Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency.

BACKGROUND: Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)-like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition. METHODS: A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA. RESULTS: Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1ß, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4+ T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy. CONCLUSIONS: ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation.

Downregulation of myeloma-induced ICOS-L and regulatory T cell generation by lenalidomide and dexamethasone therapy.

Multiple myeloma (MM) produces significant cellular and humoral immune defects. We have previously reported that MM induces CD4(+)CD25(+)FoxP3(+) cells (TRegs), via tumour expression of the immune checkpoint regulator, ICOS-L. We sought to define what impact the immunomodulatory drug lenalidomide, alone or with dexamethasone, has on TReg cell generation. Lenalidomide pre-treatment of MM cell lines reduced TReg generation and the concomitant TReg:TEff (CD4(+)CD25(+)FoxP3(-): effector T cells) ratio, as a consequence of reduced ICOSL transcription. Dexamethasone did not affect surface ICOS-L expression but did induce TReg cell apoptosis without impacting on TEff cell survival. Combined lenalidomide and dexamethasone significantly reduced both TReg induction and the TReg:TEff cell ratio. In vivo, serial analysis of the TReg:TEff ratio in MM patients on lenalidomide-dexamethasone therapy revealed a progressive reduction towards age-matched control values, though not complete correction. Our data demonstrate for the first time immune synergism to explain the observed immune-modulation associated with lenalidomide-dexamethasone therapy.

General anesthesia suppresses normal heart rate variability in humans.

The human heart normally exhibits robust beat-to-beat heart rate variability (HRV). The loss of this variability is associated with pathology, including disease states such as congestive heart failure (CHF). The effect of general anesthesia on intrinsic HRV is unknown. In this prospective, observational study we enrolled 100 human subjects having elective major surgical procedures under general anesthesia. We recorded continuous heart rate data via continuous electrocardiogram before, during, and after anesthesia, and we assessed HRV of the R-R intervals. We assessed HRV using several common metrics including Detrended Fluctuation Analysis (DFA), Multifractal Analysis, and Multiscale Entropy Analysis. Each of these analyses was done in each of the four clinical phases for each study subject over the course of 24 h: Before anesthesia, during anesthesia, early recovery, and late recovery. On average, we observed a loss of variability on the aforementioned metrics that appeared to correspond to the state of general anesthesia. Following the conclusion of anesthesia, most study subjects appeared to regain their normal HRV, although this did not occur immediately. The resumption of normal HRV was especially delayed on DFA. Qualitatively, the reduction in HRV under anesthesia appears similar to the reduction in HRV observed in CHF. These observations will need to be validated in future studies, and the broader clinical implications of these observations, if any, are unknown.

Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity.

BACKGROUND: Carnitine palmitoyltransferase-1 (CPT1) is a rate-limiting step of mitochondrial ß-oxidation by controlling the mitochondrial uptake of long-chain acyl-CoAs. The muscle isoform, CPT1b, is the predominant isoform expressed in the heart. It has been suggested that inhibiting CPT1 activity by specific CPT1 inhibitors exerts protective effects against cardiac hypertrophy and heart failure. However, clinical and animal studies have shown mixed results, thereby creating concerns about the safety of this class of drugs. Preclinical studies using genetically modified animal models should provide a better understanding of targeting CPT1 to evaluate it as a safe and effective therapeutic approach. METHODS AND RESULTS: Heterozygous CPT1b knockout (CPT1b(+/-)) mice were subjected to transverse aorta constriction-induced pressure overload. These mice showed overtly normal cardiac structure/function under the basal condition. Under a severe pressure-overload condition induced by 2 weeks of transverse aorta constriction, CPT1b(+/-) mice were susceptible to premature death with congestive heart failure. Under a milder pressure-overload condition, CPT1b(+/-) mice exhibited exacerbated cardiac hypertrophy and remodeling compared with wild-type littermates. There were more pronounced impairments of cardiac contraction with greater eccentric cardiac hypertrophy in CPT1b(+/-) mice than in control mice. Moreover, the CPT1b(+/-) heart exhibited exacerbated mitochondrial abnormalities and myocardial lipid accumulation with elevated triglycerides and ceramide content, leading to greater cardiomyocyte apoptosis. CONCLUSIONS: CPT1b deficiency can cause lipotoxicity in the heart under pathological stress, leading to exacerbation of cardiac pathology. Therefore, caution should be exercised in the clinical use of CPT1 inhibitors.

