Neurological Manifestations of Primary Immunodeficiencies

Primary immunodeficiencies (PID) are a heterogeneous group of disorders  with a variable clinical spectrum of manifestations. The central nervous system may be involved in PIDs with symptoms which may present initially or develop at later stages. Neurological manifestations of primary immunodeficiencies are common with diverse pathologic mechanisms. Neurological deficits may be mild or they may greatly influence the course of the disease with major impacts on the quality of life of the patients. Physical examination may give the clinician valuable clues to the cause of PIDs that underlie the neurological signs. Certain neurological abnormalities may later signify a PID. Therefore physicians should be aware of the neurological features accompanying immunodeficiencies.  Neuromascular abnormality presenting with ataxia(ataxia-telangiectasia) , flaccid paralysis after live poliovirus immunization (combined or antibody deficiencies) ,pernicious anaemia (CVID), cognitive impairment, nystagmus and cerebellar, spinal and peripheral neuropathies(Chediac-Higashi syndrome), seizures, ataxia and occulomotor and reflex abnormalities(Griscelli syndrome) are examples of neurologic features seen in different immunodeficiency syndromes. Early recognition and treatment is important to prevent or reduce future irreversible neurological sequelae. The aim of this study is to review the neurological manifestations of different primary immunodeficiency syndromes

Ispitivanje značajka domova djece s alergijskim rinitisom i astmom

The prevalence of allergic diseases, especially asthma and allergic rhinitis, has dramatically increased during the last decades. Mite and cockroach, which are the most common allergens in house dust, are the major indoor allergens in asthmatic and allergic rhinitis patients. The aim of this study was to compare the association between age of dwelling and some other home characteristics in asthmatic and allergic rhinitis children, who had positive skin prick test to mite and cockroaches, with allergic patient with negative skin test. Thirty-six asthmatic and allergic rhinitis children with positive skin prick test to mite and cockroach allergens, and 34 allergic rhinitis and asthmatic children with negative skin prick test to these allergens were enrolled in this study. Data on home characteristics, including age of homes, kind of carpeting, floor of home and number of rooms in the building, were collected by telephone questionnaire. The mean age of buildings was higher in the group of children sensitive to mite and cockroach (22.4±12.9 vs. 16.3±13.9 years), but the difference was not significant. However, when patients sensitive to mite only were compared to control patients, the difference was significant (p=0.025). There was no significant difference in the number of floor, rooms, kind of carpet and other features of building between the case and control group. There was a significant relationship between mite allergy and building age, which could be important for the policy of allergy control in the society. However, further studies are needed to clarify the association between more specific home characteristics and allergy diseases.Učestalost alergijskih bolesti, poglavito astme i alergijskog rinitisa, bilježi znatan porast posljednjih desetljeća. Grinje i žohari kao najčešći alergeni u kućnoj prašini glavni su alergeni na koje nailaze osobe s alergijom i alergijskim rinitisom u zatvorenom prostoru. Cilj ovoga istraživanja bio je usporediti povezanost starosti objekta i neke druge značajke domova kod djece s astmom i alergijskim rinitisom te s pozitivnim kožnim testom na grinje i žohare s vrijednostima istih kod djece s astmom i alergijskim rinitisom, ali s negativnim kožnim testom na grinje i žohare. U studiju je bilo uključeno 36 djece s astmom i alergijskim rinitisom te s pozitivnim kožnim testom na grinje i žohare i 34 djece s astmom i alergijskim rinitisom, ali s negativnim kožnim testom na grinje i žohare. Podatci o značajkama doma uključujući starost zgrade, vrst zidne obloge, kat i broj soba u zgradi prikupljeni su telefonskim anketiranjem roditelja. Srednja starost zgrade u kojoj žive bila je veća kod djece osjetljive na grinje i žohare nego u djece koja nisu pokazala osjetljivost na ove alergene (22,4±12,9 prema 16,3±13,9 years), ali razlika nije bila značajna. Međutim, kad su s kontrolnom skupinom uspoređena djeca osjetljiva samo na grinje, tada je razlika bila značajna (p=0,025). Nije bilo nikakve razlike između dviju skupina u odnosu na kat, broj soba, vrst zidne obloge i druge značajke zgrade. Dakle, utvrđena je značajna povezanost alergije na grinje i starosti zgrada, što bi moglo biti važno u planiranju aktivnosti za suzbijanje alergije u društvu. Potrebna su daljnja ispitivanja kako bi se pojasnila udruženost nekih specifičnih značajka zgrada i alergijskih bolesti

