Peeling skin syndrome: genetic defects in late terminal differentiation of the epidermis

In this issue, Israeli and colleagues confirm that homozygous mutations in corneodesmosin (CDSN) cause type B peeling skin syndrome (PSS), an autosomal recessive skin disorder. The deletion mutation described resulted in a frameshift, producing a downstream premature stop codon and early truncation of the protein. The recently described CDSN nonsense mutation in another PSS family also resulted in protein truncation and nonsense-mediated mRNA decay. Type B generalized PSS can now be clearly distinguished from acral PSS, caused by mutations in transglutaminase 5. This directly affects cornified envelope cross-linking rather than corneodesmosome adherence. These observations provide new insight into the molecular defects underlying two closely related forms of PSS.     

Peeling skin diseases: 21 cases from Turkey and a review of the literature

Background Peeling skin diseases (PSD) refer to a group of rare autosomal recessive dermatosis which are characterized by spontaneous, continual peeling of the skin. Three different clinical pictures can be distinguished: Inflammatory PSD also referred to as peeling skin syndrome (PSS) type B, non‐inflammatory PSD also referred to as PSS type A, and localized forms i.e. acral type PSS. Objective To characterize the clinical and histopathological features of PSD in Turkey. Methods We retrospectively reviewed the medical records and clinical photographs of patients who were given diagnosis of PSD and conducted histopathological evaluation of skin biopsies to identify the site of cleavage. Also we evaluated the cases including age, gender, age onset, clinical and histological findings, family history, associated disorders and PSD type. Results Twenty‐one patients with PSD were seen at Gulhane School of Medicine in Ankara between the years 1994 and 2010 in this retrospective study. All patients were men. Their ages were between 20 and 26 years (22.44 ± 2.30, Mean age ± SD). Of the patients, eight cases (40%) were type A, eight cases (40%) were type B, and five cases (20%) were acral type PSS. Eleven cases (52%) had parental consanguinity. Keratoderma, cheilitis, keratosis pilaris, melanonichia, clubbing, hyperhidrosis, onychodystrophy were observed in eight cases as an accompanying disorder. Conclusions In this case series, PSD occurred rarely and also showed generally mild course of disease in Turkey and most likely related to consanguineous of marriages. Future investigations on PSD will contribute to our progressing alternative targets for pathogenesis‐based therapy.     

Intestinal absorption of L-tryptophan in scleroderma.

The purpose of this investigation was to study the intestinal absorption of L-tryptophan and to assess the absorptive function of the intestine in scleroderma. The oral L-tryptophan loading test was performed in 31 cases of systemic scleroderma (progressive systemic sclerosis, PSS) and 3 cases of localized scleroderma. Serum levels of tryptophan and urinary excretion of indole-acetic acid (IAA) and indican (IS) were determined in order to assess intestinal absorption of tryptophan. In 10 cases the D-xylose test and in 4 cases Schilling's test was also performed. Furthermore, in vitro binding of L-tryptophan by plasma proteins in PSS and in other skin diseases as controls was studied. The normal increase in serum tryptophan after loading was noted in 17 cases (in 14 cases of PSS with a mild, slow progression in 3 cases of PSS with a severe, rapidly progressing course). In 10 of these cases, urinary excretion of IAA was higher than normal and in normal and in 3 cases excretion of urinary IS was also above normal. On the other hand, in 14 cases of severe, rapidly progressing PSS and in 2 of 3 cases of widespread linear scleroderma, serum levels of tryptophan were markedly depressed after loading, while urinary excretion of IAA and IS was normal. In all 4 cases studied, Schilling's test was normal, and only in 2 of 10 cases of PSS was the D-xylose test abnormal. It is concluded that in the majority of cases of PSS, intestinal absorpiton of tryptophan is normal as also is the absorptive function of the intestine. The slight rise in serum tryptophan after loading in some cases of PSS may be a result of increased binding of tryptophan by albumin.     

Increased calmodulin levels in fibroblasts from progressive systemic sclerosis

Calmodulin levels in cultured skin fibroblasts from patients with progressive systemic sclerosis (PSS) and healthy controls were measured by their ability to activate cyclic AMP-phosphodiesterase. Calmodulin levels were significantly increased in PSS fibroblasts compared with normal control fibroblasts. The changes in calmodulin content of PSS fibroblasts were also assessed by a radioimmunoassay. These findings suggest that an elevated level of calmodulin may play a role in the pathogenesis of PSS.     

