ABSTRACT
The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of scleroderma, is caused by mutations in the sole Arg-Gly-Asp sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the profibrotic cytokine transforming growth factor-beta (TGFbeta). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFbeta concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis, a more common acquired form of scleroderma, suggests broad pathogenic relevance.
Subject(s)
Microfilament Proteins/genetics , Mutation/genetics , Scleroderma, Systemic/congenital , Scleroderma, Systemic/genetics , Skin/pathology , Biopsy , Cell Adhesion , Cell Movement , Collagen/metabolism , DNA Mutational Analysis , Elastin/metabolism , Extracellular Matrix/metabolism , Extracellular Matrix/pathology , Family , Female , Fibrillin-1 , Fibrillins , Humans , Immunohistochemistry , Male , Mesoderm/pathology , Microfibrils/metabolism , Microfibrils/pathology , Microfilament Proteins/metabolism , Pedigree , Phenotype , Scleroderma, Systemic/pathology , Signal Transduction , Skin/ultrastructure , Syndrome , Transforming Growth Factor beta/metabolismABSTRACT
Four patients are described with stone-hard indurations of the skin and subcutaneous tissue, predominantly on the buttocks and thighs, in the areas of the thickest fascia lata and glutealis. All cases were sporadic, started in early infancy, were only slightly or not progressive, and showed no visceral involvement or immunologic abnormalities. In all, the hallmark of the disease was strikingly enlarged fascia. In one patient, typical features developed progressively for 9 years, and in two patients the changes remained abortive, limited to some areas, and not symmetrical. The fourth patient showed some similarity to profound morphea with no cutaneous involvement. Recognition of atypical or abortive cases of congenital fascial dystrophy, which is probably a variant of heterogeneous stiff skin syndrome involving exclusively fascia, is of practical importance, since no therapy is required. However, intensive rehabilitation should start in early infancy and continue throughout life. The genetic defect of molecular organization of collagen in the fascia results in formation of giant amianthoid-like collagen fibrils.
Subject(s)
Fascia/pathology , Scleroderma, Systemic/congenital , Scleroderma, Systemic/pathology , Adult , Biopsy, Needle , Child , Child, Preschool , Disease Progression , Fascia/physiopathology , Female , Humans , Prognosis , Scleroderma, Systemic/diagnosis , Skin/pathology , Skin/physiopathology , SyndromeABSTRACT
Four patients are described with stony-hard induration of the skin and deeper tissues, most pronounced on the buttocks, thighs, and legs, and with limitation of joint mobility and contractures of the lower limbs. Two patients were siblings and one was the product of a consanguineous marriage. The disorder appears to be genetically determined, but the mode of inheritance has not been established. The disease was noticed in the patients' early infancy and was not progressive. Except for functional impairment of the lungs caused by an underdeveloped thorax that resulted from pressure of the thickened thoracic fascia, there was no involvement of the viscera or muscles and no immunologic abnormalities. The most important finding was markedly thickened fascia. This hereditary connective tissue disorder has all the characteristics of the tight-skin mouse.
