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Aim To investigate the characteristics and severity of dysarthria in children and adults with ataxia telangiectasia. Method All children and adults with ataxia telangiectasia who visited our multidisciplinary outpatient clinic for ataxia telangiectasia were asked to participate in this study, which took place in March 2019. To evaluate dysarthria, we used the Radboud Dysarthria Assessment in adults (older than 18y) and the paediatric Radboud Dysarthria Assessment in children (5–18y), including the observational tasks ‘conversation’ and ‘reading’, and the speech‐related maximum performance tasks ‘repetition rate’, ‘phonation time’, ‘fundamental frequency range’, and ‘phonation volume’. Speech intelligibility was measured using the Intelligibility in Context Scale. Results Twenty‐two individuals (15 children [5–17y], seven adults [19–47y]; 14 males and eight females; mean age 19y, SD 15y 2mo) participated. Dysarthria was present in all participants and characterized by ataxic components in adults and similar uncontrolled movements in children. In most participants, speech was mildly to mildly/severely affected. Almost all participants had an abnormal score for at least one maximum performance task. Interpretation Dysarthria in ataxia telangiectasia is characterized by uncontrolled, ataxic, and involuntary movements, resulting in monotonous, unstable, slow, hypernasal, and chanted speech. What this paper adds Dysarthria in ataxia telangiectasia is characterized by uncontrolled, ataxic, and involuntary movements.Dysarthria in ataxia telangiectasia results in monotonous, unstable, slow, hypernasal, and chanted speech.Dysarthria in ataxia telangiectasia can be assessed using the Radboud Dysarthria Assessment and the paediatric Radboud Dysarthria Assessment., What this paper adds Dysarthria in ataxia telangiectasia is characterized by uncontrolled, ataxic, and involuntary movements.Dysarthria in ataxia telangiectasia results in monotonous, unstable, slow, hypernasal, and chanted speech.Dysarthria in ataxia telangiectasia can be assessed using the Radboud Dysarthria Assessment and the paediatric Radboud Dysarthria Assessment.

Bloom Syndrome (BS) is a genetic DNA repair disorder, caused by mutations in the BLM gene. The clinical phenotype includes growth retardation, immunodeficiency and a strong predisposition to different types of malignancies. Treatment of malignancies in BS patients with radiotherapy or chemotherapy is believed to be associated with increased toxicity, but clinical and laboratory data are lacking. We collected clinical data of two Dutch BS patients with solid tumors. Both were treated with radiotherapy before the diagnosis BS was made and tolerated this treatment well. In addition, we collected fibroblasts from BS patients to perform in vitro clonogenic survival assays to determine radiosensitivity. BS fibroblasts showed less radiosensitivity than the severely radiosensitive Artemis fibroblasts. Moreover, studies of double strand break kinetics by counting 53BP1 foci after irradiation showed similar patterns compared to healthy controls. In combination, the clinical cases and laboratory experiments are valuable information in the discussion whether radiotherapy is absolutely contraindicated in BS, which is the Case in other DNA repair syndromes like Ataxia Telangiectasia and Artemis.

Contains fulltext : 244271.pdf (Publisher’s version ) (Open Access) BACKGROUND: Treatment of animal models with ataxia telangiectasia (A-T) with nicotinamide riboside (NR) improved their neurological outcome and survival. OBJECTIVE: The aim of this study is to investigate the effects of NR in patients with A-T. METHODS: In this open-label, proof-of-concept study, 24 patients with A-T were treated with NR during four consecutive months. The effects of NR on ataxia, dysarthria, quality of life, and laboratory parameters were analyzed. RESULTS: During treatment, ataxia scores improved; mean total Scale for the Assessment and Rating of Ataxia and International Cooperative Ataxia Rating Scale scores decreased to 2.4 and 10.1 points, respectively. After NR withdrawal, ataxia scores worsened. In immunodeficient patients, the mean serum IgG concentration increased substantially until the end of the study period with 0.52 g/L. Untargeted metabolomics analysis revealed increased plasma levels of NR metabolites and purine nucleosides during treatment. Adverse effects did not occur. CONCLUSIONS: Treatment with NR is tolerated well and associated with improvement in ataxia and serum immunoglobulin concentrations in patients with A-T. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Ataxia Telangiectasia (AT) is a rare inherited disorder characterized by progressive cerebellar ataxia, chromosomal instability, cancer susceptibility and immunodeficiency. AT is caused by mutations in the ATM gene, which is involved in multiple processes linked to DNA double strand break repair. Immunologically, ATM mutations lead to hampered V(D)J recombination and consequently reduced numbers of naive B and T cells. In addition, class switch recombination is disturbed resulting in antibody deficiency causing common, mostly sinopulmonary, bacterial infections. Yet, AT patients in general have no clinical T cell associated infections and numbers of memory T cells are usually normal. In this study we investigated the naive and memory T cell compartment in five patients with classical AT and compared them with five healthy controls using a 24-color antibody panel and spectral flow cytometry. Multidimensional analysis of CD4 and CD8 TCRαβ+ cells revealed that early naive T cell populations, i.e. CD4+CD31+ recent thymic emigrants and CD8+CCR7++CD45RA++ T cells, were strongly reduced in AT patients. However, we identified normal numbers of stem cell memory T cells expressing CD95, which are antigen-experienced T cells that can persist for decades because of their self-renewal capacity. We hypothesize that the presence of stem cell memory T cells explains why AT patients have an intact memory T cell compartment. In line with this novel finding, memory T cells of AT patients were normal in number and expressed chemokine receptors, activating and inhibitory receptors in comparable percentages as controls. Comparing memory T cell phenotypes by Boolean gating revealed similar diversity indices in AT compared to controls. We conclude that AT patients have a fully developed memory T cell compartment despite strongly reduced naive T cells. This could be explained by the presence of normal numbers of stem cell memory T cells in the naive T cell compartment, which support the maintenance of the memory T cells. The identification of stem cell memory T cells via our spectral flow cytometric approach is highly relevant for better understanding of T cell immunity in AT. Moreover, it provides possibilities for further research on this recently identified T cell population in other inborn errors of immunity.

