Wegener granulomatosis in childhood and adolescence

Wegener granulomatosis (WG) is a necrotising granulomatous small vessel vasculitis with a clinical predilection for involvement of the upper airways, lungs and kidneys, which occurs at all ages. The aetiology of WG, like other primary systemic vasculitides, remains unknown. Existing evidence suggests an autoimmune inflammatory process, characterised by early lesions with neutrophils and endothelial cells as active participants and involvement of antineutrophil cytoplasmatic antibodies (ANCA) directed against proteinase-3 (PR3). However, other concomitant factors like infections and environmental factors also appear to be necessary for the development of WG. In addition, multiple genetic factors seem to be involved in disease susceptibility. Whereas the first publications on WG in childhood were based on case reports, some studies in recent years allow to compare clinical findings, disease course, morbidity and mortality rates for childhood and adult onset patients. Whereas most aspects of WG are similar at all ages, some features appear to be significantly different. WG in childhood is more frequently complicated by subglottic stenosis and nasal deformity while treatment-related morbidity and malignancies are less common compared to adults. Introduction of combined treatment with cyclophosphamide and glucocorticoids resulted in a dramatic improvement of patient outcome; however, commonly occurring disease relapses and the risk of chronic organ damage at all ages make long-term follow-up of all patients and the establishment of new therapeutic regimens necessary.Abbreviations ANCA antineutrophil cytoplasmatic antibodies - c-ANCA cytoplasmatic pattern of ANCA - MPO myeloperoxidase - PR3 proteinase-3 - WG Wegener granulomatosis     

Wegener's granulomatosis in pediatric patients

Wegener's Granulomatosis (WG) is a disease occurring rarely in childhood and adolescence. Together with the Churg-Strauss-Syndrome and the microscopic Polyangiitis it belongs to the vasculitis syndromes associated with ANCA. WG mostly affects the upper and lower respiratory tract and kidneys. It is characterized by a chronic development and high tendency to relapse. In cases of persistent disturbances of the respiratory system which do not have infectious or allergic geneses differential diagnosis should also consider WG.Although clinical course and prognosis have improved since the introduction of immunosuppressive therapy, WG, leading to renal failure in about one third of all cases, remains a disease which has to be taken seriously. Early treatment has been proven to improve prognosis. Due to the necessity of longterm treatment less toxic immunosuppressive therapy should be applied (e.g. Methotrexate).     

原发性肺部小血管炎16例

目的了解小儿原发性肺部小血管炎的临床特点及诊断要点,减少误诊率。方法对原发性肺部小血管炎患者16例的病理检查、抗中性粒细胞胞浆抗体(ANCA)检测、肺损害临床表现、影像学及误诊情况进行回顾性分析。结果16例中显微镜下多动脉炎(MPA)9例,韦格内氏肉芽肿病(WG)4例,变应性肉芽肿性血管炎(CCS)3例;ANCA阳性率75%;肺损害临床表现有干咳、胸痛、胸闷、咯血、呼吸困难等;胸部X线表现为多发斑片状或点状阴影、结节影、大片高密度阴影或团块影、网格状影及空洞形成。应用肾上腺皮质激素和环磷酰胺治疗后10例好转,其中8例胸片正常。放弃治疗、死亡各3例。结论小儿原发性肺部小血管炎临床表现复杂多样,诊断困难,误诊率高,应引起临床医师重视。     

Wegener's granulomatosis in childhood

The authors reviewed the medical histories and radiological examinations of five pediatric patients with a histologic diagnosis of Wegener's granulomatosis (WG) seen over a six year period in whom a total of 22 thoracic CT scans were performed. Involvement of both the upper and lower respiratory tracts was seen in all patients at presentation. One patient had subglottic stenosis necessitating tracheotomy. Pulmonary hemorrhage occurred in three patients at initial diagnosis. Classic cavitary lung nodules were seen in two patients — one at initial presentation, the other at relapse. The plain radiographic lower respiratory tract manifestations of pediatric WG were protean both at initial presentation and during follow up. Similarly, disease expression was highly variable on thoracic CT examinations but, overall, multifocal parenchymal infiltrates with or without small peripheral nodules were the commonest thoracic CT manifestations. As a consequence of cytotoxic and corticosteroid therapy the long-term prognosis of WG has improved considerably in recent years. Knowledge of the varied patterns of the primary disease and potential for iatrogenic complications are necessary for successful radiologic assessment of pediatric patients with WG.     

