CD3G gene defects in familial autoimmune thyroiditis.

The patients with CD3γ deficiency can present with different clinical findings despite having the same homozygous mutation. We report three new CD3gamma-deficient siblings from a consanguineous family with a combined T-B+NK+ immunodeficiency and their variable clinical and cellular phenotypes despite the same homozygous mutation of the CD3G gene (c.80-1G>C). We also re-evaluate a previously reported non-consanguineous family with two CD3gamma-deficient siblings with the same mutation. The median age at diagnosis was 11 years (14 months-20 years). We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE (n = 2) and atopic eczema (n = 2). While CD3(+) TCRαß+T cell percentages were low in all patients, only one had lymphopenia and 3 had CD3(+) T cell lymphopenia. Strikingly, we report frequent and multiple autoimmunity in tested heterozygous carriers in both families (n = 6; in 67%), and frequent autoimmunity in family members not available for testing (n = 5, in 80%). The results suggest that CD3G should be studied as a candidate gene for autoimmunity and that CD3gamma deficiency should be considered among other primary immunodeficiencies with predominantly autoimmune manifestations.

Could immune cells be associated with nephropathy in Fabry disease patients?

BACKGROUND: In Fabry Disease (FD), although the primary factor initiating kidney damage is glycosphingolipid accumulation, secondary conditions such as increased inflammation and fibrosis may cause this damage to progress. These processes may be induced by immune cells. Therefore, we aimed to investigate the peripheral lymphocyte subgroup analysis of the patients with FD and compare these results with healthy individuals. In addition, we performed T, B, NK, and plasma cell analyses in kidney biopsy materials and compared these kidney biopsy results with the biopsy results of patients whose kidney functions were impaired after 4 years of regular ERT. MATERIALS AND METHODS: 18 FD and 16 healthy individuals were included in the study. T-B lymphocyte and NK-cell populations were determined. We performed kidney biopsies (KBx) on 13 patients with FD prior to ERT. Of these, 4 patients had rebiopsy after 4 years of regular ERT. Immunohistochemical staining was performed to define immune cell infiltration. RESULTS: There was no statistically significant difference in terms of total, helper and cytotoxic T-lymphocyte and CD3-CD16+CD56+ natural killer (NK)-cell count (p = 0.20; p = 0.12; p = 0.76; p = 0.75, respectively).According to KBx findings prior to ERT, all patients had interstitial fibrosis (IF), podocyte vacuoles (PV), and podocyte inclusion (PI), CD3, CD4, CD8, CD16, and CD56 positivity at different levels. None of the patients had CD19, CD20, and CD138 positivity at the first biopsies. When we compared the first and the second KBx results of the two progressors, we also demonstrated that CD3+4+T-cells infiltration remained the same, whereas CD8+T cells, CD16+ and 56+NK-cells infiltration were significantly decreased. In contrast, CD20+B cells and CD138+plasma cell infiltration were significantly increased despite 4 years of ERT (15 fold and sixfold, respectively). The CD20+B and CD138+ plasma cells and IF were positively correlated with proteinuria. CONCLUSIONS: The progression of FD nephropathy and proteinuria is increased despite a long-term ERT. Immune cells, primarily B and plasma cells, might cause these unwanted consequences.

Type III bare lymphocyte syndrome associated with a novel RFXAP mutation: a case report.

Type III bare lymphocyte syndrome (BLS) is a severe combined immunodeficiency disease caused by the absence of MHC Class II expression associated with low expression of class I molecules. Here, we report a case with type III BLS who lacked RFXAP (Regulatory factor X-associated protein) expression as a result from a novel mutation introducing a premature stopcodon in DE-region at amino acid 73.

Anaphylaxis in Turkish children: a multi-centre, retrospective, case study.

BACKGROUND: Anaphylaxis is a serious and potentially lethal systemic reaction affecting more than one organ or system. OBJECTIVE: We aimed to describe the demographic characteristics, clinical features, causes, settings, and administered therapy in Turkish children. METHODS: This retrospective, case note study included all children referred to the outpatient clinics of the Pediatric Allergy Departments of the participating study centres from 1 July 1999 to 30 June 2009 for investigation of anaphylaxis or who were seen by us at the moment of the reaction during the same period and who met the clinical criteria of anaphylaxis. RESULTS: Two hundred and twenty-four cases of anaphylaxis were reported in 137 children (88 boys, P = 0.0001). The mean ± SD age at the referral was 7.7 ± 4.2 years (range: 4 months-17 years). Ninety-eight episodes (43.8%) occurred at home. The symptoms were cutaneous in 222 (99.1%) episodes, respiratory in 217 (96.9%), neuro-psychiatric in 118 (52.7%), cardiovascular in 92 (41.1%), and gastrointestinal in 88 (39.3%). Biphasic reaction was reported in seven episodes (3.1%, 95% CI: 1.5-6.3). Death occurred in one case (0.4%, 95% CI: 0.08-2.4). Treatment was available in 158 episodes (70.5%). Of them, 148 (93.7%) received antihistamines, 132 (83.5%) corticosteroids, 51 (32.3%) epinephrine, and 17 (10.8%) beta-2-mimetics. The causative agents were foods in 86 (38.4%) episodes, hymenoptera venom in 84 (37.5%), drugs and medications in 47 (21.0%), and latex in 5 (2.2%). In two episodes (0.9%), the causative agent was unidentified. Allergy to the trigger was known prior to anaphylaxis in 116 (51.8%) episodes. An epinephrine auto-injector had been prescribed for 70 children (51.1%). CONCLUSIONS AND CLINICAL RELEVANCE: Anaphylaxis was seen significantly more in boys. Most of the reactions occurred at home. Foods were the most frequent cause. Epinephrine, the first-line treatment of anaphylaxis, was administered in only a third of the children.