Genomic structure and genetic drift in C57BL/6 congenic metabolic mutant mice.

We used a genome-wide single nucleotide polymorphism (SNP) approach to characterize the genomic structures of four representative C57BL/6 (B6) congenic mutant mouse lines to include the A) long-chain acyl-CoA dehydrogenase (Acadl), B) melanocortin 3 receptor (Mc3r), C) endothelial nitric oxide synthase (Nos3), and D) a replacement of mouse apolipoprotein E (Apoe) by human apolipoprotein E-2 (APOE2). We wanted to evaluate the size and flanking genes of the 129 strain origin mutant allele intervals on the B6 background. Additionally, we wanted to evaluate genetic drift among not only the four mutant lines and their respective B6 origin substrains, but also the drift between two commonly used B6 lines obtained from Jackson Laboratory and Taconic. Overall, we found a range of 129 origin interval sizes in the congenic mutant lines analyzed that ranged from a ~2.8 kb human sequence for APOE2 embedded in a 129S6 interval to the largest being a ~16 Mb fragment containing the targeted Nos3 (eNos) gene. Given the range of 129 strain interval sizes, we found 129 strain flanking genes via annotation in genome data bases ranging from one gene both upstream and downstream of the APOE2 allele to seven genes-upstream and five genes-downstream at the Nos3 locus. Furthermore, we found fourteen SNP differences between the Jackson Laboratory and Taconic B6 mice. These genetic differences were associated with marked adiposity differences between the two B6 substrains. This study demonstrates both the fidelity and the caveats of using congenic gene targeted mouse models and recognizing the importance of selecting the appropriately matched wild-type control mouse line.

Deficiency in short-chain fatty acid beta-oxidation affects theta oscillations during sleep.

In rodents, the electroencephalogram (EEG) during paradoxical sleep and exploratory behavior is characterized by theta oscillations. Here we show that a deficiency in short-chain acyl-coenzyme A dehydrogenase (encoded by Acads) in mice causes a marked slowing in theta frequency during paradoxical sleep only. We found Acads expression in brain regions involved in theta generation, notably the hippocampus. Microarray analysis of gene expression in mice with mutations in Acads indicates overexpression of Glo1 (encoding glyoxylase 1), a gene involved in the detoxification of metabolic by-products. Administration of acetyl-L-carnitine (ALCAR) to mutant mice significantly recovers slow theta and Glo1 overexpression. Thus, an underappreciated metabolic pathway involving fatty acid beta-oxidation also regulates theta oscillations during sleep.

Acadl-SNP based genotyping assay for long-chain acyl-CoA dehydrogenase deficient mice.

The long-chain acyl-CoA dehydrogenase (LCAD) (Acadl=gene; LCAD=protein) deficient mouse model has been important in evaluating the role of mitochondrial fatty acid oxidation of long-chain fatty acids in metabolic disorders. The insertion vector-based gene targeting strategy used to generate this model has made it difficult to distinguish homozygous and heterozygous genotypes containing targeted Acadl alleles in LCAD-deficient mice. Herein, we describe the design and validation of Acadl SNP genotyping methods capable of distinguishing between heterozygous and homozygous LCAD-deficient mice. The Acadl SNP genotyping assays are effective at allelic discrimination of both C57BL/6 and 129 mouse strain-based Acadl alleles under conditions including, both low purity and quantity genomic DNA templates. This makes the method practical and provides the necessary tools for genotyping the LCAD-deficient mouse model.

Experience of a systematic approach to care and prevention of fragility fractures in New Zealand.