Wegener's granulomatosis in a 15-year-old boy

Wegener's granulomatosis (WG) is an uncommon systemic vasculitis that is rarely encountered in children. A 15-year old boy presented with a one-month history of nasal obstruction, hemorrhagic rhinorrhea, malaise, fever, anorexia and weight loss, together with high values of inflammatory markers, microscopic hematuria and progressive decrease of renal functions. Renal biopsy revealed rapidly progressive crescentic glomerulonephritis with rare findings of interstitial and periglomerular granulomas. The diagnosis of WG was established and intravenous methylprednisolone and cyclophosphamide therapy followed by oral application of prednisone and azathioprine led to a complete clinical and laboratory remission of the disease. The second renal biopsy performed after 28 months of treatment did not show any activity of the process. Currently, the boy is without any clinical or laboratory signs of active disease. Since untreated WG has a fatal prognosis, early diagnosis and appropriately aggressive immunosuppressive therapy are necessary for a favorable outcome.     

Wegener's granulomatosis in the pediatric age group.

Six cases of Wegener's granulomatosis (WG) occurring in patients younger than 21 years are described. Only 11 other cases in the pediatric age group have been reported, and all 17 of these patients had the onset of the disease during the second decade of life. Wegener's granulomatosis is a systemic disease characterized by a clinical triad of paranasal sinus and nasal mucosa involvement, pulmonary infiltration and cavitation, and renal disease with hematuria. The most common presenting symptoms are malaise and fever, sinusitis, epistaxis, and hematuria. Most patients have roentgenographic evidence of pulmonary and sinus disease and laboratory evidence of renal involvement on initial evaluation. The prognosis of WG was formerly dismal; more than 90% of patients died in less than two years, but with recent therapeutic regimens, more than 50% of these patients are surviving. The treatment we recommend consists of nitrogen mustard with adrenocorticotropic hormone or prednisone for the induction of remission, followed by cyclophosphamide and prednisone as maintenance drugs. This regimen has proved effective in inducing a remission in four of four patients.     

胎儿Oddi括约肌的结构演变及临床意义

为研究正常胎儿Ｏｄｄｉ括约肌结构发育和功能的关系，取４例新鲜胎儿尸体标本，其中男１８例，女３０例，胎龄２０～４０周，分别用于组织学及电子显微镜图像立体定量分析研究。发现胚胎２０周胰胆管即在十二指肠壁内合流，存在“Ｕ”型“Ｖ”型和“Ｙ”型三种合流方式；胆总管未端肌（即Ｏｄｄｉ括约肌一部分）随胎龄增加逐渐增厚（Ｐ＜０．０５）；胚胎２０周Ｏｄｄｉ括约肌肌细胞内即有线粒体，随胎龄增大、线粒体体积增大、数量增多（Ｐ ＜０．０１），与同胎龄胆总管中下段平滑肌细胞内线粒体相比，后者体积小、数量少（Ｐ＜０．０１或Ｐ＜０．０５）。结果表明：胚胎２０周胰胆管合流已完成，Ｏｄｄｉ括约肌具有独特的括约功能，随生长发育逐渐完善；胆总管中下段平滑肌也具有运动功能，但远不及Ｏｄｄｉ括约肌功能强。     

Transcatheter Closure of Abnormal Vessels and Arteriovenous Fistulas With the Amplatzer Vascular Plug 4 in Patients With Congenital Heart Disease

Although vascular plugs allow the interventional closure of medium-sized to large abnormal vessels, their application is limited by the need for long sheaths or large guiding catheters. The authors report their experience with the new Amplatzer vascular plug 4 (AVP 4), a self-expanding spindle-shaped occluder made of Nitinol wire mash, which can be placed through 4-Fr catheters with an internal diameter of 0.038 in. or larger. From October 2009 until June 2012, 14 AVP 4 devices were deployed in 12 patients (ages, 0.3–48.8 years). Nine patients had venovenous or arteriovenous collaterals in functional univentricular hearts. One patient had pulmonary atresia with a ventricular septal defect and major aortopulmonary collateral arteries, and one patient had a pulmonary arteriovenous fistula. One child had a large coronary artery fistula to the right atrium. The authors used AVP 4 devices with diameters of 4–8 mm. In all the patients, the AVP 4 was implanted successfully. No occluder dislocations and no complications related to the procedure occurred. Complete vessel occlusion was achieved in seven cases. In seven additional cases, a residual shunt was present at the end of the procedure while the patients were still fully heparinized. In 2 of 14 vessels, the decision was made to place additional devices to abolish residual shunting. According to the authors’ experience, the AVP 4 allows safe and effective occlusion of medium-size and large abnormal vessels. It is also well suited for tortuous high-flow vessels such as coronary or pulmonary arteriovenous fistulas. In case of a suboptimal position, it is possible to reposition the occluder with ease. Further studies are needed to determine whether initial residual shunting in heparinized patients disappears during follow-up care. The AVP 4 represents a valuable new device for the interventional treatment of complex congenital vessel malformations.     

