Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes.

The mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover 2 novel human genetic defects in signal recognition particle receptor alpha (SRPRA) and SRP19, constituents of the mammalian cotranslational targeting machinery, and characterize their roles in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the SRP genes, HAX1, and ELANE, and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP deficiency on neutrophil granulocyte development. In a heterologous cell-based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking, and homeostasis are critically important for the differentiation of neutrophil granulocytes.

Determining reference ranges for lymphocyte proliferation responses to phytohemagglutinin and Bacillus Calmette-Guérin in Iranian children.

PURPOSE: To establish reference ranges (RRs) for stimulation index of T cell proliferation triggered by phytohemagglutinin (PHA-SI) and Bacillus Calmette-Guérin (BCG-SI). METHODS: This study investigated data from 359 healthy children and 35 patients with cellular immunodeficiency as positive controls (2010-2021). We applied a colorimetric-based method (BrdU) to measure proliferation and determine the RRs at the 2.5th and 97.5th percentiles (95% confidence intervals). A cross-validation approach was performed. RESULTS: In healthy controls, the RRs for PHA-SI and BCG-SI ranged between 3 and 5.2 and 2.52 to 5.2, respectively. PHA-SI and BCG-SI were in Severe Combined Immunodeficiency (SCID) patients from 1.2 to 2.5 and 0 to 2, while in Mendelian susceptibility to mycobacterial diseases (MSMD) patients, 2.53 to 4.5 and 0.74 to 2.2, respectively. The thresholds' accuracy was checked for testing reference intervals with diagnostic effects. CONCLUSION: This study establishes PHA-SI and BCG-SI reference ranges to aid in diagnosing and treating congenital immunodeficiency diseases.

Clinical, immunological and molecular findings of 8 patients with typical and atypical severe combined immunodeficiency: identification of 7 novel mutations by whole exome sequencing.

Severe combined immunodeficiency (SCID) is one of the severe inborn errors of the immune system associated with life-threatening infections. Variations in SCID phenotypes, especially atypical SCID, may cause a significant delay in diagnosis. Therefore, SCID patients need to receive an early diagnosis. Here, we describe the clinical manifestations and genetic results of four SCID and atypical SCID patients. All patients (4 males and 4 females) in early infancy presented with SCID phenotypes within 6 months of birth. The mutations include RAG2 (p.I273T,p.G44X), IL7R (p.F361WfsTer17), ADA (c.780+1G>A), JAK3 (p.Q228Ter), LIG4 (p.G428R), and LAT (p.Y207fsTer33), as well as a previously reported missense mutation in RAG1 (p.A444V). The second report of LAT deficiency in SCID patients is presented in this study. Moreover, all variants were confirmed in patients and their parents as a heterozygous state by Sanger sequencing. The results of our study expand the clinical and molecular spectrum associated with SCID and leaky SCID phenotypes and provide valuable information for the clinical management of the patients.

Molecular findings and clinical manifestations of 18 Iranian children with Griscelli syndrome type 2: Two novel homozygote mutations in RAB27A gene in a patient.

Griscelli syndrome type 2 (GS2) is an autosomal recessive immunodeficiency characterized by hair hypopigmentation, recurrent fever, hepatosplenomegaly and pancytopenia. This study aims to find new genetic changes and clinical features in 18 children with GS2 caused by the RAB27A gene defect. In all, 18 Iranian children with GS2 who presented with silver grey hair and frequent pyogenic infection were included in this study. After recording demographic and clinical data, PCR sequencing of the RAB27A gene was performed for all exons and exon-intron boundaries. Two patients in this study were subjected to whole-exome sequencing followed by Sanger sequencing. Light microscopy study of hair showed large irregular clumps of pigment with the absence of giant granules on the blood smear. Mutation analysis of the RAB27A gene identified two novel missense mutations as homozygous in a patient, one in exon 2, c.140G>C and another in exon 4, c.328G>T. In addition, for 17 other patients, 6 reported mutations were obtained including c.514_518delCAAGC, c.150_151delAGinsC, c.400_401delAA, c.340delA, c.428T>C and c.221A>G. The mutation c.514_518delCAAGC was the most frequent and found in 10 patients; this mutation may be considered a hotspot in Iran. Early diagnosis and treatment of RAB27A deficiency can contribute to better disease outcomes. In affected families, genetic results could be urgently needed to make a timely decision about haematopoietic stem cell transplantation and prenatal diagnosis.

Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.

BACKGROUND: In order to support the comprehensive classification of Leukocyte Adhesion Deficiency-I (LAD-I) severity by simultaneous screening of CD11a/CD18, this study assessed clinical, laboratory, and genetic findings along with outcomes of 69 LAD-I patients during the last 15 years. METHODS: Sixty-nine patients (40 females and 29 males) with a clinical phenotype suspected of LAD-I were referred to Immunology, Asthma, and Allergy research institute, Tehran, Iran between 2007 and 2022 for further advanced immunological screening and genetic evaluations as well as treatment, were enrolled in this study. RESULTS: The diagnosis median age of the patients was 6 months. Delayed umbilical cord separation was found in 25 patients (36.2%). The median diagnostic delay time was 4 months (min-max: 0-82 months). Forty-six patients (66.7%) were categorized as severe (CD18 and/or CD11a: below 2%); while 23 children (33.3%) were in moderate category (CD18 and/or CD11a: 2%-30%). During the follow-ups, 55.1% of children were alive with a mortality rate of 44.9%. Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints. Genetic analysis of the patients revealed 14 previously reported and three novel pathogenic mutations in the ITGB2 gene. The overall survival of patients with and without hematopoietic stem cell transplantation was 79.3% and 55.6%, respectively. CONCLUSION: Physicians' awareness of LAD-I considering delayed separation of umbilical cord marked neutrophilic leukocytosis, and variability in CD11 and CD18 expression levels, and genetic analysis leads to early diagnosis and defining disease severity. Moreover, the prenatal diagnosis would benefit families with a history of LAD-I.

Molecular profile of specific IgE to allergenic components in allergic adults using allergen nano-bead array.

BACKGROUND: An increasing interest in the field of molecular diagnosis of allergy has been developed in recent years and it goes to be as the routine in vitro protocol in allergy diagnosis. friendly allergen nano-bead array (FABER) is a new multiplex assay for the evaluation of specific IgE against 244 allergens including whole extracts and allergenic molecules. The research intended to assess the pattern of IgE sensitization to allergenic components of allergens in allergic adults using FABER 244. METHODS: Sixty patients with allergic diseases entered this cross-sectional study. Specific IgE to 122 whole allergens extracts and 122 allergenic components were assessed using an allergen nano-bead array (FABER) for all patients. This test includes inhalant and food allergens. RESULTS: Thirty-seven patients were male (61.7%). The mean (SD) age of patients was 30.73(±6.87) years. As the allergen nano-bead array results showed, Lolium perenne (63.3%), Phleum pratense (60%) and Platanus acerifolia (51.7%) were considered as the most common IgE sensitizations to the aeroallergen extracts. Moreover, Lol p 1, Phl p 1.0102 and Cup a 1 were found as the most frequent allergenic components in our allergic patients. Among protein families, CCD-bearing proteins, expansin, cysteine protease and profilin families illustrated the highest allergic sensitization. CONCLUSIONS: The results of the present study demonstrated that despite the higher prevalence of sensitization to Salsola kali (47.2%) using extract-based assays in the previous phase of this research, allergenic components of grasses (Lol p 1, Phl p 1.0102), Cup a 1 as well as Sal k1 as the major components of Cupressuss arizonica and Salsola kali showed the higher sensitization, respectively, in adults' allergic patients using FABER test.

A fludarabine and melphalan reduced-intensity conditioning regimen for HSCT in fifteen chronic granulomatous disease patients and a literature review.

