Scleroderma-like Skin Changes Research Articles

Rheumatological complaints in H syndrome: from inflammatory profiling to target treatment in a case study

BackgroundH Syndrome is a rare genetic condition caused by biallelic pathogenic variants in the SLC29A3 gene. It is characterized by a wide range of clinical manifestations, many of which are related to the immune-rheumatological field. These include scleroderma-like skin changes, deforming arthritis, and enlarged lymph nodes. The condition also features cardiac and endocrine defects, as well as hearing loss, for which the immune pathogenesis appears less clear. Immunomodulatory medications have been shown to improve many symptoms in recent experiences.Case presentationA 21-year-old girl was referred to our institute after being diagnosed with H syndrome. Her medical history was characterized by the development of finger and toe deformities, which developed since the first years of life and progressively worsened with clinodactyly. At 6 years of age, she was diagnosed with diabetes mellitus without typical autoantibodies and with bilateral sensorineural hearing loss. She also complained of frequent episodes of lymphadenopathy, sometimes with colliquation and growth retardation due to pancreatic insufficiency. It wasn’t until the genetic diagnosis of H syndrome that the continual increase in acute phase reactants was noticed, suggesting that an immunological pathogenesis may be the source of her problems. During her visit to our institute, she reported serious pain in both feet and hands and difficulty walking due to knee arthritis and muscle contractures. Conventional therapy with steroid injection in affected joints and methotrexate only led to partial improvement. After a thorough assessment of her inflammatory profile showing a high interferon score, the girl received treatment with baricitinib. Furthermore, based on recent data showing that SLC29A3 deficiency results in interferon production because of Toll-like Receptor 7 activation in lysosomes, hydroxychloroquine was also added. The combination of the two drugs resulted for the first time in a rapid and persistent normalization of inflammatory markers, paralleled by a dramatic improvement in symptoms.ConclusionsWe describe the results of inhibiting IFN inflammation in H syndrome and discuss how JAK inhibitors and antimalarials might represent a mechanistically based treatment for this orphan drug disorder.

O-09 A rare cause of acute pancreatitis: Werner Syndrome

Abstract Introduction Lipodystrophies are rare disorders characterized by loss of body fat resulting in leptin deficiency. Patients are predisposed to metabolic complications such as severe insulin resistance, hypertriglyceridemia, and hepatic steatosis. Werner syndrome (WS) is among the progeroid syndromes in the classification of lipodystrophy. Due to its extremely rare occurrence, it can often be overlooked by the clinician. Clinical Case A 19 years old male patient hospitalized for non-biliary acute pancreatitis was consulted for hypertriglyceridemia and hyperglycemia. He had no history of any disease or medication use. His sister was diagnosed with type 2 diabetes mellitus at age 29. She was using linagliptin and gliclazide for 3 years. She had short stature (147 cm) and low body weight (40 kg) and had scleroderma-like skin findings. The patient also had short stature (157 cm) and low body weight (41 kg). He had scleroderma-like skin findings and generalized loss of subcutaneous adipose tissue. The laboratory results were; glucose, 261 mg/dl; creatinine, 0.46 mg/dl; ALT, 24 U/l; lipase, 161 U/l; HbA1c, 9.6%; triglyceride, 799 mg/dl; HDL, 9.6 mg/dl; LDL, 75 mg/dl; c-peptide, 4.3 ng/dl. The thyroid function test results (TSH: 29.7 µIU/ml, fT4: 6.81 pmol/L, Anti-TPO: negative) were consistent with primary hypothyroidism. Hepatosteatosis was observed in abdominal ultrasonography. We initiated intensive insulin, metformin as well as fenofibrate and levothyroxine treatment. The patient needed high insulin doses (60 IU/day). Measured serum leptin levels were found to be low (2.11 ng/ml) in suspicion of lipodystrophy. Genetic analysis of the patient and his sister showed homozygous mutation in the WRN gene (c.1105C>T p.Arg369Ter, Homozygous) which was compatible with WS. The patient was started on leptin analog therapy in a clinical trial. Conclusion WS is an exceptionally rare autosomal recessive genetic disorder characterized by premature aging and multisystemic complications. The clinical features encompass scleroderma-like skin changes, short stature, low body weight, alopecia, cataracts, osteoporosis, and a propensity for atherosclerotic complications and malignancies. Impaired glucose tolerance is reported in 15%–20% of WS subjects, diabetes mellitus in 55%–70%, and dyslipidemia in 60%–85%. The presence of hypertriglyceridemia, diabetes mellıtus and generalized lack of subcutaneous adipose tissue led us to suspect from lipodystrophy. Although acute pancreatitis due to hypertriglyceridemia can be seen in lipodystrophy (15-20%), first presentation of WS presenting with acute pancreatitis is very rare in the literature. The most common mutation in non-Japanese patients in WRN gene is c.1105 C>T (18.6%). Metreleptin, an analog of human leptin, is shown to ameliorate the metabolic derangements. WS remains a diagnostic challenge due to its rarity, atypical presentation, and should be kept in mind in patients with severe dyslipidemia and insulin resistance.