Prenatal Diagnosis of Leukocyte Adhesion Deficiency Type-1 (Five Cases from Iran with Two New Mutations)

Leukocyte adhesion deficiency type-1(LAD-1) is one of the autosomal recessive immunodeficiency diseases that results from mutation in integrin beta 2 (ITGB2) gene. The aim of this study was to investigate molecular prenatal diagnosis of LAD-1. Four pregnant women with five fetuses (one twin fetus) with clinical and laboratory diagnosis of LAD-1 in their previous children were studied. The chorionic villus sampling (CVS) was obtained when mothers were in 10-12th weeks of gestation. Mutation analysis of ITGB2 gene for affected children revealed 3 misssense mutations (c.382G>A,   a   novel   mutation,   c.2146G>C,   and   c.715G>A)   and   one   splice  site novel mutation (c.1877+2T>C). All parents were heterozygous for these mutations. Consideration of affected gene regions for five CVS samples showed two homozygotes and one heterozygote for mutant allele and two homozygotes for normal allele. Interestingly, one  of  the  twin  fetuses  was  affected  and  another  was  normal.  Briefly, two  cases  of CVS samples were affected and three cases of remained CVS samples were unaffected. This is the first report of prenatal diagnosis of LAD-1 from Iran with two new mutations that can be used for genetic and prenatal diagnosis for all patients suspected to LAD1 and can be helpful to prevent the birth of affected children with LAD-1. This  abstract  was presented  in  the  Second  International  Congress  of  Immunology, Asthma and Allergy, Tehran, Iran 2013

