Congenital collagenopathies increased the risk of inguinal hernia developing and repair: analysis from a nationwide population-based cohort study.

Herein, we aimed to explore whether male patients with congenital collagen diseases had a higher risk of inguinal herniation than patients without these diseases. Data were retrospectively collected from the National Health Insurance Research Database of Taiwan. The study cohort included 1,801 male patients diagnosed with congenital collagen diseases based on the ICD-9 CM diagnostic codes; after propensity score matching, the control group comprised 6,493 men without congenital collagen diseases. The primary endpoint was inguinal hernia repair during the observation period. During a median follow-up period of 133.9 months, the risk of inguinal herniation in the collagen group was significantly higher than that in the control group (HR = 2.237, 95% CI 1.646-3.291, p < 0.001). This phenomenon was observed in patients younger than 18 years (HR: 3.040, 95% CI 1.819-5.083, p < 0.001) and in those aged 18-80 years (HR: 1.909, 95% CI 1.186-3.073, p < 0.001). Asian men with congenital collagen diseases are at a high risk of developing inguinal hernias, regardless of age. Detailed physical examination and patient education should be performed for these patients to prevent inguinal herniation.

Clinical and Genetic Characteristics of COL2A1-Associated Skeletal Dysplasias in 60 Russian Patients: Part I.

The significant variability in the clinical manifestations of COL2A1-associated skeletal dysplasias makes it necessary to conduct a clinical and genetic analysis of individual nosological variants, which will contribute to improving our understanding of the pathogenetic mechanisms and prognosis. We presented the clinical and genetic characteristics of 60 Russian pediatric patients with type II collagenopathies caused by previously described and newly identified variants in the COL2A1 gene. Diagnosis confirmation was carried out by new generation sequencing of the target panel with subsequent validation of the identified variants using automated Sanger sequencing. It has been shown that clinical forms of spondyloepiphyseal dysplasias predominate in childhood, both with more severe clinical manifestations (58%) and with unusual phenotypes of mild forms with normal growth (25%). However, Stickler syndrome, type I was less common (17%). In the COL2A1 gene, 28 novel variants were identified, and a total of 63% of the variants were found in the triple helix region resulted in glycine substitution in Gly-XY repeats, which were identified in patients with clinical manifestations of congenital spondyloepiphyseal dysplasia with varying severity, and were not found in Stickler syndrome, type I and Kniest dysplasia. In the C-propeptide region, five novel variants leading to the development of unusual phenotypes of spondyloepiphyseal dysplasia have been identified.

Tuberculosis o colagenosis: un dilema diagnóstico / Tuberculosis or collagenosis: a diagnostic dylemma

Introducción: Colagenosis y tuberculosis comparten síntomas y signos, pero además, el trastorno autoinmune y los tratamientos inmunosupresores que reciben los pacientes con colagenosis, los hacen más vulnerables a esta infección, lo que puede constituir un dilema diagnóstico. Objetivo: Contribuir al conocimiento de la relación entre tuberculosis y colagenosis. Presentación de casos: Se presentan tres adolescentes con tuberculosis, atendidos en el Centro de Referencia Nacional para la Tuberculosis Infantil. Dos enfermos tenían diagnóstico previo de colagenosis (artritis idiopática juvenil y polimiositis) con tratamiento esteroideo en exacerbaciones o continuo desde hacía un año, respectivamente. El tercero presentó un síndrome febril prolongado con pleuresía y pericarditis, con sospecha de lupus eritematoso diseminado. Se diagnosticó tuberculosis por test de mantoux hiperérgico. El tratamiento fue prolongado con esteroides, drogas antituberculosas y pericardiotomía al inicio del proceso, con evolución tórpida y fallo de tratamiento. Todo el tiempo se trató de descartar una enfermedad del colágeno. Se confirmó por cultivo la tuberculosis en los tres pacientes y la evolución final fue satisfactoria. Se exponen las características de cada enfermo y se analiza la relación entre ambas entidades. Conclusiones: Se presentan tres casos que ejemplifican la relación entre tuberculosis y colagenosis(AU)

