Manish Butte

Staphylococcus aureus and Hyper-IgE Syndrome.

Int J Mol Sci. 2020 Dec 01;21(23):

Authors: Park B, Liu GY

Abstract
Hyper-immunoglobulin E syndrome (HIES) is a primary immunodeficiency disease characterized by recurrent Staphylococcus aureus (S. aureus) infections, eczema, skeletal abnormalities and high titers of serum immunoglobulin E. Although the genetic basis of HIES was not known for almost a half century, HIES most frequently exhibits autosomal dominant trait that is transmitted with variable expressivity. Careful genetic studies in recent years identified dominant-negative mutations in human signal transducer and activator of transcription 3 (STAT3) gene as the cause of sporadic and dominant forms of HIES. The STAT3 mutations were localized to DNA-binding, SRC homology 2 (SH2) and transactivating domains and disrupted T helper 17 (TH17) cell differentiation and downstream expression of TH17 cytokines IL-17 and IL-22. Deficiency of IL-17 and IL-22 in turn is responsible for suboptimal expression of anti-staphylococcal host factors, such as neutrophil-recruiting chemokines and antimicrobial peptides, by human keratinocytes and bronchial epithelial cells. TH17 cytokines deficiency thereby explains the recurrent staphylococcal lung and skin infections of HIES patients.

PMID: 33271763 [PubMed – in process]

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Hyper IgE syndrome (Job syndrome) in Syria: a case report.

Oxf Med Case Reports. 2020 Nov;2020(11):omaa106

Authors: Awad R, Kakaje A

Abstract
Hyper IgE syndrome (HIES) is a medical condition that can be sporadic or hereditary. It consists of multiple overlapping primary immunodeficiency conditions and is characterized by a classical triad of high immunoglobulin E (IgE) levels, recurrent pneumonia with pneumatocele and recurrent cold skin abscesses from staphylococcus infections. Eosinophilia is also common in HIES patients. HIES is often underdiagnosed in Syria as it cannot be confirmed without genetic testing, which is unavailable across Syria for HIES. We present the first case from Syria of a suspected child with HIES that has some additional distinct features. Other cases in a regional country carried atypical novel mutations, which may indicate that these mutations may exist in Syria as well. However, our case had findings that were not reported with other HIES cases. Determining these genes in the case presented was not possible, and future studies need to overcome this hurdle.

PMID: 33269088 [PubMed]

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Authors’ Response to “Chalazia, A Late Manifestation of Primary Immunodeficiency Disorders”.

Ocul Immunol Inflamm. 2020 Dec 02;:1

Authors: Nieves-Moreno M, Granados M, Noval S

PMID: 33264031 [PubMed – as supplied by publisher]

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Ecthyma gangrenosum due to Pseudomonas aeruginosa sepsis as initial manifestation of X-linked agammaglobulinemia: a case report.

BMC Pediatr. 2020 Dec 01;20(1):540

Authors: Huang H, Bai K, Fu Y, Yan J, Li J

Abstract
BACKGROUND: X-linked agammaglobulinemia (XLA, OMIM#300,300), caused by mutations in the Bruton tyrosine kinase (BTK) gene, is a rare monogenic inheritable immunodeficiency disorder. Ecthyma gangrenosum is a cutaneous lesion caused by Pseudomonas aeruginosa that typically occurs in patients with XLA and other immunodeficiencies.
CASE PRESENTATION: We report the case of a 20-month-old boy who presented with fever, vomiting, diarrhea, and ecthyma gangrenosum. Blood, stool, and skin lesion culture samples were positive for P. aeruginosa. A diagnosis of XLA was established, and the c.262G > T mutation in exon 4 of BTK was identified with Sanger sequencing. Symptoms improved following treatment with antibiotics and immunoglobulin infusion.
CONCLUSIONS: Primary immunodeficiency (i.e., XLA) should be suspected in male infants with P. aeruginosa sepsis, highlighting the importance of genetic and immune testing in these patients.

PMID: 33261572 [PubMed – in process]

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Inborn errors of thymic stromal cell development and function.

