CANDLE syndrome is caused by mutations in PSMB8, a gene recently reported to cause "JMP" syndrome (joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced childhood-onset lipodystrophy) in adults.
Despite the tremendous success of IL-1 blocking therapy, the use of these agents in a wider spectrum of autoinflammatory conditions has uncovered disease subsets that are not responsive to IL-1 blockade, including the recently discovered proteasome-associated autoinflammatory syndromes such as chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperatures (CANDLE), Japanese autoinflammatory syndrome with lipodystrophy (JASL), Nakajo-Nishimura syndrome (NNS) and joint contractures, muscle atrophy, panniculitis induced lipodystrophy (JMP), and urge the continued quest to characterize additional dysregulated innate immune pathways that cause autoinflammatory conditions.
Despite the tremendous success of IL-1 blocking therapy, the use of these agents in a wider spectrum of autoinflammatory conditions has uncovered disease subsets that are not responsive to IL-1 blockade, including the recently discovered proteasome-associated autoinflammatory syndromes such as chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperatures (CANDLE), Japanese autoinflammatory syndrome with lipodystrophy (JASL), Nakajo-Nishimura syndrome (NNS) and joint contractures, muscle atrophy, panniculitis induced lipodystrophy (JMP), and urge the continued quest to characterize additional dysregulated innate immune pathways that cause autoinflammatory conditions.
Emery-Dreifuss muscular dystrophy (EDMD), clinically characterized by scapulo-humero-peroneal muscle atrophy and weakness, multi-joint contractures with spine rigidity and cardiomyopathy with conduction defects, is associated with structural/functional defect of genes that encode the proteins of nuclear envelope, including lamin A and several lamin-interacting proteins.
Further, the evidence of TGF β2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.
Loss of function mutations in FK506-binding protein 10 (FKBP10), encoding the FKBP65 protein, result in recessive OI and Bruck syndrome, of which the latter is additionally characterized by joint contractures.
Loss-of-function mutations in B3GAT3 are associated with a complex connective tissue phenotype characterized by disproportionate short stature, skeletal dysplasia, facial dysmorphism, spatulate distal phalanges and -to a lesser extent- joint contractures, joint hypermobility with dislocations, cardiac defects and bone fragility.
Loss-of-function mutations in capillary morphogenesis gene 2 (CMG2/ANTXR2), a transmembrane surface protein, cause hyaline fibromatosis syndrome (HFS), a severe genetic disorder that is characterized by large subcutaneous nodules, gingival hypertrophy and severe painful joint contracture.
Mutations in GLE1 cause two recessive subtypes of arthrogryposis multiplex congenita (AMC), a condition characterized by joint contractures at birth, and all previously reported patients died in the perinatal period.
Mutations in the lamin A/C gene should be sought in any infant with dystrophic features and normal tissue immunochemical studies; especially in the presence of moderately elevated serum creatine kinase, predominant axial and humeroperoneal weakness, spine rigidity, and joint contractures.
Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65-kDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass.