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Congenital fascial dystrophy: Stiff skin syndrome—a human counterpart of the tight-skin mouse
Congenital fascial dystrophy: Stiff skin syndrome-a human counterpart of the tight-skin mouse Stefania J ablonska, MD,a Hans Schubert, MD,b and Ichiro Kikuchi, MDc Warsaw, Poland, Erfurt, East Germany, and Kiyatake, Japan Four patients are described with stony-hardindurationof the skin and deeper tissues, most pronounced on the buttocks, thighs, and legs, and with limitation ofjoint mobilityand contractures of the lower limbs. Two patients weresiblings 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 functionalimpairmentof the lungscaused by an underdeveloped thorax that resulted from pressureof the thickened thoracic fascia, there was no involvement of the viscera or muscles and no immunologic abnormalities. The most important finding wasmarkedlythickened fascia. Thishereditary connective tissue disorder has all the characteristics of the tight-skin mouse. (J AM ACAD DERMATOL 1989;21:943-50.) In 1971 Esterly and McKusick1 described four patients with mild hirsutism, limitation of joint mobility, and localized areas of stony-hard skin. The patients had no other abnormalities and no increased excretion of mucopolysaccharides in the urine. The authors stressed that the skin was normal in appear':' ance and texture but was immovable and rock-hard. In three patients the disease was congenital. Alcian blue (pH 2.5) and colloidal iron stained throughout the dermis or in the papillary dermis, and the staining was partially removed by hyaluronidase digestion. The material disclosed by the alcian blue stain was similar in reactivity to that of normal dennis; in the one nonfamilial case, large numbers of metachromatic granules were noted in a skin fibroblast culture. Because the disease did not correspond to any known collagen disease or mucopolysaccharidosis, the authors suggested the possibility of a unique connective tissue disorder, specifically, a defective regulation of mucopolysaccharide synthesis by fibroblasts, which could modify the formation of collagen fibers and their function, A similar patient was seen with joint immobility, From the Departmentsof Dermatology, Warsaw School of Medicine," ErfurtSchoolofMedicine,bandMiyazakiMedicalCollege.Kiyatake, C Accepted for publication Nov. 21, 1988. Reprint requests: S. Jablonska, MD, Department of Dermatology, Warsaw Schoolof Medicine, 02·008 Warsaw, Poland. 16/1/14913
stony-hard skin, and no mucopolysacchariduria (R. Winkelmann, personal communication). Like Esterly and Mckusick, he excluded the diagnosis of scleroderma and scleredema and concluded that this disease was not a mucopolysaccharidosis. We describe a patient observed for more than 10 years with stony-hard induration of the skin and deeper tissues, most pronounced in the buttocks, thighs, and legs, with limitation ofjoint mobility and particularly extensive contractures in the lower Iimbs.? There was no visceral or bone involvement. The disease was noted in early childhood and was nonprogressive, although contractures of the knees, hips, and elbows became more pronounced with age. No abnormallyincreasedmucopolysaccharideswere revealed in the skin or urine or in fibroblast culture. Studies disclosed increased collagen synthesis by the fibroblasts derived from the deeper portions of the skin, a high rate of total collagen synthesis per cell, and a high ratio of collagen synthesis to total protein synthesis. The synthesized collagen pattern suggested the production of fairly normal collagen chains; production of fibronectin and mucopolysaccharides was normal. The fascia was found to be four times thicker than normal, whereas the muscles were not involved. Electron microscopy of the fascia showed the presence of large amiartthoid-like collagen fibers and bundles of aggregated microfibrils. We suggested a possible disturbance of the extracellular organiza-
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Fig. 1. Patient 1. Deep indurations on lower limbs, buttocks, and, to lesser extent, on trunk and upper limbs. Short stature and tiptoe gait was caused by contractures in knees and hips, and extensive scoliosis. Hands and feet were not involved.
tion of collagen fibrils related to some alteration in biosynthesis or a turnover of matrix proteoglycans, or both. We proposed the name congenital fascial dystrophy to stress the noninflammatory and seemingly hereditary nature of the disease. Kikuchi et al. 3 published three cases classified as stiffskin syndrome. There was consanguinity in one family, and in another family a father and daughter were affected. In a girl in whom the disease was noticed when she was 4 years of age, histologic examination of the skin revealed colloidal iron-reactive material removed by hyaluronidase pretreatment.