Wegener's granulomatosis in childhood

Wegener's granulomatosis (WG) is a rare disease in pediatric patients. The case of a 14-year-old girl with generalized WG is described and the pediatric literature reviewed. Thirty additional cases of WG in childhood have been traced in previous studies. Diagnostic problems are discussed in the context of clinical, radiological and biopsy findings.     

Repetitive prenatal glucocorticoids increase lung endothelial nitric oxide synthase expression in ovine fetuses delivered at term

Antenatal administration of glucocorticoids has been shown to improve postnatal lung function after preterm birth in the ovine fetus. Mechanisms of steroid-induced lung maturation include increased surfactant production and altered parenchymal lung structure. Whether steroid treatment also affects lung vascular function is unclear. Because nitric oxide contributes to the fall in pulmonary vascular resistance at birth, we hypothesized that the improvement of postnatal lung function of preterm lambs after treatment with prenatal glucocorticoids may be in part caused by an increase in endothelial nitric oxide synthase (eNOS) activity. To determine whether glucocorticoid treatment increases lung eNOS expression, we measured eNOS protein content by Western blot analysis of distal lung homogenates and immunostaining of formalin-fixed lungs from ovine fetuses delivered at preterm and term gestation after prenatal administration of glucocorticoids. Treatment protocols were followed in which ewes were treated with intramuscular betamethasone (0.5 mg/kg) at single or multiple doses at weekly intervals, and fetuses were delivered at 125, 135, or 145 d gestation. All groups were compared with saline-treated controls. Western blot analysis of whole lung homogenates demonstrated a 4-fold increase in eNOS protein content in lambs treated with repetitive doses of glucocorticoids and delivery at term (145 d; p < 0.002). In addition, a small increase in lung eNOS protein content was seen in lambs treated with a single dose of betamethasone at 128 d gestation with delivery at 135 d gestation. In comparison with control animals, there were no differences in lung eNOS content from the remaining lambs treated with glucocorticoids when delivery occurred at preterm ages (125 and 135 d). Immunostaining showed eNOS predominantly in the vascular endothelium in all vessel sizes. Pattern of staining was not altered by treatment with antenatal glucocorticoids. We conclude that maternal treatment with glucocorticoids increases lung eNOS content after multiple doses and delivery at term gestation. We speculate that antenatal glucocorticoids may up-regulate eNOS but that the timing and duration of steroid administration appears to be critical to this response.     

Tissue engineered vessels: Cells to telomeres

Vascular diseases continue to affect people of all ages, and therapies are continually being improved. Cardiovascular tissue engineering is becoming an established field that will enable the replacement or modification of diseased tissues. Although commonly thought to affect older populations, cardiac disease afflicts many pediatric patients who come with a different set of needs. Particularly, with congenital defects, an engineered construct must be able to grow with the patient to avoid costly, repeated surgeries. Of the wide variety of congenital cardiac defects observed today, many concern the vessels in and around the heart. The selection of a proper cell source and attention to cellular lifespan are important factors that dictate the success of a vascular graft. Engineered blood vessels have been constructed from both synthetic and biological materials, using cells from human, bovine, and porcine species. Smooth muscle and endothelial cells taken from vessel explants, as well as cells derived from bone marrow, have been utilized to generate extracellular matrix components needed for conduit construction. The limited lifespan of these cells, especially after weeks in culture, has been addressed with the use of the telomerase enzyme. The catalytic subunit of telomerase, hTERT, has been used to maintain telomere length and consequently extend cellular lifespan. This review looks at current research that is expanding the vessel tissue engineering field by implementing novel use of cells and telomerase.     

Takayasu's Arteritis Coexisting with Wegener's Granulomatosis in a Teenager with Renal Insufficiency: Case Report

A case of Wegener's granulomatosis (WG) coexisting with Takayasu's arteritis (TA) in a 12-year-old girl is presented. She presented with fulminant and severe renal insufficiency due to crescentic glomerulonephritis. At autopsy, aortic lesions of Takayasu's arteritis coexisted with pulmonary and renal findings of WG, and the patient's serum at autopsy had an elevated level of antineutrophil cytoplasmic antibodies (ANCA). Both forms of vasculitis have been thought to be triggered by infectious agents and it is postulated that this occurrence accounts for the coexistence of the two forms of vasculitis in this case. Received February 20, 1998; accepted August 31, 1998.     