Objective Patients with classic ataxia–telangiectasia (A–T) generally die in the second or third decade of life. Clinical descriptions of A–T tend to focus on the symptoms at presentation. However, during the course of the disease, other symptoms and complications emerge. As long-term survivors with classic A–T develop a complex multisystem disorder with a largely unknown extent and severity, we aimed to comprehensively assess their full clinical picture. Methods Data from Dutch patients with classic A–T above the age of 30 years were retrospectively collected. In addition, we searched the literature for descriptions of classic A–T patients who survived beyond the age of 30 years. Results In the Dutch cohort, seven classic A–T patients survived beyond 30 years of age. Fourteen additional patients were retrieved by the literature search. Common problems in older patients with classic A–T were linked to ageing. Most patients had pulmonary, endocrine, cardiovascular, and gastro-intestinal problems. All patients had a tetraparesis with contractures. This led to immobilization and frequent hospital admissions. Most patients expressed the wish to no longer undergo intensive medical treatments, and waived follow-up programs. Conclusions Paucity of descriptions in the literature, and withdrawal from medical care complicate the acquisition of follow-up data on the natural history of long-term survivors. Irrespective of these limitations, we have obtained impression of the many problems that these patients face when surviving beyond 30 years of age. Awareness of these problems is needed to guide follow-up, counselling, and (palliative) care; decisions about life-prolonging treatments should be well considered.

Background: We aimed to expand the number of currently known pathogenic PNKP mutations, to study the phenotypic spectrum, including radiological characteristics and genotype-phenotype correlations, and to assess whether immunodeficiency and increased cancer risk are part of the DNA repair disorder caused by mutations in the PNKP gene.Methods: We evaluated nine patients with PNKP mutations. A neurological history and examination was obtained. All patients had undergone neuroimaging and genetic testing as part of the prior diagnostic process. Laboratory measurements included potential biomarkers, and, in the context of a DNA repair disorder, we performed a detailed immunologic evaluation, including B cell repertoire analysis.Results: We identified three new mutations in the PNKP gene and confirm the phenotypic spectrum of PNKP-associated disease, ranging from microcephaly, seizures, and developmental delay to ataxia with oculomotor apraxia type 4. Irrespective of the phenotype, alpha-fetoprotein is a biochemical marker and increases with age and progression of the disease. On neuroimaging, (progressive) cerebellar atrophy was a universal feature. No clinical signs of immunodeficiency were present, and immunologic assessment was unremarkable. One patient developed cancer, but this was attributed to a concurrent von Hippel-Lindau mutation.Conclusions: Immunodeficiency and cancer predisposition do not appear to be part of PNKP-associated disease, contrasting many other DNA repair disorders. Furthermore, our study illustrates that the previously described syndromes microcephaly, seizures, and developmental delay, and ataxia with oculomotor apraxia type 4, represent the extremes of an overlapping spectrum of disease. Cerebellar atrophy and elevated serum alpha-fetoprotein levels are early diagnostic findings across the entire phenotypical spectrum. (C) 2020 The Author(s). Published by Elsevier Inc.

ATM is often dubbed the master regulator of the DNA double stranded break (DSB) response. Since proper induction and repair of DNA DSBs forms the core of immunological diversity, it is surprising that patients with ataxia telangiectasia generally have a mild immunodeficiency in contrast to other DSB repair syndromes. In this review, we address this discrepancy by delving into the functions of ATM in DSB repair and cell cycle control and translate these to adaptive immunity. We conclude that ATM, despite its myriad functions, is not an absolute requirement for acquiring sufficient levels of immunological diversity to prevent severe viral and opportunistic infections. There is, however, a more clinically pronounced antibody deficiency in ataxia telangiectasia due to disturbed class switch recombination.

Antibody replacement therapy for patients with antibody deficiencies contains only IgG. As a result, concurrent IgM and IgA deficiency present in a large proportion of antibody deficient patients persists. Especially patients with IgM deficiency remain at risk for recurrent infections of the gastrointestinal and respiratory tract. The lack of IgM in the current IgG replacement therapy is likely to contribute to the persistence of these mucosal infections because this antibody class is especially important for complement activation on the mucosal surface. We evaluated whether supplementation with IgM increased serum bactericidal capacity in vitro. Serum was collected from a patient with agammaglobulinemia and supplemented with purified serum IgM to normal levels. Antibody and complement deposition on the bacterial surface was determined by multi-color flow cytometry. Bacterial survival in serum was determined by colony-forming unit counts. We present a patient previously diagnosed with agammaglobulinemia due to CD79A (Igα) deficiency revealing a novel pathogenic insertion variant in the CD79a gene (NM_001783.3:c.353_354insT). Despite IgG replacement therapy and antibiotic prophylaxis, this patient developed a Campylobacter jejuni spondylodiscitis of lumbar vertebrae L4–L5. We found that serum IgM significantly contributes to complement activation on the bacterial surface of C. jejuni. Furthermore, supplementation of serum IgM augmented serum bactericidal activity significantly. In conclusion, supplementation of intravenous IgG replacement therapy with IgM may potentially offer greater protection against bacterial infections, also in the context of increasing antibiotic resistance.

Contains fulltext : 174098.pdf (Publisher’s version ) (Open Access) Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy). Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG2 deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG2 levels (HR 7.8, 95%CI 1.7-36.2), respectively. If high risk treatment trials will become available for AT, those patients with factors indicating the poorest prognosis might be considered for inclusion first.

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.