Introduction: Collagenosis and tuberculosis share similar symptoms and manifestations; and in addition, the autoimmune disorder and inmunosuppressive treatments that patients with collagenosis receive make them more vulnerable to this infection which can constitute a diagnostic dylemma. Objective: To contribute to a better knowledge on the relation among tuberculosis and collagenosis. Cases presentation: Three adolescents suffering collagenosis are presented. They were attended in the National Reference Center for Children Tuberculosis. Two of the patients had previous diagnostic of collagenosis (juvenile idiopatic arthritis and polymyositis) with steroids treatment in exacerbations or continuous since a year ago. The third patient presented a prolonged febrile syndrome with pleurisy and pericarditis, with suspicions of disseminated lupus erythematosus. Tuberculosis was diagnosed by the test of hyperergic Mantoux. The treatment was prolonged with steroids, antiturberculosis drugs and pericardiotomy at the beginning of the process, with bad evolution and failure of the treatment. All the time it was intended to rule out collagen disease. Tuberculosis was confirmed by culturing in the three patients and final evolution was satisfactorily. Characteristics of each patient were exposed and it was analyzed the relation among both diseases. Conclusions: Three cases that exemplify the relation among tuberculosis and collagenosis(AU)

Genetic identification of a common collagen disease in puerto ricans via identity-by-descent mapping in a health system.

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic BioMe biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, COL27A1, with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.

[Ocular involvement in rheumatoid arthritis, connective tissue diseases and vasculitis]. / Augenbeteiligung bei rheumatoider Arthritis, Kollagenosen und Vaskulitiden.

There are many interfaces between ophthalmologists and rheumatologists. On the one hand ophthalmologists face the question if an inflammation of the eye is caused by systemic inflammatory rheumatic diseases and on the other hand rheumatologists have to consider that ocular manifestations are relatively common in some inflammatory rheumatic diseases. Furthermore, these ocular manifestations may influence therapeutic decisions of the rheumatologist. This article summarizes which ocular inflammations can be associated with rheumatoid arthritis, connective tissue diseases and vasculitides. The description of acute anterior uveitis in spondyloarthritis and in juvenile idiopathic arthritis is omitted in this article but will be dealt with elsewhere in this issue.

Bone turnover markers and the factors associated with atypical femur fractures among Japanese patients.

Many previous reports have indicated that atypical femur fractures (AFFs) are associated with the administration of bisphosphonates (BPs). A number of risk factors and hypotheses regarding the pathogenesis of AFFs have been reported to date. The purpose of the present study was to identify the factors associated with AFFs in Japanese individuals and to elucidate the association between bone metabolism and AFFs by evaluating bone turnover markers (BTMs). We prospectively reviewed all patients with femur fractures and identified the patients with AFFs and typical femur fractures (TFFs). We collected the demographic and clinical data that were relevant to the present study, namely age, gender, affected side, affected site, concomitant medical history, and comorbid conditions, and measured the levels of BTMs within 24h after trauma. Welch's test and Fisher's exact probability test were used for the statistical analyses. A total of 338 patients, including 10 patients with AFFs and 328 patients with TFFs, were analyzed under the inclusion criteria. The use of BPs (p<0.001) and collagen disease and chronic granulomatous disease (CD/CGD) (p=0.025) were more frequently observed in patients with AFFs than in patients with TFFs, while the levels of BTMs, including N-terminal propeptides of type 1 procollagen (P1NP), isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b) and undercarboxylated osteocalcin (ucOC) were significantly lower in patients with AFFs than in patients with TFFs. Furthermore, the level of TRACP-5b was found to be significantly lower in patients with atypical subtrochanteric fractures than in atypical diaphyseal fractures (p=0.025). Moreover, the levels of P1NP (p=0.016) and TRACP-5b (p=0.015) were found to be significantly lower in patients with AFFs than in patients with TFFs in a subgroup analysis of BPs users. The use of BPs was considered to be a factor associated with AFFs. Our comparison of the BTMs in patients with AFFs and TFFs indicated that the severe suppression of bone turnover was associated with the pathogenesis of AFFs. The extent of the influence of suppressed turnover on the pathogenesis of AFFs may differ depending on the fracture site.