Chronic granulomatous disease (CGD) is a life-threatening immunodeficiency condition. To date, hematopoietic stem cell transplantation (HSCT) is the only curative modality. We prospectively studied the outcomes of fifteen CGD patients undergoing HSCT with fludarabine and melphalan plus anti-thymocyte globulin (ATG). Most of the donors were fully matched siblings (n = 12). Cyclosporine A and methylprednisolone were used for graft-versus-host disease (GVHD) prophylaxis. CGD diagnosis had been suspected upon clinical symptoms and was confirmed in all patients by an abnormal neutrophil functional assay. The three-year overall survival (OS) and event-free survival (EFS) rates were 73.3% and 46.7%, respectively. With the median follow-up time of 33.12 months, the mean OS and EFS were 42.6 and 26.8 months; respectively. Eleven patients (73.33%) achieved full donor chimerism. Two stable mixed chimerisms with no sign of the underlying disease (13.33%) and two secondary graft failure (13.33%) occurred as well. The cumulative incidence of transplant-related mortality was 23.1% and it was two times more in adults compared with children. Three years GVHD-FS (free survival) was 57.8% in all patients and it was 70% and 42.9% in children and adults, respectively. Our results indicate that fludarabine, melphalan, and ATG have relatively favorable outcomes in CGD patients. Also, we suggest that HSCT should be performed as soon as a suitably matched donor is found.

Genetic Study of Hereditary Angioedema Type I and Type II (First Report from Iranian Patients: Describing Three New Mutations).

BACKGROUND: Hereditary Angioedema (HAE) is a rare autosomal dominant immunodeficiency disease with mutation in C1 inhibitor gene (SERPING1) which deficient and dysfunction of C1-INH protein result in HAE type I or type II, respectively. The present study aimed to define the genetic spectrum of HAE type I and type II among Iranian patients. METHODS: Thirty-four patients with clinical phenotype of recurrent edematous attacks in face, upper and lower limbs, hands, and upper airway entered the study. Mutations in SERPING1 were analyzed using PCR and Sanger Sequencing. In addition, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to discover large deletions or duplications in negative screening samples by Sanger. RESULTS: Twenty-three patients were diagnosed with HAE type I and 11 with HAE type II. Fourteen distinctive pathogenic variations including five frameshift (p.G217Vfs*, p.V454Gfs*18, p.S422Lfs*9, p.S36Ffs*21, p.L243Cfs*9), seven missense (p.A2V, p.G493R, p.V147E, p.G143R, p.L481P, p.P399H, p.R466C), one nonsense (p.R494*), and one splicing defect (C.51 + 2 T˃C), which three of these mutations were identified novel. However, no mutation was found in seven patients by Sanger sequencing and MLPA. CONCLUSION: Final diagnosis with mutation analysis of HAE after clinical evaluation and assessment of C1INH level and function can prevent potential risks and life-threatening manifestations of the disorder. In addition, genetic diagnosis can play a significant role in facilitating early diagnosis, pre-symptomatic diagnosis, early diagnosis of children, asymptomatic cases, and those patients who have the borderline biochemical results of C1-INH deficiency and/or C4.

Immunological effects of convalescent plasma therapy for coronavirus: a scoping review.

BACKGROUND: Preliminary studies revealed the safety and effectiveness of convalescent plasma (CP) therapy for patients with coronavirus. In this study, we aimed to evaluate and summarize the available evidence on CP therapy, identify the research gap regarding the immunological response to CP therapy and pave the road for future studies. METHODS: This study was conducted according to the Hilary Arksey and Lisa O'Malley framework. To find out the relevant studies, we searched PubMed, Scopus and Embase databases up to 30th May 2021. Data have been extracted according to three categories: (1) patients' characteristics, (2) clinical and immunological responses to CP therapy and (3) pre-infusion screening of the CP samples. RESULTS: A total of 12,553 articles were identified. One hundred fifty-four studies met the inclusion criteria for full-text review. More than half of the included studies (112 studies, (75.6%)) concluded satisfactory outcomes and or safety of CP infusion in patients. Results of studies showed the efficacy of CP therapy in clinical improvement (101 studies), decreasing in the level of inflammatory factors (62 studies), elimination or decreasing in viral load (60 studies), and induction or increase in antibody response (37 studies). Despite these promising results, the results of the 49 studies revealed that CP therapy was ineffective in the survival of patients, clinical improvement, viral infection elimination or decrease in the inflammatory factor levels. Furthermore, the adaptive immune response was evaluated in 3 studies. Information related to the pre-infusion screening for human leukocyte antigen/human neutrophil antigen (HLA/HNA) antibodies was not reported in most of the studies. Our gap analysis revealed that the influence of the CP infusion on the adaptive immune and inflammatory responses in patients with coronavirus needs further investigation. CONCLUSIONS: Based on the results of most included studies, CP infusion was safe and resulted in clinical improvement of patients and decreasing the viral load. The effect of the CP infusion on adaptive immune response and inflammatory cytokines in patients with coronavirus needs further investigation.

