A gain-of-function mutation of STAT1: A novel genetic factor contributing to chronic mucocutaneous candidiasis

Heterozygous gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) have increasingly been identified as a genetic cause of autosomal-dominant (AD) chronic mucocutaneous candidiasis (CMC). In this article, we describe a 33-year-old man who experienced chronic refractory candidiasis, recurrent otitis media, and pneumonia resulting in bronchiectasis, severe oral and esophageal candidiases with strictures associated with hypothyroidism and immune hemolytic anemia. His son also suffered from persistent candidiasis, chronic diarrhea, poor weight gain, and pneumonia that resulted in his demise because of sepsis. The immunological workup showed that an inverse CD4/CD8 ratio and serum immunoglobulins were all within normal ranges. The laboratory data revealed failure in response to Candida lymphocyte transformation test. In addition, by Sanger sequencing method, we found a heterozygous mutation, Thr385Met (T385M), located in the DNA-binding domain of STAT1, which was previously shown to be GOF. These findings illustrate the broad and variable clinical phenotype of heterozygous STAT1 GOF mutations. However, more clinical information and phenotype–genotype studies are required to define the clinical phenotype caused by AD STAT1 GOF

From variant of uncertain significance to likely pathogenic in two siblings with atypical RAG2 Deficiency: a case report and review of the literature

Abstract Background Severe combined immunodeficiencies (SCIDs) are hereditary disorders characterized by impaired T and B cell function, resulting in significant immune system dysfunction. Recombination-activating gene (RAG) mutations account for a substantial proportion of SCID cases. Here, we present two sibling cases of SCID caused by a novel RAG2 gene mutation. Case Presentation The index case was an 8-year-old boy who had a history of recurring infections. After a comprehensive immunological workup, the initial diagnosis of agammaglobulinemia was revised to combined immunodeficiency (CID). The patient underwent hematopoietic stem cell transplantation (HSCT) but succumbed to cytomegalovirus (CMV) infection. His brother, a 4-month-old boy, presented with CMV chorioretinitis. Leaky SCID was diagnosed based on genetic tests and immunological findings. The patient received appropriate treatment and was considered for HSCT. Both siblings had a homozygous RAG2 gene variant, with the first case classified as a variant of uncertain significance (VUS). The presence of the same mutation in the second brother, and the clinical phenotype, supports considering the mutation as likely pathogenic. Conclusions This case report highlights a novel RAG2 gene mutation associated with CID. The classification of a VUS may evolve with accumulating evidence, and additional studies are warranted to establish its pathogenicity. Proper communication between genetic counselors and immunologists, accurate documentation of patient information, increased public awareness, and precise utilization of genetic techniques are essential for optimal patient management

Cystic fibrosis and congenital adrenal hyperplasia: A rare occurrence with diagnostic dilemmas, similarities and contradictions

Cystic fibrosis (CF) is a hereditary syndrome composed of exocrine gland dysfunction involving multiple systems which if untreated may result in chronic respiratory infections, pancreatic enzyme deficiency and failure to thrive. The association between CF and other inherited diseases or congenital anomalies is rare. We describe a rare case of CF with concomitant congenital adrenal hyperplasia (CAH). 21- Hydroxylase deficiency accounts for most CAH cases. Varity in clinical phenotypes depends on the amount of enzymatic activity which in turn depends on different combination of gene mutations. The genes of CAH and CF are located in different locations. The chance of these diseases coexisting in our patient would be a rare combination. However, such a case will be more frequent in our population than others because of consanguineous marriage and common ancestors. There are diagnostic difficulties, similarities and contradictions between two diseases and they are pointed out

The role of molecular diagnosis in anaphylactic patients with dual or triple-sensitization to Hymenoptera venoms

