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This article presents a report on the postmortem diagnosis of chronic granulomatous disease (CGD). This report is in the form of a case study. The subject of this study was an 11 year old boy, who was admitted to hospital with right upper lobe pneumonia. He Was prescribed amoxicilin, followed after a week by erythromycin. In spite of aggressive and supportive care he died. The granulomatous inflammation of the lungs, liver and spleen seen on postmortem histopathology. Because of the fulminant disease course no immunological investigations were performed before death. However, 20 percent of the mother's neutrophils had reduced oxidative burst activity, suggesting a carrier state for X linked CGD.

Presentation characteristics were reviewed in 14 children from 12 families with malignant infantile osteopetrosis seen at two large referral centres for bone marrow transplantation. Children from six of these families presented initially with symptoms of hypocalcaemia. These comprised early or late neonatal convulsions in six cases (corrected serum calcium < 1.5 mmol/l), and vomiting and irritability (serum calcium 1.68 mmol/l) in another. One other related child had severe and persistent jittering episodes almost certainly attributable to hypocalcaemia. In seven of eight cases, these symptoms developed during the first 14 days of life. Although occasionally reported previously, malignant infantile osteopetrosis remains essentially unrecognised as a cause of neonatal hypocalcaemia, often resulting in diagnostic confusion and delay. This is important in the context of curative haemopoietic stem cell transplantation where preservation of sight may depend on early intervention. [ABSTRACT FROM AUTHOR]

Background: Although severe T cell immunodeficiency in DiGeorge anomaly is rare, previous studies of humoral function in these patients have found no antibody abnormalities but have not examined the response to polysaccharide antigens. Isolated cases of autoimmunity have been reported. Several patients with 22q11.2 deletion attending our immunology clinic suffered recurrent sinopulmonary infection or autoimmune phenomena.Aims: To investigate humoral immunodeficiency, particularly pneumococcal polysaccharide antibody deficiency, and autoimmune phenomena in a cohort of patients with 22q11.2 deletion.Methods: A history of severe or recurrent infection and autoimmune symptoms were noted. Lymphocyte subsets, immunoglobulins, IgG subclasses, specific vaccine antibodies, and autoantibodies were measured. Subjects were vaccinated with appropriate antigens as indicated.Results: Of 32 patients identified, 26 (81%) had severe or recurrent infection, of which 13 (50%) had abnormal serum immunoglobulin measurements and 11/20 >/=4 years old (55%) had an abnormal response to pneumococcal polysaccharide. Ten of 30 patients (33%) had autoimmune phenomena; six (20%) were symptomatic.Conclusions: Humoral immunodeficiency is more common than previously recognised in patients with 22q11.2 deletion. Normal T cell function and immunoglobulin levels do not exclude poor specific antibody responses. Patients should be referred for formal immunological assessment of cellular and humoral immune function. [ABSTRACT FROM AUTHOR]

Aims -- To evaluate outcome following neonatal bone marrow transplantation (BMT) for severe combined immunodeficiency (SCID) when there is a family history of a previously affected sibling, and to compare results with those published for in utero BMT. Methods -- A retrospective review of cases referred and transplanted between 1987 and 1999, focusing on infectious and graft versus host disease (GvHD) complications after BMT, and T and B lymphocyte function. Thirteen patients received 18 stem cell transplants: four whole marrow, one cord blood, 10 parental T cell depleted (TCD) haplo-identical, and three TCD unrelated donor BMT. Nine were conditioned with busulphan and cyclophosphamide. Results -- All are alive and well (six months to 11.5 years after BMT). Six had grade I-II acute GvHD and two chronic GvHD (now resolved). Three had a top up BMT for poor T cell function, one had a third BMT for graft failure and chronic GvHD, and one had a third BMT for graft failure. Twelve have good in vitro proliferation to T cell mitogens, and all have normal serum IgA levels. Three receive intravenous immunoglobulin; for one of these, it is less than one year since BMT. Nine are above the 2nd centile, and 10 of 12 old enough to be assessed have normal neuro- development. Conclusion -- These results are better than those published for in utero BMT for SCID. Early postnatal BMT should be the preferred option in neonatal SCID. [ABSTRACT FROM AUTHOR]