Current smoking is an independent risk factor for new-onset diabetes mellitus during highdose glucocorticoid treatment.

AIMS/INTRODUCTION: Although high-dose glucocorticoids have been reported to cause new-onset diabetes mellitus (glucocorticoid-induced diabetes mellitus), its risk factors have remained to be determined. We investigated the risk factors related to glucocorticoid-induced diabetes mellitus diagnosed within 2 months after the high-dose treatment (newly treated with an initial high dose of > 20 mg prednisolone (PSL) equivalent per day for at least more than 6 months) in collagen vascular diseases. METHODS: A total of 2,631 patients with collagen vascular diseases was registered between 1986 and 2006 in the Chiba-Shimoshizu Rheumatic Cohort. We analyzed 681 patients newly treated with high-dose glucocorticoid who did not have diabetes mellitus and/or its previous diagnosis (age: 46.3 ± 16.7 years, PSL dose: 40.0 ± 14.1 mg/day). Glucocorticoid-induced diabetes mellitus was diagnosed by two or more glucose measurements in patients with fasting glycaemia ≥ 7 mmol/L and 120 minutes post-load glycaemia ≥ 11.1 mmol/L. RESULTS: Glucocorticoid-induced diabetes mellitus was observed in 26.3% of patients, and the glucocorticoid-induced diabetes mellitus group had higher age, higher BMI, lower rates of females and systemic lupus erythematosus, higher rates of smoking, alcohol use, and microscopic polyangiitis. Multivariate logistic regression analysis demonstrated that the risk of glucocorticoid-induced diabetes mellitus was independently higher in every 10-year increment of initial age with adjusted odds ratio (OR) 1.556 (95% confidence interval: 1.359 - 1.783), in every 1 kg/m2 increment of BMI with OR 1.062 (1.002 - 1.124), in current smoking with OR 1.664 (1.057 - 2.622), and in every 10 mg increment of initial dose of prednisolone with OR 1.250 (1.074 - 1.454). CONCLUSIONS: High-dose glucocorticoids caused diabetes mellitus with high prevalence within a short period, and current smokers should be considered at higher risk of glucocorticoidinduced diabetes mellitus in addition to age, BMI, and initial dose.

[Degenerative lesions of the peripheral retina]. / Lésions dégénératives de la périphérie rétinienne.

Degenerative lesions of the peripheral retina are present from teenage years onwards and increase with age. These abnormabilities are frequent, some of them being benign while others predispose to retinal tears and detachment. In the latter case, the lesions are rhegmatogenous and may justify prophylactic treatment by laser photocoagulation. We distinguish congenital lesions of the peripheral retina and intraretinal, chorioretinal and vitreoretinal degenerations. The holes and tears observed in 2% of the population consist of round atrophic holes, "horseshoe" tears, oral dialyses and giant tears.

Suspected collagen disorders in the bleeding disorder clinic: a case-control study.

Disorders of collagen are associated with a mild bleeding tendency because of the potential abnormal interaction of collagen, von Willebrand factor (VWF) and platelets required during primary haemostasis and due to generalized soft tissue fragility. Abnormal collagen may contribute to bleeding in existing mucocutaneous bleeding disorders, but the prevalence in this setting is unknown. Generalized symptomatic joint hypermobility (SJH) is common in collagen disorders and may be objectively measured. To assess the association between symptomatic joint hypermobility and mucocutaneous bleeding disorders, we performed a case-control study in which case subjects were 55 consecutive individuals who had visited our bleeding disorder clinic with a diagnosis of von Willebrand disease, low von Willebrand factor levels, mild platelet function disorder or undefined bleeding disorder. Controls were 50 subjects without a bleeding disorder, and were age and gender matched to the cases. All subjects were assessed with: (i) Beighton score for joint hypermobility, (ii) revised Brighton criteria, (iii) Condensed MCMDM1-VWD bleeding questionnaire, and (iv) haemostasis laboratory studies. The prevalence of SJH/suspected collagen disorder in the bleeding disorder clinic was 24% (13/55) compared with 2% (1/50) in the control population (OR 15, 95% CI 2-121). Seventy-seven per cent of bleeding disorder clinic SJH subjects (10/13) had a prior personal or family history of Ehlers-Danlos, Benign Joint Hypermobility Syndrome or Osteogenesis Imperfecta (OI). Symptomatic joint hypermobility was associated with increased odds of an underlying mucocutaneous bleeding disorder. These findings suggest that a collagen disorder is common and often unrecognized in the bleeding disorder clinic as a potential contributor to the bleeding symptoms.