This narrative review describes efforts to improve the care and prevention of fragility fractures in New Zealand from 2012 to 2022. This includes development of clinical standards and registries to benchmark provision of care, and public awareness campaigns to promote a life-course approach to bone health. PURPOSE: This review describes the development and implementation of a systematic approach to care and prevention for New Zealanders with fragility fractures, and those at high risk of first fracture. Progression of existing initiatives and introduction of new initiatives are proposed for the period 2022 to 2030. METHODS: In 2012, Osteoporosis New Zealand developed and published a strategy with objectives relating to people who sustain hip and other fragility fractures, those at high risk of first fragility fracture or falls and all older people. The strategy also advocated formation of a national fragility fracture alliance to expedite change. RESULTS: In 2017, a previously informal national alliance was formalised under the Live Stronger for Longer programme, which includes stakeholder organisations from relevant sectors, including government, healthcare professionals, charities and the health system. Outputs of this alliance include development of Australian and New Zealand clinical guidelines, clinical standards and quality indicators and a bi-national registry that underpins efforts to improve hip fracture care. All 22 hospitals in New Zealand that operate on hip fracture patients currently submit data to the registry. An analogous approach is ongoing to improve secondary fracture prevention for people who sustain fragility fractures at other sites through nationwide access to Fracture Liaison Services. CONCLUSION: Widespread participation in national registries is enabling benchmarking against clinical standards as a means to improve the care of hip and other fragility fractures in New Zealand. An ongoing quality improvement programme is focused on eliminating unwarranted variation in delivery of secondary fracture prevention.

Perioperative reductions in circulating lymphocyte levels predict wound complications after excisional breast cancer surgery.

OBJECTIVE: Postoperative wound complications after excisional surgery for primary breast cancer can result in patients requiring additional treatments and delay adjuvant therapy and are associated with worse prognoses.We investigated factors that might predispose patients to wound complications. BACKGROUND: A number of patient characteristics have been associated with wound complications, but there is currently no quantitative measure of the risk of their occurrence. Our hypothesis was that wound complications are related, in part, to the immune status of patients. METHODS: We recruited patients undergoing surgery for primary breast cancer and determined their circulating levels of various immune cells shortly before and after surgery as a measure of immune status. RESULTS: One hundred seventeen patients were recruited; 16 (13.7%) developed wound complications. The following patient and tumor characteristics were associated with higher wound complication rates: diabetes (P = 0.02); larger tumors (T2/3 vs T1; P = 0.02); metastatic axillary nodes (P = 0.006). With respect to immune status, no significant differences in preoperative levels of circulating immune cells were detected between patients who developed wound complications and those who did not. However, patients who developed complications showed greater reductions in lymphocyte levels 4 hours postoperatively than those who did not (P <0.001). Multivariate analyses demonstrated that falls in lymphocyte levels of greater than 20% or 50% 4 hours postoperatively acted as a significant and independent predictor of wound complications (P < 0.005 and P < 0.0001,respectively). CONCLUSIONS: Perioperative changes in lymphocyte levels could provide a practical predictive marker for wound complications on which selective antibiotic prophylaxis could be based.

Primary antibody deficiency syndromes.

PURPOSE OF REVIEW: The primary antibody deficiency syndromes are a rare group of disorders presenting at any age, with complex polygenic disorders, most commonly the common variable immunodeficiency disorders (CVIDs), predominating. With increasing patient survival on immunoglobulin therapy, there is an increasing focus on the complications of these disorders. Research into the cause of CVIDs has made use of the increased understanding of immune regulatory systems and B-cell signalling events and has made significant progress in the past 12 months. RECENT FINDINGS: Prevalence data from different geographical regions have been supplemented by more detailed incidence data on primary antibody deficiencies, revealing trends in diagnosis and management. Continued exploration of the role of genetic variations in TACI in CVID populations has improved our understanding of possible pathogenic events. The key role of naturally occurring regulatory T cells in the development of immune dysregulation in CVIDs has become more apparent. The role of dysfunction of the innate immune system in pathogenesis of CVID has begun to emerge. Novel clinical presentations of these disorders continue to be described. SUMMARY: The recent findings in these areas will allow more precise prognostic and diagnostic information to be available for individual patients. The challenge remains to separate primary disease-causing factors from secondary disease-modifying phenomena.