Background: CD40 ligand (CD40L) deficiency is a rare X linked immunodeficiency disorder leading to recurrent bacterial infection, with cryptosporidial enteritis and subsequent hepatic cirrhosis. Bone marrow transplantation offers the only cure.Objective: To analyse retrospectively the outcome of bone marrow transplantation for this condition in one centre.Design: A retrospective case note analysis was performed, identifying all patients with CD40L deficiency who had undergone bone marrow transplantation between May 1988 and December 2000. Details of pre-existing infection, pretransplantation immunological and infective data, transplant procedure (particularly donor type and HLA match), conditioning regimen, and marrow manipulation were analysed. Post-transplantation data including infective episodes, engraftment details, immune function, complications, and outcome were recorded.Results: Eight boys (age 1-14 years, median 5.75) had transplants. Six received T cell depleted unrelated donor marrow. Four survive and have normal immune function. Six had previous Pneumocystis carinii pneumonia and three had histological liver damage. Survival was associated with younger age at transplantation and normal liver histology.Conclusions: Bone marrow transplantation can be curative in CD40L deficiency. Better outcome is associated with younger age at transplantation and normal liver histology. [ABSTRACT FROM AUTHOR]

Background: Pneumocystis carinii is an important pathogen in immunodeficiency but may be an unrecognised cause of respiratory compromise.Objectives: To ascertain the incidence of P carinii pneumonia (PCP) at presentation of severe combined immunodeficiency (SCID), whether it had been diagnosed, and the effect of treatment on outcome.Setting: The supraregional paediatric bone marrow transplant unit for primary immunodeficiencies at Newcastle General Hospital.Methods: Retrospective case note review of infants referred with a diagnosis of SCID from 1992 to 1998.Results: Ten of 50 infants had PCP at presentation; only one was diagnosed before transfer. Eight were diagnosed by bronchoalveolar lavage and two by lung biopsy. In only one was P carinii identified in nasopharyngeal secretions. Five required ventilation for respiratory failure but all were successfully treated with co-trimoxazole and methylprednisolone with or without nebulised budesonide. Nine survived to bone marrow transplantation and four are long term survivors after bone marrow transplantation; no deaths were related to PCP.Conclusions: PCP is a common presenting feature of SCID but is rarely recognised. Bronchoalveolar lavage or lung biopsy are needed for diagnosis. Treatment with co-trimoxazole is highly successful. [ABSTRACT FROM AUTHOR]

Discusses the role of the gene encoding nuclear factor kappa-beta essential modulator in anhidrotic ectodermal dysplasia and immunodeficiency. Essential role of the protein in the activation of the transcription factor that affects human development, skin homeostasis and immunity; Implications on acute pediatrics.

A child with colitis was treated for Crohn's disease, diagnosed on history, clinical and colonoscopic findings, radiolabelled white cell bowel scan, and colonic histology. After septicaemia caused by an unusual organism, further investigation lead to a diagnosis of chronic granulomatous disease (CGD). The granulomatous colitis of CGD is clinically, histologically, and on white cell scanning, indistinguishable from that in Crohn's disease and should be considered in atypical cases. Infection with unusual 'pseudomonads' should prompt the exclusion of this disorder. [ABSTRACT FROM AUTHOR]

The article describes the case of a 13-year old girl with a history of left limb movement and falls presumed to be vasovagal faints. The girl suffered from left arm weakness and speech difficulties following a collapsed. Medical record shows the girl's mood swings, self-harming behaviors, development of a right hand preference having previously been left hand dominant, inability to walk upstairs, appeared confused and wandered about the house looking for objects which she thought had been lost.