HLA-B*1502 in Iranian Children with Anticonvulsant Drugs-Induced Skin Reactions

How to Cite This Article: Tonekaboni SH, Jafari N, Mansouri M, Jabbehdari S, Eftekhari R, Chavoshzadeh Z, Abdollah Gorji F, Mesdaghi M. HLA-B*1502 in Iranian Children with Anticonvulsant Drugs-Induced Skin Reactions. Iran J Child Neurol. Spring 2017; 11(2):26-30. AbstractObjectiveAnticonvulsant drugs can cause various forms of skin drug reactions, ranging from exanthema to severe blistering reactions. An association between HLA-B*1502 allele and severe skin reactions have been reported.Materials & Methods Fifteen patients with severe skin reactions following treatment with anticonvulsant drugs (Carbamazepine, lamotrigine, phenobarbital, primidone) and 15 controls (age-matched epileptic patients taking similar anticonvulsants without drug eruption) were included. They were referred to Mofid Children’s Hospital in Tehran, Iran, between Jan 2012 to Jan 2014. Genomic DNA was extracted from peripheral blood of all patients and HLA- B*1502 genotype was detected by real-time PCR.Results None of the patients was positive for HLA- B*1502, but two patients in control group had positive HLA- B*1502.Conclusion The HLA- B*1502 is not correlated with severe anticonvulsant drugs -induced skin reactions in Iranian children. References 1.Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology 2005; 209: 123 –9.2.McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė D, Carrington M, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011; 364(12):1134-43.3.Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’er I, Floratos A, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genetic 2009; 41:816–9.4.Amstutz U, Ross CJ, Castro-Pastrana LI, Rieder MJ, Shear NH, Hayden MR, Carleton BC. CPNDS Consortium; HLA-A 31:01 and HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children. Clin Pharmacol Ther 2013; 94(1):142-9.5.Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, Ng MH. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia 2007; 48(5):1015-8.6.Zeng T, Long YS, Min FL, Liao WP, Shi YW. Association of HLA-B*1502 allele with lamotrigine-induced Stevens– Johnson syndrome and toxic epidermal necrolysis in Han Chinese subjects: a meta-analysis. Int J Dermatol 2015; 54(4):488-93.7.Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993; 129(1):92-6.8. Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006; 16(4):297-306.9. Wang Q, Zhou JQ, Zhou LM, Chen ZY, Fang ZY, Chen SD, et al. Association between HLA-B*1502 allele and carbamazepine-induced severe cutaneous adverse reactions in Han people of southern China mainlan. Seizure 2011; 20 (6):446-8.10. Li LJ, Hu FY, Wu XT, An DM, Yan B, Zhou D. Predictive markers for carbamazepine and lamotrigine-induced maculopapular exanthema in Han Chinese. Epilepsy Res 2013; 106 (1-2):296-300.11. Kim SH, Lee KW, Song WJ, Kim SH, Jee YK, Lee SM, et al; Adverse Drug Reaction Research Group in Korea. Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans. Epilepsy Res 2011; 97 (1-2):190-7.12. Criado PR, Criado RFJ, Avancini JM, Santi CG. Drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS): a review of current concepts. An Bras Dermatol 2012; 87(3):435–49.13. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical genetics: a marker for Stevens– Johnson syndrome. Nature 2004; 428: 486.14. Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, Ng MH. Association between HLA-B*1502 allele and antiepileptic drug induced cutaneous reactions in Han Chinese. Epilepsia 2007; 48: 1015–8.15. Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, et al. Carbamazepine and phenytoin induced Stevens–Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia 2008; 49:2087–91.16. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, et al. HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens– Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 2008; 9: 1617–22.17. Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics 2006; 7: 813–8.18. Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, Lohitnavy M, Tassaneeyakul W. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens- Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol 2013; 149(9):1025-32

Fourth Update on the Iranian National Registry of Primary Immunodeficiencies: Integration of Molecular Diagnosis

Background The number of inherited diseases and the spectrum of clinical manifestations of primary immunodeficiency disorders (PIDs) are ever-expanding. Molecular diagnosis using genomic approaches should be performed for all PID patients since it provides a resource to improve the management and to estimate the prognosis of patients with these rare immune disorders. Method The current update of Iranian PID registry (IPIDR) contains the clinical phenotype of newly registered patients during last 5 years (2013–2018) and the result of molecular diagnosis in patients enrolled for targeted and nextgeneration sequencing. Results Considering the newly diagnosed patients (n = 1395), the total number of registered PID patients reached 3056 (1852 male and 1204 female) from 31 medical centers. The predominantly antibody deficiency was the most common subcategory of PID (29.5%). The putative causative genetic defect was identified in 1014 patients (33.1%) and an autosomal recessive pattern was found in 79.3% of these patients. Among the genetically different categories of PID patients, the diagnostic rate was highest in defects in immune dysregulation and lowest in predominantly antibody deficiencies and mutations in the MEFV gene were the most frequent genetic disorder in our cohort. m

Autoimmune versus Non-autoimmune Cutaneous Features in Monogenic Patients with Inborn Errors of Immunity