Journal of the American Academy of Dermatology
Fig. 2. Patient 2. Sister of patient 1 has similar indurations on lower limbs and buttocks. Limitation of motion in knees and hips was less pronounced.
In addition, large, spindle-shaped cells stained metachromatically. The patient had hypertrichosis of the face and of the genital areas, and knuckle padlike lesionson the fingers and toes. Her skin was not as stony-hard as that of the other patients. After the abnormal fascia was reported as a hallmark of the disease, Kikuchi et al.3 reevaluated the cases and found collagenization of the subcutaneous tissue and abnormal fascia in two instances." They concluded that the pattern of stiff skin syndrome
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varies and that two different entities should be recognized: a skin syndrome caused by a local abnormality of mucopolysaccharide metabolism and the congenital fascial dystrophy. We present four additional cases of this novel scleroderma-like, genetically determined disease that appears remarkably similar to the condition of the inbred tight skin mouse.5-7 CASE REPORTS
Case 1 A man born in 1944 is the brother of patient 2. The parents were unrelated, and four other siblings were healthy. The disease began in early infancy with stonyhard indurations of the skin and deeper tissue of the buttocks and thighs. It spread to the trunk and arms and became almost generalized. The hands and feet were spared, and the distal parts of the limbs were less involved. The lower limbs had pronounced contractures. As a child the patient had frequent respiratory infections. Otherwise his development was satisfactory except for short stature. When the patient was 17 years of age, scleroderma was diagnosed, and he was treated with EDTA, penicillin, hyaluronidase, and physiotherapy, with no effect. We saw him first at age 32 years. His stature was short (149 em), and his weight was 49.5 kg. The patient's skin was tight and firmly bound to the underlying tissues, and it could not be pinched on the buttocks, thighs, lumbar area, shoulders, and upper aspect of the arms. There was limitation of mobility of several joints, particularly of the knees and hips (Fig. 1). The patient had scoliosis, a characteristic tiptoe posture, and a peculiar manner of walking. At follow-up 11 years later there was no deterioration of his condition except for some progression of his pulmonary restrictive changes.
Case 2 The sister of patient 1 was born in 1959. Induration of the buttocks and thighs was noted when the patient was 3 years old. She has been hospitalized several times with a diagnosis of scleroderma and, as her brother, she was treated with no effect. We saw her for the first time at age 15 years. She was well developed both mentally and physically but was of short stature. The patient had widespread stony-hard induration of the skin and underlying tissues in the same areas as her brother. She also had scoliosis and limited mobility in the knees and hips. Contractures were less pronounced in patient 2 than in her brother (Fig. 2). There was a sharp demarcation of the induration at the inguinal canal (Fig. 3). The patient is now 32 years old and has given birth to an apparently healthy girl. Her disease was not progressive.
Fig. 3. Patient 2. Sharp demarcation of subcutaneous indurations at inguinal canal. Skin above canal appears to be normal, slightly less movable.
Case 3 A man born in 1940 was first seen by us when he was 29 years old. His parents were healthy and allegedly unrelated, and his only brother was healthy. Indurations were noted in his first year of life, and limited mobility of the knees and hips was noted when the patient was 2 years of age. Since then the skin and underlying tissues, especially those of the buttocks, thighs, legs, and arms, have slowly and progressively hardened. The patient had tiptoe stature because of contractures of the knees and hips and had a peculiar manner of walking. The hands and feet were uninvolved, but there was pronounced hypertrichosis in the lumbar region and on the lower limbs (Fig. 4, A). The patient's thorax became progressively thinner, in contrast to his well-developed shoulder muscles (Fig. 4, B). Restrictive pulmonary changes progressed despite intensive therapy.