Semin Immunopathol. 2020 Nov 30;:

Authors: Kreins AY, Maio S, Dhalla F

Abstract
As the primary site for T cell development, the thymus is responsible for the production and selection of a functional, yet self-tolerant T cell repertoire. This critically depends on thymic stromal cells, derived from the pharyngeal apparatus during embryogenesis. Thymic epithelial cells, mesenchymal and vascular elements together form the unique and highly specialised microenvironment required to support all aspects of thymopoiesis and T cell central tolerance induction. Although rare, inborn errors of thymic stromal cells constitute a clinically important group of conditions because their immunological consequences, which include autoimmune disease and T cell immunodeficiency, can be life-threatening if unrecognised and untreated. In this review, we describe the molecular and environmental aetiologies of the thymic stromal cell defects known to cause disease in humans, placing particular emphasis on those with a propensity to cause thymic hypoplasia or aplasia and consequently severe congenital immunodeficiency. We discuss the principles underpinning their diagnosis and management, including the use of novel tools to aid in their identification and strategies for curative treatment, principally transplantation of allogeneic thymus tissue.

PMID: 33257998 [PubMed – as supplied by publisher]

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Molecular Genetic Architecture of Monogenic Pediatric IBD Differs from Complex Pediatric and Adult IBD.

J Pers Med. 2020 Nov 26;10(4):

Authors: Jezernik G, Mičetić-Turk D, Potočnik U

Abstract
Inflammatory bowel disease (IBD) manifests as a complex disease resulting from gene-environment interactions or as a monogenic disease resulting from deleterious mutations. While monogenic IBD is predominantly pediatric, only one-quarter of complex IBD is pediatric. In this study, we were the first to systematically compare genetic architecture between monogenic and complex pediatric and adult IBD on genetic and molecular pathway levels. Genes reported as causal for monogenic pediatric IBD and related syndromes and as risk factors for pediatric and adult complex IBD were analyzed using CytoScape and ClueGO software tools to elucidate significantly enriched Gene Ontology (GO) terms. Despite the small overlap (seven genes) between monogenic IBD genes (85) and complex IBD loci (240), GO analysis revealed several enriched GO terms shared between subgroups (13.9%). Terms Th17 cell differentiation and Jak/STAT signaling were enriched in both monogenic and complex IBD subgroups. However, primary immunodeficiency and B-cell receptor signaling pathway were specifically enriched only for pediatric subgroups, confirming existing clinical observations and experimental evidence of primary immunodeficiency in pediatric IBD patients. In addition, comparative analysis identified patients below 6 years of age to significantly differ from complex pediatric and adult IBD and could be considered a separate entity.

PMID: 33255894 [PubMed]

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A Novel Non-frameshift ADA Deletion Detected by Whole Exome Sequencing in an Iranian Family with Severe Combined Immunodeficiency.

Iran J Allergy Asthma Immunol. 2020 Feb 01;19(1):94-101

Authors: Talebi T, Biglari A, Shahroeei M, Changi-Ashtiani M, Dinmohammadi H, Navabi SS, Parvaneh N, Bossuyt X, Shahani T, Rokni-Zadeh H

Abstract
Severe combined immunodeficiency (SCID) comprises a heterogeneous group of genetic disorders caused by early defects in the development and function of T cells. Other lymphocyte lineages (B and/or natural killer cells) are variably affected. With a worldwide frequency of approximately 1:50,000 live births, SCID may result from diverse mutations in over 16 genes. Whole-exome sequencing (WES) provides an opportunity for parallel screening of all those genes. This approach is also useful for genetic diagnosis in parents whose infant expired before genetic testing. Here, we describe a heterozygous novel non-frameshift deletion (c.587_598del p.196_199del) in the adenosine deaminase (ADA) gene identified by WES in healthy parents of an expired child with SCID. The mutation was subsequently confirmed to be homozygous in the deceased baby whose left-over blood sample volume was insufficient for direct WES analysis. In conclusion, we here describe a novel mutation in ADA, a well-known SCID gene.

PMID: 32245326 [PubMed – indexed for MEDLINE]

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Persons Living With Primary Immunodeficiency Act as Citizen Scientists and Launch Prospective Cohort Body Temperature Study.