Cutaneous manifestations are one of the most common presentations among patients with inborn errors of immunity (IEI). These skin manifestations are often among the first presenting features in the majority of patients preceding the IEI diagnosis. We studied 521 available monogenic patients with IEI listed in the Iranian IEI registry up to November 2022. We extracted each patient's demographic information, detailed clinical history of cutaneous manifestations, and immunologic evaluations. The patients were then categorized and compared based on their phenotypical classifications provided by the International Union of Immunological Societies. Most patients were categorized into syndromic combined immunodeficiency (25.1%), non-syndromic combined immunodeficiency (24.4%), predominantly antibody deficiency (20.7%), and diseases of immune dysregulation (20.5%). In total, 227 patients developed skin manifestations at a median (IQR) age of 2.0 (0.5-5.2) years; a total of 66 (40.7%) of these patients initially presented with these manifestations. Patients with cutaneous involvement were generally older at the time of diagnosis [5.0 (1.6-8.0) vs. 3.0 (1.0-7.0) years; p = 0.022]. Consanguinity was more common among patients who developed skin disorders (81.4% vs. 65.2%, p < 0.001). The overall skin infection rate and the type of dominant pathogens were significantly different among the IEI patients in different phenotypical classifications (p < 0.001). Atopic presentation, including urticaria, was highly prevalent among patients with congenital defects of phagocytes (p = 0.020). The frequency of eczema was also significantly higher among cases with both syndromic and non-syndromic combined immunodeficiency (p = 0.009). In contrast, autoimmune cutaneous manifestations, including alopecia and psoriasis, were most common in patients with immune dysregulation (p = 0.001) and defects in intrinsic or innate immunity (p = 0.031), respectively. The presence of autoimmune cutaneous complications significantly improved the survival rate of IEI patients (p = 0.21). In conclusion, cutaneous manifestations were observed in nearly 44% of Iranian patients with monogenic IEI. A considerable number of patients with cutaneous involvements developed these disorders as their first manifestation of the disease, which was particularly noticeable in patients with non-syndromic combined immunodeficiency and phagocytic defects. The neglected skin disorders in IEI patients might delay diagnosis, which is generally established within a 3-year interval from the development of skin-related problems. Cutaneous disorders, especially autoimmune features, might indicate a mild prognosis in IEI patients

Global systematic review of primary immunodeficiency registries

Introduction During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear. Areas covered Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients. Expert opinion Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.Peer reviewe

Cutaneous cytomegalovirus infection in a child with hyper IgE and specific defects in antibody response to protein vaccines

Cytomegalovirus (CMV) infection is a common opportunistic systemic infection in immunocompromised patients, but skin involvement is rare. Herein, we report a 10 year-old girl from consanguineous parents who was referred to our center because of disseminated maculopapular rash. She had history of upper and lower respiratory tract infections. In immunological studies, increased serum IgE level and decreased responses to tetanus and diphtheria were detected. Polymerase chain reaction (PCR) examination of bronchoalveolar lavage and serum sample revealed the presence of CMV. Early diagnosis of cutaneous CMV and appropriate treatment are the key actions in management of patients with underlying immunodeficiencies to avoid further complications

Autoimmune Lymphoproliferative Syndrome; A Case Report

Autoimmune lymphoproliferative syndrome is a disorder of lymphoid system regulation characterized by chronic splenomegaly, lymphadenopathy and autoimmune phenomena especially immune-mediated cytopenias. The hallmark of the disease is the presence in peripheral blood and lymphoid tissue of increased numbers of a normally rare T lymphocyte subset, usually referred to as “double-negative” T cells. Here the authors report a 16-year-old boy when he was first hospitalized for diffuse petechiae, purpura and epistaxis at 9 years of age.One year later,he was readmitted for high fever and recurring cytopenia. On examination several enlarged, nontender lymph nodes involving cervical and submandibular areas and a huge spleen were detected.Lymph node biopsy was performed two times. According to flowcytometry of peripheral blood and immunophenotyping of lymph node tissues which revealed increased numbers of CD3+CD4-CD8-T lymphocytes, autoimmune lymphoproliferative syndrome was suggested for him. Autoimmune lymphoproliferative syndrome should be considered in differential diagnosis of any patient with unexplained Coomb’s positive cytopenias, hypergammaglobulinemia, generalized lymphadenopathy and splenomegaly. The confirmation of the diagnosis should be based upon genetic analysis and detection of the affected genes involved in fas pathway