Background Myasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date. Methods We performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders. Results We confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10-13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders. Discussion Our gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms. [ABSTRACT FROM AUTHOR]

The emerging group of autoinflammatory diseases (AIDs) is caused by a dysregulation of the innate immune system while lacking the typical footprint of adaptive immunity. A prominent subgroup of AIDs are inflammasomopathies, which are characterised by periodic flares of cutaneous signs as well as systemic organ involvement and fever. The range of possible skin lesions is vast, ranging from urticarial, erysipelas-like and pustular rashes to erythematous patches, violaceous plaques and eventual necrosis and ulceration. This review provides a structured overview of the pathogenesis and the clinical picture with a focus on dermatological aspects of inflammasomopathies. Current treatment options for these conditions are also discussed. [ABSTRACT FROM AUTHOR]

Syndromes with lymphatic malformations show phenotypic variability within the same entity, clinical features that overlap between different conditions and allelic as well as locus heterogeneity. The aim of this review is to provide a comprehensive clinical genetic description of lymphatic malformations and the techniques used for their diagnosis, and to propose a flowchart for genetic testing. Literature and database searches were performed to find conditions characterised by lymphatic malformations or the predisposition to lymphedema after surgery, to identify the associated genes and to find the guidelines and genetic tests currently used for the molecular diagnosis of these disorders. This search allowed us to identify several syndromes with lymphatic malformations that are characterised by a great heterogeneity of phenotypes, alleles and loci, and a high frequency of sporadic cases, which may be associated with somatic mutations. For these disorders, we found many diagnostic tests, an absence of harmonic guidelines for molecular diagnosis and well-established clinical guidelines. Targeted sequencing is the preferred method for the molecular diagnosis of lymphatic malformations. These techniques are easy to implement and have a good diagnostic success rates. In addition, they are relatively inexpensive and permit parallel analysis of all known disease-associated genes. The targeted sequencing approach has improved the diagnostic process, giving patients access to better treatment and, potentially, to therapy personalised to their genetic profiles. These new techniques will also facilitate the prenatal and early postnatal diagnosis of congenital lymphatic conditions and the possibility of early intervention. [ABSTRACT FROM AUTHOR]

Background: There is little evidence about either prevention or treatment of childhood arterial ischaemic stroke (AIS). However, drugs that regulate the immune and inflammatory response could theoretically prevent occurrence or recurrence of AIS. Additionally, as an acute treatment, they may limit the neurological damage caused by AIS. Here, we systematically review the evidence on the use of immunotherapy in childhood AIS.Design: A systematic review of publications in databases Embase and Medline from inception. All types of evidence were included from trials, cohorts, case-control and cross-sectional studies and case reports.Results: 34 reports were included: 32 observational studies and 2 trials. Immunotherapy was used in two key patient groups: arteriopathy and acute infection. The majority were cases of varicella and primary angiitis of the central nervous system. All three cohorts and 80% of the case studies were treated with steroids. Recurrence rates were low. Analytical studies weakly associated steroids with lower odds of new stroke and neurological deficits, and better cognitive outcomes in the context of Moyamoya disease and tuberculosis.Conclusions: Immunotherapies are used in children with AIS, mainly as steroids for children with arteriopathy. However, there is currently little robust evidence to either encourage or discourage this practice. There is weak evidence consistent with the hypothesis that in certain children at risk, steroids may both reduce the risk of occurrent/recurrent stroke and enhance neurological outcomes. As the potential benefit is still uncertain, this indicates that a trial of steroids in childhood AIS may be justified. [ABSTRACT FROM AUTHOR]

Background: Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ~1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. Methods: We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. Results: We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). Conclusions: This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results. [ABSTRACT FROM AUTHOR]