Treatment of phenylalanine hydroxylase deficiency

In phenylalanine hydroxylase deficiency detected by screening treatment in early life, both age at start of treatment and phenylalanine control during treatment are the major determinants of eventual psychological status. The influence of phenylalanine control declines with age but executive performance is influenced by hyperphenylalaninaemia at all ages. In a few subjects neurological deterioration has been reported years after relaxing or stopping treatment. MRI changes in brain white matter are present in most subjects no longer on a strict diet. These changes are usually reversible and closely related to phenylalanine status at the time of investigation. Whether or not the changes point to a specific vulnerability of white matter remains uncertain, although MRI changes were particularly prominent in subjects with neurological disability and may be irreversible in such subjects. Policies on treatment have to take account of these findings.     

Intellectual development of phenylketonuria children treated early--a longitudinal study. 10 years' concomitant psychological study in The Netherlands

Since 1st September 1974 almost all newborns in The Netherlands have been screened for phenylketonuria (PKU). Data collected between then and 1 October 1984 are presented, with respect to the intellectual functioning of 69 patients who received early treatment for PKU. Wherever possible, psychological testing was carried out at four key ages, namely 1.0 years, 2.0 years, 4.6 years, 6.6 years. The results of the tests revealed no differences in the mental levels of these patients and healthy children at any of the key ages. Also no sex differences at key ages 1 and 2 years related to this variable were found. The longitudinal course of the intellectual development in the first four and a half years was stable. The necessity for the continuation of screening and the collection of psychosocial data is discussed.     

Retinopathy of prematurity: Recommendations for screening

Retinopathy of prematurity (ROP) is a disorder of the developing retinal blood vessels of the preterm infant. New recommendations for screening and treatment of ROP have been published in the past few years. Current evidence suggests that screening infants with gestational ages of 30 6/7 weeks or less (regardless of birth weight) and birth weights of 1250 g or less is a strategy with a very small likelihood that an unscreened baby would have treatable ROP. Individual centres may choose to extend birth weight screening criteria to 1500 g. Initial screening should be performed at 31 weeks' postmenstrual age in infants with gestational ages of 26 6/7 weeks or less at birth, and at four weeks' chronological age in infants with gestational ages of 27 weeks or more at birth by an ophthalmologist skilled in the detection of ROP. Follow-up examinations are conducted according to the ophthalmologist's recommendation. Infants with high-risk prethreshold ROP and threshold ROP are referred for retinal ablative therapy. Developing processes for ROP screening, documenting results and communicating results to parents as well as health professionals involved in the infant's care are important responsibilities for all nurseries providing care for preterm infants.     

Treatment of sickle cell disease in early childhood in Jamaica

The Jamaican sickle cell cohort study, based on neonatal diagnosis of all cases of sickle cell disease among 100,000 consecutive births, has identified acute splenic sequestration (ASS) and pneumococcal disease as the most important complications in early life. The etiology of ASS is unknown and prophylaxis is therefore not possible. For first attacks, attention has been directed to parental education to achieve earlier diagnosis. Recurrent attacks may be prevented by prophylactic splenectomy. A controlled trial on the prevention of pneumococcal disease has indicated many pneumococcal septicemias in children given the 14 valent pneumococcal vaccine between the ages of 6 months and 3 years. No pneumococcal isolations occurred during the same period in children given monthly long-acting prophylactic penicillin. A controlled trial of folate supplementation for 1 year in children aged 6 months to 4 years indicated no difference between control and treatment groups in hemoglobin levels or weight and height velocity. The MCV was 4 fl less in the supplemented group. A controlled trial of feeder vessel photocoagulation in the therapy of proliferative retinopathy indicated significantly less vitreous hemorrhage in treated patients, but choroidal neovascularisation was a common complication of xenon arc therapy, and retinal tears commonly followed the use of the Argon laser. A new trial of scatter therapy is in progress.     

