M. van Deuren

Clinical spectrum of ataxia-telangiectasia in adulthood

Objective: To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype–phenotype relationship for mutations in the ATM gene. Methods: Retrospective analysis of the clinical characteristics and course of disease in 13 adult patients with variant A-T of 9 families and 6 unrelated adults with classic A-T and mutation analysis of the ATM gene and measurements of ATM protein expression and kinase activity. Results: Patients with variant A-T were only correctly diagnosed in adulthood. They often presented with extrapyramidal symptoms in childhood, whereas cerebellar ataxia appeared later. Four patients with variant A-T developed a malignancy. Patients with classic and variant A-T had elevated serum α-fetoprotein levels and chromosome 7/14 rearrangements. The mildest variant A-T phenotype was associated with missense mutations in the ATM gene that resulted in expression of some residual ATM protein with kinase activity. Two splicing mutations, c.331 + 5G>A and c.496 + 5G>A, caused a more severe variant A-T phenotype. The splicing mutation c.331 + 5G>A resulted in less ATM protein and kinase activity than the missense mutations. Conclusions: Ataxia-telangiectasia (A-T) should be considered in patients with unexplained extrapyramidal symptoms. Early diagnosis is important given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment. Measurement of serum α-fetoprotein and chromosomal instability precipitates the correct diagnosis. There is a clear genotype–phenotype relation for A-T, since the severity of the phenotype depends on the amount of residual kinase activity as determined by the genotype.

The allopurinol hypersensitivity syndrome

We describe a 61-year-old male patient who was treated with allopurinol and developed fever, a skin rash, eosinophilia and severe renal and liver dysfunction. We discuss the allopurinol hypersensitivity syndrome as a serious complication of the use of allopurinol, and briefly review the aetiology, prevention and treatment modalities.

Kinetics of tumour necrosis factor-alpha, soluble tumour necrosis factor receptors, interleukin 1-beta and its receptor antagonist during serious infections.

Tumour necrosis factor-α (TNF) and interleukin-1β (IL-1β) are the central mediators in the genesis of sepsis. The proinflammatory effects of these cytokines are counteracted in vivo by natural inhibitors. Soluble TNF receptors (sTNFR) are shed upon inflammatory stimuli such as IL-1β and TNF itself. Circulating TNF can be complexed by these receptors, thus preventing TNF from binding to effector cells. The binding of IL-1β to its receptor can be blocked by high concentrations of interleukin-1 receptor antagonist (IL-1Ra), which is produced and released upon nearly the same stimuli as IL-1β. This review presents some aspects of the kinetic behaviour of native sTNFR and of the production of native IL-1Ra during severe infections. It appears that in fulminant septicaemia, the plasma concentration of TNF is increased only transiently, during the very early stage of the infection. The concentration of sTNFR, in contrast, remains elevated much longer, probably due to a slower clearance. During the acute stage of severe infectious diseases, peripheral blood cells cannot be stimulated to produce IL-1β. The production of IL-1Ra, in contrast, is not affected. Thus, the kinetic behaviour and regulation of TNF and IL-1β, is different from that of their antiinflammatory counterparts.

Pre-admission clinical course of meningococcal disease and opportunities for the earlier start of appropriate intervention: a prospective epidemiological study on 752 patients in the Netherlands, 2003–2005

To improve the timeliness of health care delivery to patients with meningococcal disease, the early disease evolution and clinical manifestation at admission were studied in all 752 patients with invasive meningococcal disease in the Netherlands in 2003–2005. Eighty-eight percent (88%) had serogroup B disease. The case fatality rate (CFR) was 6.7% overall, but reached 16% among adults over 50xa0years of age. The CFR was similar for serogroups B (6.3%) and C (5.2%). Admission followed 17 h (median) after the onset of symptoms. The CFR in patients admitted within 12xa0h, 12–18xa0h, 18–36xa0h or >36xa0h after the first symptoms was 10.2, 7.8, 3.5 and 2.2%, respectively. Only 60% of patients had skin lesions, and admission followed 2xa0h (median) later. Earlier recognition can be achieved when non-petechial clues are included in the diagnosis. A short duration of disease before admission is a simple tool in the recognition of patients with severe disease.

Primary immunodeficiencies in the Netherlands : National patient data demonstrate the increased risk of malignancy

PURPOSEnTo analyze the data of the national registry of all Dutch primary immune deficiency (PID) patients, according to the European Society for Immunodeficiencies (ESID) definitions.nnnRESULTSnIn the Netherlands, 745 patients had been registered between 2009 and 2012. An overall prevalence of 4.0 per 100,000 inhabitants was calculated. The most prevalent PID was predominantly antibody disorder (PAD) (60.4%). In total, 118 transplantations were reported, mostly hematopoietic stem cell transplantations (HSCT). Almost 10% of the PID patients suffered from a malignancy, in particular lymphoma and skin cancer. Compared to the general Dutch population, the relative risk of developing any malignancy was 2.3-fold increased, with a >10-fold increase for some solid tumors (thymus, endocrine organs) and hematological disease (lymphoma, leukemia), varying per disease category.nnnCONCLUSIONSnThe incidence rate and characteristics of PID in the Netherlands are similar to those in other European countries. Compared to the general population, PID patients carry an increased risk to develop a malignancy.