Haemophagocytic syndrome, or haemophagocytic lymphohistiocytosis (HLH), is a hyperinflammatory disorder characterised by uncontrolled activation of the immune system. It can result from mutations in multiple genes involved in cytotoxicity or occur secondary to a range of infections, malignancies or autoimmune rheumatic diseases. In the latter case, it is also known as macrophage activation syndrome (MAS). Characteristic features are persistent fever, hepatosplenomegaly, petechial/purpuric rash, progressive cytopenias, coagulopathy, transaminitis, raised C reactive protein, falling erythrocyte sedimentation rate, hypertriglyceridaemia, hypofibrinogenaemia and extreme hyperferritinaemia often associated with multi-organ impairment. Distinguishing HLH from systemic sepsis can present a major challenge. Criteria for diagnosis and classification of HLH and MAS are available and a serum ferritin >10 000 µg/L is strongly supportive of HLH. Without early recognition and appropriate treatment, HLH is almost universally fatal. However, with prompt referral and advancements in treatment over the past two decades, outcomes have greatly improved. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency (CVID) is a primary antibody deficiency characterised by hypogammaglobulinaemia, impaired production of specific antibodies after immunisation and increased susceptibility to infections. CVID shows a considerable phenotypical and genetic heterogeneity. In contrast to many other primary immunodeficiencies, monogenic forms count for only 2-10% of patients with CVID. Genes that have been implicated in monogenic CVID include ICOS, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), TNFRSF7 (CD27), IL21, IL21R, LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R1, VAV1, RAC2, BLK, IKZF1 (IKAROS) and IRF2BP2. With the increasing number of disease genes identified in CVID, it has become clear that CVID is an umbrella diagnosis and that many of these genetic defects cause distinct disease entities. Moreover, there is accumulating evidence that at least a subgroup of patients with CVID has a complex rather than a monogenic inheritance. This review aims to discuss current knowledge regarding the molecular genetic basis of CVID with an emphasis on the relationship with the clinical and immunological phenotype. [ABSTRACT FROM AUTHOR]

Background Cowden's syndrome is a rare, autosomal dominant disease caused by mutations in the phosphoinositide 3-kinase and phosphatase and tensin homolog (PTEN) gene. It is associated with hamartomatous polyposis of the gastrointestinal tract, mucocutaneous lesions and increased risk of developing certain types of cancer. In addition to increased risk of tumour development, mutations in PTEN have also been associated with autoimmunity in both mice and humans. Until now, however, an association between Cowden's syndrome and immune deficiency has been reported in a single patient only. Methods and results Two patients with Cowden's syndrome and an increased frequency of infections were investigated for possible underlying immunodeficiency. In one patient, hypogammaglobulinaemia with a functional antibody deficiency was identified, while the other patient had a persisting CD4+ T cell lymphopenia (with normal antibody production). Conclusions Our data indicate that Cowden's syndrome may be associated with both T cell and B cell immune dysfunction. We recommend that patients with Cowden's syndrome and an increased frequency of nfections are investigated for associated immunodeficiency. [ABSTRACT FROM AUTHOR]

Objectives To compare the immunogenicity and safety of the bivalent human papillomavirus (HPV)16/18 vaccine between female patients with juvenile idiopathic arthritis ( JIA) and healthy female adolescents. Methods 68 patients and 55 healthy girls aged 12-18 years were included in a prospective controlled observational cohort and were vaccinated at 0, 1 and 6 months. Primary outcomes were immunogenicity expressed as seropositivity rate after three vaccine doses at 7 and 12 months and HPV-specific geometric mean antibody concentrations. Secondary outcomes were HPV16/18-specific memory B cell responses in a subset of participants and safety, defined as adverse events and the effect of vaccination on JIA disease activity. Results All participants were seropositive for HPV16 and HPV18 at 7 months. One patient turned seronegative at 12 months for HPV16/18. No significant differences were found between patients and controls in HPV-specific antibody concentrations; however, antibody concentrations were consistently lower in patients. No effect of methotrexate on HPV16 antibodies (p=0.79) or HPV18 antibodies (p=0.37) was detected. All patients on anti-TNFα treatment were seropositive after vaccination. The kinetics of HPV16/18 memory B cell responses was comparable between patients and controls, but the magnitude of B cell responses at 7 and 12 months appeared lower in patients. No relevant differences in adverse events were found. HPV vaccination did not aggravate JIA disease. Conclusions The bivalent HPV16/18 vaccine is mmunogenic and well tolerated in JIA patients. However, HPV-specific antibodies and B cell responses tended to be ower in patients compared with healthy controls. Clinical trial listing NCT00815282 [ABSTRACT FROM AUTHOR]

