Research

Humoral deficiency in three paediatric patients with genetic diseases.

Allergol Immunopathol (Madr). 2016 Feb 29;

Authors: Calvo Campoverde K, Gean E, Piquer Gibert M, Martinez Valdez L, Deyà-Martínez A, Rojas Volquez M, Esteve-Sole A, Juan M, Plaza AM, Alsina L

Abstract
BACKGROUND: Primary immunodeficiencies (PID) represent a heterogeneous group of genetic disorders characterised by poor or absent function in one or more components of the immune system. Humoral or antibody immunodeficiencies are the most common form of PID, of which common variable immunodeficiency (CVID) is the most frequent symptomatic form. CVID is usually characterised by hypogammaglobulinaemia with poor antibody specificity, and an increased susceptibility to infections, autoimmunity and lymphoproliferation. Fewer than 10% of CVID patients have a known monogenic basis. Several chromosomal abnormalities (chromosome 18q-syndrome, monosomy 22, trisomy 8 and trisomy 21) are currently identified as causes of hypogammaglobulinaemia, and can manifest with recurrent infections and mimic CVID.
METHODS: Review of clinical charts and laboratory results of paediatric patients followed in the outpatient clinic of PID with a diagnosis of genetic disease and humoral immunodeficiency.
RESULTS: Three patients with different genetic diseases (19p13.3 deletion, a ring 18 chromosome and Kabuki syndrome), were identified. During follow-up, they developed signs and symptoms suggestive of humoral deficiency mimicking CVID, despite which immunoglobulin levels were quantified with considerable delay with respect to symptoms onset, and specific management was subsequently delayed.
CONCLUSIONS: Patients with genetic abnormalities and recurrent infections should be evaluated for hypogammaglobulinaemia. An early diagnosis of humoral deficiency can allow treatment optimisation to prevent complications and sequelae.

PMID: 26947896 [PubMed – as supplied by publisher]

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Identifying Mutations of the Tetratricopeptide Repeat Domain 37 (TTC37) Gene in Infants With Intractable Diarrhea and a Comparison of Asian and Non-Asian Phenotype and Genotype: A Global Case-report Study of a Well-Defined Syndrome With Immunodeficiency.

Medicine (Baltimore). 2016 Mar;95(9):e2918

Authors: Lee WI, Huang JL, Chen CC, Lin JL, Wu RC, Jaing TH, Ou LS

Abstract
Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare, autosomal recessive and severe bowel disorder mainly caused by mutations in the tetratricopeptide repeat domain 37 (TTC37) gene which act as heterotetrameric cofactors to enhance aberrant mRNAs decay. The phenotype and immune profiles of SD/THE overlap those of primary immunodeficiency diseases (PIDs).Neonates with intractable diarrhea underwent immunologic assessments including immunoglobulin levels, lymphocyte subsets, lymphocyte proliferation, superoxide production, and IL-10 signaling function. Candidate genes for PIDs predisposing to inflammatory bowel disease were sequencing in this study.Two neonates, born to nonconsanguineous parents, suffered from intractable diarrhea, recurrent infections, and massive hematemesis from esopharyngeal varices due to liver cirrhosis or accompanying Trichorrhexis nodosa that developed with age and thus guided the diagnosis of SD/THE compatible to TTC37 mutations (homozygous DelK1155H, Fs*2; heterozygous Y1169Ter and InsA1143, Fs*3). Their immunologic evaluation showed normal mitogen-stimulated lymphocyte proliferation, superoxide production, and IL-10 signaling, but low IgG levels, undetectable antibody to hepatitis B surface antigen and decreased antigen-stimulated lymphocyte proliferation. A PubMed search for bi-allelic TTC37 mutations and phenotypes were recorded in 14 Asian and 12 non-Asian cases. They had similar presentations of infantile onset refractory diarrhea, facial dysmorphism, hair anomalies, low IgG, low birth weight, and consanguinity. A higher incidence of heart anomalies (8/14 vs 2/12; P = 0.0344, Chi-square), nonsense mutations (19 in 28 alleles), and hot-spot mutations (W936Ter, 2779-2G>A, and Y1169Ter) were found in the Asian compared with the non-Asian patients. Despite immunoglobulin therapy in 20 of the patients, 4 died from liver cirrhosis and 1 died from sepsis.Patients of all ethnicities with SD/THE with the characteristic triad of T nodosa, hepatic cirrhosis, and intractable enteropathy have low IgG, poor vaccine response and/or decreased antigen-stimulated lymphocyte proliferation. This is now better classified into the subgroup of “well-defined syndromes with immunodeficiency” (the update termed as “combined immunodeficiencies with associated or syndromic features”) than “predominantly antibody deficiencies” in the update PIDs classification, and requires optimal interventions.