Taxane-induced scleroderma-like skin changes – review of the literature and case report

Abstract: Taxanes (paclitaxel, docetaxel) are antineoplastic agents used in advanced ovarian, breast, lung, head and neck cancer. Diverse cutaneous adverse reactions associated with taxane administration have been reported such as bullous eruption, onycholysis, acral erythema, erythema multiforme, pustular eruption, scleroderma-like skin changes of both upper and lower extremities. Here, we report a case of 48-year-old female patient, who presented for consultation with rheumatologist with complaints of hand and finger oedema and stiffness. Oedema and mild skin thickening of the fingers and hands were evident at physical examination. Inflammatory joint pain, synovitis, Raynaud’s phenomenon and trophic changes were not present. Standard laboratory tests i.e., complete blood count and biochemistry tests were within normal values. The patient was euthyroid. Immunological tests were negative (antinuclear antibodies; antibodies against extractable nuclear antigens – dsDNA, Sm, RNP, Scl-70; antiphospholipid antibodies – anticardiolipin, anti-beta-2-glycoprotein; anti-CCP antibody and rheumatoid factor). Capillaroscopic examination did not reveal signs of microangiopathy. Skin biopsy was perfomed in the area of a proximal phalanx and the histological examination revealed dermal oedema and superficial scant perivascular infiltrate containing lymphocytes and histiocytes. The patient had undergone an operation for breast cancer 13 years ago and subsequent second operation because of cancer recurrence 7 years ago. After the second operation chemotherapy was performed that included 1 cycle with paclitaxel and 4 cycles with docetaxel. The analysis of the case led to the conclusion that the scleroderma-like skin changes of the fingers and hands are induced by taxane administration in the past. The patient received corticosteroid treatment for 7 months with gradual resolution of symptoms.

A rare case report: Werner syndrome

Abstract Introduction Werner syndrome (WS), also known as adult progeria, is a rare autosomal recessive syndrome caused by pathogenic loss of function of the WRN gene on chromosome 8p12. WS is characterized by signs of premature aging in young adults, including short stature, graying of hair, bilateral cataracts, and scleroderma-like skin changes. A thin, high-pitched voice is characteristic of patients. In addition, diabetes mellitus, cardiovascular disease and osteoporosis can also be seen at an increased rate. Patients have an increased thyroid neoplasms, malignant melanoma and meningioma. There is no specific or effective treatment for this rare syndrome. In this case, we aimed to present our patient with this rare syndrome. Clinical case A 28-year-old male patient was admitted for diabetes regulation and foot ulcers. In the patient's history, it was learned that he did not gain weight and did not gain sufficient height since the age of 14. He had been receiving insulin therapy for uncontrolled diabetes for about 10 years. He had cataract surgery at the age of 18. In our evaluation, there were scleroderma-like skin changes on the distal parts of both lower extremities. The patient's hair turned gray. His voice was high-pitched. Two of his siblings looked like him. One sibling who looked like him died at the age of 34. In the laboratory tests; FPG:306 mg/dL and HbA1C:11. The patient had hypergonadotropic hypogonadism. Rheumatological disease examination was normal. No pathological features were observed in lower extremity doppler examinations. Werner syndrome was considered in the patient who did not have sufficient height growth during adolescence, graying of the hair, a history of cataracts, scleroderma-like skin changes, and an elderly appearance. Malignancy scans of the patient were found to be normal. Genetic counseling was given to the patient and his family. The patient was taken to outpatient follow-up. Conclusion Werner syndrome is a rare disease. It is important to recognize patients in the early period, to prevent disease-related complications, especially in terms of the risk of malignancy development.

