Clinical correlates of pain in adults with hard-to-heal leg ulcers: a cross-sectional study.

OBJECTIVE: Pain is a complex symptom associated with hard-to-heal (chronic) leg ulcers that is often poorly managed. The objective of this study was to gain greater understanding by investigating relationships between physical and psychosocial factors, and pain severity in adults with hard-to-heal leg ulcers. METHOD: A secondary analysis of data collected for a longitudinal, observational study of adults with hard-to-heal leg ulcers was undertaken. Data were collected over a 24-week period, including variables relating to sociodemographics, clinical variables, medical status, health, ulcer and vascular histories, and psychosocial measures. Multiple linear regression modelling was used to determine the independent influences of these variables on pain severity, as measured with a Numerical Rating Scale (NRS). RESULTS: Of 142 participants who were recruited, 109 met the inclusion criteria for this study, of whom: 43.1% had venous ulcers; 41.3% had mixed ulcers; 7.3% had arterial ulcers; and 8.3% had ulcers from some other cause. The final model explained 37% (adjusted r2=0.370) of the variation in the pain NRS scores. Controlling for analgesic use, salbutamol use (p=0.005), clinical signs of infection (p=0.027) and ulcer severity (p=0.001) were significantly associated with increased pain, while the presence of diabetes (p=0.007) was significantly associated with a decrease in pain. CONCLUSION: Pain is a highly complex and pervasive symptom associated with hard-to-heal leg ulcers. Novel variables were identified as being associated with pain in this population. The model also included wound type as a variable; however, despite being significantly correlated to pain at the bivariate level of analysis, in the final model, the variable did not reach significance. Of the variables included in the model, salbutamol use was the second most significant. This is a unique finding that, to the authors' knowledge, has not been previously reported or studied. Further research is required to better understand these findings and pain in general.

The burden of costs on health services from patients with venous leg ulcers in Singapore.

Healthcare costs arising from venous leg ulcers (VLU) are expected to increase due to an aging population and increased prevalence of comorbidities. We aim to estimate the healthcare resources incurred by VLU patients, and to quantify the extent to which predictors explain variation in cost-related outcomes. Retrospective patient-level cohort data for VLU patients were analysed using generalised linear regression models. Data were extracted from a tertiary hospital registry in Singapore, between 2013 and 2017. The outcome variables were length of stay per admission; inpatient and outpatient bill per admission; whether a patient underwent a surgical treatment of the venous system; and, whether they visited the emergency department. Cost outcomes were reported in Singapore dollars (S$). A total of 162 VLU patients were included with a mean age of 67.5 (±14.4). For the inpatient setting the mean length of stay was 8.1 days and the mean inpatient bill was S$7886. For outpatients, the mean number of dressings was 29.4, and mean outpatient bill was S$6962. Heart disease patients incurred longer hospital stays and larger inpatient bills per admission and females had greater odds of undergoing a surgical procedure on the venous system. Certain VLU patient groups were found to be associated with larger cost outcomes.

Matrix metalloproteinase (MMP)-1 and MMP-2, but not COX-2 serve as additional predictors for chronic venous ulcer healing.

Chronic venous ulcers affect 1% of the adult population and are associated with a marked reduction in quality of life, especially if healing is prolonged. Several matrix metalloproteinases (MMPs) appear to be involved in the pathophysiology of chronic venous ulcer healing, but their exact role is still unclear. Cyclooxygenase-2 (COX-2) is an important enzyme in prostanoid synthesis, induced during inflammation in chronic venous ulcer. The first aim of our study was to compare the expression of MMP-1, MMP-2, and COX-2 in wound tissue to that in normal skin. The second aim was to observe the expression of the above factors in 29 chronic venous ulcers in 22 patients at the beginning and 4 weeks later in relation to healing rates and final healing outcome after 24 weeks. The enrolled population was divided into two groups, healed and non-healed wounds after 24 weeks. The intensity of expression of MMP-1, MMP-2 and COX-2 was assessed for each ulcer in paired wound biopsy samples and wound size measurements using laser triangulation at the beginning and after 4 weeks of observation. Initial healing rates in the first 4 weeks were calculated and proved to be an important predictive factor of healing in 24 weeks. Decreases in MMP-1 and MMP-2 after 4 weeks of observation were distinct, positive predictors for ulcer healing. Healing odds were 3.7 times higher for a decrease in MMP-1 and 2.1 times higher for a decrease in MMP-2 compared to the healing odds for a non-decrease in MMP-1 and MMP-2. In conclusion, a decrease in MMP-1 and MMP-2, but not COX-2, in wound biopsy samples after 4 weeks of observation can predict better healing of chronic venous ulcer.

