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2019 Update on Primary Immunodeficiency Disorders by the International Union of Immunological Societies.

June 21, 2020 By Manish Butte

2019 Update on Primary Immunodeficiency Disorders by the International Union of Immunological Societies.

Indian Pediatr. 2020 Jun 15;57(6):565-567

Authors: Bargir UA, Madkaikar MR

Abstract
International Union of Immunological Societies working group recently updated the human inborn errors of immunity. This classification includes 65 new disorders that have been added since the last classification in 2018. This article highlights the important aspects of new classification for the benefit of general pediatricians.

PMID: 32562400 [PubMed – as supplied by publisher]

Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series.

June 21, 2020 By Manish Butte

Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series.

J Clin Immunol. 2020 Jun 19;:

Authors: Lhomme F, Peyrard T, Babinet J, Abou-Chahla W, Durieu I, Moshous D, Neven B, Rohrlich PS, Albinni S, Amiranoff D, Dumont MD, Lortholary O, Héritier S, Marguet C, Suarez F, Fischer A, Blanche S, Hermine O, Mahlaoui N

Abstract
BACKGROUND: X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype.
METHODS: We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types.
RESULTS: The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well.
CONCLUSION: This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.

PMID: 32562208 [PubMed – as supplied by publisher]

Immediate adverse reactions to intravenous immunoglobulin in primary immune deficiencies: a single center experience.

June 20, 2020 By Manish Butte

Immediate adverse reactions to intravenous immunoglobulin in primary immune deficiencies: a single center experience.

Turk J Pediatr. 2020;62(3):379-386

Authors: Nain E, Kıykım A, Kasap NA, Barış S, Özen A, Aydıner EK

Abstract
BACKGROUND AND OBJECTIVE: Adverse reactions related to intravenous immunoglobulin (IVIG) infusions vary from 1 to 81%, with an average of 20%. They may be classified as immediate; occurring during the infusion itself or delayed; occurring after the infusion has been ceased. In the present study, we aimed to evaluate the frequency of immediate adverse reactions due to IVIG infusions in primary immune deficiency (PID) patients.
METHODS: The study population was composed of 109 patients. A total of 763 infusions were recorded for demographic data and adverse reactions.
RESULTS: The participants included 32 girls (29%) and 77 boys (71%). The mean age was 11.8 ± 5.7 years (0.6- 33.5 years). Early adverse events (AE) were recorded in 34 (4.5%) among 763 IVIG infusions including 30 mild (88.2%), 3 moderate (8.8%) and 1 severe (2.9%). The most common immediate adverse reactions were fever (29.4%) and headache (29.4%). The risk of AE was higher among primary antibody deficiency (PAD), compared to combined immunodeficiency (OR 2.61, 95%CI 1.061-6.475; p = 0.037).
CONCLUSIONS: Use of various intravenous immunoglobulin treatments should be considered with regard to side effect profiles observed. In our cohort, PID patient experienced mostly mild AE; PAD was associated with an increased risk of AE.

PMID: 32558411 [PubMed – in process]

Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency.

June 20, 2020 By Manish Butte

Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency.

Leukemia. 2020 Jun 18;:

Authors: Kozyra EJ, Pastor VB, Lefkopoulos S, Sahoo SS, Busch H, Voss RK, Erlacher M, Lebrecht D, Szvetnik EA, Hirabayashi S, Pasaulienė R, Pedace L, Tartaglia M, Klemann C, Metzger P, Boerries M, Catala A, Hasle H, de Haas V, Kállay K, Masetti R, De Moerloose B, Dworzak M, Schmugge M, Smith O, Starý J, Mejstrikova E, Ussowicz M, Morris E, Singh P, Collin M, Derecka M, Göhring G, Flotho C, Strahm B, Locatelli F, Niemeyer CM, Trompouki E, Wlodarski MW, European Working Group of MDS in Childhood (EWOG-MDS)

Abstract
Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.

PMID: 32555368 [PubMed – as supplied by publisher]

Gastric tuberculosis mimicking liver abscess – A case report.

June 20, 2020 By Manish Butte

Gastric tuberculosis mimicking liver abscess – A case report.

Indian J Tuberc. 2020 Apr;67(2):274-276

Authors: Bhut B, Ghoshal UC, Verma A

Abstract
Tuberculosis of the stomach is quite rare, both as a primary or secondary infection. It has varied presentation ranging from non-specific abdominal pain and constitutional symptoms to hematemesis, gastric outlet obstruction and pyrexia of unknown origin. Here, we report a rare, interesting case of locally advanced gastric tuberculosis, which morphologically mimicked liver abscess initially in a young, immunocompetent patient presenting with fever and abdominal pain. The disease was diagnosed by GeneXpert MTB/RIF assay, and responded well to antituberculosis medication without surgery. Clinicians must bear in mind that, even in the absence of immunodeficiency, as in this case, tuberculosis can involve any site in the gastrointestinal tract and may present with a variety of presentation and infiltrating adjacent organ that might be mistaken as malignancy. This is first case report of gastric tuberculosis, which is locally advanced with adjacent liver infiltration initially thought to be left lobe liver abscess.

