Scleroderma-like Skin Changes Research Articles

Progeroid syndrome with scleroderma‐like skin changes associated with homozygous R435C LMNA mutation

Hutchinson-Gilford progeria is a rare genetic disorder resulting from mutations in the LMNA gene encoding lamin A/C. In addition to the classical phenotype usually caused by the 1824C>T mutation of LMNA, a number of atypical progeroid syndromes have been described. They have some distinct features, such as skeletal deformities or scleroderma-like skin changes. The underlying defect is usually a homozygous mutation of LMNA, or a combined defect of LMNA and another gene, for example, ZMPSTE-24. We present a 2-year-old girl born to consanguineous parents affected by progeroid syndrome with scleroderma-like skin changes. Genetic analysis revealed the homozygous LMNA mutation 1303C>T (R435C). The same heterozygous mutation was found in the patient's parents and 11 other family members. The progeroid syndrome in our patient shares the signs of two laminopathies: progeria and restrictive dermatopathy. Two other children in the family died at the age of 2 due to a disease similar to that in the proposita. On the basis of the family pedigree we presume that these children probably had the same homozygous LMNA mutation. Scleroderma-like skin changes in infants, associated with growth retardation and dysmorphic features, suggest premature aging syndrome, requiring genetic testing and counseling of asymptomatic carriers of LMNA mutations.

Werner’s syndrome: a quite rare disease for differential diagnosis of scleroderma

Werner's syndrome (WS) is an autosomal recessive disorder characterized by premature aging. The main features of the disease are scleroderma-like skin appearance, premature atherosclerosis, short stature, diabetes mellitus, early osteoporosis and early aging. Herein, we describe a patient with WS, who has scleroderma-like skin changes and discuss the literature about WS as a disease in the differential diagnosis of systemic sclerosis.

Systemic Lupus Erythematosus Associated with Paclitaxel Use in the Treatment of Ovarian Cancer

Over the last years, scleroderma-like skin changes have been reported with two of the taxanes, docetaxel and paclitaxel, but specific antibodies were not found in any of those cases. Recently, paclitaxel was linked to cutaneous lupus erythematosus in two cancer patients, showing high titers of serum anti-Ro (SS-A) antibody. To our knowledge, this is the first known case of a patient with serologically confirmed systemic lupus erythematosus secondary to paclitaxel use.

Nephrogenic systemic fibrosis following the administration of extracellular gadolinium based contrast agents: is the stability of the contrast agent molecule an important factor in the pathogenesis of this condition?