The prevalence and diagnostic significance of eosinophilic pleural effusions: a meta-analysis and systematic review.

BACKGROUND: Eosinophilic pleural effusion (EPE) is defined by an eosinophil count of ≥10% in the pleural fluid and often caused by air or blood in the pleural space. The diagnostic significance of EPEs is still a matter of debate. OBJECTIVE: The objective of this study was to systematically review the medical literature to evaluate the diagnostic significance of EPEs. METHODS: Electronic databases were searched from 1950 to April 2010 to perform a meta-analysis. Data were extracted using standardized forms, and pooled odds ratios with 95% confidence intervals were calculated. A logistic regression analysis was also performed to evaluate the association between the pleural eosinophil counts and the likelihood of underlying causes of EPEs. RESULTS: We identified a total of 687 cases of EPE. The most common cause of EPEs was malignancy (26%) followed by idiopathic (25%) and parapneumonic (13%) effusions. The likelihood of malignancy or tuberculosis was somehow lower in EPEs than in non-EPEs, but the differences were not statistically significant. The prevalence of malignancy was significantly lower in the group of patients that required a pathologic confirmation (21 vs. 30%; p = 0.01). The likelihood of malignancy was inversely correlated with the pleural fluid eosinophil counts. The likelihood of idiopathic effusion was significantly higher in EPEs than in non-EPEs. CONCLUSIONS: Malignancy was the most common cause of EPEs. EPEs appeared to be a negative predictor of malignancy when a pleural fluid eosinophil count was extremely high. EPEs were more likely to be idiopathic as compared with non-EPEs.

Pelvic organ prolapse and collagen-associated disorders.

INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) and other disorders, such as varicose veins and joint hypermobility, have been associated with changes in collagen strength and metabolism. We hypothesized that these various disorders were more prevalent in both POP patients and their family members. METHODS: In this study, the prevalence of various collagen-associated disorders, including POP, was compared between POP patients (n = 110) and control patients (n = 100) and their first and second degree family members. RESULTS: POP patients reported a higher prevalence of varicose veins, joint hypermobility and rectal prolapse and were more likely to have family members with POP as compared to the control group (p < 0.01). In contrast, the family members of the POP group did not report a higher prevalence of collagen-associated disorders compared to the family members of the control group (p = 0.82). CONCLUSIONS: POP and other collagen-associated disorders may have a common aetiology, originating at the molecular level of the collagens.

Acquired reactive perforating collagenosis: current status.

Acquired reactive perforating collagenosis is a unique perforating dermatosis, characterized clinically by umbilicated hyperkeratotic papules or nodules and histologically by a focal hyperkeratosis in direct contact with transepidermal perforating dermal collagen. Several inflammatory or malignant systemic diseases may coexist with acquired reactive perforating collagenosis. The possible biochemical or immunological mechanisms of the systemic diseases, potentially responsible for the development and appearance of acquired reactive perforating collagenosis, are still under investigation. Several topical treatments, ultraviolet B phototherapy and allopurinol p.o. administration may be effective.

[Epidemiology of collagen diseases].

Collagen diseases have been generally thought to be rare, but the number of patients with rheumatoid arthritis(RA) becomes over 700,000 in recent days. In addition, the survival rate has markedly increased, but many lupus patients are still suffering from so called intractable organ involvements such as severe lupus nephritis and CNS lupus, etc. The main purposes of the treatment for RA are to prevent bone/cartilage destruction, to improve the quality of life(QOL) of patients, and to improve prognosis. For these purposes, new type of drugs such as biologic agents are introduced, and showing remarkable effects comparing with conventional DMARDs. But the side effects and cost of these agents are becoming problems. To overcome these problems, the epidemiology that can clearly show the benefits of these agents on daily life of patients is becoming much more important issue.

