Funda Erol Cipe

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life‐threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single‐gene inborn errors of IFN‐γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.

Diagnosis of Immediate Hypersensitivity to β-Lactam Antibiotics Can Be Made Safely with Current Approaches

Background: Diagnosing immediate hypersensitivity to β-lactam antibiotics is still a significant problem. Recently, a new penicillin testing reagent was introduced to the market. In this study, the recommendations of the European Network of Drug Allergy (ENDA) for the diagnosis of immediate reactions to β-lactams were followed, and the negative predictive value of this approach with currently available reagents was assessed. Methods: Eighty patients (age range: 6–74 years) with a history of immediate reactions to β-lactams were included. All cases underwent skin testing with benzylpenicilloyl-polylysine (PPL) and minor determinant mixture (MDM), followed by the culprit drug if necessary. If this step was negative, a drug provocation test was offered. If this step also yielded a negative result, then the patients were recommended to use β-lactam antibiotics in future whenever their use was indicated. Results: Overall, 29 patients (36.2%) were diagnosed as β-lactam allergic. The majority of the cases (72.4%) were diagnosed by positive skin tests to either PPL or MDM, whereas 10.3% were diagnosed by skin testing with culprit drugs and 17.2% with drug provocation tests. Regarding the use of the tested drug in the long term, almost half of the contacted patients had had an indication to use the tested drug and the majority had taken the whole course without problems. Conclusions: Although currently available new penicillin tests provide sufficient allergy data, all the steps recommended by ENDA should be followed in the diagnosis of immediate reactions to β-lactams. If these steps are negative, the patients usually tolerate β-lactams and only a few develop mild, non-life-threatening reactions in the long term.

Late onset hemorrhagic cystitis in a hematopoietic stem cell recipient: Treatment with intravesical hyaluronic acid

Çipe Erol F, Soygür T, Doğu F, Erdoğan Ö, Bozdoğan G, İkincioğulları A. Late onset hemorrhagic cystitis in a hematopoietic stem cell recipient: Treatment with intravesical hyaluronic acid.
Pediatr Transplantation 2010: 14:E79–E82.

Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomologous end joining pathways of DNA repair mechanisms have been identified as responsible for radiosensitive SCID. Here, we present a 3-year-old girl patient with severe growth retardation, bird-like face, recurrent perianal abscess, pancytopenia, and polydactyly. Firstly, she was thought as Fanconi anemia and spontaneous DNA breaks were seen on chromosomal analysis. After that DEB test was found to be normal and Fanconi anemia was excluded. Because of that she had low IgG and IgA levels, normal IgM level, and absence of B cells in peripheral blood; she was considered as primary immunodeficiency, Nijmegen breakage syndrome. A mutation in NBS1 gene was not found; then Cernunnos/XLF deficiency was investigated due to clinical similarities with previously reported cases. Homozygous mutation in Cernunnos/XLF gene (NHEJ1) was identified. She is now on regular IVIG prophylaxis and has no new infection. Fully matched donor screening is in progress for bone marrow transplantation which is curative treatment of the disease. In conclusion, the patients with microcephaly, bird-like face, and severe growth retardation should be evaluated for hypogammaglobulinemia and primary immunodeficiency diseases.

ITK Deficiency: How can EBV be Treated Before Lymphoma?

To the Editor: IL-2 inducible T-cell kinase (ITK) deficiency has been identified as an autosomal recessive form of lymphoproliferative disease.[1] Until now, four different mutations have been identified in the ITK gene including missense (c.C1085T);[1] nonsense (c.C1764G;[2] c.C49T (as in our patients);[3]) and frameshift (c.468delT[4,5]) mutations. Here, we present two affected siblings with a homozygous nonsense mutation in the ITK gene.