Interstitial lung disease in a patient with premature aging: Suspected Werner syndrome

Werner syndrome (WS) is a rare inherited autosomal recessive disease that can be diagnosed with cardinal signs without the genetic testing. Some features that are consistent with WS include premature aging, loss, and graying hair, scleroderma-like skin changes. We report a 42-year-old man with cardinal signs of WS who also developed interstitial lung disease (ILD). The patient had past medical history (PMHx) of atypical left femur fracture in his early 30s from unknown causes. Also, he had loss and graying hair, salt-on-pepper skin changes, associated with squeaky voice, muscle wasting, and osteoporosis. He had worsening symptoms of dyspnea on exertion and was found with bilateral diffuse subpleural reticular opacities with slight mid- to lower-lung predominance and mild bronchiectasis without honeycombing or ground-glass airspace opacities on chest computed tomography (CT) scan. Other causes of ILD were excluded as patient routine laboratories and rheumatologic workup was negative. Werner syndrome presents similar features with other telomerase-associated diseases such as mutations of telomerase complexes [telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT)]. Werner syndrome can be difficult to diagnose because it is a rare genetic disease that begins to show symptoms and signs after 10 or 20-year-olds, but the diagnosis is recognized after 30s. Few cases have been reported about the association of WS and ILD, but both diseases are aging diseases. This case might be the first case reported in Puerto Rico of Werner syndrome associated with ILD. Early referral and treatment is important to improve patients’ quality of life and life expectancy by slowing the progression of the disease.

Progeria (Hutchinson-Gilford Syndrome): Literature Review and Clinical Case

Progeria, or Hutchinson-Gilford Syndrome is a rare disease from the group of laminopathies characterized by premature aging with skin, bones and cardiovascular system lesions. Pathogenesis is based on pathogenic variants in the LMNA gene leading to anomalies in the nuclear membrane morphology, gene expression disruption, chromatin structure changes, mitochondrial dysfunction, DNA repair and alternative splicing defects, and telomere shortening acceleration. Major manifestations of the disease are: skin lesions (scleroderma-like syndrome and pigmented lesions), lipodystrophy, late teeth eruption, teeth crowding, alopecia, nail dystrophy, osteolysis of distal phalanges, hip joints valgus deformation, joints contractures, atherosclerosis, hearing loss, early heart attacks and strokes. Scleroderma-like skin changes, osteoporosis, flexion contractures of hands’ interphalangeal joints, and hip joints osteoarthritis require differential diagnosis with rheumatic diseases. The basic strategy in management of patients with progeria is the prevention and treatment of its cardiovascular manifestations (early strokes and heart attacks, arterial hypertension, and atherosclerosis), as well as the increase of patients’ quality of life and daily activity. The efficacy of therapy in patients with progeria via the use of farnesyltransferase inhibitors (monotherapy; combination with bisphosphonates or statins), retinoids, and 1,25(OH)2 — vitamin D3 is studied. This literature review is updated with clinical case description of a girl with progeria. The diagnosis was confirmed by sequencing of the LMNA gene (Sanger), and previously described pathogenic variant in exon 11 (c.1824C>T, rs58596362) in the heterozygous state (p.Gly608Gly, NM_170707.3) was revealed.