川芎素对系统性硬皮病患者循环内皮细胞的影响

目的观察系统性硬皮病(PSS)患者循环内皮细胞(CEC)数量的变化,了解PSS患者的血管内皮细胞受损伤情况及川芎素对PSS患者血管内皮细胞的影响,探讨川芎素治疗PSS的疗效机理。方法使用川芎素治疗PSS患者38例,观察治疗前后CEC的数量变化,以53例健康人的CEC数量作为对照比较。结果经川芎素治疗后,38例PSS患者的皮肤硬化、末梢疼痛、冷感、溃疡指数均有明显的改善(P<0.01)。治疗前PSS患者的CEC数量(3.40±1.27个/0.9μL)明显高于健康对照组(1.13±0.48个/0.9μL),治疗后随着临床症状、体征的好转,CEC数量也显著下降(1.80±0.58个/0.9μL)。结论川芎素治疗PSS不仅能显著改善临床症状和体征,而且对PSS患者的血管内皮细胞损伤也有较好的治疗和保护作用。     

HLA in systemic scleroderma (PSS) and familial scleroderma

HLA in systemic scleroderma (PSS), including three familial cases, is reported. Three families in which one sister developed PSS and another sister suffered from either PSS (family 1), mixed connective tissue disease (MCTD) (family 2), or Sjögren's syndrome (SjS) (family 3) were described. The elder sister in family 1 died of respiratory insufficiency caused by scleroderma lung. The sisters in family 2 both had SjS, anti SS-A antibodies, and HLA A2-Bw55-Cwl-DRw8 haplotype in common. The elder sister with PSS in family 3 also had SjS and Hashimoto's thyroiditis. HLA in 28 PSS patients including these 3 familial cases were analyzed with 4 MCTD and 4 generalized morphea patients. HLA A2, Bw46, DR2, DRw8, DRw6 and DQw1 antigens were more frequently found in the PSS patients than in the controls. HLA DRw6 was the only antigen that was positive in common in the 3 familial cases. In those patients with anti topoisomerase I antibodies, HLA DR2 antigen was found more frequently than in the controls. Some, but not all, of these results were similar to the previous reports on HLA in PSS. Further investigations on more patients and the other members of these families would be necessary to clarify the significance of these results.     

Clinical correlations and prognosis based on hyaluronic acid serum levels in patients with progressive systemic sclerosis

The serum levels of hyaluronic acid (sHA) were measured using an affinoimmunoenzymatic assay in patients with distal (n = 16) and proximal (n = 15) progressive systemic sclerosis (PSS) and in 31 controls. The severity of PSS was evaluated using a standardized organ-involvement score. The mean sHA was significantly higher in the patients with PSS than in controls (mean +/- SD:80 +/- 43.4 micrograms/l vs. 42.3 +/- 19.1 micrograms/l, P less than 0.001). sHA was significantly higher in patients with proximal PSS than in patients with distal PSS (106.4 +/- 44.6 micrograms/l vs. 55.4 +/- 23.8 micrograms/l, P less than 0.001). A positive correlation was found between sHA and the disease score (r = 0.67, P less than 0.001). sHA was also correlated with lung diffusion capacity for carbon monoxide (r = 0.70, P less than 0.001), but only in the those patients who had abnormal lung function, and therefore presumably had lung PSS involvement. We suggest that sHA could be an indicator of the degree of systemic involvement in PSS. Its prognostic value and possible use in the follow up of patients with PSS remain to be clarified.     

Type IV collagen and laminin levels in the sera from patients with systemic scleroderma (PSS)

Serum type IV collagen 7S and laminin P1 levels were measured with radioimmunoassay in 33 patients with systemic scleroderma (PSS), 6 localized scleroderma (LS), and one mixed connective tissue disease (MCTD). Serum type IV collagen 7S levels were higher in PSS (5.11 +/- 1.11 ng/ml:m +/- SD) and LS (4.68 +/- 0.46 ng/ml) than in normal controls (3.90 +/- 0.85 ng/ml) (p less than 0.001). Serum laminin P1 levels were also significantly higher in PSS (1.75 +/- 0.34 U/ml) and LS (1.38 +/- 0.20 U/ml) compared to the controls (1.19 +/- 0.16 U/ml) (p less than 0.001 and p less than 0.01, respectively). A significant correlation between these two values in PSS was found (r = 0.465, p less than 0.02). These results suggest that the measurements of these values may serve as a marker of PSS.     

