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Context: Five different activating PTH/PTH-related peptide (PTHrP) receptor (PTHR1) mutations have been reported as causes of Jansen metaphyseal chondrodysplasia (JMC), a rare disorder characterized by severe growth plate abnormalities and PTH-independent hypercalcemia.Objectives: Assess the natural history of clinical and laboratory findings in 24 patients with JMC and characterize the disease-causing mutant receptors in vitro.Patients and Methods: The H223R mutation occurred in 18 patients. T410P, I458R and I458K each occurred in single cases; T410R was present in a father and his two sons. Laboratory records were analyzed individually and in aggregate.Results: Postnatal calcium levels were normal in most patients, but elevated between 0.15 and 10 years (11.8 +/- 1.37 mg/dL) and tended to normalize in adults (10.0 +/- 1.03 mg/dL). Mean phosphate levels were at the lower end of the age-specific normal ranges. Urinary calcium/creatinine (mg/mg) were consistently elevated (children, 0.80 +/- 0.40; adults, 0.28 +/- 0.19). Adult heights were well below the 3rd percentile for all patients, except for those with the T410R mutation. Most patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and two had advanced chronic kidney disease. The five PTHR1 mutants showed varying degrees of constitutive and PTH-stimulated cAMP signaling activity when expressed in HEK293 reporter cells. The inverse agonist [L-11,dW(12),W-23,Y-36] PTHrP(7-36) reduced basal cAMP signaling for each PTHR1 mutant.Conclusions: Except for T410R, the other PTHR1 mutations were associated with indistinguishable mineral ion abnormalities and cause similarly severe growth impairment. Hypercalciuria persisted into adulthood. An inverse agonist ligand effectively reduced in vitro PTH-independent cAMP formation at all five PTHR1 mutants, suggesting a potential path toward therapy.

Objective. Polyarteritis nodosa (PAN) is a rare disease of childhood. The aims of this study were to describe the clinical features, treatment, and outcome of systemic childhood PAN and to identify predictors of relapse. Methods. A single-center retrospective medical records review of children with PAN fulfilling the European League Against Rheumatism (EULAR)/Paediatric Rheumatology European Society (PRES)/Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria who were seen over a 32-year period was performed. Data on demographic and clinical features, treatments, relapses (recurrence of clinical signs/symptoms or occurrence of new symptoms after initial remission requiring escalation or resumption of immunosuppressive therapy), and deaths were recorded. A disease activity score was retrospectively assigned using the Paediatric Vasculitis Activity Score (PVAS) instrument. Cox regression analysis was used to identify significant predictors of relapse. Results. Sixty-nine children with PAN were identified; 55% were male, and their median age was 8.5 years (range 0.9–15.8 years). Their clinical features at presentation were fever (87%), myalgia (83%), skin (88%), renal (19%), severe gastrointestinal (GI) (10%), and neurologic (10%) involvement. The PVAS at presentation was 9 of 63 (range 4–24). Histopathologic analysis of the skin showed necrotizing vasculitis in biopsy samples from 40 of 50 children. Results of selective visceral arteriography suggested the presence of PAN in 96% of patients. Treatment included cyclophosphamide and corticosteroids (83%), plasma exchange (9%), and biologic agents (after 2002; 13%). The relapse rate was 35%, and the mortality rate was 4%. Severe GI involvement was associated with increased risk of relapse (P 0.031), while longer time to induce remission (P 0.022) and increased cumulative dose of cyclophosphamide (P 0.005) were associated with lower relapse risk. Conclusion. Childhood PAN is a severe inflammatory disease of insidious onset and variable clinical presentation. Relapses occurred more frequently in those with severe GI involvement. A higher cumulative dose of cyclophosphamide was associated with a lower risk of relapse.

Summary Superantigens (SAgs) are potent stimulators of T cells bearing specific Vβ T cell receptors (TCR) and may play a role in the pathogenesis of Kawasaki syndrome (KS), although despite 15 years of intense study this area remains controversial. Because SAgs can cause Vβ restricted T cell activation in the absence of Vβ skewing the aims of this study were to describe a flow cytometric protocol to study both CD4 and CD8 Vβ repertoires, and CD69 expression across the CD4 and CD8 Vβ repertoire in children with KS. Sixteen children with KS were studied. There was no significant increase in overall peripheral blood CD4 or CD8 T cell activation as determined by CD69 expression. However, Vβ restricted CD4 and/or CD8 activation was observed in eight of 11 (72%) of the KS patients, a finding not observed in healthy controls. Thirteen of 16 (81%) of the KS patients had evidence of either Vβ skewing (particularly CD4 Vβ2 and Vβ5·1) and/or Vβ restricted activation. Three patients had Vβ restricted activation in the absence of skewing. We suggest that these preliminary observations highlight the many layers of complexity when considering T cell activation in KS, which could explain some of the conflicting studies regarding peripheral blood T cell activation and Vβ skewing. It is likely that in order to move forward with this debate a combination of detailed microbiological, immunological and molecular techniques applied to individual patients will be required ultimately to prove or refute the SAg hypothesis of KS.