Light induced stimulation and delay of cardiac activity.

This article shows the combination of light activatable ion channels and microelectrode array (MEA) technology for bidirectionally interfacing cells. HL-1 cultures, a mouse derived cardiomyocyte-like cell line, transfected with channelrhodopsin were stimulated with a microscope coupled 473 nm laser and recorded with custom built 64 electrode MEAs. Channelrhodopsin induced depolarization of the cell can evoke action potentials (APs) in single cells. Spreading of the AP over the cell layer can then be measured with good spatiotemporal resolution using MEA recordings. The possibility for light induced pacemaker switching in cultures was shown. Furthermore, the suppression of APs can also be achieved with the laser. Possible applications include cell analysis, e.g. pacemaker interference or induced pacemaker switching, and medical applications such as a combined cardiac pacemaker and defibrillator triggered by light. Since current prosthesis research focuses on bidirectionality, this system may be applied to any electrogenic cell, including neurons or muscles, to advance this field.

Frequency of Treg cells is reduced in CVID patients with autoimmunity and splenomegaly and is associated with expanded CD21lo B lymphocytes.

INTRODUCTION: Common variable immunodeficiency is a heterogeneous antibody deficiency syndrome with autoimmune and inflammatory complications in a significant proportion of patients. The study was designed to evaluate the role of T regulatory (Treg) cells in common variable immunodeficiency (CVID) patients with autoimmunity. METHODS: The number and frequency of Treg cells (CD4(+), CD25(hi), Foxp3(+)) were evaluated in patients and controls, and Foxp3 expression in different subgroups of CVID patients with common clinical manifestations was compared. RESULTS: CVID patients had significantly fewer Treg cells than controls, and low frequency of Treg cells was associated with expansion of CD21(lo) B cells in patients. Patients with autoimmunity had significantly reduced frequency but normal numbers of regulatory T cells, whilst patients with splenomegaly had significant reduction in frequency and number of regulatory T cells. CONCLUSION: Foxp3 is useful on its own or as an adjunct to classify CVID patients although the possibility of reduction in Treg cells as a secondary phenomenon cannot be excluded.

Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models.

Mouse models have been designed for a number of fatty acid oxidation defects. Studies in these mouse models have demonstrated that different pathogenetic mechanisms play a role in the pathophysiology of defects of fatty acid oxidation. Supplementation with L-carnitine does not prevent low tissue carnitine levels and induces acylcarnitine production having potentially toxic effects, as presented in very-long-chain acyl-CoA dehydrogenase (VLCAD)-deficient mice. Energy deficiency appears to be an important mechanism in the development of cardiomyopathy and skeletal myopathy in fatty acid oxidation defects and is also the underlying mechanism of cold intolerance. Hypoglycemia as one major clinical sign in all fatty acid oxidation defects occurs due to a reduced hepatic glucose output and an enhanced peripheral glucose uptake rather than to transcriptional changes that are also observed simultaneously, as presented in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice. There are reports that an impaired fatty acid oxidation also plays a role in intrauterine life. The embryonic loss demonstrated for some enzyme defects in the mouse supports this hypothesis. However, the exact mechanisms are unknown. This observation correlates to maternal hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, as observed in pregnancies carrying a long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)-deficient fetus. Synergistic heterozygosity has been shown in isolated patients and in mouse models to be associated with clinical phenotypes common to fatty acid oxidation disorders. Synergistic mutations may also modulate severity of the clinical phenotype and explain in part clinical heterogeneity of fatty acid oxidation defects. In summary, knowledge about the different pathogenetic mechanisms and the resulting pathophysiology allows the development of specific new therapies.