Influence of education on primary care physicians' knowledge on childhood allergy as a systemic disease and the atopic march.

BACKGROUND: There are many educational events for physicians in different countries covering one or some of the allergic diseases. Most of these educational events have been reported to improve care by the physicians. The aim of this study was to determine the baseline knowledge of general practitioners (GP) regarding the systemic nature of childhood allergy and atopic march, and to assess the influence of an educational event on this baseline knowledge. METHODS: Two hundred and two GPs from five different cities in Turkey who attended education seminars were enrolled. All GPs were received the questionnaire both before and after the seminar. The questionnaire had statements about the systemic nature of childhood allergies and the atopic march, and GPs were asked to mark their degree of agreement as (completely true, partially true, wrong). RESULTS: Mean age of GPs was 38.6±6.0 years. Mean duration after graduation from medical faculty was 13.9±6.5 years. There was significant improvement in answers after education. The statement "Frequency of allergic rhinitis and asthma is not as high as expected in children with atopic dermatitis" was regarded "wrong" by 60.9% but increased to 94.3% after the education (p<0.001). Systemic nature of allergy was approved by 72.8%, which increased to 99% after the education (p<0.001). Adrenalin as first line treatment in anaphylaxis treatment was appreciated by a higher number of GPs with the education (p<0.001). CONCLUSION: Many GPs lack updated information about the systemic nature of paediatric allergic diseases and a single educational event may improve their knowledge significantly.

B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele.

Homozygous CD19 mutations lead to an antibody deficiency due to disruption of the CD19 complex and consequent impaired signaling by the B-cell antigen receptor. We studied the effects of heterozygous CD19 mutations on peripheral B-cell development and antibody responses in a large family with multiple consanguineous marriages. Sequence analysis of 96 family members revealed 30 carriers of the CD19 mutation. Lymphocyte subset counts were not significantly different between carriers and noncarriers in three different age groups (0-10 years; 11-18 years; adults). B cells of carriers had reduced CD19 and CD21 median expression levels, and had reduced proportions of transitional (0-10 years) and CD5(+) B cells (adults). CD19 carriers did not show clinical signs of immunodeficiency; they were well capable to produce normal serum Ig levels and had normal responses to primary and booster vaccinations. The frequency of mutated Vκ alleles was not affected. Heterozygous loss of CD19 causes some changes in the naive B-cell compartment, but overall in vivo B-cell maturation or humoral immunity is not affected. Many antibody deficiencies are not monogenetic, but likely caused by a combination of multiple genetic variations. Therefore, functional analyses of immune cell function should be carried out to show whether heterozygous mutations contribute to disease.

Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).

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.

Down syndrome associated with severe combined immunodeficiency: a case report.

An 8-month-old boy was admitted to the hospital because of recurrent bronchopneumonia and gastrointestinal tract infections. On physical examination, he had hypotonia, mental retardation, microcephaly with flat facies, low nasal bridge, small nose, small ears. Laboratory evaluation revealed Down syndrome, lymphopenia, hypogammaglobulinemia, reduced proportions of the peripheral blood lymphocytes with an inverted CD4/CD8 ratio and markedly reduced mitogen response of the lymphocytes. We report here unique case of Down syndrome associated with severe combined immunodeficiency.

An intensive approach to the treatment of disseminated BCG infection in a SCID patient.

There is an appreciable mortality associated with BMT in patients with SCID and advanced BCG infection. We present a girl with T-B+ SCID complicated by spina ventosa and disseminated BCG osteitis after receiving a fully matched sibling marrow transplant. Considerable progression characterised by two clinical activations and multiple pleural and perivertebral abscess formations occurred with conventional anti-mycobacterial chemotherapy. She finally recovered with full immune reconstitution after BMT and intensive treatment comprising five conventional and alternative agents that she received for 36 months. No side-effects and/or complications have been seen other than hearing loss.

Granulocyte-macrophage colony stimulating factor (rh-GM-CSF) in the treatment of chemotherapy-induced neutropenia.