Abstract Background The poly-sensitization to Hymenoptera venom makes it difficult to select genuine allergens for immunotherapy and increases patients’ costs. The objective of this study was to determine the culprit allergen in dual or triple-sensitized patients to three Hymenoptera venoms through molecular diagnosis and evaluating the results of incorporating the molecular diagnosis with skin tests. Methods Thirty-two patients with anaphylactic reactions and dual or triple-sensitization to Hymenoptera venoms in skin tests entered this study. IgE-sensitization to whole extracts and molecules of Apis mellifera (Api m), Vespula vulgaris (Ves v), and Polistes dominulus (Pol d) was evaluated utilizing ALEX or ImmunoCAP. Results Twenty-nine patients (90.6%) were male. IgE-sensitization to at least one of the allergenic molecules related to Apis mellifera, Vespula vulgaris, and Polistes dominulus was seen in 59.4, 53.1, and 21.9%, respectively. Among 32 patients, 14 (43.8) and 8 (25%), were mono-sensitized to Api m and Ves v components in ALEX, respectively. Double sensitization to Hymenoptera was identified in 18.8% of patients in ALEX. Api m 1+/Api m 2−/Api m 10− and Ves v 1+/Ves v 5+ demonstrated the most prevalent sensitizations patterns in our patients. Conclusions The molecular diagnosis of IgE-sensitization to Hymenoptera venoms can be valuable, especially in patients who show dual or triple-sensitization in skin tests, as the ALEX results revealed mono and double-sensitization to Hymenoptera venoms in 22 and 6 patients, respectively. Regarding the high cost and adverse reactions of venom immunotherapy, especially for two or three venoms, incorporating the molecular diagnosis alongside skin tests for accurate diagnosis of the culprit venom could help decrease costs for patients

Periodic Severe Angioedema without Exogenous Hormone Exposure

Hereditary angioedema (HAE) is characterized by recurrent attacks of skin and mucosal swelling in any part of the body including the digestive and respiratory tract which generally improve spontaneously within 12-72 hours. The underlying mechanism in HAE is related to bradykinin dysregulation which causes these attacks not to respond to common treatment strategies including epinephrine/corticosteroid or adrenaline. There are several types of HAE with different etiology but with the same clinical picture. Type 1 is due to the deficiency of C1 Inhibitor (C1-INH) protein and type 2 is related to dysfunctional C1-INH protein. The third type of HAE which comprises the minority of cases is associated with the normal amount and function of C1-INH protein. The presented case in this report was a 15-years old girl with a history of spontaneous angioedema attacks from the age of 14. The frequency of attacks was initially every two months but consequently increased to every two weeks after using some hormonal medications for ovarian cyst. Each episode has lasted around 10 days without any symptoms in between. Complement studies including C4, C1q, and C1-INH protein, both quantitative and qualitative, were reported as normal. A genetic assessment revealed a mutation in the exon 9 on the gene related to factor XII, hence the diagnosis of HAE type 3 was confirmed. This was a rare type of angioedema with normal amount and function of C1-INH protein which is predominantly seen in women during periods of imbalanced estrogen increments like pregnancy, lactation, and menopause, and hence it is responsive to hormonal manipulation strategies such as the use of progesterone containing medications.

Genetic Analysis of 13 Iranian Families With Leukocyte Adhesion Deficiency Type 1

Background and Aim: Leukocyte adhesion deficiency type 1 is a rare, autosomal recessive disorder that results from mutations in the ITGB2 gene. This gene encodes the CD18 subunit of β2 integrin leukocyte adhesion cell molecules. Leukocyte adhesion deficiency type 1 is characterized by recurrent bacterial infections, impaired wound healing, inadequate pus formation, and delayed separation of the umbilical cord. Materials and Methods: Blood samples were taken from 13 patients after written consent had been obtained. Genomic DNA was extracted, and ITGB2 exons and exon-intron boundaries were amplified by polymerase chain reaction. The products were examined by Sanger sequencing. Results: In this study, 8 different previously reported mutations (intron7+1G>A, c.715G>A, c.1777 C>T, c.843del C, c.1768T>C, c.1821C>A, Intron7+1G>A, c.1885G>A) and 2 novel mutations (c.1821C>A; p.Tyr607Ter and c.1822C>T; p.Gln608Ter) were found. Conclusions: c.1821C>A (p.Tyr607Ter) and c.1822C>T (p.Gln608Ter) mutations should be included in the panel of carrier detection and prenatal diagnosis

Immune endotyping and gene expression profile of patients with chronic rhinosinusitis with nasal polyps in the aspirin-exacerbated respiratory disease (AERD) and the non-AERD subgroups