Case 4 A 51-year-old Japanese housewife was first seen in 1985 with generalized stiff skin and limited joint mobility, both of which had been present since childhood (Fig.
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A Fig. 4. Patient 3. A, Extensive indurations of lower limbs, well demarcated at inguinal canal. In this patient, there was pronounced hypertrichosis on limbs and at lumbar area. B, Characteristically narrow thorax with normally developed shoulder muscles. Hands and face were uninvolved.
5). Her parents were cousins, but no other members ofher family were affected. The patient was short in stature (142 em, 46 kg), with generalized induration of the skin and limitation of joint mobility, especially of the knees, hips, shoulders, and elbows, She walked abnormally, and all extensor aspects of her extremities were stiff. The most characteristic feature was thickening of the fascia, best visualized by xeroradiography (Fig. 6). The fascia appeared thickest in the inguinal regions (Fig. 7). Intralesional injections of triamcinolone acetonide into the fascia produced only transient local improvement and were discontinued. The patient's generalized stiff skin remained essentially unchanged.
Laboratory examination In all patients, results of routine laboratory studies were normal. No immunologic abnormalities were found. Immunofluorescence studies of the skin and muscles yielded negative findings. No abnormalities in muscle enzymes were detected. Electromyography disclosed no abnormalities, and capillary microscopic findings were normal.
Histologic examination Mucopolysacchariduria was absent. Genetic studies showed normal karyotypes in lymphocytes and skin fibroblasts. Skin biopsy specimens showed thickening and homogenization of the connective tissue stroma, with slight inflammatory infiltrations around the superficial blood vessels and a somewhat decreased number of skin appendages. In the subcutis, proliferation oftheeonnectivetissue with an increased number of fibroblasts was seen (Fig. 8). Alcian blue at pH 2.5 to 5.0 showed slight staining between the collagen fibers, but toluidine blue and periodic acid-Schiff did not stain . Deep biopsy specimens obtained from indurated areas of the thigh showed a remarkably thick fascia with abundant hyalinized collagenous tissue, scant fibroblasts, and no inflammatory infiltrate. The muscle tissue was normal (Figs. 9 to 11). Electron microscopy of the deep skin and subcutis revealed fibroblasts with a branched system of rough endoplasmic reticulum with distended lumina and exocytotic vesicles. Collagen fibers appeared normal. Electron microscopy of the fascia disclosedbundles of aggregated microfibrils and scant large, amianthoid-like collagen fibers.
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Fig. 6. Case4. Xeroradiographyvisualizes considerably thickened fascia.
Fig. 5. Patient 4. Indurationsof limbswith flexion contractures, mainly of hips, knees, and, to lesser extent, of shoulders and elbows. DISCUSSION
We present four cases of an apparently genetically determined, scleroderma-like disease of connective tissue. Previous studies provided evidence of increased collagen synthesis accompanied by elevated activity of prolyl hydroxylase and lysyl hydroxylase; transferase activity was normal. 2 We have confirmed and extended our previous findings concerning the noninflammatory involvement of fascia in this novel disorder. The disease has a characteristic clinical pattern: rock-hard skin firmly bound to the underlying tissues, especially remarkable in areas with abundant fascia. The skin is immovable but normal in appearance and texture. Bones and muscles are unaffected. Despite an increased synthesis and accumulation
Fig. 7. Patient 4. Indurations are well demarcated at buttocks and inguinal canal, corresponding to areas of most developed fascia.
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Journal of the American Academy of Dermatology
Fig. 8. Case 1. Photomicrographs of skin show thickening of connective tissue stroma and increased number of fibroblasts in subcutis with replacement of subcutaneous fat by proliferating collagen. Skin appendages are preserved. A, Slight inflammatory infiltrates are present around superficial blood vessels. (Hematoxylin-eosin stain; X60.) B, Higher-power view of same specimen shows fibroblast proliferation around hair follicles and sweat ducts. (Hematoxylin-eosin stain; X180.)
of collagen in the skin and subcutis, as in systemic scleroderma.s-? this disease differs by virtue of its genetic characteristics: early onset, absence of Raynaud's phenomenon and involvement of the viscera and muscles, absence of immunologic abnormalities, nature and localization of the indurations, and absence of inflammatory and vascular changes. Sclerodermatomyositis and scleredema had been previously diagnosed in our patients.