Plasma somatomedin-C levels in systemic sclerosis

We have measured the plasma levels of somatomedin-C (SM-C) or insulin-like growth factor I (IGF-I) in 13 patients with progressive systemic sclerosis (PSS) and age and sex matched healthy controls. We found the plasma SM-C levels to be within normal limits in all the patients. Thus, if somatomedin-C plays a role in the pathogenesis of PSS, it is more likely to be at the fibroblast receptor level or in the synthetic response of fibroblasts to SM-C.     

OCCUPATIONAL OR EXTRINSIC STIMULATION FACTORS AND INITIAL SIGNS OF PROGRESSIVE SYSTEMIC SCLEROSIS

Forty-eight patients with progressive systemic sclerosis (PSS) (man-woman ratio, 7:41) were studied, and detailed questionnaires were used to clarify the relationship between occupational stresses and the initial signs of PSS. All of the patients were right-handed. Raynaud sign was seen in 37 of the 48 patients (77.1%) as the predominant initial sign of PSS, and it first was noticed on the right index and middle fingers. Three sets of extrinsic aggravating factors, vibration stress, fine hand work with mental stress, and exposure to cold, were believed to be related closely to the development of the initial signs because the initial signs appeared after long-term exposure to the extrinsic factors.     

申克氏孢子丝菌出芽方式、细胞分裂的超微结构观察

本文在电镜下观察了中克氏孢子丝菌(沈阳株)的出芽方式及细胞分裂的超微结构,发现孢子丝菌的出芽方式为内分芽型,双相性移行时菌丝机械性断裂为菌丝断片,其分裂繁殖方式为全分芽型.在分生孢子形成上具有多形性.在菌丝相中,见到本菌株具有假轴状分生孢子柄,可形成多个顶生分生孢子,故符合孢子丝菌.本文获得的结果可供对本菌株的分类、命名等参考.     

Neural Blockade,Urokinase and Prostaglandin E1 Combination Therapy for Acute Digital Ischemia of Progressive Systemic Sclerosis

To treat severe painful digital ulcers on progressive systemic sclerosis (PSS) patients, we developed a new combination therapy which included neural blockade, intravenous urokinase, and prostaglandin E1 infusion. All of these are already recognized treatments for circulatory disturbances in PSS. Although each of them alone has a limited effect on the painful ischemic attack in PSS; in stepwise combination, neural blockade for release of vascular spasm and pain, prostaglandin E1 for further vasodilatation, and urokinase for thrombolysis were effective in the treatment of digital ischemia in two PSS patients. This therapy reduced the necrotic areas predicted before therapy and saved fingers from amputation. It also relieved the intolerable digital pain and effected the recovery of digital function.     

Die Extrakorporale Photopherese bei Progressiver Systemischer Sklerodermie: Unterscheidung von Respondern und Non‐Respondern

Background: The benefit of extracorporeal photopheresis (ExP) in progressive systemic sclerosis (PSS) is controversial. There is limited experience with the long‐term use of ExP in PSS. The purpose of the present study was to distinguish between responders and non‐responders by using ExP in PSS and to evaluate activation markers for PSS. Patients and methods: 20 subjects with PSS were treated for 12 months with ExP (interval: 1x/month) as an immunomodulating monotherapy (11/20) or combination therapy (9/20). The course of PSS was assessed by both specially designed clinical score and serological parameters (CRP, ANA, beta‐galactosidase, P‐III‐P, CD4/CD8‐ratio, TNF‐alpha, Il‐2‐R, Il‐6). Results: After 12 cycles of ExP, 30 % of the subjects showed a partial remission and 25 %, stable disease (55 % responders) while 45 % had a progression (non‐responders). Although there was no correlation between the clinical course and the serological parameters, an increase of beta‐galactosidase during therapy marked a progression of PSS in non‐responders. Responders with a short PSS‐course before ExP, moderate ANA titres, normal TNF‐alpha levels and lack of Scl‐70 had a good prognosis. Conclusions: About the half of the subjects with PSS profited by the long‐term use of ExP. Thereby the mild immunomodulating effect of ExP seems to be insufficient to control markedly progressive courses of PSS.     