[Thin glomerular basement membrane disease]. / La nefropatia a membrane basali sottili.

Thin glomerular basement membrane disease (TBMD) is a hereditary nephropathy characterized by thinning of the glomerular basement membrane evinced by electron microscopy and, clinically, by isolated hematuria without extrarenal manifestations. Familial aggregation is found in 50-60% of cases, with autosomal dominant transmission. TBMD is considered to belong to the type IV collagen spectrum of diseases, since heterozygous mutations of the COL4A3 or COL4A4 gene have been detected in more than 30% of patients. The disease is found in 1-2% of biopsies, but the prevalence in the general population may be higher. The differential diagnosis with Alport's syndrome may be difficult and requires accurate family investigations, immunohistochemical evaluation of type IV collagen alpha chains in renal tissue and, if appropriate, genetic studies. Progression towards chronic renal failure, although rare, has been reported in some patients, and may be related to the phenotypical variability of COL4A3/COL4A4 mutations, to a missed Alport syndrome, or to superimposed glomerular disease. Patients suffering from TBMD and affected relatives should be periodically examined for signs of disease progression and informed about the possibility of transmitting the autosomal recessive form of Alport's syndrome.

[Acquired reactive perforating collagenosis associated with diabetes mellitus and renal insufficiency requiring dialysis]. / Erworbene reaktiv perforierende Kollagenose bei Diabetes mellitus und dialysepflichtiger Niereninsuffizienz.

HISTORY: A 60-year-old man with diabetes mellitus and chronic renal insufficiency needing hemodialysis was admitted with a 3 months history of multiple hyperkeratotic papules on the trunk and extremities partly ulcerated with a keratotic central plug. INVESTIGATIONS: Laboratory tests revealed elevated levels of blood urea nitrogen, creatinine, and HbA (1c). Histopathology showed vertical strands of collagen perforating from the ulcerated lesions. COURSE, DIAGNOSIS AND TREATMENT: The biopsy specimen was consistent with acquired reactive perforating collagenosis. The progression was stopped and secondary wound healing was initiated after two weeks of therapy with allopurinol and PUVA. CONCLUSION: Acquired reactive perforating collagenosis should be considered when ulcera with oystershell-like keratotic plugs are found especially in patients with predisposing diseases like diabetes and renal insufficiency. A good interdisciplinary cooperation between internist and dermatologist is crucial for the early recognition by histopathology and the immediate treatment.

[Sicca syndrome in major collagen diseases]. / Sindromul Sicca în colagenozele majore.

The purpose of this paper is to diagnose the patients with ocular sicca syndrome in major collagenosis, to evaluate the clinical and histopathological lesions, related to stage of the disease and to establish significant correlations between the different clinical tests for qualitative and quantitative determination of lacrimal tear and the severity of ocular disorders. Dry eye disease is a very common disorder of tear film in collagen diseases. The gender ratio is 6/1 female/man. The most severe dry eye symptoms are also presented at women. The diagnostic and the treatment of dry eye rest difficult because of lack of accepted diagnostic criteria and lack of standardized, specific diagnostic tests. The results of this study have revealed that the ophthalmologic examination is necessary to all the patients with collagenosis who present ocular symptoms. The ophthalmological exam will contain qualitative and quantitative tests of lacrimal evaluation and a methodic biomicroscopic examination of corneo-conjunctival surface without and with vital staining. Rheumatoid arthritis is the collagen diseases which most frequently associates ocular sicca syndrome in mild and medium clinical forms.

Incidence of pulmonary hypertension and its clinical relevance in patients with interstitial pneumonias: comparison between idiopathic and collagen vascular disease associated interstitial pneumonias.