Abstract Background Chronic Rhinosinusitis (CRS) is a paranasal sinus inflammatory disease and is divided into two subgroups defined as CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays a T helper (Th)2 biased phenotype, and based on sensitivity or tolerance to aspirin or non-steroidal anti-inflammatory drugs (NSAID), is further subdivided into Aspirin-exacerbated respiratory disease (AERD) and non-AERD groups. Considering the challenge of diagnosis and treatment in patients with CRSwNP, particularly the AERD subtype, and the significance of endotyping in these patients, we examined the immune profile and endotyping based on gene expression analysis in the AERD and the non-AERD groups of patients with CRSwNP. Material and method In this study, 21 patients were enrolled and were categorized into AERD (N = 10) and non-AERD (N = 11) groups based on their sensitivity to aspirin. After the special washing period, nasal polyps were biopsied in both groups, and the infiltration of eosinophils, neutrophils, plasma cells, and lymphocytes was compared between the AERD and the non-AERD groups. Also, gene expression levels of transcription factors including Tbet, GATA3, RoRγt, and FoxP3 and inflammatory cytokines including interleukin (IL)1β, IL1RAP (IL1 receptor accessory protein), IL2, IL4, IL5, IL10, IL13, IL17, TNFα, and IFNγ were investigated by quantitative Real-time PCR (qRT-PCR). Statistical analyses were performed using analytical tests including Kolmogorov–Smirnov, Mann-Whitney, and T-test. A P value less than 0.05 was considered statistically significant. Results The mean ± SD age of the studied groups was 37 ± 8.7 years old (21–50) for the AERD, and 40.4 ± 7.7 years old (31–52) for the non-AERD. LMS/EPOS/SNOT scores and pulmonary function tests showed no difference between the two groups. Serum immunoglobulin E (IgE) levels were found to be higher in patients with AERD (p = 0.04), however, the peripheral blood counts of eosinophils were comparable in the two groups. In the histopathologic analysis, the AERD group showed higher percentages of eosinophils (p = 0.04), neutrophils (p = 0.04), and plasma cells (p = 0.04) than the non-AERD group. Additionally, the gene expression levels of GATA3 (p = 0.001), IL4 (p = 0.04), IL5 (p = 0.007), and IL17 (p = 0.03) were significantly higher in the AERD than the non-AERD groups. Conclusion Higher gene expression levels of GATA3, IL4, IL5, and IL17 were observed in the AERD group compared with the non-AERD group. These findings point to distinct patterns of inflammation in patients with AERD, with a predominance of Th2 inflammation

Common Causes of Anaphylaxis in Children

Background Anaphylaxis is an acute, systemic, and potentially fatal allergic reaction. Many things can cause anaphylaxis potentially but some agents are more common like some foods (milk, egg, soy, wheat, peanut, tree nut, shellfish, and fish), insect stings, medications, latex, and food-dependent exercise-induced anaphylaxis. The goal of this study is to show the common causes of anaphylaxis among the children with anaphylaxis history who were referred to the Immunology, Asthma and Allergy Research Institute (IAARI) during a 4-year period (2005-2009).Methods and Materials During those 4 years, we registered all children (<14 years old) with a history of anaphylactic reaction. To prove the cause of anaphylaxis, we performed skin prick tests with suspected agents according to their history and measured specific IgE against them by the ImmunoCAP test. Recognition of common allergens was based on having a positive history for 1 allergen and positive skin prick test or specific IgE for that at the same time, or having positive results from both tests when the allergen was unclear. Idiopathic anaphylaxis was a reaction when any known allergen and positive tests were not obtained.Results One hundred ninety-three nonfatal anaphylactic attacks among 63 children were recognized. In total, the most current cause of anaphylaxis in children was food (89.7%). Milk (49.3%) and wheat (26.1%) were the most common. Other foods were egg (8.7%), nuts (2.8%), and spices (2.8%). Six children (8.7%) were sensitive to multiple food allergens like milk, egg, and wheat. Five (7.1%) of 63 patients had anaphylactic attack because of stinging. Wasp was the trigger in 3 (4.3%) of them and honeybee was the cause in 1 (1.4%). The last one was because of unknown hymenoptera. There were 2 idiopathic cases of all 63 patients.Conclusions Food allergens, especially milk and wheat, are the most common cause of anaphylaxis in children. Because anaphylaxis can be fatal, it is advisable to recognize its causes in different communities to prevent recurrent attacks. Keywords: anaphylaxis, common causes, childre