Sclerodermatomyositis, however, features inflammatory changes of muscle and has a later onset. Scleredema is an inflammatory process, is nonhereditary, has a later onset, and has a different distribution of induration and a different course from those in our patients. Kikuchi et al.4 suggested that there were two varieties of the disease: one with increased acid mucopolysaccharides in the dermis in the absence ofmu-
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Fig. 9. Case 1. Photomicrograph of deep biopsyspecimen from thigh. Markedly thickened fascia (F) with no inflammatoryinfiltrates. M, Normal muscle. (van Gieson stain; X60.)
Fig. 10. Case 2. Photomicrographof considerablythickened fascia with fibers of variable size) shape, and stainability.Some fasciaare verylarge and coarse. (van Gieson stain, X180.)
copolysacchariduria, and another variety, congenital fascial dystrophy, caused by increased accumulation of collagen. Compared with the cases we describe, the nonfamilial case of Esterly and Mckusick' had a later onset and numerous metachromatic granules in the skin fibroblastculture, and one case previously described by Kikuchi et al.4 had less skin induration. The presence of large, metachromatically stained spindle cells in the reticular dermis could be classified as unusual cutaneous mucopolysaccharidosis in both cases.
There is a striking similarity between congenital fascial dystrophy and the alterations in collagen metabolism described in the tight skin (TSK) mouse.P? This dominant mutant of the inbred B 1O.D 2/58 N/SN mouse strain is characterized by scleroderma-like alterations in collagen metabolism, an excessive accumulation of collagen in the dermis and subcutaneous tissue, and thickened skin that is firmly bound to the underlying tissues. This scleroderma-like condition differs from scleroderma because it lacks inflammatory features, atrophy of skin
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Fig. 11. Case 4. Photomicrograph shows considerably thickened, homogenized, irregularly shaped fascia. (Hematoxylin-eosin stain; X300.)
appendages, immunologic abnormalities, visceral involvement, and vascular changes. The hereditary increase in collagen synthesis, thickened skin and hypodermis, replacement of subepidermal tissue by newly deposited collagen, and, in some areas, thickened fascia are characteristic both of the TSK mouse and of congenital fascial dystrophy.f 7 Jimenez et al,? described the connective tissue hypertrophy in the TSK mouse as "hypertrophic subdermal connective tissue extending deep into the underlying musculature and attaching firmly to it." Menton et a1. 6 stated that "this thick layer of fascia appears to be continuous with the comiective tissue of the epimysium of the body wall musculature forming what appears to be a very firm attachment." A relative abundance of acid mucopolysaccharides has also been demonstrated in the dermis and hypodermis and in the subcutaneous connective tissue in the TSK mouse.' Moreover, electron microscopy has disclosed a mass of microfibrils lacking periodicity and containing individual collagen fibrils 5-features similar to those of congenital fascial dystrophy.l The characteristic clinical and pathologic features of congenital fascial dystrophy, which differ from all other known
collagen diseases and mucopolysaccharidoses, argue for its recognition as a novel nosologic entity. REFERENCES
1. Esterly NS, McKusick VA. Stiff skin syndrome. Pediatrics 1971;47:360-9. 2. Jablonska S, Groniowski J, Krieg T, et al. Congenital fascial dystrophy: a noninflammatory disease of fascia-the stiff skin syndrome. Pediatr Dermatol 1984;2:87-97. 3. Kikuchi I, Inoue S, Hamada K, et al. Stiff skin syndrome. Pediatr Dermatol 1985;3:48-53. 4. Kikuchi I, Inoue S, Takasaki N. Stiff skin syndrome. In: Urabe H, Kimura M, Yamamoto K, et ai, cds. Proceedings of the fourth International Congress of Pediatric Dermatology, June 7-10,1986 Tokyo: University of Tokyo Press, 1987;629-32. 5. Green MC, Sweet HO, Bunker LE. Tight-skin, a new mutation of the mouse causing excessivegrowth of connective tissue and skeleton. Am J Pathol 1976;82:493-512. 6. Menton DN, Hess RA, Lichtenstein JR, et al. The structure and tensile properties of the skin of tight-skin (Tsk) mutant mice. J Invest Dermatol 1978;70:4-10. 7. Jimenez SA, Millan A, Bashey RI. Scleroderma-like alterations in collagen metabolism occurring in the TSK (tight skin) mouse. Arthritis Rheum 1984;27:180-5. 8. Krieg T, Ludcrschmidt C, Weber L, et al, Scleroderma fibroblast: some aspects on in vivo assessment of collagen synthesis. Arch Dermatol Res 1981;270:263-72. 9. Fleischmajer R, Perlish JS, Krieg T, et al. Variability in collagen and fibronectin synthesis by scleroderma fibroblasts in primary culture. J Invest Dermatol 1981;76: 400-7.