Nephrogenic systemic fibrosis (NSF) was first described in 1997 in patients with end-stage renal disease (ESRD) [1]. It is characterised by scleroderma-like skin changes that mainly affect the limbs and trunk. The induration of the skin can progress to cause flexion contracture of the joints. The fibrotic changes may also affect other organs such as muscles, heart, liver and lungs [1–7]. The disease can be aggressive in some patients, leading to serious physical disability or even death [1]. Recently, it has been suggested that extracellular gadolinium based contrast agents (Gd-CA) might have a causal relation with NSF [4–7]. According to a recent editorial there are more than 150 patients who have developed NSF following administration of Gd-CA. Strikingly, the overwhelming majority (,90%) followed administration of the non-ionic agent gadodiamide (only 15% of all Gd-CA injections worldwide are gadodiamide) [7]. This was completely unexpected considering the good safety records of all Gd-CA, including gadodiamide [8]. According to the manufacturer (GE Healthcare, Waukesha, WI) gadodiamide has been administered to about 30 million patients since its introduction for clinical use in 1993 without high incidence of important adverse effects [6]. Hence, this recently observed strong association between NSF and gadodiamide requires an explanation. Currently, there are seven extracellular Gd-CA available for clinical use (Table 1). They are all chelates containing the Gd ion (Gd). The configuration of the molecules is either linear or cyclic. They are available as ionic or non-ionic preparations (Table 1). The important difference between these agents that could be of relevance to patients with advanced renal impairment (GFR ,30 ml min) and a factor in the development of NSF is the stability of the chelate molecule [6]. Gd-CA are eliminated from the body through the kidneys and biological half-life in patients with normal renal function is 1.5 h. In patients with advanced renal impairment, elimination half-life can be prolonged to 30 h or more [9]. Patients on haemodialysis would require three consecutive dialysis sessions over 6 days to remove 97% of the administered dose of Gd-CA from the body. Continuous ambulatory peritoneal dialysis for 20 days eliminates 69% of the injected dose of Gd-CA [10]. Transmetallation is likely to occur when the Gd-chelate remains in the body for a long period, as is the case in patients with ESRD, including those on dialysis. Transmetallation of Gd-CA leads to release of free gadolinium through replacement of the Gd within the chelate molecule by body cations such as zinc or copper [11]. Free gadolinium is highly toxic and animal studies showed that it can cause splenic degeneration, central lobular necrosis of the liver and a variety of haematological abnormalities [9, 12]. Therefore, it is crucially important that Gd should be strongly attached to a chelate to avoid its toxic effects. Understanding the synthesis of metal chelates is somewhat difficult, especially for those of us who have no deep knowledge in chemistry. However, the author of the article attempted to present some of the chemical principles involved in the production of Gd-chelate in a simplified manner, hopefully without important compromise of scientific accuracy. The gadolinium ion has Address correspondence to: Professor Sameh K Morcos, Consultant Radiologist, Department of Diagnostic Imaging, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK. E-mail: sameh.morcos@sth.nhs.uk The British Journal of Radiology, 80 (2007), 73–76

Hemosiderin deposits in chronic graft‐vs.‐host disease related myopathy

Chronic graft-vs.-host disease (cGVHD) occurs in 20-50% of patients who survive for at least 100 d after allogeneic stem cell transplantation (SCT). cGVHD includes scleroderma-like skin changes, chronic cholangitis, obstructive lung disease and general wasting syndrome. Polymyositis or myopathy are rare manifestations of cGVHD with approximately 40 reported cases. Polymyositis accompanied by hemosiderin deposits in cGVHD has been reported only once, and there are no reports on lipofuscin deposits in skeletal muscle cells in cGVHD. We report here on a 56-yr-old male who underwent allogeneic SCT in 1999 for osteomyelofibrosis and progressive hematopoietic insufficiency. In February 2004, the patient was hospitalized for progressive muscular weakness with loss of the ability to walk. Laboratory tests demonstrated normal values for serum creatine kinase, aldolase and lactic dehydrogenase; the ferritin level was highly elevated. The femoral muscle biopsy showed mostly perifascicular atrophy as well as numerous subsarcolemmal hemosiderin and lipofuscin deposits. Intravenous administration of the chelating agent deferoxamine was ineffective. Three weeks later the patient died of aspiration pneumonia. Interestingly, autopsy disclosed moderate hemosiderin deposits in the liver, the organ usually involved in hemosiderosis.

Atteinte unguéale et infiltration sclérodermiforme du visage au cours d’une amylose systémique

Mucocutaneous involvement in systemic amyloidosis occurs in 29 to 40 p. 100 of cases. Nail abnormalities are infrequent in AL amyloidosis. We report an original case of AL amyloidosis associated with cutaneous and integument alterations and scleroderma-like infiltration of the face. A 73 year-old woman was hospitalized because of weight loss and asthenia. She had been treated 4 years earlier with chemotherapy for a IgG-type multiple myeloma with complete resolution of the underlying monoclonal gammapathy. Cutaneous examination showed nail dystrophy of all fingernails associated with scleroderma-like skin changes on the chin and lips. Histopathologic study of a chin biopsy confirmed the presence of amyloid deposits in the dermis. Laboratory data were normal, without signs of recurrence of multiple myeloma. We report an original case of a patient who developed two unusual cutaneous manifestations associated with AL amyloidosis. Moreover, there was no correlation between the severity of the cutaneous lesions and the extent of the underlying hematological disease.