Ataxia telangiectasia (A-T) is a severe neurodegenerative disorder with variable immunodeficiency. Together with the Dutch A-T community, we investigated the opinion of A-T parents on an early A-T diagnosis in the asymptomatic phase of the disease. During an annual national meeting for A-T patients and families, the topic of an early A-T diagnosis was discussed in relation to the recent introduction of neonatal screening for severe combined immunodeficiency (SCID) in the Netherlands. Based on the discussion, individual arguments were identified and processed into a questionnaire, which was sent out to 64 A-T parents (32 families). Arguments included were insecurity to diagnosis, possible medical advantages, appropriate genetic counseling and family planning, loss of “golden” year(s), and early cancer screening for parents. The response rate was 55% (n = 35 parents). Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference. Conclusion: The majority of parents of a child with A-T would have preferred an early diagnosis during the asymptomatic phase of the disease, because the uncertainty during the diagnostic process had had a major impact on their lives. In addition, the knowledge of being carriers of an ATM gene mutation influenced decisions about family planning. Parents who opposed against an early diagnosis emphasized the joy of having a seemingly healthy child until diagnosis.What is Known:• Ataxia telangiectasia (A-T) is a devastating DNA repair disorder with a huge impact on quality of life of patients and their parents.• Patients with A-T may incidentally be identified at birth as the consequence of neonatal screening for severe combined immunodeficiency (SCID).What is New:• The majority of Dutch parents of A-T patients (74%) would have preferred an early diagnosis of their child in the asymptomatic phase of the disease.• Major arguments for an early A-T diagnosis were (1) the experienced insecurity in diagnostic trajectories and its impact on families and (2) the knowledge of being ATM mutation carriers when deciding about family planning. An argument against an early diagnosis is losing the joy of having a seemingly healthy child until diagnosis.

Fanconi anaemia (FA), ataxia telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and Bloom syndrome (BS) are clinically distinct, chromosome instability (or breakage) disorders. Each disorder has its own pattern of chromosomal damage, with cells from these patients being hypersensitive to particular genotoxic drugs, indicating that the underlying defect in each case is likely to be different. In addition, each syndrome shows a predisposition to cancer. Study of the molecular and genetic basis of these disorders has revealed mechanisms of recognition and repair of DNA double-strand breaks, DNA interstrand crosslinks and DNA damage during DNA replication. Specialist clinics for each disorder have provided the concentration of expertise needed to tackle their characteristic clinical problems and improve outcomes. Although some treatments of the consequences of a disorder may be possible, for example, haematopoietic stem cell transplantation in FA and NBS, future early intervention to prevent complications of disease will depend on a greater understanding of the roles of the affected DNA repair pathways in development. An important realization has been the predisposition to cancer in carriers of some of these gene mutations.

ObjectiveTo describe and classify the neurologic trajectories in patients with mild neurologic forms of ataxia telangiectasia (A-T) from the Dutch A-T cohort, combined with patients reported in the literature.MethodsClinical, genetic, and laboratory data of 14 patients with mild neurologic phenotypes of A-T from the Dutch cohort were analyzed and combined with corresponding data from the literature. A mild neurologic phenotype was defined by a later onset, nonataxia presenting or dominant feature, or slower progression compared to the classic A-T phenotype. Neurologic trajectories were classified based on age at onset, presenting feature, and follow-up data.ResultsOne hundred five patients were included in the study. Neurologic trajectories were categorized into 6 groups: patients with childhood-onset extrapyramidal (EP) features with cerebellar symptoms developing later (group 1; 18 patients), childhood-onset cerebellar symptoms, with EP features developing later (group 2; 35 patients), childhood- to adolescence-onset dystonia, without cerebellar symptoms (group 3; 23 patients), childhood- to adolescence-onset isolated cerebellar symptoms (group 4; 22 patients), childhood- to adult-onset prominent muscle weakness (group 5; 2 patients), and patients with adult-onset EP features, with anterior horn cell disease arising subsequently (group 6; 5 patients).ConclusionsThis systematic study of the different motor abnormalities and their course over time in patients with mild phenotypes of A-T, enabled us to recognize 6 essentially different phenotypic patterns. Awareness of these different trajectories of motor abnormalities in milder forms of A-T will contribute to a reduction of diagnostic delay in this severe multisystem disorder.

Item does not contain fulltext Patient registries are instrumental for clinical research in rare diseases. They help to achieve a sufficient sample size for epidemiological and clinical research and to assess the feasibility of clinical trials. The European Society for Immunodeficiencies (ESID) registry currently comprises information on more than 25,000 patients with inborn errors of immunity (IEI). The prerequisite of a patient to be included into the ESID registry is an IEI either defined by a defect in a gene included in the disease classification of the international union of immunological societies, or verified by applying clinical criteria. Because a relevant number of patients, including those with common variable immunodeficiency (CVID), representing the largest group of patients in the registry, remain without a genetic diagnosis, consensus on classification of these patients is mandatory. Here, we present clinical criteria for a large number of IEI that were designed in expert panels with an external review. They were implemented for novel entries and verification of existing data sets from 2014, yielding a substantial refinement. For instance, 8% of adults and 27% of children with CVID (176 of 1704 patients) were reclassified to 22 different immunodeficiencies, illustrating progress in genetics, but also the previous lack of standardized disease definitions. Importantly, apart from registry purposes, the clinical criteria are also helpful to support treatment decisions in the absence of a genetic diagnosis or in patients with variants of unknown significance.

Ataxia Telangiectasia (AT) is named after the two key clinical features that characterize its classical phenotype, namely a progressive cerebellar gait disorder (ataxia) and vascular anomalies (telangiectasias) visible in the conjunctivae and skin. AT is an autosomal recessively inherited disorder, caused by mutations in the ATM gene that encodes the ATM protein. While the ataxia is subject of many publications, the telangiectasias are under emphasised. We here describe the observation that the absence or presence of ATM protein and the level of residual ATM kinase activity are related to the occurrence of telangiectasias and describe the clinical consequences of these vascular malformations. Finally, we hypothesize that ATM dysfunction dysregulates angiogenesis.

Bloom’s syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected, and immunoglobulin serum levels were measured at different time points. In addition, we performed immune phenotyping of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20–80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion, BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR. Electronic supplementary material The online version of this article (10.1007/s10875-017-0454-y) contains supplementary material, which is available to authorized users.