stony-hard skin, and no mucopolysacchariduria (R. Winkelmann, personal communication). Like Esterly and Mckusick, he excluded the diagnosis of scleroderma and scleredema and concluded that this disease was not a mucopolysaccharidosis. We describe a patient observed for more than 10 years with stony-hard induration of the skin and deeper tissues, most pronounced in the buttocks, thighs, and legs, with limitation ofjoint mobility and particularly extensive contractures in the lower Iimbs.? There was no visceral or bone involvement. The disease was noted in early childhood and was nonprogressive, although contractures of the knees, hips, and elbows became more pronounced with age. No abnormallyincreasedmucopolysaccharideswere revealed in the skin or urine or in fibroblast culture. Studies disclosed increased collagen synthesis by the fibroblasts derived from the deeper portions of the skin, a high rate of total collagen synthesis per cell, and a high ratio of collagen synthesis to total protein synthesis. The synthesized collagen pattern suggested the production of fairly normal collagen chains; production of fibronectin and mucopolysaccharides was normal. The fascia was found to be four times thicker than normal, whereas the muscles were not involved. Electron microscopy of the fascia showed the presence of large amiartthoid-like collagen fibers and bundles of aggregated microfibrils. We suggested a possible disturbance of the extracellular organiza-
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Fig. 1. Patient 1. Deep indurations on lower limbs, buttocks, and, to lesser extent, on trunk and upper limbs. Short stature and tiptoe gait was caused by contractures in knees and hips, and extensive scoliosis. Hands and feet were not involved.
tion of collagen fibrils related to some alteration in biosynthesis or a turnover of matrix proteoglycans, or both. We proposed the name congenital fascial dystrophy to stress the noninflammatory and seemingly hereditary nature of the disease. Kikuchi et al. 3 published three cases classified as stiffskin syndrome. There was consanguinity in one family, and in another family a father and daughter were affected. In a girl in whom the disease was noticed when she was 4 years of age, histologic examination of the skin revealed colloidal iron-reactive material removed by hyaluronidase pretreatment.
Journal of the American Academy of Dermatology
Fig. 2. Patient 2. Sister of patient 1 has similar indurations on lower limbs and buttocks. Limitation of motion in knees and hips was less pronounced.