Are skin prick tests really safe? A case of anaphylaxis caused by skin prick testing with inhalant allergens

Skin prick test (SPT) which is widely used to demonstrate an immediate IgE-mediated allergic reaction is a major diagnostic work-up in the field of allergic diseases. SPT is cheap, easily performed and provides a response within a few minutes. This test is generally considered a very safe procedure. Although the frequency of systemic reactions caused by extracts of inhalant allergens is extremely low, it is slightly increased if food, latex, drug, or hymenoptera venom extracts are used. It is reported that the overall risk of inducing anaphylaxis due to SPT is less than 0.02%. Here, we report an unexpected case of anaphylaxis induced by SPT that was performed with commercial inhalant extracts in an asymptomatic asthmatic boy. A nine-year-old boy admitted to our outpatient clinic of pediatric allergy unit because of chronic cough and recurrent wheezing episodes. The boys had attended the emergency unit of our hospital twice in the previous two months complaining of wheezing and cough symptoms and he was treated with inhaled beta 2 agonists and steroids. His brother also had physician-diagnosed asthma. Physical examination of the case was completely normal. Pulmonary function tests were also in normal limits. As he was symptom free and he had no remarkable finding in the examination, SPT was performed on the same day of admission with commercial extracts (Allergopharma, Rheinbek, Germany) of Dermatophagoides pteronyssinus, Dermatophagoides farinae, grasses, tree pollens, cereals, wild grass pollens, animal danders, molds and a positive (histamine chlorhydrate 1%) and a negative (saline solution) control. The total number of allergens evaluated in this patient was 12. The allergens were applied on the forearms of the patient with the prick-puncture method using single point lancets. Five minutes after the SPT, the patient became pale, urticarial lesions began on his face, cough and respiratory distress started. His pulse rate was 150/min and the blood pressure found as 70/45 mmHg. He was immediately treated with intramuscular epinephrine 1:1000 (0.01 ml/kg), oral cetirizine (0.25 mg/kg), methylprednisolone (1 mg/kg/dose, intramuscular) and inhaled beta 2-agonists. He felt better in 5 min; respiratory distress and hypotension were fully recovered in 15 min. The SPT resulted strongly positive with pseudopodia for house dust mites, with whealing and erythema greater than the histamine reaction sizes of erythema/whealing: histamine 20/8, D. pteronyssinus, 25/12, D. farinae 25/15 mm). Laboratory investigations were performed one day after the anaphylaxis. Total IgE level was 310 kU/L, specific IgE levels (CAP System; Pharmacia, Uppsala, Sweden) were positive for D. pteronyssinus (90 kU/L, class 5) and D. farinae (92 kU/L, class 5). Skin tests are considered a safe diagnostic procedure. Recent surveys suggest that the overall risk of inducing anaphylactic reactions by SPT is less than 0.02%. Systemic reactions and fatalities have been reported mainly in association with intradermal testing. Based on the literature, the risk of fatality due to SPT is extremely remote, and severe/anaphylactic reactions are rare. In a large epidemiologic survey, Turkeltaub and Gergen found no anaphylactic reactions after SPT. Anaphylaxis during skin tests with inhalant allergens has been published very rarely. Lin et al. reported two cases of non-fatal systemic reaction induced by intradermal skin testing, and three reactions after SPT were described by Valyasevi et al. with inhalant allergens. Vanin et al. also reported an eight-year-old asthmatic boy who developed an anaphylactic reaction after SPT performed with commercial extracts like in our case. We present a child who developed an anaphylactic reaction after SPT with commercial inhalant extracts in this article. The clinical diagnosis based on signs and symptoms such as respiratory symptoms and hypotension occurred 5 min after the SPT. Vasovagal reaction was not considered in this patient because he had urticaria and respiratory distress which are not expected findings in vasovagal reaction. In addition, all of the symptoms improved in a short time with anaphylaxis treatment. Although SPT are generally accepted as very safe procedures, it should be known that these tests have a potential risk of anaphylaxis even in asymptomatic pediatric patients as reported in this case. Physicians should be aware of this potential danger and they should always avoid performing these tests if they do not have the necessary emergency equipment and medications available.

HLA-haploidentical transplantations for primary immunodeficiencies: a single-center experience.

Cipe FE, Dogu F, Aytekin C, Yuksek M, Kendirli T, Yildiran A, Bozdogan G, Karatas D, Reisli I, Dalva K, Arpacı F, Ikinciogullari A. HLA‐haploidentical transplantations for primary immunodeficiencies: A single‐center experience.

HAX-1 deficiency: Characteristics of five cases including an asymptomatic patient.