Prevalence and factors associated with ulcer-related pain in persons with chronic leg ulcers-an explorative study.

AIMS AND OBJECTIVES: The aims of this study were to explore the prevalence of background pain and identify demographic, clinical and psychosocial factors associated with moderate to severe background pain in persons with leg ulcers. BACKGROUND: All chronic leg ulcers are potentially painful. Research indicates that 80% of persons with chronic leg ulcers experience wound-related background pain. However, studies on factors associated with pain have small samples and findings are inconclusive. DESIGN: Exploratory cross-sectional study. METHOD: This quantitative study recruited persons with chronic leg ulcers (N = 252) from two wound care clinics using consecutive sampling method. Data were obtained through screening interview, clinical examination and questionnaires. Logistic regression with stepwise backwards elimination was used to identify factors associated with moderate to severe background pain. The STROBE checklist for cross-sectional studies was used for reporting this study. RESULTS: Background pain was reported by 64% of the participants. Inferential statistical analyses suggest that between 58% and 69% of persons with chronic leg ulcers suffer from this type of pain. Factors associated with moderate to severe pain were older age, female gender, reduced sleep quality and diminished health status. In the final model, reduced sleep quality increased the likelihood of having moderate to severe pain in persons with good health status while not in persons with diminished health status. CONCLUSION: Ulcer-related background pain is common in persons with chronic leg ulcers. Older females reporting insomnia symptoms also had increased risk of moderate to severe ulcer-related background pain. These participants also perceived their health status to be better. RELEVANCE TO CLINICAL PRACTICE: This study demonstrates that ulcer-related background pain and associated factors needs more attention in clinical practice. Furthermore, nurses and other healthcare professionals should integrate biopsychosocial strategies to assess and manage ulcer-related background pain.

A possible role for inducible arginase isoform (AI) in the pathogenesis of chronic venous leg ulcer.

Chronic venous ulcer (CVU) is a major cause of chronic wounds of lower extremities and presents a significant financial and resource burden to health care systems worldwide. Defects in the vasculature, matrix deposition, and re-epithelialization are the main histopathological changes believed to impede healing. Supplementation of the amino acid arginine that plays a crucial role in the interactions that occur during inflammation and wound healing was proven clinically to improve acute wound healing probably through enhancing activity of inducible arginase (AI) locally in the wounds. However, the possible mechanism of arginine action and the potential beneficial effects of AI/arginine in human chronic wounds remain unclear. In the present study, using biopsies, taken under local anesthesia, from adult patients (n = 12, mean age 55 years old) with CVUs in lower extremities, we investigated the correlation between AI distribution in CVUs and the histopathological changes, mainly proliferative and vascular changes. Our results show a distinct spatial distribution of AI along the ulcer in the epidermis and in the dermis with the highest level of expression being at the ulcer edge and the least expression towards the ulcer base. The AI cellular immunoreactivity, enzymatic activity, and protein levels were significantly increased towards the ulcer edge. Interestingly, a similar pattern of expression was encountered in the proliferative and the vascular changes with strong correlations between AI and the proliferative activity and vascular changes. Furthermore, AI cellular distribution was associated with increased proliferative activity, inflammation, and vascular changes. Our findings of differential expression of AI along the CVU base, edge, and nearby surrounding skin and its associations with increased proliferative activity and vascular changes provide further support to the AI implication in CVU pathogenesis. The presence of high levels of AI in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.

PredyCLU: A prediction system for chronic leg ulcers based on fuzzy logic; part II-Exploring the arterial side.

