age at onset ranging from birth to 15 years, and severity ranging from infantile death due to autoimmune thrombocytopenia to isolated skeletal dysplasia in a 36-year-old patient. They stated that all reported ACP5 mutations appeared functionally null, with an absence of TRAP expression in blood.
In a Turkish sister and brother with spondyloenchondrodysplasia without immune dysregulation or neurologic abnormalities, de Bruin et al. (2016) performed exome sequencing and identified homozygosity for a frameshift mutation in the ACP5 gene (171640.0010). The authors noted that the mutation had previously been reported by Briggs et al. (2011) in an Egyptian girl who had spondyloenchondrodysplasia with immune dysregulation, including elevated antinuclear antibody and anti-dsDNA antibody titers, microglobulinemia, and rheumatic fever with hypogammaglobulinemia.
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