Factor XIII in scleroderma: in vitro studies

The administration of Factor XIII (FXIII) produces a beneficial effect on the skin lesions in about 50% of the treated patients with progressive systemic sclerosis (PSS). The effect of FXIII on various skin fibroblast functions (proliferation, attachment, biosynthetic activity and mechanical properties) was investigated in vitro using normal and PSS strains. In cell culture, most of the PSS fibroblast strains synthesized excessive amounts of collagen. Other cell functions such as adhesion to collagen I or III, to fibronectin, retraction of collagen lattices, proliferation in low serum concentration and degradation of newly synthesized collagen were not significantly different. The addition of FXIII (I U/ml) inhibited the synthesis of collagen by normal fibroblasts and reduced it in PSS fibroblasts to a level similar to that of normal fibroblasts. This effect was observed for cells cultured on plastic or in a collagen lattice. In the latter, an increased amount of collagen degradation was observed. No significant effect of FXIII on the other cell functions was noted. Excessive collagen production by PSS fibroblasts can be repressed by FXIII in vitro by at least two distinct mechanisms: a reduction of collagen synthesis and an increased degradation of the newly synthesized collagen.     

Clinical classification of vasculitis

Clinical classification of vasculitis is needed to facilitate diagnosis and management of the disease as well as to assign patients to defined groups for clinical studies. Caliber and size of the vessels predominantly involved strongly influence the clinical features of the different forms of vasculitis and therefore are one major criterion for classification. As such, panarteritis nodosa involves medium-sized vessels and presents on the skin with subcutaneous nodules and livedo racemosa, while it does not cause glomerulonephritis. Leukocytoclastic vasculitis (LcV) involves the small vessels, resulting in palpable purpura, and sometimes also in glomerulonephritis. The classification systems of the American College of Rheumatology (ACR) and of the Chapel Hill Consensus Conference (CHCC) have gained wide acceptance. Yet, they need to be updated, especially with regard to LcV, the most common vasculitis of the skin. Here distinctions must be made for prognostic, diagnostic and therapeutic reasons between IgG/IgM- and IgA-associated LcV (Henoch-Schoenlein purpura, HSP), as well as between HSP of children and HSP of adult age. The latter bears the highest, while IgG/IgM-associated LcV bears the lowest risk for complications. This update on the clinical classification of vaculitis is based on the ACR and CHCC system and focuses on those forms which regularly cause cutaneous symptoms. It provides a survey on the vasculitic syndromes and should help in deciding when i) extensive diagnostic procedures are needed in patients with LcV, ii) therapy should be less or more aggressive, e.g. in cutaneous versus systemic PAN, iii) therapy should be promptly initiated, e.g. when any form of severe, ANCA-associated vasculitis is suspected.     

Fibrinolytic therapy for progressive systemic sclerosis and tissue fibrinolytic activity in affected skin.

In our present study, impairment of tissue fibrinolytic activity was observed in the affected skin of patients with progressive systemic sclerosis (PSS) by fibrinolytic autography. We treated PSS with a fibrinolytic agent, urokinase, based on the idea that the impairment of tissue fibrinolytic activity is implicated in the development of PSS. Two patients with PSS have responded favorably well to administration of Urokinase.     