Peripheral arterial disease (PAD) and its most severe form, critical limb ischaemia (CLI), are very common clinical conditions related to atherosclerosis and represent the major causes of morbidity, mortality, disability, and reduced quality of life (QoL), especially for the onset of ischaemic chronic leg ulcers (ICLUs) and the subsequent need of amputation in affected patients. Early identification of patients at risk of developing ICLUs may represent the best form of prevention and appropriate management. In this study, we used a Prediction System for Chronic Leg Ulcers (PredyCLU) based on fuzzy logic applied to patients with PAD. The patient population consisted of 80 patients with PAD, of which 40 patients (30 males [75%] and 10 females [25%]; mean age 66.18 years; median age 67.50 years) had ICLUs and represented the case group. Forty patients (100%) (27 males [67.50%] and 13 females [32.50%]; mean age 66.43 years; median age 66.50 years) did not have ICLUs and represented the control group. In patients of the case group, the higher was the risk calculated with the PredyCLU the more severe were the clinical manifestations recorded. In this study, the PredyCLU algorithm was retrospectively applied on a multicentre population of 80 patients with PAD. The PredyCLU algorithm provided a reliable risk score for the risk of ICLUs in patients with PAD.

Limb salvage procedure in immunocompromised patients with therapy-resistant leg ulcers-The value of ultra-radical debridement and instillation negative-pressure wound therapy.

The purpose of this study was to analyse the outcome of our established triple treatment strategy in therapy-resistant deep-thickness chronic lower leg ulcers. This limb salvage approach consists of ultra-radical surgical debridement, negative-pressure wound therapy (NPWT) with or without instillation, and split-thickness skin grafting. Between March 2003 and December 2019, a total of 16 patients and 24 severe cases of lower leg ulcers were eligible for inclusion in this highly selective population. A total of seven patients received immunosuppressive medication. Complete wound closure was achieved in 25% and almost 90% of included lower leg ulcer cases after 3 and 24 months of our triple treatment strategy, respectively. The overall limb salvage rate was 100%. Bacterial colonisation of these wounds was significantly reduced after multiple surgical debridements and NPWT. Fasciotomy and radical removal of devitalised tissue such as deep fascia, tendons, and muscles combined with NPWT showed promising results in terms of the overall graft take rate. This treatment strategy was considered as last resort for limb salvage in such a critically ill and immunocompromised patient population. Surgeons should be aware of its efficacy and consider the triple treatment strategy especially if no other limb salvage option remains.

Role of hospital anxiety and depression on the healing of chronic leg ulcer: A prospective study.

A chronic leg ulcer is a debilitating illness, owing to the local condition of the wound and a decrease in physical activity and productivity, resulting in anxiety and depression among patients. The study aimed to find any association of anxiety and depression in the healing of chronic wounds. A total of 125 patients with chronic leg ulcers were enrolled in the study. HADS questionnaire assessment followed the local wound examination in all patients. A follow-up assessment of the ulcer was done after appropriate local treatment, and data analysed with the HADS scale. In the present study, the ROC curve showed a cutoff value of 14 for the HADS score in predicting ulcer status (non-healing vs healed) after 30 days. A total of 54.4% (68) patients had a HADS score ≥ 14 and 39% (49) were true positive for the non-healing wound at a 1-month follow-up. This study revealed a sensitivity and specificity of 83.1% and 71.2%, respectively (P-value <.001), and diagnostic accuracy of 76.8%, for HADS score > 14 in the detection of non-healing ulcers. Chronic leg ulcers should be subjected to HADS assessment and if found significant corrective measures must be instituted for improving wound healing.

The current spectrum of contact sensitization in patients with chronic leg ulcers or stasis dermatitis - new data from the Information Network of Departments of Dermatology (IVDK).

BACKGROUND: Patients with lower leg dermatitis, chronic venous insufficiency or chronic leg ulcers have a high prevalence of contact sensitization. OBJECTIVES: To identify the current spectrum of contact allergens in these patients. PATIENTS AND METHODS: Data of the Information Network of Departments of Dermatology on 5264 patients with the above diagnoses from the years 2003 to 2014 (study group) were compared with data on 4881 corresponding patients from 1994 to 2003 (historical control group) and with a current control group without these diagnoses (n = 55 510). RESULTS: Allergic contact dermatitis was diagnosed less frequently in the study group than in the historical control group (25.9% versus 16.9%; p < 0.001), and contact sensitization to most allergens had declined. The allergen spectrum, however, was largely unchanged. Important allergens are Myroxylon pereirae (balsam of Peru) (14.8% positive reactions), fragrance mix I (11.4%), lanolin alcohol (7.8%), colophonium (6.6%), neomycin sulfate (5.0%), cetearyl alcohol (4.4%), oil of turpentine (3.1%), and paraben mix (2.6%). Patch testing with additional series showed sensitization to Amerchol L-101 (9.7%), tert-butyl hydroquinone (8.7%), framycetin sulfate (5.0%), and gentamicin sulfate (3.1%). CONCLUSIONS: Topical preparations for treating the above-mentioned conditions should not contain fragrances, Myroxylon pereirae, and colophonium. The special allergen spectrum has to be considered in patch testing.