Scleroderma as a paraneoplastic syndrome and tumors associated with scleroderma

Patients with systemic scleroderma, or systemic sclerosis (SS), have an increased risk of developing malignant neoplasms. Cancer can be diagnosed immediately prior to SS symptoms, at the stage of diagnosis and years after SS diagnosis. The first two cases may indicate scleroderma-like paraneoplastic syndrome. In this case, the main mechanism of paraneoplastic syndrome development is associated with immune system activation by antigens, expressed by tumor cells, which leads to the development of antibodies that cross-react with body tissues, causing damage and secondary regeneration. Thus, cancer induces autoimmunity – mutation-specific T-cell immune response, and pathogenetic mechanisms can be the same for fibrogenesis and oncogenesis.SS clinical and laboratory characteristics that indicate paraneoplastic etiology include minimum time difference between diagnosing scleroderma and cancer, as well as oncopathology in a patient’s or family cancer history, late disease onset (after 50 years), SS symptoms in a man, sudden onset and rapid progression of clinical symptoms, expressed or atypical SS symptoms (malaise, fever, significant weight loss), asymmetric or absent Raynaud syndrome, antibodies against RNA polymerase III, absence of anticentromeric antibodies and anti-Scl70, deviations in laboratory tests indicating possible oncopathology (anemia, hypercalcemia, hypergammaglobulinemia), no response to SS treatment, disappearance of SS symptoms after anticancer treatment and their appearance when cancer reactivation. On the other hand, patients with scleroderma have an increased risk of all types of cancer, with men at higher risk than women. Continuous autoimmune stimulation, B-cell activation, chronic inflammatory process and fibrosis in SS patients can lead to malignant transformation in certain organ systems, especially in lungs.The most important risk factor for lung cancer in SS patients is interstitial lung disease, requiring special attention from a physician. In addition to lung cancer, SS patients more likely than the general population suffer from malignant hematologic diseases, esophageal cancer, hepatocellular carcinoma and bladder cancer. Scleroderma-like skin changes are also possible when cytotoxic drugs are used to treat cancer (docetaxel, paclitaxel, bleomycin, etc.), as well as during radiation therapy.

Sclerodermalike syndromes: Great imitators

Sclerodermalike syndromes (SLSs) comprise diseases with mucin deposition (eg, scleromyxedema, scleredema), with eosinophilia (eg, eosinophilic fasciitis), metabolic or biochemical abnormalities (eg, nephrogenic systemic fibrosis), or endocrine disorders (eg, POEMS syndrome, or polyneuropathy, organomegaly, endocrinopathy, monoclonal lymphoproliferative disorder, and hypothyroidism). Chronic graft-versus-host disease may also show sclerodermalike skin changes. Inherited progeria syndromes with early aging (eg, Werner syndrome) and a heterogeneous group of hereditary disorders with either skin thickening (eg, stiff skin syndrome) or atrophy and tightening (eg, acrogeria) can also imitate classic systemic sclerosis (SSc). In addition, SLSs can be provoked by several drugs, chemicals, or even physical injury (eg, trauma, vibration stress, radiation). In SLSs, the distribution of skin involvement seems to be atypical compared with SSc. The acral skin involvement is usually missing, and lack of Raynaud phenomenon, scleroderma-specific antinuclear antibodies, the absence of scleroderma capillary pattern, and internal organ manifestations indicate the presence of an SLS. Skin involvement is sometimes nodular, and the underlying tissues can also be affected. For the differential diagnosis, a skin biopsy of the deeper layers including fascia and muscle is required. Histology does not always allow differentiation between SSc and SLSs; therefore, the diagnosis is often based on the distribution, quality of cutaneous involvement, and other accompanying clinical features.

A clinical case of a patient with scleroderma-like syndrome in chronic graft-versus host disease

Chronic graft versus host disease is observed within the fi rst 100 days following allogeneic haematopoietic stem cell transplantation and can affect all tissues and organs (in 80% of the cases, it affects the skin). There are some clinical correspondences between chronic graft versus host disease and certain autoimmune diseases, such as systemic scleroderma, Sjogren‘s syndrome, autoimmune hepatitis. We present a case of a 54-year-old man with manifested diffuse, scleroderma-like skin changes, which occurred about a year and a half after allogenic bone marrow transplantation from an unrelated donor due to a blast transformation of chronic myelomonocytic leucosis type 2. The patient was treated in a haematology clinic with corticosteroids, 10 photophoresis sessions, Ciclosporin, Tacrolimus, Mycophenolate mofetil, Imatinib. It has been assumed that this is a case of chronic graft versus host disease resistant to corticosteroids, and Methotrexate 25 mg/weekly every other month was prescribed with no significant clinical improvement. In terms of the differential diagnosis, the question remains whether or not this is a case of paraneoplastic systemic scleroderma – autoimmune phenomena accompanying malignancy and often preceding it for months.