Objective: To systematically review the evidence regarding long-term prophylaxis in the prevention or reduction of attacks in hereditary angio-oedema (HAE). Design: Systematic review and meta-analysis. Data sources: Electronic databases were searched up to April 2011. Two reviewers selected the studies and extracted the study data, patient characteristics and outcomes of interest. Eligibility criteria for selected studies: Controlled trials for HAE prophylaxis. Results: 7 studies were included, for a total of 73 patients and 587 HAE attacks. Due to the paucity of studies, a meta-analysis was not possible. Since two studies did not report the number of HAE attacks, five studies (52 patients) were finally included in the summary analysis. Four classes of drugs with at least one controlled trial have been proposed for HAE prophylaxis. All those drugs, except heparin, were found to be more effective than placebo. In the absence of direct comparisons, the relative efficacies of these drugs were determined by calculating a RR of attacks (drug vs placebo). The results were as follows: danazol (RR=0.023, 95% CI 0.003 to 0.162), methyltestosterone (RR=0.054, 95% CI 0.013 to 0.163), ε-aminocaproic acid (RR=0.095, 95% CI 0.025 to 0.356), tranexamic acid (RR=0.308, 95% CI 0.195 to 0.479) and C1-INH 0.491 (95% CI 0.395 to 0.607). Conclusions: Few trials have evaluated the benefits of HAE prophylaxis, and all drugs but heparin seem to be effective in this setting. Since there are no direct comparisons of HAE drugs, it was not possible to draw definitive conclusions on the most effective one. Thus, to accumulate evidence for HAE prophylaxis, further studies are needed that consider the dose--efficacy relationship and include a head-to-head comparison between drugs, with the active group, rather than placebo, as the control. [ABSTRACT FROM AUTHOR]

Immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome is a rare disorder in humans caused by germ-line mutations in the FOXP3 gene, a master transcriptional regulator for the development of CD4 regulatory T (Treg) cells. This T cell subset has global inhibitory functions that maintain immune homeostasis and mediate self-tolerance. Treg developmental deficiency or dysfunction is a hallmark of IPEX. It leads to severe, multi-organ, autoimmune phenomena including enteropathy, chronic dermatitis, endocrinopathy and other organ-specific diseases such as anaemia, thrombocytopenia, hepatitis and nephritis. In this review, the genetic, immunological and clinical characteristics of IPEX syndrome are described, and the impact of heritable mutations on the function of Treg cells highlighted. [ABSTRACT FROM AUTHOR]

Background Osteopetrosis is a life-threatening, rare disorder typically resulting from osteoclast dysfunction and infrequently from failure to commitment to osteoclast lineage. Patients commonly present in infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, and bone marrow failure. In ∼70% of the patients there is a molecularly defined failure to maintain an acid pH at the osteoclast-bone interface (the ruffled border) which is necessary for the bone resorptive activity. Methods and results In eight patients with infantile osteopetrosis which could be cured by bone marrow transplantation, the study identified by homozygosity mapping in distantly related consanguineous pedigrees a missense mutation in a highly conserved residue in the SNX10 gene. The mutation segregated with the disease in the families and was carried by one of 211 anonymous individuals of the same ethnicity. In the patients' osteoclasts, the mutant SNX10 protein was abnormally abundant and its distribution altered. The patients' osteoclasts were fewer and smaller than control cells, their resorptive capacity was markedly deranged, and the endosomal pathway was perturbed as evidenced by the distribution of internalised dextran. Conclusions SNX10 was recently shown to interact with vacuolar type H+-ATPase (V-ATPase) which pumps protons at the osteoclast-bone interface. Mutations in TCIRG1, the gene encoding a subunit of the V-ATPase complex, account for the majority of cases of osteopetrosis. It is speculated that SNX10 is responsible for the vesicular sorting of V-ATPase from Golgi or for its targeting to the ruffled border. A mutation in SNX10 may therefore result in 'secondary V-ATPase deficiency' with a failure to acidify the resorption lacuna. Determination of the sequence of the SNX10 gene is warranted in molecularly undefined patients with recessive 'pure' osteopetrosis of infancy. [ABSTRACT FROM AUTHOR]