PMID: 32553327 [PubMed – in process]

Safety and efficacy of abatacept in patients with treatment-resistant SARCoidosis (ABASARC) – protocol for a multi-center, single-arm phase IIa trial.

June 20, 2020 By Manish Butte

Safety and efficacy of abatacept in patients with treatment-resistant SARCoidosis (ABASARC) – protocol for a multi-center, single-arm phase IIa trial.

Contemp Clin Trials Commun. 2020 Sep;19:100575

Authors: Frye BC, Rump IC, Uhlmann A, Schubach F, Ihorst G, Grimbacher B, Zissel G, Quernheim JM

Abstract
Introduction: Sarcoidosis is a granulomatous systemic disease that becomes chronic in approximately one third of affected patients resulting in quality of life and functional impairment. Immunosuppressive drugs other than steroids represent alternative therapeutic options, but side effects like liver and bone marrow toxicity or increased susceptibility to infections limit their use. Pathophysiological studies in sarcoidosis patients demonstrate altered regulatory T-cell functions with a reduced expression of CTLA-4 (CD152) and prolonged inflammation. Therefore, interfering with CTLA-4 using abatacept might be a therapeutic option in sarcoidosis similar to rheumatoid arthritis therapy.
Methods/design: This is a multicenter prospective open-labeled single arm phase II study addressing the safety of abatacept in sarcoidosis patients. 30 patients with chronic sarcoidosis requiring immunosuppressive therapy beyond 5 mg prednisolone equivalent will be treated with abatacept in combination with corticosteroids for one year in two centers.The primary endpoint is the number and characterization of severe infectious complications under treatment with abatacept.Secondary endpoints are the rate of all infections, patient-related outcomes (assessed by questionnaires), lung function and immunological parameters including alveolar inflammation assessed by bronchoaveolar lavage.
Discussion: This is the first trial of abatacept in patients with sarcoidosis. It is hypothesized that administration of abatacept is safe in patients with chronic sarcoidosis and can limit ongoing inflammation. Patients’ wellbeing is assessed by established questionnaires. Immunological work-up will highlight the effect of abatacept on inflammatory pathways in sarcoidosis.
Trial registration: The trial has been registered at the German Clinical Trial Registry (Deutsches Register Klinischer Studien, DRKS) with the identity number DRKS00011660.

PMID: 32551397 [PubMed]

Typhim vi immunization assists to discriminate primary antibody responses in hematological malignancies.

June 20, 2020 By Manish Butte

Typhim vi immunization assists to discriminate primary antibody responses in hematological malignancies.

MethodsX. 2020;7:100936

Authors: Ochoa-Grullón J, Orte C, Rodríguez de la Peña A, Guevara-Hoyer K, Cordero Torres G, Fernández-Arquero M, Serrano-García I, Recio MJ, Pérez de Diego R, Sánchez-Ramón S

Abstract
Assessment of specific antibody (Ab) production to polysaccharide antigens is clinically relevant, identifying patients at risk for infection by encapsulated bacteria and thus enabling a more rigorous selection of patients that can benefit of immunoglobulin replacement therapy. Classically, the gold-standard test is the measurement of antibody production to pure polysaccharide pneumococcal (PPV) immunization. Several factors, including introduction of conjugate vaccination schedule, serotyping analysis, high baseline Ab levels, have hindered the evaluation of polysaccharide antigens. This is even more difficult in secondary immunodeficiencies (SID), where patients can show secondary responses despite lack of primary antibody responses and present with recurrent or severe infections. Assessment of specific Ab production to pure Salmonella typhi Vi polysaccharide (TV) immunization has been proposed as a complementary test to PPV, given its low seroprevalence. To set the optimal cut-off value for PPV and TV response in SID, we tested different biostatistical methodologies, including ROC analysis, Youden index, Union index and Closest-topleft in a cohort of 42 SID patients and 24 healthy controls. The statistically chosen cut-offs value pre-post TV Ab ratio was ≥5, (sensitivity of 90%, specificity of 100%) and a postvaccination TV concentration of 28.5 U/mL (sensitivity of 90%, specificity of 95%), showing relevant clinical correlate.

PMID: 32551240 [PubMed]

Identification of 22q11.2 deletion syndrome via newborn screening for severe combined immunodeficiency. Two years’ experience in Catalonia (Spain).