OBJECT: This study was undertaken to investigate the frequency of pulmonary hypertension (PH), and clinical parameters associated with PH in patients with idiopathic interstitial pneumonias (IIPs) and collagen vascular disease-associated interstitial pneumonias (CVD-IPs). PATIENTS AND METHODS: Retrospective analyses were performed in 163 consecutively enrolled patients (78 IIPs and 85 CVD-IPs) who were being evaluated for PH by Doppler echocardiography. PH was defined as an estimated systolic pulmonary artery pressure (sPAP) of > or = 40 mmHg. The frequency of PH was evaluated and clinical parameters were compared between patients with PH and those without PH. RESULTS: Among patients successfully evaluated for sPAP by echocardiography, 20 of 70 (28%) patients with IIPs and 17 of 80 (21%) patients with CVD-IPs had PH. Among patients with IIP and CVD-IP, those with PH were more frequently treated with supplemental oxygen. Patients with IIP who had PH tended to be older and had decreased % diffusion capacity of carbon monoxide (%DLCO). Additionally, in patients with IIP, sPAP was negatively correlated with %DLCO. However, this association was not found in patients with CVD-IP. Patients with CVD-IP who had PH were predominantly male. CONCLUSION: PH was frequently observed in patients with both IIPs (28%) and CVD-IPs (21%) in the chronic phase of the disease. PH should be evaluated in patients with IPs who need supplemental oxygen, IIP patients with decreased diffusing capacity, and in patients with CVD-IP.

The relationship between frequency and intensity of fears and a collagen condition.

Encouraged by the positive relationship between joint laxity and panic anxiety, our objective in this study was to compare widespread cultural fears in subjects with and without joint hypermobility syndrome and to assess whether this relationship is sustained for common fears as well. A sample consisting of 1,305 subjects from a rural town were assessed for joint hypermobility syndrome using Beighton's criteria. We assessed fear intensity and frequency using a modified version of the Fear Survey Schedule (FSS-III). Intense fears, defined with a score of 3-4, were compared between hypermobile and nonhypermobile subjects. The analysis was carried out separately for men and women. Nonparametric analysis was applied throughout. Joint hypermobility syndrome was found in 19.9% (141) of women and 6.9% (41) of men. Concerning the fear survey, when we compared the groups with and without joint hypermobility, the mean total scores for both genders were significantly higher for the hypermobile group. When we analyzed each item individually, 43 out of the 44 most severe fears in women and 36 out of the 39 in men, scores were significantly higher in the hypermobile group. We found significant differences between subjects with and without joint hypermobility when assessing specific fears, reinforcing the hypothesis that intensity of fears is greater in subjects with joint hypermobility syndrome. These results show that the association of joint laxity and phobic anxiety is sustained for intense fears and might represent a susceptibility factor for these anxiety conditions.

Fever of unknown origin: what is remarkable in the elderly in a developing country?

OBJECTIVES: To investigate fever of unknown origin (FUO) in 97 patients and compare geriatric and adult population. METHODS: We investigated 97 (22 elderly) patients with FUO using the criteria of Petersdorf and Beeson [Medicine 40 (1961) 1] hospitalized between January 1990 and May 2005 at Hacettepe University Hospital. RESULTS: Infectious diseases were the most common cause in the adult (33.3%) and the elderly (45.5%) patients both. Neoplasms were seen in 18.7; 4.5% and collagen vascular diseases were diagnosed in 9.3; 4.5% of the adults and the elderly respectively. Tuberculosis accounted for 60% of all the infectious causes and empirical anti-tuberculous treatment served as a diagnostic method in 43% of the cases with tuberculosis. Lymphadenopathy was more common among the adults with FUO. A diagnosis could be reached in all the elderly patients with a very high erythrocyte sedimentation rate (ESR>100mm/h). At the end of the hospitalization, 14.7% (11/75) of the adult patients and 13.6% (3/22) of the elderly patients died. CONCLUSION: Geriatric patients with FUO usually have characteristics similar to the adult patients with respect to the hospitalization time, diagnosis, and inpatient mortality. Lymphoid organ hyperplasia might be expected less frequently and very high ESR might be a more reliable indicator of systemic disease in the elderly. Empirical anti-tuberculous treatment plays an important diagnostic role in the developing countries with a higher prevalence of tuberculosis.