Objectives: Indeterminate intestinal inflammation may result from a variety of inflammatory conditions in addition to ulcerative colitis and Crohn disease. The primary systemic vasculitides may present with intestinal inflammation and an indeterminate colitis. We set out to describe a series of children with primary systemic vasculitis who initially presented with clinical features suggestive of inflammatory bowel disease (IBD) to establish criteria that might help discriminate between IBD and primary systemic vasculitis. Methods: Ten children (6 boys, median age at presentation 8.9 years, range 0.9-14.5 years) satisfied inclusion criteria. Results: All had abdominal pain, weight loss, diarrhea (6 of 10 bloody) and laboratory evidence of a severe acute phase response. Extraintestinal clinical features included vasculitic rash, renal impairment, myalgia, testicular pain and polyarthritis. Endoscopy showed vascular changes or other macroscopic findings suggestive of vasculitis in 5 of 10 patients. Gut histology revealed indeterminate chronic inflammatory mucosal changes and one patient with small artery fibrinoid necrosis in the submucosal vessels. Extraintestinal biopsy was performed in 6 patients and had a higher yield for the demonstration of vasculitis than intestinal biopsy. The results of selective visceral angiography was suggestive of vasculitis in all patients, but was normal in 7 cases of treatment-unresponsive classic IBD. Treatment comprised corticosteroid and azathioprine in all patients. Cyclophosphamide was given to 7 of 10 patients. Conclusions: Extraintestinal manifestations and inflammatory responses that may be disproportionate to the degree of intestinal inflammation provide clues to the presence of an underlying primary systemic vasculitis, and these data suggest that selective visceral angiography plays a key role in the diagnosis of vasculitis in this context. It is important to identify and treat any vasculitic component because failure to do so may result in consequential morbidity or mortality.

Objective. Microparticles are released from endothelial cells in response to a variety of injurious stimuli and recently have been shown to be increased in a number of diseases associated with endothelial dysfunction. This study examined endothelial microparticle (EMP) and platelet microparticle (PMP) profiles in children with systemic vasculitis to test the hypothesis that EMPs may provide a noninvasive means of examining endothelial activation or injury. Methods. The study cohort comprised 39 children with systemic vasculitis at various stages of disease activity, 24 control children with febrile disease, and a control group of 43 healthy subjects. Plasma was ultra-centrifuged at 17,000g for 60 minutes, and the microparticle pellets were examined using flow cytometry. Results. Plasma from patients with active systemic vasculitis contained significantly higher numbers of E-selectin-positive EMPs compared with that from patients in remission, healthy controls, or febrile disease controls (P = 0.000 for each). A similar result was obtained for the numbers of EMPs expressing the marker CD105. There was also a significant increase in PMPs expressing CD42a in the active vasculitis group as compared with the other groups, but this difference was not significant for PMPs expressing P-selectin. The EMP counts correlated with the Birmingham Vasculitis Activity Score and the acute-phase reactant levels in the patients with systemic vasculitis, but there was a poor correlation overall between EMP counts and the acute-phase reactant levels in the febrile disease controls. Conclusion. EMPs may provide a window to the activated endothelium and could provide important pathophysiologic insights into the vascular injury associated with vasculitis of the young.

Objective. To study the clinical spectrum of Behcet's disease (BD) in childhood, and to report our experience of using thalidomide. Method. Ten children, diagnosed with BD, were studied retrospectively. Results. The median (range) age at first presentation was 4 (1.2-12.0) yr, at diagnosis was 11 (3-15) yr and the follow-up period was 4.1 (0.6-6.3) yr. Oral ulcers were present in all patients (100%), genital ulcers were present in six (60%), peri-anal ulcers were present in three (30%), skin manifestations were present in nine (90%), intracranial hypertension was present in two (20%), mild gastrointestinal symptoms were present in five (50%), joint symptoms were present in six (60%), ocular lesions were present in five (50%), but only one child had anterior and posterior uveitis. Therapeutically, a range of drugs was used, including colchicine, that resulted in good responses in five children. Thalidomide (1 mgukguweek to 1 mgukguday) was used in five children who were unresponsive to other immunosuppressive agents. It resulted in complete remission in three children and less frequent milder oral ulcers in two. Neuropathy developed in two children and in one it was irreversible. Conclusion. BD in children is similar to the disease in adults. Thalidomide provided a useful therapeutic option for severe oral and genital ulceration which was unresponsive to other therapies. Awareness of the danger of axonal neuropathy and teratogenesis at all times during thalidomide therapy is crucial. A low dose is probably as effective as higher doses.

The prevalence of antineutrophil cytoplasmic antibodies (ANCA) was studied in 12 children with Wegener's granulomatosis. The serum samples were taken in the active phase of disease and were screened for ANCA by indirect immunofluorescence with normal neutrophils and enzyme linked immunosorbent assay (ELISA) using crude neutrophil extract, proteinase 3, myeloperoxidase, cathepsin G, lactoferrin, and elastase as antigens. Of these 12 patients, 10 were positive for ANCA in the active phase of their illness, and they showed a predominantly cytoplasmic ANCA staining pattern on indirect immunofluorescence. There were high titres of ANCA directed against crude neutrophil extract, proteinase 3, myeloperoxidase, and cathepsin G. IgM isotypes occurred as commonly as IgG isotypes. Therefore, screening for ANCA is usually but not invariably positive in children with Wegener's granulomatosis. Specific diagnosis still relies on clinical and pathological features, and the value of ANCA in the diagnosis of paediatric Wegener's granulomatosis requires further study.

Renal scarring associated with vesico-ureteric reflux (VUR), most commonly detected in young children, is associated with a significant risk of developing hypertension in later life. Hypertension in reflux nephropathy contributes significantly to morbidity including deterioration of renal function. The mechanism of onset of hypertension is not clear although abnormalities of the renin-angiotensin system and sodium/potassium ATPase activity have been described in some cases. It is becoming clear that radiologically detectable renal scars or small kidneys may histologically indicate a variety of diagnoses. Prediction of the risk of developing hypertension in individual cases is difficult and therefore regular follow-up remains the only current means of recognising these subjects. Although prevention of renal scar development in children with VUR may offer some benefit in reducing the incidence of hypertension, there is no uniform action that can definitely achieve this, particularly in the very young, before any urinary infection occurs. Primary VUR seems to be a disorder with mendelian dominant inheritance and location of the gene may offer some hope of early identification within certain families. Timely introduction of preventative measures may then be possible even though reservations exist about their effectiveness.