The most common allergens according to skin prick test: The role of wheal diameter in clinical relevancy.

The skin prick test (SPT) could be applied as a useful in vivo method for the detection of sensitization in epidemiological and diagnostic studies if the wheal size is ideally evaluated. We focused on SPT wheal size to identify sensitization pattern to common inhalant and food allergens. In this cross-sectional study, SPT results were obtained from a total of 972 allergic patients. Common allergen extracts for SPT were selected according to the type of allergic diseases, and the geographical pattern. SPT with food allergens was performed for patients with atopic dermatitis (AD) and chronic urticaria (CU). A total of 461 male (47.4%) and 511 female (52.6%) participated in this study (median age: 31 years). The majority of individuals were affected with allergic rhinitis (AR) (n = 624) and asthma (n = 224); while 129 and 67 patients suffered from AD and CU, respectively. The most common aeroallergens were Russian thistle (52.1%) and lamb's quarter (50.7%) with the largest wheal diameter. The wheal size of lamb's quarter was significantly different between patients with asthma and AR (P<.001). In addition, a significant difference was detected in wheal diameter in response to the Russian thistle between patients with AR and AD (P = .001). Shrimp (23.6%) and Peanut (22.5%) caused the most common food sensitization in patients with AD and CU. Having in mind the most common weed pollens including the Russian thistle and lamb's quarter, preventive strategies, such as, removing unwanted weeds or preventing them from growing, avoidance, and specific immunotherapy may be crucial for better disease control.

Molecular, Immunological, and Clinical Features of 16 Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease.

PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, triggered by non-tuberculous mycobacteria or Bacillus Calmette-Guérin (BCG) vaccines and characterized by severe diseases. All known genetic etiologies are inborn errors of IFN-γ-mediated immunity. Here, we report the molecular, cellular, and clinical features of patients from 15 Iranian families with disseminated disease without vaccination (2 patients) or following live BCG vaccination (14 patients). METHODS: We used whole blood samples from 16 patients and 12 age-matched healthy controls. To measure IL-12 and IFN-γ, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for the patients. RESULTS: Eight patients affected as a result of parental first-cousin marriages. Seven patients originated from multiplex kindred with positive history of death because of tuberculosis or finding the MSMD-related gene mutations. Two patients died due to mycobacterial disease at the ages of 8 months and 3.7 years. The remaining patients were alive at the last follow-up and were aged between 2 and 13 years. Patients suffered from infections including chronic mucocutaneous candidiasis (n = 10), salmonellosis (n = 2), and Leishmania (responsible for visceral form) (n = 2). Thirteen patients presented with autosomal recessive (AR) IL-12Rß1 deficiency, meaning their cells produced low levels of IFN-γ. Bi-allelic IL12RB1 mutations were detected in nine of patients. Three patients with AR IL-12p40 deficiency (bi-allelic IL12B mutations) produced low levels of both IL-12 and IFN-γ. Overall, we found five mutations in the IL12RB1 gene and three mutations in the IL12B gene. Except one mutation in exon 5 (c.510C>A) of IL12B, all others were previously reported to be loss-of-function mutations. CONCLUSIONS: We found low levels of IFN-γ production and failure to respond to IL12 in 13 Iranian MSMD patients. Due to complicated clinical manifestations in affected children, early cellular and molecular diagnostics is crucial in susceptible patients.

Genetic and molecular findings of 38 Iranian patients with chronic granulomatous disease caused by p47-phox defect.