Contains fulltext : 137474.pdf (Publisher’s version ) (Closed access) Alpha-fetoprotein (AFP) is present in fetal serum in concentrations up to 5,000,000 mug/l. After birth, AFP gene expression is turned down with a subsequent fall of the serum concentrations of this albumin-like protein to 'adult values' of circa 0.5-15 mug/l from the age of 2 years onwards. Irrespective of its assumed important functions, individuals with AFP deficiency appear fully healthy. The other way around, the presence of AFP in the circulation after the first years of life doesn't seem to harm, since individuals with 'hereditary persistence of AFP' are also without clinical abnormalities. During pregnancy, AFP (in maternal serum) has long been recognized as a marker for congenital anomalies of the fetus. Equally well known is AFP as biomarker for hepatocellular carcinoma and some other malignancies. There are at least four neurodegenerative disorders, all inherited as autosomal recessive traits and characterized by the presence of cerebellar ataxia, abnormal ocular movements, and neuropathy, for which an elevated concentration of serum AFP is an important diagnostic biomarker. The availability of a reliable biomarker is not only important during screening or diagnostic processes, but is also relevant for objective follow-up during (future) therapeutic interventions.

Item does not contain fulltext Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype-phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling. 01 november 2013

Translesion DNA synthesis, a process orchestrated by monoubiquitinated PCNA, is critical for DNA damage tolerance. While the ubiquitin-conjugating enzyme RAD6 and ubiquitin ligase RAD18 are known to monoubiquitinate PCNA, how they are regulated by DNA damage is not fully understood. We show that NBS1 (mutated in Nijmegen breakage syndrome) binds to RAD18 after UV irradiation and mediates the recruitment of RAD18 to sites of DNA damage. Disruption of NBS1 abolished RAD18-dependent PCNA ubiquitination and Polη focus formation, leading to elevated UV sensitivity and mutation. Unexpectedly, the RAD18-interacting domain of NBS1, which was mapped to its C terminus, shares structural and functional similarity with the RAD18-interacting domain of RAD6. These domains of NBS1 and RAD6 allow the two proteins to interact with RAD18 homodimers simultaneously and are crucial for Polη-dependent UV tolerance. Thus, in addition to chromosomal break repair, NBS1 plays a key role in translesion DNA synthesis., 放射線の修復蛋白NBS1放によるRAD18を介した損傷乗り越えDNA合成の開始. 京都大学プレスリリース. 2011-09-02.

Objective: To describe cognitive and speech-language functioning of patients with ataxia-telangiectasia (A-T) in relation to their deteriorating (oculo)motor function.Design: Observational case series.Methods: Cognitive functioning, language, speech and oral-motor functioning were examined in eight individuals with A-T (six boys, two girls), taking into account the confounding effects of motor functioning on test performance.Results: All patients, except the youngest one, suffered from mild-to-moderate/severe intellectual impairment. Compared to developmental age, patients showed cognitive deficits in attention, (non) verbal memory and verbal fluency. Furthermore, dysarthria and weak oral-motor performance was found. Language was one of the patients' assets.Conclusion: In contrast to the severe deterioration of motor functioning in A-T, cognitive and language functioning appeared to level off with a typical profile of neuropsychological strengths and weaknesses. Based on our experiences with A-T, suggestions are made to determine a valid assessment of the cognitive and speech-language manifestations.

Contains fulltext : 97774.pdf (Publisher’s version ) (Closed access) Background: Non-infective cutaneous granulomas with unknown pathogenesis occur in various primary immunodeficiencies (PIDs) including ataxia telangiectasia (A-T). Objective: To find a common immunological denominator in these cutaneous granulomas. Methods: The dermatological and immunological features of 4 patients with A-T and cutaneous granulomas were described. The literature on skin granulomas in A-T and in other PIDs is reviewed. Results: All 4 A-T patients had progressive granulomas on their limbs and showed decreased IgG and IgA concentrations with normal IgM levels. They had a marked decrease in B cells and naive T cells coinciding with the appearance of the cutaneous granulomas. Similar B- and T-cell abnormalities were described in patients with other PIDs with skin granulomas. Conclusions: We hypothesize that the pathogenesis of these skin granulomas is related to immune dysregulation of macrophages due to the absence of naive T cells with an appropriate T-cell receptor repertoire and the unopposed activity of gammadelta T cells and/or natural killer cells.

Artemis deficiency is known to result in classical T-B- severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical T-B- SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5' splice-site or an intronic point mutation creating a novel 3' splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 30 splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts. Genes and Immunity (2011) 12, 434-444; doi:10.1038/gene.2011.16; published online 10 March 2011

Contains fulltext : 69091.pdf (Publisher’s version ) (Closed access) BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICF patients. OBJECTIVE: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype-phenotype correlations in ICF patients. METHODS: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. Results and CONCLUSIONS: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n = 41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (n = 39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICF patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in DNMT3B, suggesting genetic heterogeneity. No genotype-phenotype correlation was found between patients with and without DNMT3B mutations.

Contains fulltext : 70218.pdf (Publisher’s version ) (Closed access) A case of gastrointestinal zygomycosis in a 10-month-old boy with chronic granulomatous disease (CGD) is presented. Zygomycetes are an uncommon cause of fungal disease in CGD patients and gastrointestinal zygomycosis has not been previously described in individuals with CGD. To improve outcome, a timely and correct diagnosis is of utmost importance.

Contains fulltext : 53635.pdf (Publisher’s version ) (Closed access) Immunodeficiency-centromeric instability-facial dysmorphism syndrome, characterized by variable immunodeficiency, centromeric instability, and facial anomalies caused by epigenetic dysregulation resulting in hypomethylation, is caused in many patients by mutations in DNMT3B, a DNA methyltransferase gene; associated infections are a major cause of serious sequelae and death. Hematopoietic stem cell transplantation may improve the clinical course in immunodeficiency-centromeric instability-facial dysmorphism syndrome. We report 3 unrelated patients with persistent infections and intestinal complications who successfully underwent hematopoietic stem cell transplantation after nonmyeloablative or myeloablative conditioning regimens using HLA-matched donors. In all cases, donor chimerism led to resolution of intestinal complications and infections, growth improvement, and correction of the immunodeficiency.