Craniometaphyseal and craniodiaphyseal dysplasia are rare genetic disorders of bone due to modelling errors of long bones and skull bones. These syndromes present with multiple ENT symptomatology from an early age. The diagnostic distinction can now be made radiologically by serial skeletal survey which is important for prognosis. We review the clinical, radiological, computed tomography (CT) scan, otological, audiological and histopathological findings in two cases with craniodiaphyseal, and two cases with craniometaphyseal dysplasia, and report our experiences of medical and surgical treatment to date.In the craniodiaphyseal dysplasia, the hearing abnormality progressed from an initial conductive to a mixed loss on serial audiometric follow up. Temporal bone CT scans showed narrowing of the middle ear cavity, internal auditory meatus, and facial nerve canal at the geniculate ganglion. Benefits from choanal stenosis surgery, craniofacial remodelling and dacrocystorhinostomy were shortlived. Calcitriol therapy with a low calcium diet did not alter the clinical course of progression in our cases. The underlying defect, causing net bone formation in these phenotypically similar syndromes, appears to be different when based on the differing biochemical responses to calcitriol and bone biopsy findings. Increased numbers of osteoblasts were found in bone biopsies from both cases with craniodiaphyseal dysplasia.Early recognition is crucial in these conditions as therapy directed at the underlying bony defect has the best chance of success if initiated in infancy (Cole et al., 1988; Fanconi et al., 1988; Key et al., 1988).

SUMMARY Fifty-nine children with acute Kawasaki disease (KD), a childhood vasculitis, were compared with 35 children with fever due to infection and 48 healthy children. Levels of soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1)in the healthy children were double those found in adults. All three soluble cell adhesion molecules and von Willebrand factor (vWF) were higher in the children with KD than in the healthy children, but only sE-selectin, a marker for activated endothelial cells, and sICAM-1 were higher than in the febrile children. The high levels of vWF in KD appear to reflect the prominent acute-phase reaction. This information can help us to understand further the complex interactions between cytokines. circulating inflammatory cells and the vascular endothelium, and may lead to new therapeutic avenues in KD and other inflammatory diseases and vasculitides.

SUMMARY To confirm the presence of antiendothelial cell antibodies (AECA) and study the clinical value of their measurement in Kawasaki disease (KD), sera from patients with KD were assessed for binding to human umbilieal vein endothelial cells (HUVEC) using a cellular based ELISA, and for complement-mediated cytotoxicity using 111 In-labelled HUVEC. In the ELISA assay, IgM AECA were detected in 16/22 sera, whereas IgG AECA were only present in one out of 19 sera. There was a significant difference in IgM AECA titres when comparing patients with controls. Eight out of 16 sera showed cytotoxicity against HUVEC, and this was significantly enhanced when HUVEC were pretreated with tumour necrosis factor (TNF). IgM AECA titres measured by ELISA were positively correlated with their cytotoxicity. The findings suggest that IgM class AECA in sera from patients with KD are detectable by ELISA method, and that some of these antibodies. 50% in this study, can mediate complement-dependent cytotoxicity against endothelial cells.

Hypertension in children and adolescents has been gaining ground in cardiovascular medicine, mainly due to the advances made in several areas of pathophysiological and clinical research. These guidelines arose from the consensus reached by specialists in the detection and control of hypertension in children and adolescents. Furthermore, these guidelines are a compendium of scientific data and the extensive clinical experience it contains represents the most complete information that doctors, nurses and families should take into account when making decisions. These guidelines, which stress the importance of hypertension in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, should act as a stimulus for governments to develop a global effort for the early detection and suitable treatment of high pressure in children and adolescents. J Hypertens 27:1719-1742 Q 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.2010 Asociaci?n Espa?ola de Pediatr?a. Published by Elsevier Espana. All rights reserved.

OBJECTIVES: To describe the biologic treatment regimens and report the efficacy and safety of biologic therapies in a multicentre series of children with primary systemic vasculitis (PSV). METHODS: This was a retrospective descriptive case series of children with PSV treated with biologic therapy between February 2002 and November 2007. Primary retrospective outcome assessment measures were: daily corticosteroid dose; Birmingham Vasculitis Activity Score (BVAS); and adverse events (including infection rate). RESULTS: Twenty-five patients median age 8.8 (range 2.4-16) years; 11 male with active PSV (n = 6 with anti-neutrophil cytoplasmic antibody associated vasculitides, n = 11 with polyarteritis nodosa, n = 7 with unclassified vasculitis and n = 1 with Behcet's disease) were treated with biologic agents including infliximab (n = 7), rituximab (n = 6), etanercept (n = 4), adalimumab (n = 1) or multiple biologics sequentially (n = 7). Overall, there was a significant reduction in BVAS from a median of 8.5 (range 5-32) at start of therapy to 4 (range 0-19) at median 32 months follow-up (P = 0.003) accompanied by significant reduction in median daily prednisolone requirement from 1 (range 0.2-2) to 0.25 (range 0-1) mg/kg/day, P = 0.000. For those receiving multiple biologic agents sequentially, a similar clinical improvement was observed with corticosteroid sparing. Infections occurred in 24%, the most severe in those receiving infliximab. CONCLUSION: Our data provide retrospective evidence of efficacy of these agents, and highlight the associated infectious complications. Further multicentre standardization of treatment protocols and data collection to inform clinical trials of biologic therapy in systemic vasculitis of the young is required

Four children (two boys and two girls) with hypoparathyroidism, renal insufficiency, and developmental delay are described. They were the products of consanguineous marriages in three related Asian families presenting over a six year period. All the children died within the first 15 months of life despite treatment. Postmortem examination on one child showed absent parathyroid glands. We believe these children represent a previously undescribed syndrome that appears to be inherited in an autosomal recessive manner.