Cartilage hair hypoplasia: Heterogeneity in clinical features and management among siblings

Background: Cartilage-hair hypoplasia (CHH), caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene, is associated with diverse immune abnormalities including combined immune deficiency (CID). Most patients with CHH are managed with supportive measurements, while few have received allogeneic hematopoietic stem cell transplantations (HSCT). The progression of the immune abnormalities and the impact of HSCT in patients with CHH and CID have not been well characterized. Methods: The clinical and laboratory findings of 2 siblings diagnosed in infancy with CHH and CID due to the common 70A>G mutation in RMRP, including the effects of HSCT performed in 1 of them, were compared. Results: Both patients suffered from recurrent respiratory infections at early age with reduced T cells numbers and responses. Patient 1 immune function continued to deteriorate leading to HSCT from an HLA-matched sibling at 4.5 years of age. The patient suffered acute and chronic graft versus host disease of the skin with residual mild joint contractures and scleroderma-like skin changes. Seven years after HSCT patient 1 has normal immune function. Immune evaluations of patient 2 in the first years of life indicated mild improvement. The patient did not have a suitable related HSCT donor and the family elected to continue with supportive care. At 7 years of age, patient 2 is clinically well and thriving with persistent T cell abnormalities. Conclusions: Close monitoring of immune function in early life for patients with CHH and CID as well as the availability of suitable donors assists in determining management, including HSCT. Statement of novelty: The manuscript demonstrates the importance of close monitoring and personalized approach in the management of patients affected by CHH.

Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS

Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL.To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to ~100× average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes.As expected for non-malignant tissues, the patient's mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM_033360.3:c.183A>C, NP_203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood.Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS, perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL.

Hutchinson-Gilford progeria syndrome

To report a case of Hutchinson-Gilford progeria syndrome (HGPS). Peripheral blood samples were collected from a 5-year-old boy with HGPS and his parents. DNA was extracted from these samples, and PCR was performed to amplify exon 11 of the LMNA gene and its flanking sequences followed by DNA sequencing. The patient presented with scleroderma-like skin changes all over the body, growth retardation, distinctive facial features and hypotrichosis. His hip and knee joints could not be straightened completely, giving a horse-riding stance. A heterozygous mutation C.1824C>T was identified in exon 11 of the LMNA gene in the patient but not in either of his parents. A retrospective analysis was carried out on 18 Chinese patients with genetically diagnosed HPGS. Of them, 9 classical cases were all sporadic with a heterozygous mutation of C.1824C>T. None of the patients with classical HPGS showed abnormality at birth, but all of them developed symptoms within 1 year after birth. Boys were more frequent to be affected by classical HPGS than girls, with the male/female ratio being 2:1. There was a familial tendency for the occurrence of atypical HPGS, and boys and girls appeared to be affected by HPGS at a similar probability. Three families with atypical HPGS all showed a homozygous LMNA mutation c.1579C>T. Key words: Progeria; DNA mutational analysis; Molecular diagnostic techniques; Genetic phenomena; Genes, LMNA