Contains fulltext : 52246.pdf (Publisher’s version ) (Closed access) BACKGROUND: Patients with facioscapulohumeral muscular dystrophy (FSHD) show a contraction of the D4Z4 repeat array in the subtelomere of chromosome 4q. This D4Z4 contraction is associated with significant allele-specific hypomethylation of the repeat. Hypomethylation of D4Z4 is also observed in patients with phenotypic FSHD without contraction of D4Z4 and in patients with the immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, an unrelated disease that does not present with muscular dystrophy and is in part caused by DNMT3B mutations. METHODS: In order to identify the gene defect and to find the pathogenetic epigenetic pathway in phenotypic FSHD, we have aimed to identify the differences and commonalities in phenotypic FSHD and ICF by 1) investigation of DNA methylation of non-D4Z4 repeat arrays, 2) analysis of mitogen-stimulated lymphocytes to detect pericentromeric abnormalities involving chromosomes 1, 9, and 16, 3) determination of IgA, IgG, and IgM levels, and 4) mutational analysis of candidate genes to identify a second disease locus involved in the pathogenesis of phenotypic FSHD. RESULTS: Our results do not show epigenetic or phenotypic commonalities between phenotypic FSHD and ICF other than the earlier observed D4Z4 hypomethylation. We could not identify any mutations in the candidate genes tested for. CONCLUSION: Our data suggest that in phenotypic FSHD hypomethylation is restricted to D4Z4 and that phenotypic FSHD and ICF do not share a defect in the same molecular pathway.

The life-threatening Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome is a genetically heterogeneous autosomal recessive disorder. Twenty percent of patients cannot be explained by mutations in the known ICF genes DNA methyltransferase 3B or zinc-finger and BTB domain containing 24. Here we report mutations in the cell division cycle associated 7 and the helicase, lymphoid-specific genes in 10 unexplained ICF cases. Our data highlight the genetic heterogeneity of ICF syndrome; however, they provide evidence that all genes act in common or converging pathways leading to the ICF phenotype., Immunodeficiency-centromeric instability-facial anomalies syndrome is a life threatening autosomal recessive disorder caused by mutations in DNMT3B and ZBTB24. Here Thijssen et al. identify mutations in CDCA7 and HELLS in previously unexplained cases.

Contains fulltext : 48438.pdf (Publisher’s version ) (Open Access) We report the data from a long-term study of 31 human immunodeficiency virus type 1 (HIV-1)-infected children who were treated with highly active antiretroviral therapy. A high proportion of the children had undetectable HIV-1 RNA levels. CD4+ T cell counts recovered and remained stable. Adverse events were observed frequently but were mostly mild.

Contains fulltext : 59285.pdf (Publisher’s version ) (Open Access) Both innate and adaptive immune responses are dependent on activation of nuclear factor kappaB (NF-kappaB), induced upon binding of pathogen-associated molecular patterns to Toll-like receptors (TLRs). In murine models, defects in NF-kappaB pathway are often lethal and viable knockout mice have severe immune defects. Similarly, defects in the human NF-kappaB pathway described to date lead to severe clinical disease. Here, we describe a patient with a hyper immunoglobulin M-like immunodeficiency syndrome and ectodermal dysplasia. Monocytes did not produce interleukin 12p40 upon stimulation with various TLR stimuli and nuclear translocation of NF-kappaB was impaired. T cell receptor-mediated proliferation was also impaired. A heterozygous mutation was found at serine 32 in IkappaBalpha. Interestingly, his father has the same mutation but displays complex mosaicism. He does not display features of ectodermal dysplasia and did not suffer from serious infections with the exception of a relapsing Salmonella typhimurium infection. His monocyte function was impaired, whereas T cell function was relatively normal. Consistent with this, his T cells almost exclusively displayed the wild-type allele, whereas both alleles were present in his monocytes. We propose that the T and B cell compartment of the mosaic father arose as a result of selection of wild-type cells and that this underlies the widely different clinical phenotype.

Item does not contain fulltext Clinical, virologic, and immunologic responses to treatment that contained either indinavir or nelfinavir (both regimens included zidovudine and lamivudine) were determined in 32 children infected with human immunodeficiency virus type 1 (HIV-1) who participated for >/= 96 weeks in a prospective, open, uncontrolled multicenter trial. The pharmacokinetics of indinavir and of nelfinavir were determined and showed large interindividual differences. After 96 weeks of therapy, 69% and 50% of the patients had an HIV-1 RNA load that was below the HIV assays' detection limits of 500 and 40 copies/mL, respectively. Virologic failure was associated with poor compliance and younger age (independent of baseline virus load and receipt of pretreatment). Relative CD4 cell counts increased significantly in relation to the median of the age-specific reference value, from a median of 44% at baseline to 94% after 96 weeks. In a high percentage of the children, clinical, virologic, and immunologic response rates to combination therapy were optimal during the initial 2 years of therapy.

Item does not contain fulltext Retrotransposon-mediated insertion of a long interspersed nuclear element (LINE)-1 or an Alu element into a human gene is a well-known pathogenic mechanism. We report a novel LINE-1-mediated insertion of a transcript from the TMF1 gene on chromosome 3 into the CYBB gene on the X-chromosome. In a Dutch male patient with chronic granulomatous disease, a 5.8-kb, incomplete and partly exonized TMF1 transcript was identified in intron 1 of CYBB, in opposite orientation to the host gene. The sequence of the insertion showed the hallmarks of a retrotransposition event, with an antisense poly(A) tail, target site duplication, and a consensus LINE-1 endonuclease cleavage site. This insertion induced aberrant CYBB mRNA splicing, with inclusion of an extra 117-bp exon between exons 1 and 2 of CYBB. This extra exon contained a premature stop codon. The retrotransposition took place in an early stage of fetal development in the mother of the patient, because she showed a somatic mosaicism for the mutation that was not present in the DNA of her parents. However, the mutated allele was not expressed in the patient's mother because the insertion was found only in the methylated fraction of her DNA.