Medical Pearl: Scleroderma-like skin changes in patients with diabetes mellitus

S cleroderma-like skin change in diabetes is a common clinical entity that has been reported in the dermatology literature as part of the diabetic hand syndrome.1-3 The purpose of this article is to highlight this condition, which is distinct from scleredema diabeticorum and scleroderma, and is not well known to dermatologists. The incidence ranges between 10% and 50%.4,5 It was initially described in 1974 by Rosenbloom and Frias6 in adolescent patients who were insulin dependent. Scleroderma-like skin change was later found to affect adult patients who were non–insulin dependent.7 Skin and joint findings are coexistent in the majority of cases, although they may coexist independently.4,8 Males and females appear to be equally affected by this disorder and no racial differences have been described thus far.

What can we learn from Werner syndrome? A biased view from a rheumatologist

Werner syndrome (WS), caused by the mutation of the RecQ3 DNA helicase gene (loss of function), manifests scleroderma-like skin changes and juvenile cataracts in addition to a variety of clinical and biochemical aging phenotypes at an early stage of life, followed by death at an average age of 46 years. WS has been nominated as a top-ranking premature aging syndrome, or a human model of accelerated aging. Analyses of clinical and biological deterioration of body systems observed in WS may shed a unique light on the role of gene(s) in the pathogenesis of systemic sclerosis (SSc) and normal human aging.

Eosinophilic Fasciitis (Shulman’s Syndrome): Case Reports and Review of the Literature

In 1974, Shulman et al. reported two patients with scleroderma-like skin changes, peripheral eosinophilia and hypergammaglobulinemia.1 This disorder was initially distinguished from progressive sys...

The prevalence of cutaneous manifestations in IDDM patients and their association with diabetes risk factors and microvascular complications.

The aim of our study was to evaluate the frequency of skin manifestations, including the diabetic hand syndrome, in young IDDM patients. In addition, we studied the relation of the cutaneous manifestations to diabetes duration, glycemic control, and microvascular complications. The frequency of skin manifestations, including the diabetic hand syndrome, were examined in 238 IDDM patients (disease duration > 5 years) and 122 healthy control subjects in a cross-sectional study. In addition, we studied the relation of the cutaneous manifestations with diabetes duration, glycemic control, BMI, microvascular complications, and stratum corneum hydration using a stepwise logistic regression. Diabetic skin manifestations were detected in 168 of 238 (71%) IDDM patients and in 18 of 122 (14%) of the control subjects. Ichthyosiform skin changes of the shins, scleroderma-like skin changes, tinea pedis, and dry scaly palms were detected in 48 vs. 7%, 39 vs. 0%, 32 vs. 7%, and 21 vs. 0.8% of the patients and control subjects, respectively. In the diabetic patients, a significant association was found between ichthyosis of the shins and scleroderma-like skin changes of the hand (P < 0.001) and between scleroderma-like skin changes and the skin dryness of the palms (P < 0.0001). When diabetic risk factors were considered, diabetes duration was significantly associated with scleroderma-like skin changes and ichthyosis of the shins (P < 0.0001). The latter was also found to be related to diabetic retinopathy (P < 0.0001). Keratosis pilaris was present in 21% of the patients versus 9% in control subjects and was found to be exclusively associated with high BMI. Acquired ichthyosis is a common finding and the most prevalent skin manifestation in young IDDM patients. The development of several skin manifestations in insulin-dependent patients seems to be related to duration of diabetes and to development of diabetic microvascular complications.