Early Onset Werner Syndrome

Werner syndrome (WS) is a rare autosomal recessive adultonset progeroid disorder characterized by the early onset of aged-appearance and age-related metabolic disorders caused by homologous mutations at the WRN helicase locus (1). The features of the syndrome were first described as sclerodermalike skin changes, short stature, gray hair and genital hypoplasia (2). Later, other endocrinological manifestations, including osteoporosis and glucose metabolism abnormalities have been shown to be the components of this syndrome. Generally, the first manifestation of the disease is absence of growth spurt (3). The incidence of WS is one per million. It is known that the frequency of this syndrome is higher in Japan as 75% of patients were reported from Japan between 1904 and 2008 (4). Case reports from Turkey are extremely rare (5,6,7,8). Symptoms of premature aging usually first develop in the third decade of life (3). Herein, we present an atypical case of WS with early onset of premature aging-related metabolic disorders. Werner syndrome (WS) is a rare autosomal recessive adult-onset progeroid disorder characterized by the early onset of aged-appearance and age-related metabolic disorders. Symptoms of premature aging usually first develop in the second-third decades of life. We report a 27-year-old female who was admitted to our clinic at the age of eighteen with hyperglycemia. She was diagnosed with diabetes and type 4 dyslipidemia at the age of seven. In her family history, her parents were first cousins and she had three healthy brothers. On her first physical examination; she had bird-like face appearance, global hair loss, beaked nose, short stature and she was overweight. She had global hair loss with gray and thin hair. Hoarseness of voice and hyperkeratosis of skin were observed. She had bilateral cataracts and moderate sensorineural hearing loss. On psychiatric examination, borderline mental retardation was detected. She had severe insulin resistance and hypertriglyceridemia despite levothyroxine, gemfibrozil, omega-3 and intensive insulin treatment. Routine lipid apheresis was performed to lower the triglyceride levels reaching 5256 mg/dL. She also had focal segmental glomerulosclerosis, hepatosteatosis, osteoporosis and epilepsy. Disease was accompanied by several congenital deformities, such as Rathke’s cleft cyst, angiomyolipoma and femoral neck hypoplasia. WS is a rare genetic disorder characterized by multiple endocrine manifestations as well as soft tissue changes. We present a case of early disturbances that were diagnosed before typical clinical signs and symptoms. We propose that WS should be kept in mind when type 2 diabetes and hyperlipidemia are diagnosed early in childhood. Turk Jem 2015; 19: 99-104

Spectrum of cutaneous manifestations of type 1 diabetes mellitus in 500 south Asian patients

Data on cutaneous manifestations of type 1 diabetes mellitus (DM) is scarce. To study the spectrum of dermatoses in patients with type 1 DM and the effects of disease duration and long-term glucose control on these cutaneous manifestations. After prior consent, clinical examination and relevant investigations were done in 500 subjects with type 1 DM enrolled between July 2011 and June 2012. Statistical tests were performed using SPSS 16. The presence of various dermatoses was correlated with the duration of diabetes. Of five hundred subjects, 339 (67·8%) had one or more dermatoses. The mean age of the patients was 16·9 ± 6·9 years (range 1-25 years) and mean total duration of diabetes was 4·43 ± 4·4 years. Cutaneous adverse effects related to insulin injections (CAII), comprising lipohypertrophy (41%), post-inflammatory hyperpigmentation (3%), lipoatrophy (0·6%) and acanthosis nigricans (0·4%), were the most common findings, followed by limited joint mobility (LJM) (16·8%), xerosis (15·8%) and scleroderma-like skin changes (10%). Patients having long-duration DM (> 4·4 years) were significantly more likely to have lipohypertrophy (P = 0·000), LJM (P = 0·000), scleroderma-like skin changes (P = 0·000), diabetic dermopathy (P = 0·000), acanthosis nigricans (P = 0·005) and skin tags (P = 0·002). Lipohypertrophy, LJM and scleroderma-like skin changes also showed significant correlation with blood glucose level. Our study suggests that cutaneous changes are common in young Asian patients with type 1 DM. Information, education and counselling of patients and care givers, and awareness among physicians is essential for the prevention and early management of these dermatoses.