Serum immunoglobulinD (IgD) concentration is usually low in healthy individuals as compared to other immunoglobulin classes. Most studies on serum IgD are concerned with serum levels in healthy adults but reference values for young children and infants are not easily available. In order to establish age specific reference values we measured IgD levels in serum of 184 healthy Icelandic children, age 0-14 years and 60 healthy blood donors age 18-63, using the ELISA technique. Special attention was paid to the youngest age groups. Results showed low IgD values in infants and young children, gradually increasing until the age of 10 but then decreasing with age. We conclude that IgD gradually increases with age in childhood as other immunoglobulin classes but later declines. These findings can be of importance in revealing the function of IgD in the immune system as well as in the diagnosis of the hyper-IgD syndrome.

DNA methylation is an important regulator of genetic information in species ranging from bacteria to humans. DNA methylation appears to be critical for mammalian development because mice nullizygous for a targeted disruption of the DNMT1 DNA methyltransferase die at an early embryonic stage. No DNA methyltransferase mutations have been reported in humans until now. We describe here the first example of naturally occurring mutations in a mammalian DNA methyltransferase gene. These mutations occur in patients with a rare autosomal recessive disorder, which is termed the ICF syndrome, for immunodeficiency, centromeric instability, and facial anomalies. Centromeric instability of chromosomes 1, 9, and 16 is associated with abnormal hypomethylation of CpG sites in their pericentromeric satellite regions. We are able to complement this hypomethylation defect by somatic cell fusion to Chinese hamster ovary cells, suggesting that the ICF gene is conserved in the hamster and promotes de novo methylation. ICF has been localized to a 9-centimorgan region of chromosome 20 by homozygosity mapping. By searching for homologies to known DNA methyltransferases, we identified a genomic sequence in the ICF region that contains the homologue of the mouse Dnmt3b methyltransferase gene. Using the human sequence to screen ICF kindreds, we discovered mutations in four patients from three families. Mutations include two missense substitutions and a 3-aa insertion resulting from the creation of a novel 3′ splice acceptor. None of the mutations were found in over 200 normal chromosomes. We conclude that mutations in the DNMT3B are responsible for the ICF syndrome.

Summary Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, a birdlike face, growth retardation, immunodeficiency, lack of secondary sex characteristics in females, and increased incidence of lymphoid cancers. NBS cells display a phenotype similar to that of cells from ataxia-telangiectasia patients, including chromosomal instability, radiation sensitivity, and aberrant cell-cycle–checkpoint control following exposure to ionizing radiation. A recent study reported genetic linkage of NBS to human chromosome 8q21, with strong linkage disequilibrium detected at marker D8S1811 in eastern European NBS families. We collected a geographically diverse group of NBS families and tested them for linkage, using an expanded panel of markers at 8q21. In this article, we report linkage of NBS to 8q21 in 6/7 of these families, with a maximum LOD score of 3.58. Significant linkage disequilibrium was detected for 8/13 markers tested in the 8q21 region, including D8S1811. In order to further localize the gene for NBS, we generated a radiation-hybrid map of markers at 8q21 and constructed haplotypes based on this map. Examination of disease haplotypes segregating in 11 NBS pedigrees revealed recombination events that place the NBS gene between D8S1757 and D8S270. A common founder haplotype was present on 15/18 disease chromosomes from 9/11 NBS families. Inferred (ancestral) recombination events involving this common haplotype suggest that NBS can be localized further, to an interval flanked by markers D8S273 and D8S88.

Contains fulltext : 117756.pdf (Publisher’s version ) (Closed access) BACKGROUND: Ataxia telangiectasia (AT) is a multisystem DNA-repair disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. Patients with AT have reduced B- and T-cell numbers and a highly variable immunodeficiency. ATM is important for V(D)J recombination and immunoglobulin class-switch recombination (CSR); however, little is known about the mechanisms resulting in antibody deficiency severity. OBJECTIVE: We sought to examine the immunologic mechanisms responsible for antibody deficiency heterogeneity in patients with AT. METHODS: In this study we included patients with classical AT plus early-onset hypogammaglobulinemia (n = 3), classical AT (n = 8), and variant AT (late onset, n = 4). We studied peripheral B- and T-cell subsets, B-cell subset replication history, somatic hypermutation frequencies, CSR patterns, B-cell repertoire, and ATM kinase activity. RESULTS: Patients with classical AT lacked ATM kinase activity, whereas patients with variant AT showed residual function. Most patients had disturbed naive B-cell and T-cell homeostasis, as evidenced by low cell numbers, increased proliferation, a large proportion CD21(low)CD38(low) anergic B cells, and decreased antigen receptor repertoire diversity. Impaired formation of T cell-dependent memory B cells was predominantly found in patients with AT plus hypogammaglobulinemia. These patients had extremely low naive CD4(+) T-cell counts, which were more severely reduced compared with those seen in patients with classical AT without hypogammaglobulinemia. Finally, AT deficiency resulted in defective CSR to distal constant regions that might reflect an impaired ability of B cells to undergo multiple germinal center reactions. CONCLUSION: The severity of the antibody deficiency in patients with AT correlates with disturbances in B- and T-cell homeostasis resulting in reduced immune repertoire diversity, which consequently affects the chance of successful antigen-dependent cognate B-T interaction.

In the present preliminary study we explored the possibility of an anticonvulsant effect of normal human immunoglobulin in an animal epilepsy model based on direct cortical stimulation in freely moving rats. After human immunoglobulin administration a significant and prolonged elevation of the threshold for convulsions was measured in 12% (l6/49) of the total group of outbred Wistar rats. In the subgroup of more than seven months old Wistar rats this was 67% (6/9). When a threshold increasing effect of immunoglobulin occurred, it was detectable within 0.5–1 hour after administration, reached its maximum after approximately two hours and continued for at least 40 hours.