J Particip Med. 2020 Nov 30;12(4):e22297

Authors: Zhang S, Henderson TS, Scalchunes C, Sullivan KE, Jongco Iii AM

Abstract
BACKGROUND: Although fever is considered a sign of infection, many individuals with primary immunodeficiency (PI) anecdotally report a lower-than-normal average body temperature on online forums sponsored by the Immune Deficiency Foundation (IDF). There is limited knowledge about the average body temperature and fever response in PI.
OBJECTIVE: This study aims to compare median body temperatures between adults with and without PI diagnoses living in the same household and to engage individuals living with PI throughout the research process.
METHODS: Patients with PI designed and launched a prospective cohort comparison study as citizen scientists. A multidisciplinary team designed and implemented a patient-informed study with continuous patient-driven input. Median body temperatures were compared between the 2 cohorts using the Mann-Whitney test with Bonferroni correction. The IDF conducted a post-study patient experience survey.
RESULTS: Data from 254 households were analyzed (254/350, 72.6% participation rate). The PI population was predominantly female (218/254, 85.8%), White (248/254, 97.6%), and with a median age of 49 years. The non-PI population was largely male (170/254, 66.9%), White (236/254, 92.9%), and with a median age of 53 years. Common variable immunodeficiency was the most common PI diagnosis (190/254, 74.8%). Of the 254 individuals with PI, 123 (48.4%) reported a lower-than-normal nonsick body temperature, whereas 108 (42.5%) reported a normal (between 97°F and 99°F) nonsick body temperature. Among individuals with PI, when infected, 67.7% (172/254) reported the absence of fever, whereas 19.7% (50/254) reported a normal fever response. The recorded median body temperature was minimally but statistically significantly higher for patients with PI in the morning. Although 22.4% (57/254) of patients with PI self-reported illness, a fever of 100.4°F or higher was uncommon; 77.2% (196/254) had a normal temperature (between 97°F and 99°F), and 16.2% (41/254) had a lower-than-normal temperature (between 95.0°F and 96.9°F) when sick. For these sick patients with PI, the median body temperature was minimally but statistically significantly higher for patients in the morning and early evening. Overall, 90.9% (231/254) of participants would be very likely to participate in future IDF studies, although 94.1% (239/254) participants had never taken part in previous studies.
CONCLUSIONS: To our knowledge, this is the first study to evaluate average body temperature in individuals with PI. Although there were small statistically significant differences in body temperatures between PI and non-PI subjects, the clinical significance is unclear and should be interpreted with caution, given the methodological issues associated with our small convenience sample and study design. As PIs are heterogeneous, more research is needed about how the fever response differs among diverse PIs compared with healthy controls. This study highlights that individuals with PI are knowledgeable about their health and can offer unique insights and direction to researchers and clinicians.

PMID: 33252341 [PubMed – as supplied by publisher]

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Hyper IgE Syndrome Associated With Warts: A First Case of Dedicator of Cytokinesis 8 Deficiency in the Philippines.

Front Pediatr. 2020;8:604725

Authors: Villanueva JCMM, Chan KW, Ong RC, Andaya AG, Lau YL, van Zelm MC, Kanegane H

Abstract
Hyper IgE syndrome (HIES) encompasses a group of primary immunodeficiency diseases (PIDs) that is characterized by severe atopy, and recurrent infections and markedly elevated serum IgE levels. The majority of HIES cases suffer from autosomal dominant mutations in the signal transducer and activator of transcription 3 gene. A minority of cases display autosomal recessive inheritance, and one form is caused by mutations in the dedicator of cytokinesis 8 (DOCK8) gene. Here we describe the first recognized and diagnosed case of DOCK8 deficiency in the Philippines. A 14 year-old-girl was referred due to recalcitrant atopic dermatitis, recurrent sinopulmonary infections, with widespread warts on the face, trunk and extremities. She had no coarse facial features or retained primary teeth, whereas she presented with widespread viral skin infections and multiple allergic diseases. Laboratory examinations revealed elevations in eosinophil count and serum IgE. The level of T-cell receptor excision circles was undetectable. The patient was suspected to have HIES with a probable DOCK8 deficiency. Genetic analysis disclosed a large genomic deletion involving exons 2-4 in the DOCK8 gene. A combination of recalcitrant atopic dermatitis, asthma, food allergies, with viral skin infections should increase the physician’s consideration of a PID. Patients with HIES accompanied by warts and T-cell deficiency can be strongly suspected to have DOCK8 deficiency.

PMID: 33251169 [PubMed]

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