Prevalence and geographical variation of dementia in New Zealand from 2012 to 2015: Brief report utilising routinely collected data within the Integrated Data Infrastructure.

OBJECTIVES: There are no national dementia epidemiological studies using New Zealand (NZ) data. NZ routinely collects health-care data within the Integrated Data Infrastructure (IDI). The study objectives were to 1) investigate late-onset dementia estimates using the IDI between 2012-2015 and compare these with 2) published estimates, and 3) variations between North and South Islands and ethnicity. METHODS: A population-based, retrospective cohort design was applied to routinely collected de-identified health/administrative IDI data. Dementia was defined by ICD-10-AM dementia codes or anti-dementia drugs. RESULTS: Approximately 2% of those aged ≥60 years had dementia, lower than published estimates. Dementia was higher in North Island; in 80- to 89-year-olds; among the Maori population when age-standardised, and 9% of all dementia cases had >1 dementia sub-type. CONCLUSIONS: To our knowledge, this is the first study ascertaining dementia estimates using NZ's whole-of-population IDI data. Estimates were lower than existing NZ estimates, for several reasons. Further work is required, including expanding IDI data sets, to develop future estimates that better reflect NZ's diverse population.

Transgenic expression of n-3 fatty acid desaturase (fat-1) in C57/BL6 mice: Effects on glucose homeostasis and body weight.

The fat-1 gene, derived from Caenorhabditis elegans, encodes for a fatty acid n-3 desaturase. In order to study the potential metabolic benefits of n-3 fatty acids, independent of dietary fatty acids, we developed seven lines of fat-1 transgenic mice (C57/BL6) controlled by the regulatory sequences of the adipocyte protein-2 (aP2) gene for adipocyte-specific expression (AP-lines). We were unable to obtain homozygous fat-1 transgenic offspring from the two highest expressing lines, suggesting that excessive expression of this enzyme may be lethal during gestation. Serum fatty acid analysis of fat-1 transgenic mice (AP-3) fed a high n-6 unsaturated fat (HUSF) diet had an n-6/n-3 fatty acid ratio reduced by 23% (P < 0.025) and the n-3 fatty acid eicosapentaenoic acid (EPA) concentration increased by 61% (P < 0.020). Docosahexaenoic acid (DHA) was increased by 19% (P < 0.015) in white adipose tissue. Male AP-3-fat-1 line of mice had improved glucose tolerance and reduced body weight with no change in insulin sensitivity when challenged with a high-carbohydrate (HC) diet. In contrast, the female AP-3 mice had reduced glucose tolerance and no change in insulin sensitivity or body weight. These findings indicate that male transgenic fat-1 mice have improved glucose tolerance likely due to increased insulin secretion while female fat-1 mice have reduced glucose tolerance compared to wild-type mice. Finally the inability of fat-1 transgenic mice to generate homozygous offspring suggests that prolonged exposure to increased concentrations of n-3 fatty acids may be detrimental to reproduction.

Connecting the dots: obesity, fatty acids and cancer.

Obesity is becoming recognized as a common co-morbidity with several disease states including cancer. There is tremendous interest to more fully understand the mechanistic connections between obesity and cancer. This commentary highlights the report by Byon et al in this issue of Laboratory Investigation. It provides an interpretation of their results in the context of other disease states involving obesity and its sequelae of excess fatty acids and increased plasminogen activator inhibitor-1 (PAI-1) concentrations. This includes obesity-related conditions, in particular metabolic syndrome, and its subphenotypes such as insulin resistance, and increased risk of myocardial infarction. The potential mechanistic tie-ins of obesity, elevated concentrations of fatty acids, as well as elevated PAI-1 levels with cancer and its risk for aggressiveness are discussed.

Cardiac hypertrophy in mice with long-chain acyl-CoA dehydrogenase or very long-chain acyl-CoA dehydrogenase deficiency.