The purpose of this study is to ascertain possible efficacy and to understand possible mechanisms of action of intramuscular or intravenous immunoglobulin (IVIg) in the treatment of intractable epilepsy, through a review of all identifiable articles on this topic. In 24 studies, none with a placebo controlled design, 368 patients with epilepsy receiving IVIg were identified. Patients' ages ranged from < 1 to 35 years, mean 7.3 years. Female/male ratio was 0.6. All patients were reported to suffer from intractable epilepsy. The average percentage of patients with an IgG2 deficiency was 25%. The total dose of IVIg varied between 0.3 and 6.8 g/kg for a period of 0.15 to 12 months. Whenever reported, adverse effects of IVIg were minimal. None of the studies reported the need of cessation of IVIg administration due to adverse effects. On the average, the mean clinical seizure reduction and the mean EEG improvement were 52% and 45%, respectively. On the average the percentage of patients with complete seizure remission and the percentage of patients with behavioral improvement were 23% and 63%, respectively. Cumulative meta-analysis of the identified articles is not possible due to the lack of controlled studies, the heterogeneity of the available studies, and the possible publication bias of unpublished negative data. Given these pitfalls, this literature study nevertheless allows some conclusions: (i) There is no formal proof of efficacy of IVIg treatment in epilepsy, and the present review underscores the need of controlled clinical trials before firm conclusions concerning efficacy can be drawn. The uncontrolled clinical observations discussed in this 'state-of-the-art' review generate suggestive evidence at best. They suggest that IVIg might be effective in some patients with intractable epilepsy, and may be considered as a safe add-on medication in various types of idiopathic and symptomatic intractable epilepsy. (ii) Review of the literature did not help in explaining intractable epilepsy or the mechanism of action of IVIg, but did permit some inferences that could serve to design future clinical and experimental approaches to IVIg administration in epilepsy.

In an add-on pilot study, a group of 15 children with cryptogenic and intractable West syndrome (3) and Lennox-Gastaut syndrome (12) received intravenous immunoglobulin (IVIg, 0.4 g/kg body weight per day for 5 consecutive days, followed by the same dose once every 2 weeks for 3 months). Five patients had been treated previously with ACTH without success. The reduction in clinical seizures averaged 70%. Electroencephalographic (EEG) recordings revealed a mean reduction in epileptic discharges of 40%. In all 15 patients, acceleration of EEG background activity occurred, and psychomotor development improved. Prior to IVIg administration, CSF examinations were normal. After IVIg administration, the serum total IgG concentration increased by an average of 76%, and the CSF IgG concentration by 44%. According to our data, IVIg crosses the blood-CSF barrier, and might be effective in the treatment of West syndrome and Lennox-Gastaut syndrome. We suggest it should be considered when other treatments, such as ACTH, have failed.

Autopsy findings for two patients with the Nijmegen breakage syndrome (NBS) are presented. This syndrome has the same type of immunologic and cytogenetic abnormalities as ataxia telangiectasia (AT). In NBS, however, microcephaly is found and progressive cerebellar ataxia and oculocutaneous telangiectasia are lacking. We demonstrate a clear neuropathologic difference between these two syndromes, as the diffuse cortical cerebellar degeneration characteristic of AT was absent in NBS. In the thymus the histologic picture was suggestive of simple dysplasia. Lymphoid tissues were slightly atrophic but otherwise structurally normal. In one of the two presented cases an extranodal diffuse large cell malignant non-Hodgkin lymphoma of B cell immunoblastic type was found in Waldeyer's ring, in the small and large intestines, and in the brain, whose sequelae had caused death. Six of the 19 patients known with certainty to have this syndrome have developed lymphoid malignancy, which indicates that these patients are prone to develop malignancies.

The light chain ratios and the concentrations of immunoglobulin G (IgG), IgA, and IgM were measured before, during, and after antileukemic therapy in 10 patients with common acute lymphoblastic leukemia. The concentrations of IgG, IgA, and IgM decreased substantially during treatment but recovered slowly after cessation of the therapy. The light chain ratios were not systematically affected, but at diagnosis the kappa/lambda ratios of total serum Igs, IgG, and in particular IgM were somewhat lower in the patient group compared with an age-matched reference group. It is concluded that, despite a decrease in serum Ig concentrations, virtually normal kappa/lambda ratios are preserved, indicating that kappa and lambda syntheses are affected to the same extent. These ratios remained normal for age during the recovery of the serum Ig concentrations; the features as described for the development of the light chain ratios in childhood were not observed.

Contains fulltext : 98126.pdf (Publisher’s version ) (Closed access) Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections. About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1). The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences. We performed homozygosity mapping in five unrelated ICF2 patients with consanguineous parents and then performed whole-exome sequencing in one of these patients and Sanger sequencing in all to identify mutations in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24) gene in four consanguineously descended ICF2 patients. Additionally, we found ZBTB24 mutations in an affected sibling pair and in one patient for whom it was not known whether his parents were consanguineous. ZBTB24 belongs to a large family of transcriptional repressors that include members, such as BCL6 and PATZ1, with prominent regulatory roles in hematopoietic development and malignancy. These data thus indicate that ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions. Because ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage, we predict that by studying the molecular function of ZBTB24, we will improve our understanding of the molecular pathophysiology of ICF syndrome and of lymphocyte biology in general.

Contains fulltext : 95645.pdf (Publisher’s version ) (Closed access) The Immunodeficiency, Centromeric region instability, and Facial anomalies (ICF) syndrome (OMIM #242860) is a rare autosomal recessive disorder caused by defective DNA methylation. Hematological disease and malignancy (macrophage activation syndrome, myelodysplastic syndrome, and Hodgkin lymphoma) have been reported in three patients. To date, there have been no reports of either epithelial or mesenchymal malignancies. We present a patient with all clinical and laboratory findings of the ICF syndrome who died of a metastatic angiosarcoma of the liver. This is the first report of a non-hematological malignancy in the ICF syndrome. The young age at which our patient developed an angiosarcoma suggests an effect of the defective DNA methylation observed in the ICF syndrome. Therefore, with improvement of recognition and treatment of the ICF syndrome, malignancy could become more common in this condition.