One of the components of NADPH oxidase is p47-phox, encoded by NCF1 gene. This study aims to find new genetic changes and clinical features in 38 Iranian patients with autosomal recessive chronic granulomatous disease (AR-CGD) caused by NCF1 gene defect. Patients who had abnormal NBT and DHR-1,2,3 assay with loss of p47-phox in Western blotting were included in this study. After recording demographic and clinical data, PCR amplification was performed followed by direct sequencing for all exons and exon-intron boundaries. The most common form of CGD in Iran was AR-CGD due to consanguinity marriages. Among patients with AR-CGD, NCF1 deficiency was found to be more common than other forms. Cutaneous involvements (53%), pulmonary infections (50%) and lymphadenopathy (29%) were more prevalent than other clinical manifestations of CGD. Mutation analysis of NCF1 gene identified five different mutations. Homozygous delta GT deletion (c.75_76delGT) was the most frequent mutation and was detected in more than 63% of families. Six families had a nonsense mutation in exon 7 (c.579G > A). Two novel mutations were found in exon 4 in two families, including a missense mutation (c.328C > T) and a nine-nucleotide deletion (c.331_339delTGTCCCCAC). Genetic detection of these mutations may result in early diagnosis and prevention of possible complications of the disease. This could be useful for timely decision-making for haematopoietic stem cell transplantation and for carrier detection as well as prenatal diagnosis of next children in the affected families. Our findings might help to predict outcomes, raise awareness and help effective treatment in these patients.

Year-to-year variation of the elemental and allergenic contents of Ailanthus altissima pollen grains: an allergomic study.

The Ailanthus altissima pollen (AAP) has been reported as an emerging aeroallergen worldwide. This paper aims at examining the allergen pattern and the elemental composition of A. altissima pollen collected during two consecutive seasons (2014 and 2015). A gel-based allergomic study and SEM coupled to energy-dispersive X-ray (EDX) analysis have been carried out in order to evaluate the allergenic and elemental composition of AAP in two consecutive years. The IgE reactive patterns of 2014 and 2015 AAP PBS extracts were compared using the serum of a 31-year-old woman suffering from severe pollinosis symptoms to AAP. The EDX analysis revealed an important year-to-year variation in the ratios of some polluting elements such as nickel, sulfur, aluminum, lead, and copper. Gel alignments and comparative immunoproteomic analyses showed differential protein expression and IgE reactive patterns between AAPs collected in 2014 and 2015 pollinating seasons. From 20 distinct IgE-reactive spots detected in AAP extracts, 13 proteins showed higher expression in 2014 sample, while 7 allergen candidates exhibited an increased expression in AAP collected in 2015. Matrix-assisted laser desorption ionization-MS/MS analyses led to the identification of 13 IgE-binding proteins with confidence, all belonging to well-known allergenic protein families, i.e., enolase, calreticulin, and pectate lyase. Overall, the 2014 AAP showed higher concentrations of urban polluting elements as well as an increased expression of allergenic pectate lyase isoforms of about 52 kDa. This study demonstrates that the implementation of allergomic tools for the safety assessment of newly introduced and invasive plant species would help to the comprehensive monitoring of proteomic and transcriptomic alterations involving environmental allergens.

Newborn screening using TREC/KREC assay for severe T and B cell lymphopenia in Iran.

T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs) are recently used for detection of T or B cell lymphopenia in neonates based on region-specific cutoff levels. Here, we report cutoffs for TREC and KREC copies useful for newborn screening and/or diagnosis of primary immunodeficiency diseases (PID) in Iran. DNA was extracted from a single 3.2 mm punch of dried blood spots collected from 2160 anonymized newborns referred to two major referral health centers between 2014 and 2016. For refinement of the cutoffs, 51 patients with a definite diagnosis of severe combined immunodeficiency, X-linked agammaglobulinaemia and combined immunodeficiency, including ataxia telangiectasia, human phosphoglucomutase 3 and Janus kinase-3 deficiency, as well as 47 healthy controls were included. Samples from patients with an X-linked hyper-IgM-syndrome, Wiskott-Aldrich syndrome and DNA ligase 4 deficiency were considered as disease controls. Triplex-quantitative real-time PCR was used. Cutoffs were calculated as TRECs < 11 and KRECs < 6 copies with an ACTB > 700 copies with sensitivity of 100% for TREC and 97% for KREC. Among thirty anonymized newborn samples (1.5%) with abnormal results for TREC and/or KREC, only twenty one available cases were retested and shown to be in the normal range except for three samples (0.15%). All of the patients with a definitive diagnosis were correctly identified based on our established TREC/KREC copy numbers. Determining cutoffs for TREC/KREC is essential for correctly identifying children with PID in newborn screening. Early diagnosis of PID patients enables appropriate measures and therapies like stem cell transplantation. This article is protected by copyright. All rights reserved.