Cardiac hypertrophy is a common finding in human patients with inborn errors of long-chain fatty acid oxidation. Mice with either very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD-/-) or long-chain acyl-coenzyme A dehydrogenase deficiency (LCAD-/-) develop cardiac hypertrophy. Cardiac hypertrophy, initially measured using heart/body weight ratios, was manifested most severely in LCAD-/- male mice. VLCAD-/- mice, as a group, showed a mild increase in normalized cardiac mass (8.8% hypertrophy compared with all wild-type (WT) mice). In contrast, LCAD-/- mice as a group showed more severe cardiac hypertrophy (32.2% increase compared with all WT mice). On the basis of a clear male predilection, we analyzed the role of dietary plant estrogenic compounds commonly found in mouse diets because of soy or alfalfa components providing natural phytoestrogens or isoflavones in cardioprotection of LCAD-/- mice. Male LCAD-/- mice fed an isoflavone-free test diet had more severe cardiac hypertrophy (58.1% hypertrophy compared with WT mice fed the same diet). There were no significant differences in the female groups fed any of the diets. Echocardiography measurement performed on male LCAD-deficient mice fed a standard diet at the age of approximately 3 months confirmed the substantial cardiac hypertrophy in these mice compared with WT controls. Left ventricular (LV) wall thickness of the interventricular septum and posterior wall was remarkably increased in LCAD-/- mice compared with that of WT controls. Accordingly, the calculated LV mass after normalization to body weight was increased by about 40% in the LCAD-/- mice compared with WT mice. In summary, we found that metabolic cardiomyopathy, expressed as hypertrophy, developed in mice because of either VLCAD deficiency or LCAD deficiency; however, LCAD deficiency was the most profound and seemed to be attenuated either by endogenous estrogen (in females) or by phytoestrogens present in the diet as isoflavones (in males).

Relaxin alters cardiac myofilament function through a PKC-dependent pathway.

The pregnancy hormone relaxin (RLX) is a powerful cardiostimulatory peptide. Despite its well-characterized effects on the heart, the intracellular mechanisms responsible for RLX's positive inotropic effects are unknown. Cardiac myofilaments are the central contractile elements of the heart, and changes in the phosphorylation status of myofilament proteins are known to mediate changes in function. The first objective of this study was to determine whether RLX stimulates myofilament activation and alters the phosphorylation of one or more myofilament proteins. RLX works through a variety of intracellular signaling cascades in different tissue types. Protein kinases A (PKA) and C (PKC) are two common molecules implicated in RLX signaling and are known to affect myofilament function. Thus the second objective of this study was to determine whether RLX mediates its myocardial effects through PKA or PKC activation. Murine myocardium was treated with recombinant H2-RLX, and cardiac myofilaments were isolated. RLX increased cardiac myofilament force development at physiological levels of intracellular Ca(2+) without altering myofilament ATP consumption. Myosin binding protein C, troponin T, and troponin I phosphorylation levels were increased with RLX treatment. Immunoblot analysis revealed an increase in myofilament-associated PKC-delta, decreases in PKC-alpha and -beta(II), but no effect on PKC-epsilon. Inhibition of PKC with chelerythrine chloride or PKC-delta with rottlerin prevented the RLX-dependent changes in myofilament function and protein phosphorylation. PKA antagonism with H-89 had no effect on the myofilament effects of RLX. This study is the first to show that RLX-dependent changes in myofilament-associated PKC alters myofilament activation in a manner consistent with its cardiostimulatory effects.

Primary antibody deficiencies: recognition, clinical diagnosis and referral of patients.

The primary antibody deficiency syndromes are a rare group of immunodeficiencies where diagnostic delay remains common due to limited awareness of the existence and heterogeneity of their presenting features. Referral for specialist assessment leads to earlier diagnosis and appropriate therapy to prevent or limit structural organ and tissue damage. Greater education of healthcare professionals is required to ensure prompt recognition and referral to specialists with expertise in the care of primary immunodeficiencies, especially since study of these rare conditions is a minor part of undergraduate and general postgraduate training. Greater awareness would lead to reduced morbidity, improved quality of life and survival outcomes in this patient group.