Five patients with hyper-immunoglobulin D syndrome (hyper-IgD syndrome) were followed up for 3 to 8 years. In all patients studied, serum IgG3 was high. IgM decreased during the follow-up in all patients. In four of the patients serum IgA was elevated. In four patients the serum IgD kappa/lambda ratio was measured and was found to be raised in all. However, the serum total light-chain ratio and IgG, IgA, and IgM kappa/lambda ratios separately were virtually normal. In two of the patients, clinical symptoms preceded the increase in serum IgD. All patients had a history of severe reactions on immunizations in early childhood. We conclude that in hyper-IgD syndrome, other immunoglobulins may also be affected, in particular, IgA, IgM, and IgG3. The IgD light-chain ratio is also disturbed. We emphasize that clinical symptoms may herald immunological changes. This may be the result of an underlying factor causing both the clinical symptoms and, later, the increasing serum IgD levels.

Values for the kappa/lambda light chain ratio in immunoglobulins G, A and M and the total kappa/lambda ratio, measured by enzyme linked immunosorbent assay, were evaluated in serum samples from different age groups (114 children, aged from 1 month to 15 years, and 20 adults). The IgG kappa/lambda ratio decreased in the first 6 months and subsequently increased slowly during childhood towards the adult value of 2.0. The IgM kappa/lambda ratio increased at a greater rate than IgG kappa/lambda ratio in the first years of life and thereafter rose slightly throughout childhood to reach an adult value of 1.7. A decreasing IgA kappa/lambda ratio was found from 1 month of age onwards to an adult value of 1.1. The pattern of total kappa/lambda ratio was similar to the IgG kappa/lambda ratio with an adult value of 2.0.

A patient is described who presented with severe congenital anemia, hydrops fetalis, immune disorder, and absent thumbs. No toxic, infectious, or metabolic cause was found to explain these symptoms. Immunologic and cytogenetic studies excluded several syndromes that combine radial ray anomalies with hematological involvement. After careful study of the literature, it is concluded that the disorder described here represents a new syndrome that can be added to a growing list of hematological-radial syndromes.

Contains fulltext : 80305.pdf (Publisher’s version ) (Closed access) Ataxia-telangiectasia (A-T) is characterised by progressive neurological abnormalities, oculocutaneous telangiectasias and immunodeficiency (decreased serum IgG subclass and/or IgA levels and lymphopenia). However, 10% of A-T patients present with decreased serum IgG and IgA with normal or raised IgM levels. As cerebellar ataxia and oculocutaneous telangiectasias are not present at very young age, these patients are often erroneously diagnosed as hyper IgM syndrome (HIGM). Eight patients with A-T, showing serum Ig levels suggestive of HIGM on first presentation, are described. All had decreased numbers of T lymphocytes, unusual in HIGM. The diagnosis A-T was confirmed by raised alpha-fetoprotein levels in all patients. To prevent mistaking A-T patients for HIGM it is proposed to add DNA repair disorders as a possible cause of HIGM.

We describe 7 cases of cartilage hair hypoplasia (CHH) with emphasis on the clinical and immunological aspects. The literature on CHH is reviewed and symptoms in 63 non-Amish cases are summarized. In this autosomal recessive disorder the immunodeficiency, hair abnormalities, and severity of skeletal involvement show extremely variable expressivity, between and within families. Two of the 3 sib-pairs among our cases demonstrate the great difference in expression within one family. At adult age roentgenological abnormalities can be very mild, or even absent. An impairment in cell-mediated immunity is present in all of our cases and seems a consistent manifestation in CHH; however, sometimes it is very subtle and without clinical symptoms.

A 9-month-old Turkish boy was diagnosed as having Griscelli disease (Chediak-Higashi-like syndrome). Clinical signs consisted of silver-grey hair and a relatively light skin colour, recurrent episodes of fever, with or without detectable infections, increasing hepatosplenomegaly, hypotonia and motor retardation. Laboratory studies showed pancytopenia of varying degree but neither inclusion bodies nor vacuoles were seen in his leucocytes. Serum immunoglobulin levels were normal except for a IgG2 deficiency. In the mixed lymphocyte reaction the stimulation capacity of the leucocytes was decreased. Microscopic examination of his hair and electron-microscopic examination of a skin biopsy further confirmed the diagnosis. Shortly before the diagnosis was made, the child developed cerebral symptoms with hemiparesis and convulsions. A CT scan suggested cell infiltration of the brain. A few weeks later the boy died of an infection.

Contains fulltext : 69862.pdf (Publisher’s version ) (Closed access) BACKGROUND: Cutaneous granulomas can occur in patients with a primary immunodeficiency disorder. In some cases, an infectious cause cannot be revealed. The pathogenesis of these granulomas still remains to be elucidated. The aim of this study was to study differences or overlap between these rare granulomas and sarcoidosis-related granulomas. METHODS: Markers for T-cell subsets (CD3, CD4, CD8 and CD45RO), Langerhans' cells (CD1a), macrophages (CD68), B cells (CD20) and NK cells (CD56) were stained immunohistochemically. The amount of CD4+ and CD8+ cells in the granulomas was counted. Results were compared with the CD4+/CD8+ ratio in peripheral blood. RESULTS: In the granulomas of two of three patients with a primary immunodeficiency disorder, the cytotoxic T cells (CD8+) outnumbered the T-helper cells (CD4+) with a counted CD4+/CD8+ ratio <2. CONCLUSIONS: A lower CD4+/CD8+ ratio was found in the cutaneous granulomas of patients with a primary immunodeficiency disorder (unclassified combined immunodeficiency, autoimmune lymphoproliferative syndrome and ataxia teleangiectasia) as compared with the patients with cutaneous sarcoidosis. The possible implications of these findings are discussed in this paper.

Contains fulltext : 71126.pdf (Publisher’s version ) (Closed access) We describe 2 children with postinfectious opsoclonus-myoclonus syndrome. Although the patients initially responded to monotherapy with methylprednisolone, intravenous immunoglobulins, or rituximab, they manifested persistent neurologic deficits and relapsing signs. Treatment with rituximab in combination with intravenous immunoglobulin, however, resulted in significant longterm clinical improvement.