Introduction Genome-wide homozygosity mapping is a powerful method for locating rare recessive Mendelian mutations. However, statistical power decreases dramatically in the presence of genetic heterogeneity. Methods The authors applied an empirical approach to test for linkage accounting for genetic heterogeneity by calculating the sum of positive per-family multipoint LOD scores (S) across all positions, and obtaining corresponding empirical p values (EmpP) through permutations. Results The statistical power of the approach was found to be consistently higher than the classical heterogeneity LOD by simulations. Among 21 first-cousin matings with a single affected child, for five families linked to a locus of interest and 16 families to other loci, S/EmpP achieved a power of 40% versus 28% for heterogeneity LOD at an α level of 0.001. The mean size of peak linkage regions was markedly higher for true loci than false positive regions. The S/EmpP approach was applied to a sample of 17 consanguineous families with Mendelian susceptibility to mycobacterial disease, leading to the identification of two mutations in IL12RB1 and TYK2 from the largest of six linkage regions at p<10-3. Conclusions The S/EmpP approach is a flexible and powerful approach that can be applied to linkage analysis of families with suspected Mendelian disorders. [ABSTRACT FROM AUTHOR]

Objective: Thymic function declines exponentially with age. Impaired thymic function has been associated with autoimmune disease in adults but has never been formally assessed in childhood autoimmunity. Therefore, thymic function in children with the autoimmune disease juvenile idiopathic arthritis (JIA) was determined. Methods: Thymic function was measured in 70 children and young adults with JIA (age range 2.1–30.8 (median 10.4)) and 110 healthy age-matched controls using four independent assays. T cell receptor excision circles (WBLogTREC/ml) and the proportion of CD4 CD45RACD31 T cells (representing recent thymic emigrants; %RTEs) were quantified and intrathymic proliferation measured by calculating the αTREC/ΣβTREC ratio. Lastly, regulatory T cells (T) of thymic origin (CD4FOXP3) were quantified in peripheral blood to assess the ability of the thymus in JIA to generate this T cell subset. Results: Thymic function was equivalent by all four parameters in JIA when compared with the control population. Furthermore, there was no consistent effect of JIA subtype on thymic function, although intrathymic proliferation was higher in the small rheumatoid factor (RF) polyarticular group. There were no significant effects of disease-modifying antirheumatic drugs (DMARDs) or oral corticosteroids on thymic function, although those with the worst prognostic ILAR (International League of Associations for Rheumatology) subtypes were also those most likely to be on a DMARD. Conclusions: It is demonstrated that children and young adults with JIA, unlike adults with autoimmune diseases, have thymic function that is comparable with that of healthy controls. The varied pathologies represented by the term “JIA” suggest this observation may not be disease specific and raises interesting questions about the aetiology of thymic impairment in adult autoimmunity. [ABSTRACT FROM PUBLISHER]

Background: About 2% of childhood episodes of invasive pneumococcal disease (IPD) are recurrent, and most remain unexplained. Objective: To report two cases of otherwise healthy, unrelated children with recurrent PD as the only clinical infectious manifestation of an inherited disorder in nuclear factor-κB(NF-κB)-dependent immunity. Results: One child carried two germline mutations in IRAK4, and had impaired cellular responses to interleukin (IL)] receptor and toll-like receptor (TLR) stimulation. The other child carried a hemizygous mutation in NEMO, associated with a broader impairment of NF-κB activation, with an impaired cellular response to IL-1R, TLR and tumour necrosis factor receptor stimulation. The two patients shared a narrow clinical phenotype, associated with two related but different genotypes. Conclusions: Otherwise healthy children with recurrent PD should be explored for underlying primary immunodeficiencies affecting the IRAK4-dependent and NEMO-dependent signalling pathways. [ABSTRACT FROM AUTHOR]