We report 101 episodes of Kawasaki disease in 100 patients seen over a 12 year period. A total of 35 patients had cardiac involvement ranging from pericardial effusion to coronary artery aneurysms with ischaemic complications, which resulted in death in one patient. Laboratory investigations showed leucocytosis, thrombocytosis, and a raised erythrocyte sedimentation rate to be common features and the first two variables were significantly associated with cardiac involvement. Treatment regimens changed over the study period. Aspirin was used in most patients often in conjunction with dipyridamole and from 1986 intravenous immunoglobulin was given routinely to those patients seen early in the illness. Additional therapeutic measures in individual patients included prostacyclin, heparin, streptokinase, and plasma exchange/exchange transfusion. Attention is drawn to the uncertainity of the long term cardiovascular consequences in the light of adults reported with premature atherosclerotic lesions of similar appearance to those seen in Kawasaki disease.

Renal tubular function was assessed in seven patients with methylmalonic acidaemia not responsive to vitamin B12. Five patients failed to concentrate their urine normally and in these patients the glomerular filtration rate was also reduced. Fractional excretion of sodium was increased in four patients, fractional excretion of potassium in one patient and in three there was a decreased tubular reabsorption of phosphate. Although possibly representing primary tubular damage these findings were thought to be consistent with adaptive changes secondary to the reduced glomerular filtration rate. Two patients had evidence of a defect of urinary acidification and several had a degree of hyporeninaemic hypoaldosteronism suggesting type 4 renal tubular acidosis. In one patient with a mild variant no renal disease was detected. Decreased renal function and tubular abnormalities were common in patients with methylmalonic acidaemia. It is likely that they are linked and essentially secondary to the tubulo-interstitial nephritis that is histologically demonstrable on renal biopsy. The failure of urinary concentrating ability and the disturbed urine acidification will contribute to the metabolic derangement during episodes of decompensation.

Ninety-one patients with Kawasaki disease were examined by cross sectional echocardiography between 1980 and 1988. In the 75 patients evaluated during the acute phase of the illness (the first month), the first echocardiographic examination was carried out at a mean time of 16 days (range 5-30) and coronary arterial lesions were seen in 21 (28%). Two patients with medium sized aneurysms had myocardial infarctions, and one died. Coronary arterial lesions persisted in 17 (23%) patients, most often in younger children. The remaining 16 patients were examined from one month to four years after their acute illnesses, and this group did not have coronary arterial abnormalities. Seven patients with coronary artery lesions have reached school age and require regular echocardiographic examination and exercise electrocardiography. Selective coronary arteriography may be indicated in some patients to identify coronary artery stenosis, which the Japanese experience has shown may progress for several years after the acute illness.

To investigate the influence of a family history of essential hypertension on abnormalities of red cell membrane sodium transport, 28 hypertensive children and their families were studied. In 15 families one or both parents had either essential hypertension or a strong family history. In 13 families neither parent had essential hypertension or a positive family history. There were significant differences between the children with a positive family history of essential hypertension compared with those without. Values are expressed as mean (SD): intracellular sodium concentration (mmol/l cells) 8.19 (2.18) compared with 6.41 (0.98); sodium efflux rate constant 0.4873 (0.1379) compared with 0.5831 (0.1104); and numbers of sodium-potassium ATPase pump sites (BMax) (nmol/l cells) 7.96 (1.71) compared with 9.56 (1.7). Significant differences were also found when the index hypertensive children were excluded and the normotensive siblings with and without hypertensive family histories were compared. These data suggest that abnormal red cell membrane sodium transport has a familial component, and although it is not caused by the hypertension it may be the earliest pathophysiological step in its development, perhaps allowing the identification of children at risk of essential hypertension.

Summary Superantigens (SAgs) are potent stimulators of T cells bearing specific Vβ T cell receptors (TCR) and may play a role in the aetiopathogenesis of systemic vasculitis, although this remains contentious. To investigate the possible aetiological role of SAgs, this study examined peripheral blood T cell Vβ repertoires in children with systemic vasculitis. FACS analysis of 17 different peripheral blood T cell Vβ families was performed in 20 healthy control children, 27 disease control children with nonvasculitic inflammatory disease, 25 children with primary systemic vasculitis, six patients with Kawasaki disease (KD) and six patients with Henoch–Schönlein purpura (HSP). There was a significantly increased variance of CD4 Vβ12 and Vβ17, and CD8 Vβ1 in the primary systemic vasculitis group compared to control and disease controls. Moreover, 80% of the primary systemic vasculitis children had one or more CD4 Vβ expansions or deletions, compared with 30% of controls (P

Background: Polyarteritis nodosa is a necrotising vasculitis of the medium sized and small muscular arteries. The inflammatory and subsequent reparative processes may alter the arterial mechanical properties. The effect of vasculitic damage on arterial distensibility has never been explored however. Aim: To determine the normal values and the effect of childhood vasculitis on arterial distensibility in children and teenagers. Methods: Distensibility of the brachioradial arterial segment was studied using pulse wave velocity (PWV ∝1/√distensibility), in 13 children with polyarteritis nodosa at a median age of 11.8 (range 4.9-16) years. As a control group, 155 healthy schoolchildren (6-18 years, 81 boys) were studied. PWV was assessed using a photoplethysmographic technique; blood pressure was measured by an automatic sphygmomanometer (Dinamap). Data from patients were expressed as z scores adjusted for age and compared to a population mean of 0 by a single sample t test. Determinants of PWV in normal children were assessed by univariate and multivariate linear regression analyses. Results: Age, height, weight, and systolic blood pressure correlated individually with the brachioradial PWV. Multivariate analysis identified age as the only independent determinant. Ten of the patients were in clinical remission, while three had evidence of disease activity at the time of study. The PWV in the patient group as a whole was significantly greater than those in healthy children (mean z score +0.99). Raised C reactive protein concentration (>2 mg/dl) in the three patients with active disease was associated with a higher PWV when compared to those in remission (z score +2.78 v +0.45). The diastolic blood pressure of the patients was higher than those of the controls (z score + 1.04) while the systolic pressure was similar (z score -0.36). Conclusions: PWV in the brachioradial arterial segment increases gradually during childhood independent of body weight, height, mass, and blood pressure. Increased PWV, and hence decreased distensibility, in this peripheral arterial segment occurs in polyarteritis nodosa and is amplified during acute inflammatory exacerbation., published_or_final_version