In addition, large, spindle-shaped cells stained metachromatically. The patient had hypertrichosis of the face and of the genital areas, and knuckle padlike lesionson the fingers and toes. Her skin was not as stony-hard as that of the other patients. After the abnormal fascia was reported as a hallmark of the disease, Kikuchi et al.3 reevaluated the cases and found collagenization of the subcutaneous tissue and abnormal fascia in two instances." They concluded that the pattern of stiff skin syndrome
Volume 21 Number 5, Part I November 1989
Congenital fascial dystrophy
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varies and that two different entities should be recognized: a skin syndrome caused by a local abnormality of mucopolysaccharide metabolism and the congenital fascial dystrophy. We present four additional cases of this novel scleroderma-like, genetically determined disease that appears remarkably similar to the condition of the inbred tight skin mouse.5-7 CASE REPORTS
Case 1 A man born in 1944 is the brother of patient 2. The parents were unrelated, and four other siblings were healthy. The disease began in early infancy with stonyhard indurations of the skin and deeper tissue of the buttocks and thighs. It spread to the trunk and arms and became almost generalized. The hands and feet were spared, and the distal parts of the limbs were less involved. The lower limbs had pronounced contractures. As a child the patient had frequent respiratory infections. Otherwise his development was satisfactory except for short stature. When the patient was 17 years of age, scleroderma was diagnosed, and he was treated with EDTA, penicillin, hyaluronidase, and physiotherapy, with no effect. We saw him first at age 32 years. His stature was short (149 em), and his weight was 49.5 kg. The patient's skin was tight and firmly bound to the underlying tissues, and it could not be pinched on the buttocks, thighs, lumbar area, shoulders, and upper aspect of the arms. There was limitation of mobility of several joints, particularly of the knees and hips (Fig. 1). The patient had scoliosis, a characteristic tiptoe posture, and a peculiar manner of walking. At follow-up 11 years later there was no deterioration of his condition except for some progression of his pulmonary restrictive changes.
Case 2 The sister of patient 1 was born in 1959. Induration of the buttocks and thighs was noted when the patient was 3 years old. She has been hospitalized several times with a diagnosis of scleroderma and, as her brother, she was treated with no effect. We saw her for the first time at age 15 years. She was well developed both mentally and physically but was of short stature. The patient had widespread stony-hard induration of the skin and underlying tissues in the same areas as her brother. She also had scoliosis and limited mobility in the knees and hips. Contractures were less pronounced in patient 2 than in her brother (Fig. 2). There was a sharp demarcation of the induration at the inguinal canal (Fig. 3). The patient is now 32 years old and has given birth to an apparently healthy girl. Her disease was not progressive.
Fig. 3. Patient 2. Sharp demarcation of subcutaneous indurations at inguinal canal. Skin above canal appears to be normal, slightly less movable.
Case 3 A man born in 1940 was first seen by us when he was 29 years old. His parents were healthy and allegedly unrelated, and his only brother was healthy. Indurations were noted in his first year of life, and limited mobility of the knees and hips was noted when the patient was 2 years of age. Since then the skin and underlying tissues, especially those of the buttocks, thighs, legs, and arms, have slowly and progressively hardened. The patient had tiptoe stature because of contractures of the knees and hips and had a peculiar manner of walking. The hands and feet were uninvolved, but there was pronounced hypertrichosis in the lumbar region and on the lower limbs (Fig. 4, A). The patient's thorax became progressively thinner, in contrast to his well-developed shoulder muscles (Fig. 4, B). Restrictive pulmonary changes progressed despite intensive therapy.
Case 4 A 51-year-old Japanese housewife was first seen in 1985 with generalized stiff skin and limited joint mobility, both of which had been present since childhood (Fig.
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A Fig. 4. Patient 3. A, Extensive indurations of lower limbs, well demarcated at inguinal canal. In this patient, there was pronounced hypertrichosis on limbs and at lumbar area. B, Characteristically narrow thorax with normally developed shoulder muscles. Hands and face were uninvolved.
5). Her parents were cousins, but no other members ofher family were affected. The patient was short in stature (142 em, 46 kg), with generalized induration of the skin and limitation of joint mobility, especially of the knees, hips, shoulders, and elbows, She walked abnormally, and all extensor aspects of her extremities were stiff. The most characteristic feature was thickening of the fascia, best visualized by xeroradiography (Fig. 6). The fascia appeared thickest in the inguinal regions (Fig. 7). Intralesional injections of triamcinolone acetonide into the fascia produced only transient local improvement and were discontinued. The patient's generalized stiff skin remained essentially unchanged.