Background: Osteopetrosis, a genetic disease characterised by osteoclast failure, is classified into three forms: infantile malignant autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IRO), and autosomal dominant osteopetrosis (ADO). Methods: We studied 49 patients, 21 with ARO, one with IRO, and 27 with type II ADO (ADO II). Results: Most ARO patients bore known or novel (one case) ATP6i (TCIRG1) gene mutations. Six ADO II patients had no mutations in CICN7, the only so far recognised gene implicated, suggesting involvement of yet unknown genes. Identical CICN7 mutations produced differing phenotypes with variable degrees of severity. In ADO II, serum tartrate resistant acid phosphatase was always elevated. Bone alkaline phosphatase (BALP) was generally low, but osteocalcin was high, suggesting perturbed osteoblast differentiation or function. In contrast, BALP was high in ARO patients. Elevated osteoclast surface/bone surface was noted in biopsies from most ARO patients. Cases with high osteoclasts also showed increased osteoblast surface/bone surface. ARO osteoclasts were morphologically normal, with unaltered formation rates, intracellular pH handling, and response to acidification. Their resorption activity was greatly reduced, but not abolished. In control osteoclasts, all resorption activity was abolished by combined inhibition of proton pumping and sodium/proton antiport. Conclusions: These findings provide a rationale for novel therapies targeting pH handling mechanisms in osteoclasts and their microenvironment. [ABSTRACT FROM AUTHOR]

Background: Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder with hypersensitivity to ionising radiation. The clinical phenotype is characterised by congenital microcephaly, mild dysmorphic facial appearance, growth retardation, immunodeficiency, and greatly increased risk for lymphoreticular malignancy. Most NBS patients are of Slavic origin and homozygous for the founder mutation 657del5. The frequency of 657del5 heterozygotes in the Czech population is 1:150. Recently, another NBS1 mutation, 643C>T(R215W), with uncertain pathogenicity was found to have higher frequency among tumour patients of Slavic origin than in controls. This alteration results in the substitution of the basic amino acid arginine with the non-polar tryptophan and thus could potentially interfere with the function of the NBSI protein, nibrin. Methods and Results: Children with congenital microcephaly are routinely tested for the 657del5 mutation in the Czech and Slovak Republics. Here, we describe for the first time a severe form of NBS without chromosomal instability in monozygotic twin brothers with profound congenital microcephaly and developmental delay who are compound heterozygotes for the 657del5 and 643C>T(R215W) NBSI mutations. Both children showed reduced expression of full length nibrin when compared with a control and a heterozygote for the 657del5 mutation. Radiation response processes such as phosphorylation of ATM and phosphorylation/stabilisation of p53, which are promoted by NBS1, are strongly reduced in cells from these patients. Conclusions: Interestingly, the patients are more severely affected than classical NBS patients. Consequently, we postulate that homozygosity for the 643C>T(R215W) mutation will also lead to a, possibly very, severe disease phenotype. [ABSTRACT FROM AUTHOR]