Coxiella burnetii infection (Q fever) in rheumatoid arthritis patients with and without anti-TNFα therapy

Q fever is a zoonosis caused by the intracellular bacterium Coxiella burnetii. The Netherlands experienced a major Q fever outbreak between 2007 and 2010, with an estimate of more than 40u2005000 infected individuals.1 Initial infection is asymptomatic in over 50% of the infected individuals or causes a mostly self-limiting febrile disease.2 However, chronic Q fever may develop months to years after initial infection. This serious, life-threatening condition presents mostly as endocarditis or infection of an aortic aneurysm or vascular prosthesis, and is accompanied by high IgG antibody titres against phase I C burnetii .3 Individuals most at risk for chronic Q fever are those with pre-existing valvulopathy, vascular aneurysm or prosthesis and yet undefined types of immune suppression.4 ,5 Tumour necrosis factor-α (TNFα) plays an important role in the defence against intracellular bacteria such as C burnetii . In vitro studies show that TNFα is involved in internalisation and intracellular killing of C burnetii in monocytes.6 ,7 In addition, C burnetii- infected TNFα knockout mice develop early bacteraemia and severe …

The angio-Behçet syndrome

Two man presented with recurrent venous thrombosis. One of them also suffered from arterial thrombosis and aneurysm. Additional history-taking revealed that both suffered from recurrent oral and/or genital ulcers, erythema nodosum and iritis. Consequently a diagnosis of angio-Behçet syndrome was made. Related to the clinical observations in these patients, we discuss the complications and the management of angio-Behçet syndrome. Treatment includes anticoagulants and immunosuppressive drugs.

Intact interferon-γ response against Coxiella burnetii by peripheral blood mononuclear cells in chronic Q fever

OBJECTIVESnQ fever is caused by Coxiella burnetii, an intracellular bacterium that infects phagocytes. The aim of the present study was to investigate whether the C.xa0burnetii-induced IFN-γ response is defective in chronic Q fever patients.nnnMETHODSnIFN-γ was measured in supernatants of C.xa0burnetii-stimulated peripheral blood mononuclear cells (PBMCs) of 17 chronic Q fever patients and 17 healthy individuals. To assess IFN-γ responses, expression profiles of IFN-γ-induced genes in C.xa0burnetii-stimulated PBMCs were studied in six patients and four healthy individuals. Neopterin was measured in PBMC supernatants (of eight patients and four healthy individuals) and in sera (of 21 patients and 11 healthy individuals). In a genetic association study, polymorphisms in genes involved in the Th1-cytokine response were analysed in a cohort of 139 chronic Q fever patients and a cohort of 220 control individuals with previous exposition to C.xa0burnetii.nnnRESULTSnIFN-γ production by C.xa0burnetii-stimulated PBMCs from chronic Q fever patients was significantly higher than in healthy controls. Many IFN-γ response genes were strongly upregulated in PBMCs of patients. Neopterin levels were significantly higher in PBMC supernatants and sera of patients. The IL12B polymorphisms rs3212227 and rs2853694 were associated with chronic Q fever.nnnCONCLUSIONSnIFN-γ production, as well as the response to IFN-γ, is intact in chronic Q fever patients, and even higher than in healthy individuals. Polymorphisms in the IL-12p40 gene are associated with chronic Q fever. Thus, a deficiency in IFN-γ responses does not explain the failure to clear the infection. The genetic data suggest, however, that the IL-12/IFN-γ pathway does play a role.

Interferon-gamma and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome

Approximately 20% of patients with acute Q fever develop Q fever fatigue syndrome (QFS), a debilitating fatigue syndrome. This study further investigates the role of C. burnetii-specific IFNγ, but also IL-2, CXCL9, CXCL10, and CXLC11 production in QFS patients. C. burnetii-specific IFNy, IL-2, CXCL9, CXCL10, and CXCL11 production were tested in ex vivo stimulated whole blood of QFS patients who recovered from their complaints (nu2009=u20098), QFS patients with persisting complaints (nu2009=u200927), and asymptomatic Q fever seropositive controls (nu2009=u200910). With the exclusion of one outlier, stimulation with C. burnetii revealed significantly higher IFNy and CXCL10 production in QFS patients with persisting complaints (medians 288.0 and 176.0xa0pg/mL, respectively) than in QFS patients who recovered from their complaints (medians 93.0 and 85.5xa0pg/mL, respectively) (pu2009=u20090.041 and 0.045, respectively). No significant differences between groups were found for C. burnetii-specific IL-2, CXCL9, and CXCL11 production. These findings point towards a difference in cell-mediated immunity in QFS patients with persisting complaints compared to those who recovered from their complaints. Such a difference may aid to eventually diagnose QFS more objectively and might serve as an indicator of its underlying etiology.

Telangiectasias: Small lesions referring to serious disorders

Telangiectasias are prominent small vessels (venules, capillaries or arterioles) that are visible as small red-purple focal lesions in the skin and mucous membranes. They can serve as a cutaneous marker for a number of primary (mostly hereditary) disorders and they can be secondary to other (systemic) diseases. Patients with telangiectasias are seen by general health practitioners, pediatricians, (pediatric) neurologists, dermatologists, and ophthalmologists. In this article we give an overview of the different disorders in which telangiectasias are a prominent feature, focusing on neurocutaneous disorders in which they serve as a marker for establishing the right diagnosis. The pattern of distribution of the telangiectasias, their age of onset and associated features are helpful to distinguish between the different disorders.