This article reviews the spectrum of vasculitic illness affecting children. Apart from the relatively common vasculitides (Henoch-Schonlein purpura, Kawasaki disease, and in worldwide terms Takayasu disease) there are a number of important but comparatively rare disorders affecting children. As in adults, there is a considerable degree of overlap between the various vasculitic syndromes in childhood. With modern therapeutic agents, the prognosis for many of the childhood vasculitides has improved; however, in spite of this, there remains a not inconsequential morbidity and mortality. It is anticipated that as our knowledge of the immunopathogenesis of this group of disorders expands, classification and treatment of vasculitis in both children and adults will improve.

Despite the publication of several expert committee guidelines for the measurement of blood pressure (BP) and the diagnosis of hypertension in children and adolescents, it was our perception and clinical experience that there still appeared to be a general lack of standardisation of BP measurement techniques and little consensus on the criteria for diagnosing hypertension. To investigate this further, we have conducted a postal survey of consultant-grade paediatricians who were members of the British Paediatric Association (BPA). A total of 1500 questionnaires were sent out and 708 analysable replies were received (47.1%). This showed that 68.6% of paediatricians routinely measured BP, at least on one occasion, in children or adolescents attending their outpatient clinics, 17.7% started at or soon after birth, 12.3% started at the age of 1 year, 20.0% at 3 years, 12.0% from 7 years of age and 3.5% from the age of 13. Only 60.5% reported that they had a choice of four or more different cuff sizes in their clinic. Forty-one percent of respondents reported that the BP was always or sometimes measured by nurses. Fifty-one percent of respondents measured diastolic BP at the phase of muffling of sound (Korotkoff phase IV), 31.9% used the disappearance of sound (phase V) whilst 15.9% claimed that they measured both end-points. The criteria for diagnosing a child as being hypertensive varied greatly; 17.9% reported that they responded to the systolic BP alone, 13.5% to the diastolic BP alone, 65.9% relied on both pressures, and 2.7% responded to either the systolic or diastolic pressure if it was raised. Furthermore, 12.9% diagnosed hypertension if the BP exceeded the 90th percentile in relation to age and 41.8% used the 95th percentile. However 45.3% of respondents employed a higher dividing line. In hospitalised children, leg blood pressures were measured routinely by 30.3%, although a further 44.0% would do so if aortic coarctation or other vascular diseases were suspected. Despite considerable variation in clinical practice, techniques and criteria, only 11.4% of clinicians would manage the patients themselves, with the remainder referring the child on to the appropriate specialist. The survey suggests a general lack of standardisation of BP measurement techniques and little consensus on the criteria for diagnosing hypertension amongst paediatricians. Simplified, shortened and updated guidelines on hypertension in paediatric practice and research are needed.

Two heterozygous PTH/PTH-related peptide (PTHrP) receptor missense mutations were previously identified in patients with Jansen's metaphyseal chondrodysplasia (JMC), a rare form of short limb dwarfism associated with hypercalcemia and normal or undetectable levels of PTH and PTHrP. Both mutations, H223R and T410P, resulted in constitutive activation of the cAMP signaling pathway and provided a plausible explanation for the abnormalities in skeletal development and mineral ion homeostasis. In the present study we analyzed genomic DNA from four additional sporadic cases with JMC to search for novel activating mutations in the PTH/PTHrP receptor, to determine the frequency of the two previously identified missense mutations, H223R and T410P, and to determine whether different mutations present with different severity of the disease. The H223R mutation was identified in three novel JMC patients and is, therefore, to date the most frequent cause of JMC. In the fourth patient, a novel heterozygous missense mutation was found that changes isoleucine 458 in the receptor's seventh membrane-spanning region to arginine (I458R). In COS-7 cells expressing the human PTH/PTHrP receptor with the I458R mutation, basal cAMP accumulation was approximately 8 times higher than that in cells expressing the wild-type receptor despite impaired surface expression of the mutant receptor. Furthermore, the I458R mutant showed higher responsiveness to PTH than the wild-type receptor in its ability to activate both downstream effectors, adenylyl cyclase and phospholipase C. Like the H223R and the T410P mutants, the I458R mutant had no detectable effect on basal inositol phosphate accumulation. Overall, the patient with the I458R mutation exhibited clinical and biochemical abnormalities similar to those in patients with the previously identified H223R and T410P mutations.

A child presented with ischaemic episodes of his left leg from the age of 2 months. He was found to have raised anticardiolipin antibodies so was started on low dose aspirin. At a three year follow up he was asymptomatic with a normal anticardiolipin antibody level while taking aspirin daily, probably for life.

Vasculitis can present in childhood. There is a wide spectrum of disease in vasculitis, with Henoch-Schönlein purpura and Kawasaki disease occurring most commonly; however, macroscopic and microscopic polyarteritis, Wegener's granulomatosis, Takayasu's disease, cutaneous polyarteritis, hypersensitivity angiitis; vasculitis associated with connective tissue disorders, such as dermatomyositis, and a number of other miscellaneous vasculitides are seen. With the current range of investigative and therapeutic tools, it is possible to diagnose and treat the majority of patients although morbidity and mortality is not inconsequential.