Biological and Immunological Aspects of Iron Deficiency Anemia in Cancer Development: A Narrative Review.

Iron Deficiency Anemia (IDA) is a universal health problem and a risk factor for the development of cancer. IDA changes the microenvironment of the human body by affecting both the biological and immunological systems. It increases DNA damage and genomic instability by different mechanisms. IDA is one of the leading causes of the imbalance between different antioxidant enzymes as well as enzymes involved in DNA damage and DNA repair systems of the body. It can affect the biogenesis/expression of microRNAs. IDA interrupts the oxidative phosphorylation energy metabolism and intestinal Cytochrome-P450 systems. It also disturbs multicellular signaling pathways involved in cell survival and helps in tumor angiogenesis. Moreover, IDA is also responsible for the functional deterioration of innate and adaptive immune systems that lead to immunological dysfunctions against invading pathogens. Genomic instability and immunological dysfunctions are the hallmarks of cancer development. In this review, we will review the evidence linking IDA to increased cancer risk.

The potential anti-inflammatory role of adiponectin in food allergy: a case-control study on children.

We aimed to assess the possible relationship between food allergy and two key adipokines - leptin and adiponectin - in children with food allergy. A total of forty patients with definite diagnosis of food allergy according to clinical history and specific IgE (sIgE) for food allergens (group I) were enrolled in this pilot study. The control group (group II) included thirty children with no evidence of allergic symptoms. Serum levels of leptin and adiponectin were measured by ELISA. Meanwhile, sIgE was measured for the eight most common food allergens by the immunoblot method in all participants. The median ages in groups I and II were 18·5 and 23·5 months, respectively. The respective Caesarean section rate was 64·9 and 16·7 % in groups I and II (P<0·001). Serum levels of adiponectin were significantly higher in the patient group compared with controls (24·11 (sd 12·14) v. 10·67 (sd 12·23) µg/ml, P<0·001), whereas no statistically meaningful difference was detected in serum leptin concentrations (P=0·92). There was a significant inverse relationship between age and adiponectin levels in group I (P=0·002, r -0·479) and group II (P=0·04, r -0·365), and it was more significant in group I. The most common allergens in the patient group were wheat (52·5 %), hazelnut (52·5 %), cow's milk (50 %) and egg white (30 %). The results of this study suggest an essential link between adiponectin and food allergy that is probably unlikely to be affected by obesity as a confounding factor.

Genetic Analysis of Patients with Two Different Types of Hyper IgM Syndrome.

BACKGROUND: Hyper IgM Syndrome (HIGM) is a rare primary immunodeficiency in which impairment of class switching recombination (CSR) and somatic hyper-mutation (SHM) leads to recurrent infections. OBJECTIVES: The aim of this study is to report the clinical and genetic features of six Iranian HIGM patients. METHODS: Six patients, who suspected to have HIGM based on two clinical findings, including recurrent infections and low levels of IgG and IgA and normal or elevated levels of IgM, were entered this study to undergo genetic studies. Sanger sequencing was applied to detect pathogenic mutations in CD40L and AID genes causing two most common forms of HIGM, which known as HIGM type 1 and 2, respectively. RESULTS: All patients who entered the study were males from unrelated families with a median age of 3.8 years. The most frequent clinical manifestation was recurrent pneumonia. Genetic studies of the patients revealed six different mutations, including five mutations in CD40L besides one mutation in AID. Two mutations in CD40L (p.F31fsX5 and p.C84S) were novel and three mutations (p. G219R, p.D62fsX18, and p.Q186X) have been previously reported. The mutation found in AID (p.E122X) was also previously described. CONCLUSION: The study results may provide valuable information for prenatal diagnosis and also for genetic counseling especially for those who have a history of primary immunodeficiency in their family.

The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency.

BACKGROUND: Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. OBJECTIVES: We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. METHODS: Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. RESULTS: DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/µL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. CONCLUSIONS: DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.