BACKGROUND Mutations in the HAX-1 gene cause an autosomal recessive form of severe congenital neutropenia (SCN), which particularly manifests with recurrent skin, lung and deep tissue infections from the first few months of life. OBJECTIVE We retrospectively evaluated the clinical and laboratory findings of the patients diagnosed with SCN carrying HAX1 gene mutations. METHODS A total of five patients with SCN, carrying a HAX1 gene mutation, were evaluated in terms of clinical and laboratory findings. Mutation analysis of the candidate genes (HAX1, ELANE and CSF3R) was performed. RESULTS All of the patients lived in Turkey; four of them were of Kurdish origin and one was Turkish. Of the five patients, three were girls and two were boys, and the mean age of the patients was 8.8 years old (range 4-15 years). The mean age of diagnosis was 25.8 months (range 2 months-5 years). The infections diagnosed included recurrent gingivitis, stomatitis, and skin and soft tissue abscesses. Developmental retardation and epilepsy were present in only one patient, whereas speech retardation was present in two. All of our patients had a HAX1 mutation, and are still alive and none of them has shown malignant transformation yet. CONCLUSION Complete blood count should be performed and absolute neutrophil count should be evaluated in patients with recurrent severe infections. In the event that neutropenia is detected, they should be investigated in terms of SCN and mutation analysis should be performed.

PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects

Background: V(D)J recombination ensures the diversity of the adaptive immune system. Although its complete defect causes severe combined immunodeficiency (ie, T−B− severe combined immunodeficiency), its suboptimal activity is associated with a broad spectrum of immune manifestations, such as late‐onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, particularly when it involves a myeloablative conditioning regimen for hematopoietic stem cell transplantation. Objective: We aimed at developing biomarkers based on analysis of the T‐cell receptor (TCR) &agr; repertoire to assist in the diagnosis of patients with primary immunodeficiencies with V(D)J recombination and DNA repair deficiencies. Methods: We used flow cytometric (fluorescence‐activated cell sorting) analysis to quantify TCR‐V&agr;7.2–expressing T lymphocytes in peripheral blood and developed PROMIDIS&agr;, a multiplex RT‐PCR/next‐generation sequencing assay, to evaluate a subset of the TCR&agr; repertoire in T lymphocytes. Results: The combined fluorescence‐activated cell sorting and PROMIDIS&agr; analyses revealed specific signatures in patients with V(D)J recombination–defective primary immunodeficiencies or ataxia telangiectasia/Nijmegen breakage syndromes. Conclusion: Analysis of the TCR&agr; repertoire is particularly appropriate in a prospective way to identify patients with partial immune defects caused by suboptimal V(D)J recombination activity, a DNA repair defect, or both. It also constitutes a valuable tool for the retrospective in vivo functional validation of variants identified through exome or panel sequencing. Its broader implementation might be of interest to assist early diagnosis of patients presenting with hypomorphic DNA repair defects inclined to experience acute toxicity during prehematopoietic stem cell transplantation conditioning.

Novel Mutation in CECR1 Leads to Deficiency of ADA2 with Associated Neutropenia

PurposeAdenosine deaminase 2 (ADA2) have been reported to cause vasculitic diseases and immunodeficiency recently. Patients present with stroke episodes and rashes mimicking polyarteritis nodosa (PAN). We report a patient who has been followed up with severe neutropenia and found an unexpectedly revealed novel mutation in CECR1 affecting ADA2.MethodsWe reviewed medical records and clinical history of the patient. No mutations in other known neutropenia genes such as ELA, G6PC3, HAX1, AP3B1, LAMTOR2, VPS13B, VPS45, GFI1, JAGN1, or WAS could be detected. Sanger sequencing was used to confirm the genetic variants in the patient and relatives.ResultsGenetic analysis by exome sequencing revealed a novel mutation in the gene CECR1 (c.G962A; p.G321E) which segregated perfectly in the relatives.ConclusionThis is the first DADA2 patient presenting with severe neutropenia. We suggest that in patients with unexplained cytopenias combined with immunodeficiency, fevers of unknown origin and high inflammation markers, DADA2 should be considered.