We studied anti-neutrophil cytoplasmic antibodies (ANCA) and anti-endothelial cell antibodies (AECA) in 58 children with acute Kawasaki disease (KD) before i.v. gamma globulin treatment, 35 children with infection and fever > 38.5 degrees C, and 48 healthy afebrile children. ANCA were studied by indirect immunofluorescence (IIF) on ethanol-fixed neutrophils and by ELISA with crude neutrophil extract as antigen. AECA were studied using ELISA on resting and activated endothelial cells. ANCA IIF was weakly positive, cytoplasmic, diffuse and homogeneous in all three groups. ANCA IIF, ANCA ELISA and AECA ELISA were no higher in KD than in febrile children. There was no difference between KD with and KD without coronary artery aneurysms. AECA differences between the KD and afebrile group were not significant after correction for total IgM. In contrast with our previous findings, we conclude that ANCA and AECA are not raised in KD compared with febrile controls. It therefore seems unlikely that they are important in the pathogenesis of vasculitis in KD.

Abnormalities of sodium-lithium countertransport have been extensively implicated in adult primary hypertension and a relationship between sodium-lithium countertransport and family history of hypertension in children has been previously found. More recently it has been suggested that increased sodium-lithium countertransport may play a part in the pathogenesis of nephropathy in insulin dependent diabetes mellitus (IDDM). Children and adolescents with IDDM and their family members were studied. In those with IDDM (n = 36, median age 14.6 years, range 9.5-19.2 years) there was no relationship between sodium-lithium countertransport (range 0.098-0.585 mmol/l red blood cells/hour) and age, blood pressure as expressed by systolic or diastolic SD scores, glycated haemoglobin, serum lipids, or intracellular sodium concentration. A positive relationship (rs = 0.44) was found between sodium-lithium countertransport and early morning urinary albumin to urinary creatinine ratio (UA/UC), expressed as the logarithm of the geometric mean of two consecutive samples, for each individual (range 0.4-22 mg/mmol). Sodium-lithium countertransport was increased in those with IDDM compared with their non-diabetic siblings, in a paired analysis (n = 26). There was no relationship between UA/UC in the children with diabetes and sodium-lithium countertransport in their parents. These studies in this population of diabetic children indicate that increased sodium-lithium countertransport may play a part in the early stages of the development of nephropathy in IDDM.

Summary OBJECTIVE Hereditary vitamin D resistant rickets (HVDRR) is characterized by severe rickets and is often accompanied by alopecia. Mutations in the gene encoding the vitamin D receptor have been found in this condition. In a patient with the characteristic phenotype we have investigated the functional defect and sequenced the gene to seek a mutation. DESIGN Patient and control cell lines prepared from skin fibroblasts and peripheral blood lymphocytes were used to measure binding of 1,25(OH)2D3 and to isolate vitamin D receptor mRNA. VDR cDNA was sequenced and transfected into receptor defective cells. PATIENT A child with alopecia diagnosed as having rickets due to resistance to 1,25(OH)2D3. MEASUREMENTS Cytosolic binding and nuclear association of 1,25(OH)2D3 were determined in patient and control cells, and functional response to 1,25(OH)2D3 assessed by measurement of 24-hydroxylase activity. VDR mRNA was prepared, reverse transcribed, and cDNA sequenced. VDR cDNA was also transfected into VDR-deficient CV-1 cells and functional response to 1,25(OH)2D3 assessed by co-transfection with a chloramphenicol acetyltransferase (CAT) reporter plasmid. RESULTS VDR from the patient were able to bind 1,25(OH)2D3 but showed no nuclear localization resulting in an absence of functional response to 1,25(OH)2D3. Sequencing revealed that the VDR coding region was normal. Expression studies of the patient's VDR showed functionally normal VDR as evidenced by normal trans-activation in the presence of 1,25(OH)2D3. CONCLUSION These data indicate a new cause of tissue resistance to 1,25(OH)2D3 which occurs in the absence of mutations in the coding region of VDR gene and which is characterized by defective nuclear localization of this receptor.

Between 1975 and 1985, 454 patients with hypertension were admitted to the Renal Unit of the Hospital for Sick Children. A total of 110 (24%) patients presented with severely raised blood pressures deemed to require emergency management. At presentation 84/110 had symptoms and signs of long standing hypertension with neurological involvement. Between 1975 and 1980 bolus intravenous injections of diazoxide and/or hydralazine were used with the aim of reducing the blood pressure to within the normal range for age in the first 12-24 hours after admission. Of 57 patients treated in this way 13 developed hypotensive complications and four, whose blood pressures returned to normal within 24 hours of admission, suffered irreversible neurological damage. Subsequently, the management changed to the use of intravenous infusions of labetalol (1-3 mg/kg/hour) and/or sodium nitroprusside (0.5-8 micrograms/kg/min) to enable a more gradual controlled reduction of blood pressure over the first 96 hours of admission. Between 1980 and 1985, 53 patients were treated using this regimen. In all cases blood pressure reduction was achieved in a more controlled manner without further neurological impairment or serious irreversible side effects. From our experience, the use of labetalol and sodium nitroprusside by incremental infusion in the critical early phase of management has resulted in improved control of accelerated hypertension without the sudden hypotensive episodes seen when bolus injections are used.

Fifty-four children referred for investigation of hypertension had renovascular disease. In eight patients it was associated with neurofibromatosis, in three with idiopathic hypercalcemia of infancy, and in five cases it followed an arteritic illness. Fibromuscular dysplasia was the underlying abnormality in the majority of cases (46%). Twenty-six patients (48%) were first seen with accelerated hypertension; 38 children (70%) had bilateral renal arterial disease, and in 41 (76%), disease of the small intrarenal vessels was found. Renal vein renin ratios indicated unilateral disease in 31 cases; the results correlated with arteriography findings in 32 (62%) of 51 patients. Eleven children also had the middle aortic syndrome, and 9 of 16 patients, investigated by cerebral arteriography because of cranial bruits or focal neurologic signs, had cerebral vascular abnormalities. Twenty patients were treated surgically--10 by reconstructive procedures, 11 by nephrectomy or heminephrectomy, and 6 by transluminal angioplasty. Of these, 9 (45%) are normotensive with no treatment, 10 have a decreased requirement for antihypertensive drugs, and 1 had no improvement. Thirty-four patients were treated medically because of the extent of their disease; two patients have died of hypertensive complications. We conclude that renal vascular disease in children is often widespread, may be associated with intracerebral vascular disease, frequently affects both kidneys, including both intrarenal and extrarenal vessels, and is therefore not always amenable to surgical intervention and cure.