Rapid Progression of Scleroderma Possibly Associated with Penicillamine Therapy

Systemic sclerosis is a disorder affecting the skin and internal organs. Its pathogenesis consists of fibrosis and vasculopathy, secondary to inflammation and immunological dysregulation. The latter may involve increased macrophage synthesis of interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF), leading to proliferation of fibroblasts and endothelial cells. The pathogenesis is probably mainly influenced by environmental factors rather than genetic factors.[1] However, chemical-associated systemic sclerosis has been linked to human leucocyte antigen (HLA)-type, chromosomal abnormalities, and enzyme deficiencies.[2] Importantly, chemical-associated systemic sclerosis cannot be distinguished pathologically or clinically from idiopathic systemic sclerosis. Scleroderma-like skin changes have been associated with several occupational compounds. Internal organs are usually not involved in these disorders. The classic syndrome is the well known toxic oil syndrome that affected 20 000 people in Spain. In this epidemic, 10% of affected people developed a chronic scleroderma-like disorder, with a positive antinuclear factor. Many of them also had HLADR3 and DR4. Other well characterised chemicals associated with scleroderma are solvents such as chlorinated, aliphatic and aromatic hydrocarbons, silica, plastic materials such as epoxy resins and vinyl chloride, detergent, herbicides, silicone prostheses, and various drugs, among which are bleomycin, amphetamine, cocaine, amfepramone (diethylpropion), pentazocine, and penicillamine.[3] In this paper, we describe a patient who presented with scleroderma and while treated with penicillamine and high-dose corticosteroids, developed rapidly progressive systemic sclerosis and normotensive scleroderma renal crisis.

Werner syndrome and genetic obesity: Speculation

Werner syndrome (WS) is a rare autosomal recessive disease with poor growth, premature aging, scleroderma-like skin changes, endocrine abnormalities, and deficiencies of adipose tissue. Could there be a genetic obesity syndrome which offers an instructive contrast to at least one form of WS? At least one form of WS might result from an enzyme defect that causes hypertriglyceridemia, hyperinsulinism, and hyperglucagonism; the defective enzyme might play a key role in the utilization of tryptophan, riboflavin (vitamin B2), or other vitamins or in the synthesis of prostaglandins that inhibit insulin secretion. At least one form of genetic obesity might result from an enzyme defect that causes hypotriglyceridemia and hyperinsulinism without hyperglucagonism; the defective enzyme might be unable to bind properly to a product that inhibits some step in the process of conversion of free fatty acid (FFA) CoA into ketoacids.

Non-infectious inflammatory fasciitis: a borderline syndrome

Inflammatory fasciitis without infection include different entity like eosinophilic fasciitis, the syndrome of eosinophilia-myalgia after tryptophan ingestion, toxic oil syndrome, exposure to trichlorethylene, phenylketonuria skin changes, the syndrome of palmar fasciitis, fasciitis in chronic graft-versus-host disease and fasciitis secondary to an adjacence process. The diagnosis of all these scleroderma-like skin changes is sometimes not easy because the clinical and sometimes the histopathological changes are bordeline manifestations with scleroderma. The most characteristic markers for non infectious fasciitis is eosinophilia and the infiltration of the fascia with eosinophilis, but it may be unremarkable or absent, only frequently present at the onset of the disease. Anamnesis is most important to guide the diagnosis. The eosinophils, but not only, may play a major role in the pathogenesis of this entity.

Chronicity of the eosinophilia-myalgia syndrome. A reassessment after three years.

To define the natural history and outcome of eosinophilia-myalgia syndrome (EMS) among a cohort of patients followed up at one center since the onset of their disease. Fifty-seven patients with well-characterized EMS were evaluated prospectively at a university hospital for 21-64 months (mean 36 months). Eighty-eight percent of the patients continue to have symptomatic disease with > 3 clinical manifestations. Fatigue (91%), muscle cramping (75%), myalgia (70%), paresthesias with objectively demonstrated hypesthesias (62%), articular symptoms (54%), scleroderma-like skin changes (44%), and proximal muscle weakness (40%) are the most common features of chronic EMS. New findings identified among this cohort include cognitive symptoms in 86% of the study group, tremor, and myoclonus. The recognition of new manifestations in EMS and ongoing clinical disease in 88% of patients highlights the chronic nature of this disorder. Continued prospective followup of a large patient base is warranted to further define the natural history of this newly recognized illness.