Laboratory examination In all patients, results of routine laboratory studies were normal. No immunologic abnormalities were found. Immunofluorescence studies of the skin and muscles yielded negative findings. No abnormalities in muscle enzymes were detected. Electromyography disclosed no abnormalities, and capillary microscopic findings were normal.
Histologic examination Mucopolysacchariduria was absent. Genetic studies showed normal karyotypes in lymphocytes and skin fibroblasts. Skin biopsy specimens showed thickening and homogenization of the connective tissue stroma, with slight inflammatory infiltrations around the superficial blood vessels and a somewhat decreased number of skin appendages. In the subcutis, proliferation oftheeonnectivetissue with an increased number of fibroblasts was seen (Fig. 8). Alcian blue at pH 2.5 to 5.0 showed slight staining between the collagen fibers, but toluidine blue and periodic acid-Schiff did not stain . Deep biopsy specimens obtained from indurated areas of the thigh showed a remarkably thick fascia with abundant hyalinized collagenous tissue, scant fibroblasts, and no inflammatory infiltrate. The muscle tissue was normal (Figs. 9 to 11). Electron microscopy of the deep skin and subcutis revealed fibroblasts with a branched system of rough endoplasmic reticulum with distended lumina and exocytotic vesicles. Collagen fibers appeared normal. Electron microscopy of the fascia disclosedbundles of aggregated microfibrils and scant large, amianthoid-like collagen fibers.
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Fig. 6. Case4. Xeroradiographyvisualizes considerably thickened fascia.
Fig. 5. Patient 4. Indurationsof limbswith flexion contractures, mainly of hips, knees, and, to lesser extent, of shoulders and elbows. DISCUSSION
We present four cases of an apparently genetically determined, scleroderma-like disease of connective tissue. Previous studies provided evidence of increased collagen synthesis accompanied by elevated activity of prolyl hydroxylase and lysyl hydroxylase; transferase activity was normal. 2 We have confirmed and extended our previous findings concerning the noninflammatory involvement of fascia in this novel disorder. The disease has a characteristic clinical pattern: rock-hard skin firmly bound to the underlying tissues, especially remarkable in areas with abundant fascia. The skin is immovable but normal in appearance and texture. Bones and muscles are unaffected. Despite an increased synthesis and accumulation
Fig. 7. Patient 4. Indurations are well demarcated at buttocks and inguinal canal, corresponding to areas of most developed fascia.
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Journal of the American Academy of Dermatology
Fig. 8. Case 1. Photomicrographs of skin show thickening of connective tissue stroma and increased number of fibroblasts in subcutis with replacement of subcutaneous fat by proliferating collagen. Skin appendages are preserved. A, Slight inflammatory infiltrates are present around superficial blood vessels. (Hematoxylin-eosin stain; X60.) B, Higher-power view of same specimen shows fibroblast proliferation around hair follicles and sweat ducts. (Hematoxylin-eosin stain; X180.)
of collagen in the skin and subcutis, as in systemic scleroderma.s-? this disease differs by virtue of its genetic characteristics: early onset, absence of Raynaud's phenomenon and involvement of the viscera and muscles, absence of immunologic abnormalities, nature and localization of the indurations, and absence of inflammatory and vascular changes. Sclerodermatomyositis and scleredema had been previously diagnosed in our patients.
Sclerodermatomyositis, however, features inflammatory changes of muscle and has a later onset. Scleredema is an inflammatory process, is nonhereditary, has a later onset, and has a different distribution of induration and a different course from those in our patients. Kikuchi et al.4 suggested that there were two varieties of the disease: one with increased acid mucopolysaccharides in the dermis in the absence ofmu-
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Fig. 9. Case 1. Photomicrograph of deep biopsyspecimen from thigh. Markedly thickened fascia (F) with no inflammatoryinfiltrates. M, Normal muscle. (van Gieson stain; X60.)