June 20, 2020 By Manish Butte

Identification of 22q11.2 deletion syndrome via newborn screening for severe combined immunodeficiency. Two years’ experience in Catalonia (Spain).

Mol Genet Genomic Med. 2019 12;7(12):e1016

Authors: Martin-Nalda A, Cueto-González AM, Argudo-Ramírez A, Marin-Soria JL, Martinez-Gallo M, Colobran R, Plaja A, Castells N, Riviere J, Tizzano EF, Soler-Palacin P

Abstract
BACKGROUND: The current scenario of newborn screening is changing as DNA studies are being included in the programs of several countries. Severe combined immunodeficiency (SCID) disorders can be detected using quantitative PCR assays to measure T-cell receptor excision circles (TRECs), a byproduct of correct T-cell development. However, in addition to SCID, other T-cell-deficient phenotypes such as 22q11.2 deletion syndrome 22q11.2 duplication syndrome, CHARGE syndrome, and trisomy 21 are detected.
METHODS: We present our experience with the detection of 22q11.2 deletion syndrome and 22q11.2 duplication syndrome in a series of 103,903 newborns included in the newborn screening program of Catalonia (Spain).
RESULTS: Thirty newborns tested were positive (low TREC levels) and five were found to have copy number variations at the 22q11 region (4 deletions and 1 duplication) when investigated with array comparative genomic hybridization technology and MLPA.
CONCLUSION: Newborn screening for SCID enables detection of several conditions, such as 22q syndromes, which should be managed by prompt, proactive approaches with adequate counseling for families by a multidisciplinary team.

PMID: 31663686 [PubMed – indexed for MEDLINE]

TASP1 mutation in a female with craniofacial anomalies, anterior segment dysgenesis, congenital immunodeficiency and macrocytic anemia.

June 20, 2020 By Manish Butte

TASP1 mutation in a female with craniofacial anomalies, anterior segment dysgenesis, congenital immunodeficiency and macrocytic anemia.

Mol Genet Genomic Med. 2019 09;7(9):e818

Authors: Balkin DM, Poranki M, Forester CM, Dorsey MJ, Slavotinek A, Pomerantz JH

Abstract
BACKGROUND: Threonine Aspartase 1 (Taspase 1) is a highly conserved site-specific protease whose substrates are broad-acting nuclear transcription factors that govern diverse biological programs, such as organogenesis, oncogenesis, and tumor progression. To date, no single base pair mutations in Taspase 1 have been implicated in human disease.
METHODS: A female infant with a new pattern of diagnostic abnormalities was identified, including severe craniofacial anomalies, anterior and posterior segment dysgenesis, immunodeficiency, and macrocytic anemia. Trio-based whole exome sequencing was performed to identify disease-causing variants.
RESULTS: Whole exome sequencing revealed a normal female karyotype (46,XX) without increased regions of homozygosity. The proband was heterozygous for a de novo missense variant, c.1027G>A predicting p.(Val343Met), in the TASP1 gene (NM_017714.2). This variant has not been observed in population databases and is predicted to be deleterious.
CONCLUSION: One human patient has been reported previously with a large TASP1 deletion and substantial evidence exists regarding the role of several known Taspase 1 substrates in human craniofacial and hematopoietic disorders. Moreover, Taspase 1 deficiency in mice results in craniofacial, ophthalmological and structural brain defects. Taken together, there exists substantial evidence to conclude that the TASP1 variant, p.(Val343Met), is pathogenic in this patient.

PMID: 31350873 [PubMed – indexed for MEDLINE]

Whole exome sequencing identifies compound heterozygous variants of CR2 gene in monozygotic twin patients with common variable immunodeficiency.

June 18, 2020 By Manish Butte

Whole exome sequencing identifies compound heterozygous variants of CR2 gene in monozygotic twin patients with common variable immunodeficiency.

SAGE Open Med. 2020;8:2050312120922652

Authors: Mat Ripen A, Ghani H, Chear CT, Chiow MY, Syed Yahya SNH, Kassim A, Mohamad SB

Abstract
Objectives: A pair of female Malay monozygotic twins who presented with recurrent upper respiratory tract infections, hepatosplenomegaly, bronchiectasis and bicytopenia were recruited in this study. Both patients were suspected with primary immunodeficiency diseases. However, the definite diagnosis was not clear due to complex disease phenotypes. The objective of this study was to identify the causative gene mutation in these patients.
Methods: Lymphocyte subset enumeration test and whole exome sequencing were performed.
Results: We identified a compound heterozygous CR2 mutation (c.1916G>A and c.2012G>A) in both patients. These variants were then confirmed using Sanger sequencing.
Conclusion: Whole exome sequencing analysis of the monozygotic twins revealed compound heterozygous missense mutations in CR2.

PMID: 32547748 [PubMed]