Toxic oil syndrome and eosinophilia-myalgia syndrome: May 8–10, 1991, World Health Organization Meeting report

In May 1991, researchers and clinicians from throughout the world met at a workshop sponsored by the Regional Office for Europe of the World Health Organization in collaboration with the Fondo de Investigación Sanitaria, Spain, and the U.S. Food and Drug Administration, National Institutes of Health, National Institutes of Mental Health, and Centers for Disease Control and Prevention to share information about two very similar diseases--toxic oil syndrome and eosinophilia-myalgia syndrome. In this paper the interpretation of conference proceedings is presented, current knowledge of the two disorders is summarized, and some possible areas for future research are mentioned. Toxic oil syndrome and eosinophilia-myalgia syndrome have many similarities. Both are related to consumer products that were presumed to be safe but have been found to have numerous trace contaminants, many of which remain to be identified, including the etiologic agents of both disorders. Both illnesses affect patients clinically by causing intense, incapacitating myalgias and a marked peripheral eosinophilia. Other rheumatologic manifestations are common in both, including arthralgias, sicca syndrome, scleroderma-like skin changes, carpal tunnel syndrome, and joint contractures. No clinical or laboratory feature has been found to be pathognomonic of either disease, and accurate diagnosis rests on the clinical judgment of the attending physician. Deaths have occurred in both diseases, and the cumulative mortality for each is approximately 2.5% for the first 2 years. Long-term complications include pulmonary hypertension, peripheral neuropathies, and joint contractures. Although treatment with corticosteroids has resulted in significant symptomatic relief in persons with either disorder, it does not alter the clinical course or long-term outcome. Research into the etiologic agents, preferred treatments, and ways to avoid similar problems in the future is needed.

Natural history of the eosinophilia-myalgia syndrome.

To describe the natural history and disease progression of the eosinophilia-myalgia syndrome and to assess the therapeutic effects of orally administered steroids on the disorder as of October 1990. Case-series analysis. A cohort of 45 patients with the eosinophilia-myalgia syndrome was followed prospectively by periodic telephone interviews and medical examinations for an average of 14 months after onset of illness. Washington state. The cases of 47 patients were reported to the Washington State Department of Health from 1 July to 12 December 1989. Two patients were unavailable for follow-up, and the remaining 45 completed the study. Patients were predominantly non-Hispanic white women (87%) with an average age of 49 years. Symptoms typically progressed from early onset of myalgia and fatigue to later development of neurologic and scleroderma-like skin changes. Six (13%) patients recovered completely within 2 to 5 months of symptom onset. After 14 months of illness, over half of the patients who initially presented with myalgia, fatigue, or scleroderma-like skin changes remained symptomatic. The average severity of each major symptom was measured using interviews and patient self-reports and has improved subjectively by at least 40%. Statistical analyses showed no significant difference in long-term symptom duration or severity between patients treated and those not treated with prednisone. The eosinophilia-myalgia syndrome is a long-term illness characterized by progressive improvement during the first 25 weeks after symptom onset, followed by a protracted phase of symptom resolution. We could not show a clear-cut benefit of prednisone in reducing the long-term severity or duration of the disease.