Adjuvant Biological Therapies in Chronic Leg Ulcers.

Current biological treatments for non-healing wounds aim to address the common deviations in healing mechanisms, mainly inflammation, inadequate angiogenesis and reduced synthesis of extracellular matrix. In this context, regenerative medicine strategies, i.e., platelet rich plasmas and mesenchymal stromal cell products, may form part of adjuvant interventions in an integral patient management. We synthesized the clinical experience on ulcer management using these two categories of biological adjuvants. The results of ten controlled trials that are included in this systematic review favor the use of mesenchymal stromal cell based-adjuvants for impaired wound healing, but the number and quality of studies is moderate-low and are complicated by the diversity of biological products. Regarding platelet-derived products, 18 controlled studies investigated their efficacy in chronic wounds in the lower limb, but the heterogeneity of products and protocols hinders clinically meaningful quantitative synthesis. Most patients were diabetic, emphasizing an unmet medical need in this condition. Overall, there is not sufficient evidence to inform routine care, and further clinical research is necessary to realize the full potential of adjuvant regenerative medicine strategies in the management of chronic leg ulcers.

Treatment in the home setting with intermittent pneumatic compression for a woman with chronic leg ulcers: a case report.

BACKGROUND: Intermittent Pneumatic Compression (IPC) is shown to improve the healing rate of Venous Leg Ulcers (VLU) in the hospital setting. The current Australian "Gold Standard" treatment according to the Australian and New Zealand Wound Management Associations' (AWMA) Prevention & Management of Venous Leg Ulcer guidelines is compression, generally in the form of bandaging then progressing to hosiery once wounds are healed to prevent recurrence. This is recommended in conjunction with other standards of wound management including; nutrition, exercise, client education and addressing underlying pathophysiology and psychosocial factors. Compression bandaging is predominantly attended by community nurses in the clients' home. Barriers to delivery of this treatment include; client concordance and or suitability for bandaging including client habitus, (shape of legs), client lifestyle, clinician knowledge and clinicians physical ability to attend bandaging, in particular for obese clients with limited mobility who pose a manual handling risk to the clinician themselves. The use of IPC may assist in mitigating some of these concerns, therefore it would seem wise to explore the use of IPC within the home setting. CASE PRESENTATION: This paper will present an original case report on the successful treatment of a woman living with chronic bilateral lower leg ulcers using IPC as an adjunct treatment in her home. This paper supports recommendations to explore the use of IPC therapy in the home setting, for treatment of chronic leg ulcers requiring compression. CONCLUSION: Use of IPC in the home is anticipated to improve client involvement, concordance, client outcomes and reduce risk to staff applying conventional compression bandaging systems, particularly for obese clients with limited mobility.

Analgesic efficacy of equimolar 50% nitrous oxide/oxygen gas premix (Kalinox®) as compared with a 5% eutectic mixture of lidocaine/prilocaine (EMLA®) in chronic leg ulcer debridement.

Chronic foot and leg ulcers are a common health problem worldwide. A mainstay of chronic ulcer therapy is sharp mechanical wound debridement requiring potent analgesia. In this prospective, controlled, single-centre, crossover design study, patients were assigned to either the administration of topical analgesia with 5% lidocaine/prilocaine cream or the inhalation of an analgesic 50% N2 O/O2 gas premix. Primary outcome parameter was level of pain at maximum wound depth during debridement as measured by a visual analogue scale. Secondary outcomes included level of pain after debridement, overall duration of treatment session, duration and completeness of debridement, and the patient's subjective perception of analgesic quality during debridement. Pain level increased from 0·60/0·94 (first/second debridement; baseline) to 1·76/2·50 (debridement) with 5% lidocaine/prilocaine and from 1·00/1·35 (baseline) to 3·95/3·29 (debridement) with 50% N2 O/O2 gas premix. Patient satisfaction was 90·48%/94·44% (first/second debridement) with topical 5% lidocaine/prilocaine analgesia and 90·48%/76·47% with the inhalation of 50% N2 O/O2 gas premix. Debridement was completed in a significantly higher percentage of 85·71%/88·89% (first/second debridement) with 5% lidocaine/prilocaine than with 50% N2 O/O2 gas premix (42·86%/58·82%) (odds ratio 6·7; P = 0·001). This study provides sound evidence that analgesia with topically administered 5% lidocaine/prilocaine cream is superior to the use of inhaled 50% N2 O/O2 gas premix in chronic leg ulcer debridement.