Scleroderma and HLA antigens

A possible HLA disease association was investigated in 40 patients (38 female, 2 male) with progressive systemic scleroderma (PSS), and 42 patients (32 female, 10 male) with morphea. HLA ABCDR/DQ, glyoxalase and properdin factor B (GLO and BF) phenotypes of patients were compared with 193 healthy controls. Four PSS family studies were performed. The following relative risk (rR) values were determined in PSS: A1 (1.38), A2 (1.39), B8 (1.67), B15 (3.22) and in morphea: A3 (1.43), B7 (1.39), B40 (1.81), BW60 (2.49), DR2 (2.38) and DRW8 (2.55), indicating a relatively weak, HLA-linked genetic predisposition for the manifestation of these dermatological disorders. The HLA "risk" antigens for the two clinically different subtypes of the disease are also different: raised A1/B8 frequencies such as those in our PSS group are related to high (or pathologic) immune response (autoimmune disorders). In contrast, A3 B7 DR2 elevations such as those recorded in our morphea group correlate with low immune response. Following exposition to certain suspected environmental factors (quartz, chemical solvents, drugs, viral fragments), the HLA phenotype may thus predipose some individuals--predominantly women--to different clinical patterns of the disease. HLA typing may thus be useful in clinical differential diagnosis (recent subtyping protocols) and possibly also for determination of the prognosis, i.e. HLA-B8 seems to be related to an acute, inflammatory course of PSS, and HLA-B7/DR2, to rather mild morphea patterns.     

Progressive Systemic Sclerosis Sine Scleroderma which Developed after Exposure to Epoxy Resin Polymerization

Progressive systemic sclerosis (PSS) sine scleroderma is well known as a special form of scleroderma. Because of its rarity, its pathogenesis has not yet been elucidated. We experienced a 33-year-old man who developed PSS sine scleroderma while working with epoxy resin polymerization. He had short white frenulum linguae, diffuse hyperpigmentation and facial telangiectasia, positive antinuclear antibody, and pulmonary dysfunction, but not acrosclerosis or sclerodactylia. Modest dermal collagen proliferation in the forearm skin confirmed PSS sine scleroderma. Epoxy resin polymerizer appears to be a potent causative agent for PSS sine scleroderma as well as for generalized morphea-like PSS.     

Clinical aspects and differential diagnosis of cutaneous lupus erythematosus

On the basis of LE cases treated at the Department of Dermatology, Düsseldorf University, during the last few years, we present the various forms of cutaneous lupus erythematosus (CLE). 72% of the patients showed discoid lupus erythematosus (DLE), whereas disseminated discoid LE (DDLE) and lupus panniculitis were found in 3% each. Lupus erythematosus tumidus (LET), as well, must be regarded as exceptional. Subacute cutaneous LE (SCLE) and systemic LE (SLE) showed nearly similar frequency (10 and 12%, resp.). Bullous LE is also very rare and must be considered a variant of SLE. The various forms of cutaneous LE can be differentiated according to clinical presentation and histopathology. Direct immunofluorescence, in contrast, has but limited diagnostic value, except with lesions on the scalp. Exact classification of cutaneous LE is the more essential, as it implies considerable therapeutic and prognostic consequences for the patient.     

Lymphokine/monokine inhibition of fibroblast proliferation and collagen production: role in progressive systemic sclerosis (PSS)

A normal fibrotic response to inflammatory stimuli appears to be dependent on the balanced production of a number of stimulatory and inhibitory fibroblast-regulatory mediators by activated mononuclear cells (MNL). To investigate whether altered mediator production contributes to the fibrosis observed in progressive systemic sclerosis (PSS), we stimulated human peripheral blood MNL with concanavalin A (Con A) and lipopolysaccharide (LPS) to produce macromolecular mediators that inhibit the proliferation and the collagen production of cultured normal human fibroblasts. The two Con A-induced mediators were lymphokines (LK) as they were exclusively produced by activated T cells and they coeluted from a Sephacryl S-200 column with a Mr of 50,000. In contrast, the two LPS-induced mediators were monokines (MK) as they were exclusively produced by activated monocytes, and they coeluted in the Mr 20,000 range. Each pair of inhibitory LK and MK may also be distinct as inhibition of collagen production still occurred in proliferatively quiescent cultures. A quantitative comparison of the levels of fibroblast-inhibitory LK/MK produced by normal volunteers and long-term PSS patients revealed that although PSS MNL produced normal levels of both collagen production inhibitory mediators, they were aberrant producers of both proliferation inhibitory mediators, being hypo-producers (-49%) of the LK and hyper-producers (+196%) of the MK. These results suggest that reduced production of proliferation inhibitory LK may allow stimulatory mediators to induce the unrestricted fibroblast proliferation observed in early active PSS, which then may be stabilized in long-term PSS by the increased production of proliferation inhibitory MK.