Morgagni hernia in infancy: report of 7 cases]

BACKGROUND: Morgagni or retrosternal hernia is a rare entity. It's representing almost 4% of all types of congenital diaphragmatic hernias in children. POPULATION AND METHODS: The data concerning 7 infants with Morgagni hernias (MH) have been retrospectively reviewed by the authors. RESULTS: Their ages at presentation ranged from 7 months to 11 years. There were 4 males and 3 females. The majority of patients had repeated chest infections. The diagnosis was made on chest radiograph and barium enema. All patients were operated through the abdomen (5 upper midline, 2 laparoscopic approach). The hernia sacs were excised and the defects repaired in all patients. DISCUSSION: Clinical awareness, early diagnosis and surgical treatment especially with laparoscopic correction, are important factors. CONCLUSION: Surgical correction is needed for asymptomatic MH in children to obviate the risk of complications and because the treatment is easy.     

Responses of small intrapulmonary arteries to vasoactive compounds in the fetal and neonatal lamb: norepinephrine, epinephrine, serotonin, and potassium chloride

Despite considerable study, the mechanisms responsible for the transition of the pulmonary circulation from the fetal to newborn life remain obscure. We compared the responses of third and fourth generation pulmonary arteries to norepinephrine, epinephrine, serotonin, and KCl from lambs 7 d preterm and 1, 7, and 21 d of age to assess differences between age and third and fourth generations of the pulmonary arterial tree during the transitional period. Preterm vessels were significantly smaller in internal diameter than all other aged vessels for both generations. Fourth generation vessel response to KCl increased with age (94 +/- 15 mg/mm2, preterm; 259 +/- 31 mg/mm2, 21 d). Third generation vessel response to KCl did not change with age (135 +/- 15 mg/mm2, preterm; 158 +/- 18 mg/mm2, 21 d). There were no differences in maximum response to norepinephrine and epinephrine between ages; however, third generation vessel response to these compounds was significantly greater (30-60% of maximum KCl response) than fourth generation vessel response (0-10%). Third and fourth generation vessels had the same maximum response to serotonin regardless of age or generation. Third generation vessels were significantly reduced in sensitivity (log molar concentration which produced 50% of the maximum response--EC50) to norepinephrine at d 1 (5.89 +/- 0.12 log molar) and 7 (5.90 +/- 0.21) compared to preterm (6.48 +/- 0.10) and 21 d of age (6.50 +/- .03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of weight changes during and after pregnancy: practical approaches

The usefulness of routine prenatal weight measurements in predicting pregnancy outcomes is still a controversial issue. Comparisons among studies and the interpretation of research findings are complicated due to the variety of indicators applied to express maternal weight changes during and after pregnancy. A review of literature was conducted to clarify the definitions and examine the strengths and limitations of methods for measuring gestational weight gain (WG) and postpartum weight changes. The reasons for weak correlations or non-significant associations between gestational WG and maternal and neonatal outcomes were probably owing to poor quality of obstetrics records and selection of wrong indicators to compute gestational WG. The choice of an indicator depends on clinical and research purpose, availability and reliability of data and cost. Considering the health implication of gestational WG, it is necessary to take into account the measurements used as initial and final weight, accuracy of gestational age estimation and the inclusion of fetal weight as part of maternal WG. Regardless of the indicators used to compute the weight changes after delivery, attention is drawn to the approach for designating prepregnancy weight, the time frame of postpartum weight measurements and the use of overlapping variables, which results in bias (part-whole correlation). It is necessary to address criticisms on the accuracy of prenatal weight measurements and the way of expressing the maternal weight changes during and after pregnancy in order to have reliable results from research.     

Hypoaldosteronism in three sibs due to 18-dehydrogenase deficiency

Three sibs all presented in the early neonatal period with a salt-losing syndrome. The salt-losing form of congenital adrenal hyperplasia was diagnosed and appropriate treatment with glucocorticosteroids, mineralocorticosteroids, and additional dietary salt started. Although early life was maintained with difficulty, with age all 3 children required decreasing amounts of replacement steroids to maintain normal plasma electrolyte balance. They were reinvestigated at the ages of 15 years and 8 years (twins), when cortisol synthesis and metabolism proved normal, but aldosterone synthesis was blocked by deficiency of 18-dehydrogenase. Rational treatment of these cases of a salt-losing syndrome in which aldosterone synthesis alone is blocked due to lack of the enzyme 18-dehydrogenase requires the administration of a mineralocorticosteroid drug only. Since deoxycorticosterone (acetate or pivalate) requires intramuscular administration, as life-long therapy oral fludrocortisone is preferable. Although fludrocortisone has glucocorticoid activity, the "hydrocortisone equivalent" effect of the small dosage used was unlikely to inhibit either pituitary corticotrophin or growth hormone production.