Neutropenic pediatric patients with solid tumors and malignant lymphomas were treated with recombinant granulocyte-macrophage colony stimulating factor (rh-GM-CSF). Eleven patients, including seven lympho-reticular malignancies, two Ewing's sarcoma and one patient in each group with the diagnosis of nasopharyngeal rhabdomyosarcoma, malignant mesenchymal tumor, entered the study. Six were females and five were males, the mean age was 10.4 yr, the range was 4 to 21 years. rh-GM-CSF was given at the dose of 5 micrograms/kg s.c. daily, starting either on the day following the last day of cytotoxic chemotherapy or when ANC < 1000/ml was determined. All patients received rh-GM-CSF for a total of seven days. Hematopoietic recovery occurred in all children except one. The response to rh-GM-CSF was achieved in a mean time of 7.4 days. Tolerance to rh-GM-CSF treatment was good. Adverse events were documented as fever, nausea, vomiting, fatigue, chills and itching. Sagittal sinus thrombosis developed in one patient 5 days following the completion of chemotherapy and rh-GM-CSF cycle. In conclusion, rh-GM-CSF can be applied during the intensive chemotherapy schedules of pediatric cancer patients.

A case of osteopetrosis with pelvic ectopic spleen: an unusual association.

A three-month-old girl was admitted to the hospital with a history of pallor. On physical examination, the liver was enlarged and a solid mass was palpated in the left abdomen. Laboratory evaluation revealed anemia and thrombocytopenia. Bone marrow was hypocellular with reduced number of megakaryocytes. Radiographic findings and scintigraphic study of the long bones were consistant with osteopetrosis. In the imaging studies, including ultrasonography, computerized tomography, magnetic resonance imaging and scintigraphic study, an ectopic spleen expanded into the bony pelvis was observed. We report here unique case of infantile osteopetrosis associated with pelvic ectopic spleen.

Vernal keratoconjunctivitis--a rare but serious comorbidity of allergic rhinitis and eustachian tube dysfunction.

OBJECTIVE: To determine the prevalence of symptoms and signs of allergic rhinitis (AR) in children with vernal keratoconjunctivitis (VKC) and evaluate eustachian tube (ET) function using tympanometry. METHODS: The patients underwent an otolaryngological examination and symptoms of rhinorrhoea, nasal obstruction, nasal itching and sneezing were evaluated for the diagnosis of AR. Tympanometry was performed by a middle ear analyzer (Impedance audiometer AZ 26, Interacoustics A/S, Assens, Denmark). Blood samples were collected for determination of peripheral blood eosinophil count (PBEC) and serum total immunoglobulin E (IgE). Allergen sensitivity was also determined by skin prick test. RESULTS: The study included 26 males (96.3%) and 1 female (3.7%) with a mean age of 12.1+/-4.4 years. Eight out of 27 subjects (29.6%) had blood eosinophilia and 11 out of 27 subjects had elevated serum IgE (40.7%). A positive skin prick test was identified for at least one allergen in 40% of patients (10/25 subjects). Symptoms and signs of AR were found in 10 subjects (37%). Median serum IgE level in subjects with AR (262.5 kU/L) was higher than without AR (40.2 kU/L) (p=0.08), whereas there were no differences in PBEC or eosinophilia percentage (p>0.05). Mean middle ear pressures in the right and left ears were -66.4 daPa (range between -268 and 4 daPa) and -57.3 daPa (range between -308 and 0daPa), respectively. The tympanometry results were abnormal in 5 subjects (18.5%) (3 type C and 2 type B tympanogram). Three out of 10 VKC patients with AR (30%) and 2 out of 17 VKC patients without AR (11.8%) had abnormal tympanograms (p=0.33). CONCLUSION: AR is commonly associated with VKC and subjects with AR are almost three times more likely to have ET dysfunction than those without. Therefore, opthalmologists should refer VKC patients to otolaryngologists to delineate associated AR and ET dysfunction. Conversely, patients with OME and/or AR who have persistent allergic eye symptoms may well benefit from opthalmologic evaluation for seasonal allergic conjunctivitis and VKC.

Acute rheumatic fever in Konya, Turkey.

BACKGROUND: Patients with acute rheumatic fever (ARF), who were admitted to Pediatric Cardiology Unit of Selçuk University Faculty of Medicine from July 1993 to 1998, were studied retrospectively to verify the clinical profile of the disease and to compare the results with those from other countries. METHODS: All patients were examined by one of the two pediatric cardiologists in our study group. Every patient had a chest X-ray, electrocardiogram and an echocardiographic investigation. Throat culture, antistreptolysin O test, C-reactive protein and sedimentation rates were investigated for each patient. RESULTS: During the study period, 274 cases with ARF were identified among patients admitted to the present institution. There were 8032 visits during the study period, giving an occurrence rate of 3.4%. Arthritis was the most common major manifestation (81.4%). It was followed by carditis (60.9%) and chorea (17.9%). Subcutaneous nodules (0.7%) and erythema marginatum (0.4%) were both seen in patients with carditis. The mitral valve was the most commonly affected valve (95.8%), followed by the aortic valve (40.1%). Two patients died and regurgitation disappeared in 21% of patients with mitral regurgitation. Fifteen patients (14%) with isolated arthritis and pure chorea had mitral regurgitation demonstrated by echocardiographic investigation but without any significant murmur. CONCLUSION: The present study indicates that ARF is still a significant problem in Konya and that recurrences can be prevented by administering a 3-week benzathine penicillin G regimen.