Skin grafting for the treatment of chronic leg ulcers - a systematic review in evidence-based medicine.

Skin grafting is one of the most common surgical procedures in the area of non-healing wounds by which skin or a skin substitute is placed over a wound to replace and regenerate the damaged skin. Chronic leg ulcers are an important problem and a major source of expense for Western countries and for which many different forms of treatment have been used. Skin grafting is a method of treatment that decreases the area of chronic leg ulcers or heals them completely, thus improving a patient's quality of life. Skin grafting is an old technique, rediscovered during the first and second world wars as the main treatment for wound closure. Nowadays, skin grafting has a pivotal role in the context of modern wound healing and tissue regeneration. The aim of this review was to track and to analyse the specific outcomes this technique achieved, especially in the last decade, in relation to venous, arterial, diabetic, rheumatoid and traumatic leg ulcers. Our main findings indicate that autologous split-thickness skin grafting still remains the gold standard in terms of safety and efficacy for chronic leg ulcers; skin grafting procedures have greater success rates in chronic venous leg ulcers compared to other types of chronic leg ulcers; skin tissue engineering, also supported by genetic manipulation, is quickly expanding and, in the near future, may provide even better outcomes in the area of treatments for long-lasting chronic wounds.

PredyCLU: a prediction system for chronic leg ulcers based on fuzzy logic; part I - exploring the venous side.

Chronic leg ulcers (CLUs) are a common occurrence in the western population and are associated with a negative impact on the quality of life of patients. They also cause a substantial burden on the health budget. The pathogenesis of leg ulceration is quite heterogeneous, and chronic venous ulceration (CVU) is the most common manifestation representing the main complication of chronic venous disease (CVD). Prevention strategies and early identification of the risk represent the best form of management. Fuzzy logic is a flexible mathematical system that has proved to be a powerful tool for decision-making systems and pattern classification systems in medicine. In this study, we have elaborated a computerised prediction system for chronic leg ulcers (PredyCLU) based on fuzzy logic, which was retrospectively applied on a multicentre population of 77 patients with CVD. This evaluation system produced reliable risk score patterns and served effectively as a stratification risk tool in patients with CVD who were at the risk of developing CVUs.

Skin graft secured by VAC (vacuum-assisted closure) therapy in chronic leg ulcers: A controlled randomized study.

INTRODUCTION: Leg ulcers are a common condition. There have been very few studies of combined therapy involving VAC (vacuum-assisted closure) and skin graft. METHODS: We performed a randomized controlled trial of VAC therapy vs. hydrocolloid dressings over 5 days following autologous grafting on chronic leg ulcers. The primary objective was to assess the difference in success (defined as a reduction in wound area of at least 50% at 1 month) between the two dressing methods. Forty-six patients with ulcers present for over one month were included. Following a 7-day hospitalization period, follow-up was performed for 3 months on an outpatient basis. RESULTS: Our study does not demonstrate a statistically significant difference, with a 45.8% success rate in the VAC group vs. 40.9% in the conventional dressing group (P=0.73). In the venous ulcer group, the success rate was 57.9% for VAC vs. 40% for conventional dressings (P=0.3). The difference in favor of VAC in this group was not statistically significant, most likely due to an insufficient number of patients studied. CONCLUSION: Our study does not demonstrate superiority of VAC associated with skin graft over conventional dressings. We observed more complications with VAC (40%) than with conventional dressings (23%) (P=0.06).

Contact sensitization to modern dressings: a multicentre study on 354 patients with chronic leg ulcers.