Ultrasound Assessment of Subcutaneous Compressibility

Eosinophilic fasciitis (EF) is an autoimmune, fibrotic disorder described initially with scleroderma-like skin changes where deep soft tissue sampling that includes fascia is frequently felt to be necessary to confirm the diagnosis. The objective of this study was to distinguish forearm involvement by EF from other fibrosing diseases and from control subjects with normal skin and fascia using B-mode ultrasound. A cross-sectional study over a 4-year period in which clinically involved forearm skin of consecutive patients with EF (n = 12), diabetic cheiroarthropathy (n = 8), diffuse systemic sclerosis (n = 23), and control subjects (n = 8) was evaluated by 12-MHz, B-mode ultrasound for degree of subcutaneous tissue compressibility, and this finding was compared with the criterion standard of clinical diagnostic criteria for each disease process. Subcutaneous compressibility in EF was significantly reduced when compared with diffuse systemic sclerosis and with control subjects. Subcutaneous thinning was observed in some patients with EF (4/12), diabetic cheiroarthropathy (4/8), and diffuse systemic sclerosis (6/23), but not in control subjects. Diabetic cheiroarthropathy and diffuse systemic sclerosis patients with subcutaneous thinning had less than 20% subcutaneous compressibility, whereas only 1 of 12 EF patients had compressibility of more than 20% regardless of subcutaneous thinning. A 12-MHz, B-mode ultrasound may be used to measure subcutaneous compressibility, thereby serving as an adjunct tool in distinguishing EF from diffuse systemic sclerosis, especially when tissue sampling is less feasible or when the result of tissue sampling is equivocal.

Paclitaxel-Related Lymphedema and Scleroderma-Like Skin Changes

Paclitaxel is an antimicrotubule agent used for the treatment of metastatic breast cancer. The development of scleroderma-like skin changes is an exceptional adverse effect. We report two patients with metastatic breast cancer treated by paclitaxel who presented an unexplained unilateral lymphedema of the upper limb. Medical work-up did not demonstrate any mechanical or tumor obstruction of the lymphatic vessels. Dermatologic examination revealed cutaneous and subcutaneous indurations and hardening of certain areas of the involved arm. The clinical suspicion of scleroderma was confirmed by histology and immunohistology. Treatment was initiated with methotrexate and methylprednisolone, resulting in a clear reduction of the lymphedema and a regression of the scleroderma. These two cases suggest a pathogenic role of paclitaxel-induced scleroderma in the subsequent development of severe localized lymphedema.

Werner syndrome. A prototypical form of segmental progeria.

Werner syndrome is a segmental progeroid disorder with onset in adolescence or early adulthood. Typical symptoms contributing to patients' prematurely aged appearance include postpubertal development of short stature, cataracts, premature greying/thinning of scalp hair, scleroderma-like skin changes and regional atrophy of subcutaneous fat tissue. In addition, an increased rate and early onset of typical age-related diseases such as type 2 diabetes mellitus, osteoporosis, atherosclerosis, and various malignancies is observed. Werner syndrome is autosomal recessively inherited and caused by mutations in the Werner gene (WRN). To date, more than 70 WRN mutations have been identified. These are spread over the entire gene and typically represent loss of function mutations. WRN encodes a RecQ type helicase involved in DNA repair and the maintenance of DNA integrity, which is reflected by an increased genetic instability in patient cells. Despite the relative rarity of Werner syndrome, its analysis provides important general insights into the roles of DNA stability and integrity for the ageing process and the development of age-associated diseases.

Dermatomyositis Presenting With Focal Scleroderma-Like Skin Changes

To describe an unusual focal scleroderma-like skin changes in patient with dermatomyositis. Review of clinical records, laboratory investigations, and muscle and skin biopsies. The patient developed unusual skin lesions characterized by symmetrical atrophy and hardening of focal skin and muscle over the lateral upper arms and posterior shoulders, and the left temporal and pectoral areas. Extensive blood work-up for scleroderma and other connective-tissue diseases was negative. A skin biopsy showed distinct pathologic features including increased interstitial mucin, hyperpigmentation, and perivascular lymphocytic inflammation without severe fibrosis. The scleroderma-like skin changes and muscle weakness improved with immunotherapy. Dermatomyositis can manifest with focal scleroderma-like skin changes clinically and reticular erythematous mucinosis-like changes pathologically, and these distinct skin changes represent a new variant of skin lesions of dermatomyositis.