Fig. 10. Case 2. Photomicrographof considerablythickened fascia with fibers of variable size) shape, and stainability.Some fasciaare verylarge and coarse. (van Gieson stain, X180.)
copolysacchariduria, and another variety, congenital fascial dystrophy, caused by increased accumulation of collagen. Compared with the cases we describe, the nonfamilial case of Esterly and Mckusick' had a later onset and numerous metachromatic granules in the skin fibroblastculture, and one case previously described by Kikuchi et al.4 had less skin induration. The presence of large, metachromatically stained spindle cells in the reticular dermis could be classified as unusual cutaneous mucopolysaccharidosis in both cases.
There is a striking similarity between congenital fascial dystrophy and the alterations in collagen metabolism described in the tight skin (TSK) mouse.P? This dominant mutant of the inbred B 1O.D 2/58 N/SN mouse strain is characterized by scleroderma-like alterations in collagen metabolism, an excessive accumulation of collagen in the dermis and subcutaneous tissue, and thickened skin that is firmly bound to the underlying tissues. This scleroderma-like condition differs from scleroderma because it lacks inflammatory features, atrophy of skin
Journal of the American Academy of Dermatology
950 Iablonska et al.
Fig. 11. Case 4. Photomicrograph shows considerably thickened, homogenized, irregularly shaped fascia. (Hematoxylin-eosin stain; X300.)
appendages, immunologic abnormalities, visceral involvement, and vascular changes. The hereditary increase in collagen synthesis, thickened skin and hypodermis, replacement of subepidermal tissue by newly deposited collagen, and, in some areas, thickened fascia are characteristic both of the TSK mouse and of congenital fascial dystrophy.f 7 Jimenez et al,? described the connective tissue hypertrophy in the TSK mouse as "hypertrophic subdermal connective tissue extending deep into the underlying musculature and attaching firmly to it." Menton et a1. 6 stated that "this thick layer of fascia appears to be continuous with the comiective tissue of the epimysium of the body wall musculature forming what appears to be a very firm attachment." A relative abundance of acid mucopolysaccharides has also been demonstrated in the dermis and hypodermis and in the subcutaneous connective tissue in the TSK mouse.' Moreover, electron microscopy has disclosed a mass of microfibrils lacking periodicity and containing individual collagen fibrils 5-features similar to those of congenital fascial dystrophy.l The characteristic clinical and pathologic features of congenital fascial dystrophy, which differ from all other known
collagen diseases and mucopolysaccharidoses, argue for its recognition as a novel nosologic entity. REFERENCES
1. Esterly NS, McKusick VA. Stiff skin syndrome. Pediatrics 1971;47:360-9. 2. Jablonska S, Groniowski J, Krieg T, et al. Congenital fascial dystrophy: a noninflammatory disease of fascia-the stiff skin syndrome. Pediatr Dermatol 1984;2:87-97. 3. Kikuchi I, Inoue S, Hamada K, et al. Stiff skin syndrome. Pediatr Dermatol 1985;3:48-53. 4. Kikuchi I, Inoue S, Takasaki N. Stiff skin syndrome. In: Urabe H, Kimura M, Yamamoto K, et ai, cds. Proceedings of the fourth International Congress of Pediatric Dermatology, June 7-10,1986 Tokyo: University of Tokyo Press, 1987;629-32. 5. Green MC, Sweet HO, Bunker LE. Tight-skin, a new mutation of the mouse causing excessivegrowth of connective tissue and skeleton. Am J Pathol 1976;82:493-512. 6. Menton DN, Hess RA, Lichtenstein JR, et al. The structure and tensile properties of the skin of tight-skin (Tsk) mutant mice. J Invest Dermatol 1978;70:4-10. 7. Jimenez SA, Millan A, Bashey RI. Scleroderma-like alterations in collagen metabolism occurring in the TSK (tight skin) mouse. Arthritis Rheum 1984;27:180-5. 8. Krieg T, Ludcrschmidt C, Weber L, et al, Scleroderma fibroblast: some aspects on in vivo assessment of collagen synthesis. Arch Dermatol Res 1981;270:263-72. 9. Fleischmajer R, Perlish JS, Krieg T, et al. Variability in collagen and fibronectin synthesis by scleroderma fibroblasts in primary culture. J Invest Dermatol 1981;76: 400-7.