Anti-netrophil cytosolic antibodies (ANCA) and anti-endothelial cell antibodies (AECA) have been identified in a wide variety of disorders, but their pathophysiological role remains unclear. ANCA appear to be particularly associated with various forms of vasculitis including Wegener's granulomatosis, Kawasaki disease and microscopic polyartiritis. Cytoplasmic staining (cANCA) on indirect immunofluorescence is associated with extrarenal disease and a perinuclear pattern (pANCA) with renal limited disease. The cANCA antigen appears to be proteinase 3 and that for pANCA myeloperoxidase. AECA have been detected in systemic lupus erythematosus, scleroderma and dermatomyositis but are also found in systemic vasculiitis. Kawasaki disease, haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura and renal allograft recipients at the time of rejection. Their presence appears to be correlated with disease activity and they may be directed against epitopes on as yet unidentified infective agents that precipitate some of the diseases in which they are found that cross-react with antigenic sites exposed on endothelial cells. Measurement of these antibodies has a diagnostic role, facilitates monitoring of disease activity and may prove valuable in understanding the pathogenesis of the diseases in which they are found.

Kawasaki disease is an acute vasculitic illness of childhood associated with significant morbidity and mortality. A cellular based enzyme linked immunosorbent assay (ELISA) was used to demonstrate the presence of antiendothelial cell antibodies in sera from children with Kawasaki disease. Twenty one of 32 patients with Kawasaki disease had raised IgM antibody titres and four had raised IgG antiendothelial antibody titres. There was a significant difference in the IgM antiendothelial cell antibody titres when comparing the patients with normals and febrile controls. The antibody titre paralleled the disease activity in patients studied serially. There was no relative increase in binding of antiendothelial cell antibodies after cytokine stimulation. These findings may be of importance in further research into the understanding of mechanisms involved in this and other forms of vasculitis in man.

Aldosterone is important in the regulation of sodium conservation by both kidney and colon. In the very preterm neonate marked urinary salt wasting occurs because of immature renal tubular function, but little is known of the ontogeny of colonic transport processes. Using an in vivo rectal dialysis technique, we have shown that in the human infant the colon has well developed salt conserving mechanisms from early in the last trimester of gestation and that aldosterone is an important regulatory hormone. Sodium transport mechanisms in the colon appear to develop before those in the kidney and it is possible that the colon is the major organ of sodium conservation in the preterm neonate.

OBJECTIVE--To evaluate the long term outcome of renal function in infants and children after diarrhoea associated haemolytic uraemic syndrome. SETTING--The Hospital for Sick Children, Great Ormond Street, and the Royal Free Hospital, London. SUBJECTS--103 children with the syndrome who presented between 1966 and 1985; 88 attended for follow up investigations (40 male, 48 female) with a mean age 11.6 (range 5.2-22.6) years and a mean duration of follow up of 8.5 (range 5.1-21.3) years. MAIN OUTCOME MEASURES--Blood pressure, ratio of early morning urine albumin to creatinine concentration, glomerular filtration rate, and plasma renin activity. RESULTS--The mean (SD) systolic blood pressure standard deviation score was 0.38 (0.67) and diastolic blood pressure SD score was 0.10 (0.76). The geometric mean ratio of overnight urine albumin to creatinine concentration was 1.27 (range 0.03-48.2), significantly higher than the value observed in 77 normal children (0.32 (0.05-1.95), p less than 0.0001). Glomerular filtration rate estimated from the plasma clearance of chromium-51 EDTA was 95.1 (22.7) ml/min/1.73 m2 surface area, and 16 children had a rate of less than or equal to 80 ml/min/1.73 m2. Significant negative correlations were found between glomerular filtration rate and urinary albumin to creatinine ratio (r = -0.41, p less than 0.0001) and glomerular filtration rate and systolic blood pressure SD score (r = -0.48, p less than 0.0001). A significant positive correlation was found between urinary albumin to creatinine ratio and systolic blood pressure SD score (r = 0.25, p = 0.02). CONCLUSIONS--After an acute episode of diarrhoea associated haemolytic uraemic syndrome 31% (27/88) of children had an increased albumin excretion, 18% (16/88) had a reduced glomerular filtration rate and 10% (9/88) had both, in association with a higher systolic blood pressure, indicating considerable residual nephropathy in this group.

Presenting features and clinical manifestations of six patients with toxic shock syndrome are reported. In four of the six cutaneous injury, sometimes trivial, occurred before the onset of symptoms and may have been a causal factor. All six children recovered. The need for early recognition and intensive management in this life threatening condition is discussed.

Acute renal failure developed in 24 (5.3%) of 456 children undergoing cardiopulmonary bypass surgery during a 2-year period. It was more common in younger children, in those with complex cardiac lesions, and in those with long overall bypass times. Fourteen (58%) recovered renal function; renal failure was responsible for death in only two. Early vigorous peritoneal dialysis is advocated after cardiopulmonary bypass surgery if there is oliguria (less than or equal to 1.0 ml urine/kg per hour) resistant to volume repletion, dopamine infusion and diuretics, intractable fluid overload, or hyperkalaemia.