The rare bone thickening disease osteopetrosis occurs in various forms, one of which is accompanied by renal tubular acidosis (RTA), and is known as Guibaud­Vainsel syndrome or marble brain disease. Clinical manifestations of this autosomal recessive syndrome comprise increased bone density, growth failure, intracerebral calcification, facial dysmorphism, mental retardation, and conductive hearing impairment. The most common cause is carbonic anhydrase II (CAII) deficiency. Several different loss of function mutations in CA2, the gene encoding CAII, have been described. To date, there have been no exceptions to the finding of CAII deficiency in patients with coexistent osteopetrosis and RTA. Most often, the RTA is of mixed proximal and distal type, but kindreds are reported in which either distal or proximal RTA predominates. We report the molecular genetic investigation of two consanguineous kindreds where osteopetrosis and distal RTA (dRTA) were both manifest. One kindred harbours a novel homozygous frameshifl alteration in CA2. In the other, CAII levels were normal despite a similar clinical picture, and we excluded defects in CA2. In this kindred, two separate recessive disorders are penetrant, each affecting a different, tissue specific subunit of the vacuolar proton pump (H+-ATPase), providing a highly unusual, novel genetic explanation for the coexistence of osteopetrosis and dRTA. The osteopetrosis is the result of a homozygous deletion in TCIRG1, which encodes an osteoclast specific isoform of subunit a of the H+-ATPase, while the dRTA is associated with a homozygous mutation in ATP6V1B1, encoding the kidney specific B1 subunit of H+-ATPase. This kindred is exceptional firstly because the coinheritance of two rare recessive disorders has created a phenocopy of CAII deficiency, and secondly because these disorders affect two different subunits of the H+-ATPase that have opposite effects on bone density, but which have only recently been determined to possess tissue specific isoforms. [ABSTRACT FROM AUTHOR]

Studies longevity in Schimke immuno-osseous dysplasia. Genetic mutations; Disease severity; Clinical symptoms.

Presents several new cases of dysosteosclerosis. Evolution of radiological findings; Analysis of pertinent topics and relevant issues; Theoretical significance to medical genetics.

Focuses on osteogenesis imperfecta (OI) which is characterised by brittle bones and caused by mutations in the type I collagen genes, COL1A1 and COL1A2. Identification made of a mutation in the carboxyl-terminal propeptide coding region of one COL1A1 allele in an infant who died with an OI phenotype that differed from the usual lethal form and had regions of increased bone density.

The ectodermal dysplasias (EDs) are a large and complex nosological group of diseases, first described by Thurnam in 1848. In the last 10 years more than 170 different pathological clinical conditions have been recognised and defined as EDs, all sharing in common anomalies of the hair, teeth, nails, and sweat glands. Many are associated with anomalies in other organs and systems and, in some conditions, with mental retardation. The anomalies affecting the epidermis and epidermal appendages are extremely variable and clinical overlap is present among the majority of EDs. Most EDs are defined by particular clinical signs (for example, eyelid adhesion in AEC syndrome, ectrodactyly in EEC). To date, few causative genes have been identified for these diseases. We recently reviewed genes known to be responsible for EDs in light of their molecular and biological function and proposed a new approach to EDs, integrating both molecular-genetic data and corresponding clinical findings. Based on our previous report, we now propose a clinical-genetic classification of EDs, expand it to other entities in which no causative genes have been identified based on the phenotype, and speculate on possible candidate genes suggested by associated "non-ectodermal" features. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor concerning inherited lower incisor hypodontia.

Hereditary angioedema is a rare and potentially fatal autosomal dominant disorder characterised by unpredictable skin, gastrointestinal tract or respiratory tract oedema. Plasma-derived C1-esterase inhibitors are effective in the prophylaxis or treatment of hereditary angioedema type I and II attacks, but must be administered intravenously. This may be problematic in patients with venous access difficulties. Icatibant, a bradykinin B2-receptor antagonist, is administered subcutaneously. In July 2008 icatibant received approval for healthcare professional-administered treatment of hereditary angioedema attacks in adults. In 2011 it received European Medicines Agency and US Food and Drug Administration licences for patient-administered treatment of hereditary angioedema attacks. Given these approvals, and with the appropriate training, icatibant could provide the opportunity for patients to self-administer treatment. This is one of the first long-term follow-up reports of patients with hereditary angioedema using self-administered icatibant. During follow-up, icatibant remained effective and patient satisfaction was high. [ABSTRACT FROM AUTHOR]