Neuromuscular manifestations of L-tryptophan-associated eosinophilia-myalgia syndrome: A histomorphologic analysis of 14 patients

The recent delineation of a clinical syndrome marked by eosinophilia, myalgia, and scleroderma-like skin changes associated with L-tryptophan use has necessitated the Centers for Disease Control to initiate a health alert. The likely association of L-tryptophan ingestion with a syndrome that mimics eosinophilic fasciitis (Shulman's syndrome) further identifies an environmental agent associated with an inflammatory sclerosing rheumatic disease process. In this report, we present the clinical, morphologic, and enzyme histochemical findings in muscle, skin, and fascia biopsies from 14 cases fulfilling the Center for Disease Control diagnostic criteria for L-tryptophan-associated eosinophilia-myalgia syndrome. The clinical syndrome reveals a high incidence of arthralgia, elbow contracture, and clinical neuropathy. The absence of significant change in creatine kinase or sedimentation rate allows for diagnostic separation from other inflammatory myopathies. Histoenzymatic features in muscle biopsies reveal a preferential epimysial-perimysial noneosinophilic infiltration characterized by acid phosphatase reactive histiocytosis, nonnecrotizing venulitis, perineural inflammation within dermis and perimysium, type II fiber atrophy with superimposed denervation features, and perifascicular alkaline phosphatase reactivity representing early neofibroplasia. The constellation of changes in skin, fascia, and muscle, with the defined clinical syndrome, allows for accurate differentiation from allied syndromes, including eosinophilic polymyositis, scleroderma, idiopathic polymyositis/dermatomyositis, polyarteritis nodosa, and toxic oil syndrome. Accurate differentiation from eosinophilic fasciitis still rests on a history of L-tryptophan ingestion.

Osteosclerosis of the phalanges in Werner syndrome.

Werner syndrome is an autosomal-recessive disease characterized by premature aging, shortness of stature, scleroderma-like skin changes, endocrine abnormalities, and cataracts. Although radiographic findings have been well documented, the presence of distinctive osteosclerotic changes in the phalanges of the hands and feet has not been emphasized in previous publications. The authors' review of radiographs of both hands in nine patients and of both feet in six patients with Werner syndrome documented the frequent occurrence of phalangeal sclerosis related predominantly to endosteal thickening. In the hand, sclerosis was present in every patient, was generally symmetric in distribution, predominated in the distal phalanges, and demonstrated an ulnar predilection. Similar changes in the phalanges of the feet were demonstrated in only two patients. The presence of osteosclerosis in the phalanges of the hand alone or both the hand and foot, when combined with osteoporosis and periarticular calcification, suggests the diagnosis of Werner syndrome.

Skin, joint, and pulmonary changes in type I diabetes mellitus.

Three hundred seventy-five patients with diabetes mellitus were examined for the presence of sclerodermalike skin changes, limited joint mobility, and vital capacity changes. Nineteen percent of patients had vital capacities 2 SDs below the mean of predicted values. There was no significant relationship between decreased vital capacities and duration of diabetes, sclerodermalike skin changes, limited joint mobility, smoking history, proteinuria, or retinopathy. Cutaneous involvement consisting of thickening, tightening, and/or a waxy quality of the skin was noted in 190 patients (51%). The severity of skin involvement correlated positively with the patients' duration of diabetes, age, severity of joint contractures, and diabetic retinopathy. Thus, sclerodermalike skin changes appear to reflect generalized connective tissue alterations in diabetes and may indicate increased risk for diabetic microvascular complications.

Sclerodermoid changes of porphyria cutanea tarda: Possible relationship to urinary uroporphyrin levels

From 1950 to 1982, fifteen patients were seen at the Mayo Clinic with a diagnosis of sclerodermoid changes of porphyria cutanea tarda. Fourteen patients had changes similar to scleroderma limited to the skin, and one patient had scleroderma-like skin changes accompanied by visceral abnormalities. Both light-exposed and unexposed areas of the body were affected. Areas of involvement included the chest, the V-shaped area of the neck, and the back, face, and shoulders. In six patients, morpheaform changes represented the presenting cutaneous sign of porphyria cutanea tarda. Follow-up examination, after treatment that included abstinence from alcohol and phlebotomy, revealed that the sclerodermoid skin changes had disappeared in six patients and improved in four. Generally, the degree of improvement of the sclerodermoid changes was proportional to the reduction of the urinary uroporphyrin levels toward normal (p = 0.02).