BACKGROUND: Modern dressings (MDs) may have a low sensitization rate, but there is a lack of prospective studies in patients with chronic leg ulcers (CLUs) to evaluate this. OBJECTIVES: To determine the rate of sensitization (contact allergy) to MDs and substances present in dressings. PATIENTS AND METHODS: A prospective multicentre study was carried out in patients with CLUs at five French dermatology departments; patch tests were performed with the European baseline series and with an additional 27 individual allergens and 10 MDs. RESULTS: Among 354 patients (226 women and 128 men) with CLUs, 59.6% had at least one positive patch test reaction to an MD and 19% had at least one sensitization to an MD. The number of positive test reactions per patient was correlated with the duration of ulcerative disease, but not with ulcer duration, the cause of the ulcer, or the presence of surrounding eczematous lesions. For 11 of 45 patients sensitized to Ialuset cream®, more detailed information could be obtained with sensitization to sodium dehydroacetate (5 cases) or Lanette SX® (3 cases). CONCLUSIONS: Sensitization to MDs is not rare. It is absolutely necessary to label all components of MDs on their packaging and to avoid some sensitizing molecules, such as colophonium derivatives or any strong sensitizers.

Clinical and histopathological responses to bee venom phonophoresis in treating venous and diabetic ulcers: a single-blind randomized controlled trial.

Introduction: Chronic venous and diabetic ulcers are hard to treat that cause patients long time of suffering as well as significant healthcare and financial costs. Purpose: The conducted study was to evaluate the efficacy of bee venom (BV) phonophoresis on the healing of chronic unhealed venous and/or diabetic foot ulcers Also, to compare the healing rate of diabetic and venous ulcers. Methodology: The study included 100 patients (71 males and 29 females) with an age range of 40-60 years' old who had chronic unhealed venous leg ulcers of grade I, grade II, or diabetic foot ulcers with type II diabetes mellitus. They randomly assigned into four equal groups of 25: Group A (diabetic foot ulcer study group) and group C (venous ulcer study group) who both received conservative treatment of medical ulcer care and phonophoresis with BV gel, in addition to group B (diabetic foot ulcer control group) and group D (venous ulcer control group) who both received conservative treatment of medical ulcer care and received ultrasound sessions only without BV gel. Wound surface area (WSA) and ulcer volume measurement (UVM) were used to assess the ulcer healing pre-application (P0), post-6 weeks of treatment (P1), and after 12 weeks of treatment (P2). In addition to Ki-67 immunohistochemistry was used to evaluate the cell proliferative in the granulation tissue of ulcers pre-application (P0) and after 12 weeks of treatment (P2) for all groups. Results: This research revealed a statistical significance improvement (p ≤ 0.0) in the WSA, and UVM with no significant difference between study groups after treatment. Regarding Ki-67 immunohistochemistry showed higher post treatment values in the venous ulcer group in comparison to the diabetic foot ulcer group. Conclusion: Bee venom (BV) provided by phonophoresis is effective adjuvant treatment in accelerating venous and diabetic foot ulcer healing with higher proliferative effect on venous ulcer. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT05285930.

Hemizygous nonsense variant in the moesin gene (MSN) leads to a new autoimmune phenotype of Immunodeficiency 50.

Here, we present the findings of an investigation involving two male siblings with juvenile total tooth loss, early-onset chronic leg ulcers, and autoimmune thyroiditis, as well as focal segmental glomerulosclerosis with associated pulmonary emphysema in one and diabetes mellitus in the other. The clinical picture and lupus anticoagulant, cryoglobulin, and cold agglutinin positivity suggested the diagnosis of antiphospholipid syndrome. Flow cytometry analysis showed immunophenotypes consistent with immune dysregulation: a low number of naive T cells, elevated CD4+ T cell counts, and decreased CD8+ T-cell counts were detected, and more than half of the T-helper population was activated. Considering the siblings' almost identical clinical phenotype, the genetic alteration was suspected in the background of the immunodeficiency. Whole exome sequencing identified a previously not described hemizygous nonsense variant (c.650G>A, p.W217X) within exon 6 of the moesin (MSN) gene localized on chromosome X, resulting in significantly decreased MSN mRNA expression compared to healthy controls. We present a putative new autoimmune phenotype of Immunodeficiency 50 (MIM300988) characterized by antiphospholipid syndrome, Hashimoto's thyroiditis, leg ulcers, and juvenile tooth loss, associated with W217X mutation of the MSN gene.