Successful Autologous Peripheral Blood Stem Cell Transplantation in 3 Women with POEMS Syndrome: A Single Centre Experience

Abstract 4504 INTRODUCTIONPOEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) is a rare multi-system disease characterized by chronic progressive polyneuropathy and plasma-cell dyscrasia. A major diagnostic criterion for POEMS is elevation of circulating vascular endothelial growth factor (VEGF), which is believed to play a pathogenic role in this disease.We report 3 cases of POEMS syndrome treated with high-dose melphalan and autologous peripheral blood stem cell transplantation (PBSCT).PATIENTS AND METHODS CASE 1A 32-year-old woman presented with a progressive gait difficulty, weakness in limb muscles, skin hyperpigmentation, axillar and laterocervical lymphoadenopathies, peripheral edema. Neurophysiological testing showed a motor and sensory axonal polyneuropathy. At laboratory testing, thrombocytosis and monoclonal gammopathy IgA-λ were detected. A biopsy of laterocervical lymphonode was positive for Castleman's disease. Initial treatment with intravenous immunoglobulin (IVIg) failed to result in clinical benefit. After cyclophosphamide 2 g plus G-CSF priming a total of 7.1×106/kg stem cells were collected from peripheral blood and used to perform double autologous transplantation at interval of 5 months following conditioning with melphalan 140 mg/sq/m. CASE 2A 48-year-old woman presented with numbness and paresthesias in foot soles, weakness in lower limbs and axillar lymphoadenopathy. Nerve conduction studies showed motor and sensor demyelinating polyneuropathy. A monoclonal gammopathy IgG K-λ was present and bone marrow biopsy was unremarkable. She was treated with prednisone and plasma exchange with progressive improvement and clinical stabilization for two years. Unfortunately she presented a relapse of neurological symptoms responding to the same therapeutic strategy. A second relapse occurred after 3 months with appearance of sensory ataxia, xerotic skin, hepatomegaly. Laboratory analysis revealed biclonal gammopathy IgG k-λ and IgA-λ and Bence Jones proteinuria (λ light chain). Radiologic studies showed lytic lesions with sclerotic rim in homerus, VII rib and iliac bone and mediastinal, axillary and iliac lymphadenopathies. The patient received cyclophosphamide 2 g and G-CSF for mobilization. Melphalan 200 mg/sq/m was administered intravenously as conditioning regimen followed by reinjection of the cells collected. CASE 3A 44-year-old woman presented with asthenia, scleroderma-like skin changes, weight loss, limb paraesthesia and weakness. Neurophysiological testing showed a motor and sensor demyelinating polyneuropathy. She presented thrombocytosis and a monoclonal IgG-λ protein at laboratory tests. Radiologic studies showed laterocervical, axillary, mediastinal lymphoadenopathies, multiple thyroid nodules and a mixed sclerotic and lytic lesion in the pelvis and in the right humeral head. Biopsy of this lesion demonstrated a plasmacytoma with λ light chain restriction. Initial treatment with IVIg was unsuccesful. She received oral therapy with melphalan and prednisone for 3 years obtaining clinical stabilization, then she was treated with monthly zoledronic acid infusion only. After 3 years she presented a relapse of neurological symptoms, appearance of hepatomegaly, axillar and laterocervical lymph nodes enlargement, peripheral edema. She therefore underwent PBSC harvesting following cyclophophamide priming (2 g), than she received melphalan (200 mg/sq/m) with CD34-selected PBSC rescue. RESULTSThe post-transplant course was uneventful other than the development of febrile neutropenia in 2 cases. Patients 1 and 2 presented a progressive improvement in strength, physical skills and peripheral neuropathy after few months. They are well with clinical stabilization after 4 and 6 years, respectively, from PBSCT. At 3 months from PBSCT, patient 3 presents progressive neurological improvement and reduction of organomegalies. CONCLUSIONSAlthough treatment for POEMS is not standardized, disseminated disease require systemic therapy. No randomized controlled trials have been conducted, but patients with POEMS have been successfully treated with PBSCT since 1998. Our cases confirm its usefulness and safety and support the idea that, although delayed intervention maintains its efficacy, PBSCT could be considered early during the disease course to obtain the best response. Disclosures:No relevant conflicts of interest to declare.

Scleroderma-like skin changes not involving the hand in a prepubertal male with type I diabetes mellitus

To our knowledge there have been no reports of scleroderma-like skin changes, not affecting the hand in prepubertal patients with Type I Diabetes Mellitus (T1DM). We report a prepubertal caucasian male with T1DM, and early morpheatype skin changes of the trunk and extremities, not involving the hand.