Renal venous PRA was measured in 49 normotensive children without renal disease undergoing routine cardiac catheterization. PRA levels did not differ significantly between both renal veins and were significantly higher in the renal veins than in the IVC. There was a constant mean ratio of 1.21 between the renal veins and the IVC at low, intermediate, and high absolute PRA levels. Three patients had a renal venous PRA ratio greater than 1.4 and the highest ratio observed was 1.55. This fidning supports 1.5 as an acceptable upper limit of normality for the interpretation of renal vein PRA ratios in the investigation of patients with suspected renal hypertension. In four patients, PRA in the renal veins was significantly lower than in the IVC. The possibility of renin removal by these kidneys is discussed.

A semi-micro method for determination of plasma renin activity (PRA) by radioimmunoassay of generated angiotensin I (AI) is described. The method permits measurement of PRA on 250 mul of plasma without loss of specificity, sensitivity, accuracy or preision. The small sample size has considerable application in terms of investigation of infants and young children. A reference range was established for healthy children on free diets. There was a 15-fold decline in PRA with age from a mean value of 1404pgAI/ml h-1 (ngAI/1. h-1) in infancy to a mean of 85 pgAI/ml h-1 (ngAI/1. h-1) in adult life.

Twenty three children aged from 5 to 16 with mild to moderate hypertension were investigated using the orally active angiotensin converting enzyme inhibitor captopril. Falls in both systolic and diastolic blood pressure after a single dose of captopril were significantly correlated with initial plasma renin activity. In addition, some information about the aetiology of hypertension was deduced from the renin response to captopril. The blood pressure response to captopril is a useful screening test for renin dependent hypertension in childhood.

A 5-year-old boy is described who presented with episodes of hypoglycaemia triggered by mild infections or fever. Subnormal glucocorticoid production was confirmed by demonstrating low urinary excretion of free cortisol, low plasma cortisol concentrations that did not rise after glucagon and ACTH stimulation, and by elevated plasma ACTH levels. The selective nature of the abnormality was confirmed by demonstrating normal plasma electrolyte concentrations and blood pressure on a salt-restricted diet. Plasma renin activity and plasma aldosterone levels were also normal and responded appropriately to salt restriction and to frusemide-induced diuresis. Starvation-induced hypoglycaemia was associated with raised levels of blood ketone bodies and low blood alanine concentrations. Catecholamine secretion during hypoglycaemia was reduced. Glucocorticoid replacement therapy was effective in restoring normal glucose homeostasis.

Renal venous renin activity was measured in 50 children with hypertension. Main renal vein and segmental renal vein sampling was feasible in children as young as 15 months. In all cases in which there was a clear difference in renin secretion between the kidneys--that is, a main vein renin ratio above 1.5--surgery, when undertaken, successfully restored normal blood pressure. Most of the children with main renal vein renin ratios below 1.5 had bilateral disease or apparently normal kidneys. Segmental renal vein sampling contributed useful information additional to that provided by main renal vein measurements and permitted identification of local sources of renin production. In children with renal transplants who developed hypertension renal vein renin measurements helped in determining the cause and facilitating the management of the raised blood pressure.

The following measurements were made in normal children, children with primary hypertension, and children with secondary hypertension: erythrocyte intracellular sodium concentration, total sodium efflux rate constant, and maximum binding of ouabain to erythrocytes reflecting the number of sodium/potassium adenosine triphosphatase pump sites. Children with primary hypertension had a significantly higher mean erythrocyte intracellular sodium concentration (8.2 compared with 6.6 and 6.7 mmol/l cells), and significantly lower total sodium efflux rate constant (0.5071 compared with 0.6983 and 0.6197) and maximum binding of ouabain to erythrocytes (9.1 compared with 11.7 and 11.0 nmol/l cells) than normal children and children with secondary hypertension, respectively.

Neurological symptoms in hypertensive subjects may be a reflection of intracranial vascular disease and not just a consequence of hypertension. Two hypertensive children with renovascular disease, neurological symptoms, and severe cerebral arterial disease were treated by extracranial-intracranial arterial bypass surgery with improvement of symptoms and easier control of blood pressure. Where revascularisation surgery is appropriate, this should be undertaken before neurological complications arise.

We report a 4-year-old child with Weber-Christian panniculitis who subsequently developed histologically proven chronic active hepatitis, pancreatitis and extensive lipoatrophy. An "LKM" variant autoantibody was detected in the serum and a favourable response has been seen with immunosuppressive therapy. These findings lend support to the concept of Weber-Christian being an "auto-immune" disease.

In studies of the X chromosomes of two unrelated boys with adrenal hypoplasia, glycerol kinase deficiency, Duchenne muscular dystrophy, and mental retardation, conventional G banding did not reveal any numerical or structural abnormality, but direct DNA analysis with the X short-arm probes 754, C7, and OCT revealed a deletion in 1 of these patients. It is likely that both boys have a deletion at Xp21 affecting a number of closely linked disease-specific gene loci.

Both systolic and diastolic pressures can be measured in children with the mercury sphygmomanometer, the Arteriosonde and the Infrasonde. Estimates made blindly with these instruments were compared with directly measured intra-arterial blood pressures in 50 children aged between 4 days and 14 years. Systolic and diastolic estimates with the three techniques showed highly significant correlations with simultaneous intra-arterial measurements (P less than 0.001). The Infrasonde diastolic estimates were least satisfactory and the slope of the regression line against the intra-arterial pressure differed significantly from unity (y=0.54x+29.53). In 11 small children a satisfactory diastolic estimate could not be obtained with the mercury sphygmomanometer. While the mercury sphygmomanometer should remain the standard hospital equipment, an Arteriosonde would be valuable if it is difficult to hear Korotkoff's sounds on auscultation and if a diastolic pressure is required. For research investigations into childhood blood pressure an Arteriosonde or mercury sphygmomanometer, coupled with a device to exclude observer bias, is probably most suitable. Although the Infrasonde is not sufficiently accurate for research purposes, it is acceptable for routine ward use.