PMID: 26945392 [PubMed – as supplied by publisher]

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Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases.

J Allergy Clin Immunol. 2016 Feb 27;

Authors: Conti F, Lugo-Reyes SO, Blancas Galicia L, He J, Aksu G, Borges de Oliveira E, Deswarte C, Hubeau M, Karaca N, de Suremain M, Guérin A, Baba LA, Prando C, Guerrero GG, Emiroglu M, Öz FN, Yamazaki Nakashimada MA, Gonzalez Serrano E, Espinosa S, Barlan I, Pérez N, Regairaz L, Guidos Morales HE, Bezrodnik L, Di Giovanni D, Dbaibo G, Ailal F, Galicchio M, Oleastro M, Chemli J, Danielian S, Perez L, Ortega MC, Soto Lavin S, Hertecant J, Anal O, Kechout N, Al-Idrissi E, ElGhazali G, Bondarenko A, Chernyshova L, Ciznar P, Herbigneaux RM, Diabate A, Ndaga S, Konte B, Czarna A, Migaud M, Pedraza-Sánchez S, Zaidi MB, Vogt G, Blanche S, Benmustapha I, Mansouri D, Abel L, Boisson-Dupuis S, Mahlaoui N, Bousfiha AA, Picard C, Barbouche R, Al-Muhsen S, Espinosa-Rosales FJ, Kütükçüler N, Condino-Neto A, Casanova JL, Bustamante J

Abstract
BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients.
OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD.
METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria.
RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients.
CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

PMID: 26936803 [PubMed – as supplied by publisher]

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B-cell Lymphoproliferative Disorders Associated with Primary and Acquired Immunodeficiency.

Surg Pathol Clin. 2016 Mar;9(1):55-77

Authors: Low LK, Song JY

Abstract
The diagnosis of lymphoproliferative disorders associated with immunodeficiency can be challenging because many of these conditions have overlapping clinical and pathologic features and share similarities with their counterparts in the immunocompetent setting. There are subtle but important differences between these conditions that are important to recognize for prognostic and therapeutic purposes. This article provides a clinicopathologic update on how understanding of these B-cell lymphoproliferations in immunodeficiency has evolved over the past decade.

PMID: 26940268 [PubMed – in process]

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[Lymphocytes B and primary immunodeficiencies].

Rev Alerg Mex. 2016 Jan-Mar;63(1):58-70

Authors: López-Herrera G

Abstract
Primary antibody deficiencies represent the most frequent genetic diseases of the immune system and the first to be recognized along immunology history. The antibodies were recognized as part of the humoral immune system long ago, and after immunoglobulin discovery, the first antibody immunodeficiency were recognized and named as “agammaglobulinemia”, followed by the common variable immunoendeficiency and the hyper-IgM syndrome. The following discoveries in immunology history made possible the understanding of these pathologies, for example: the discoveries of B cells, pre-B cells, the signaling pathway directed by the antigen receptor and many other cellular and molecular mechanisms. Primary antibody deficiencies have been studied for a long time and the discoveries of new syndromes have been helpful in the understanding of immunological mechanisms that take place in our organism. Then, this manuscript pretends to review the relevant findings in the history of immunology, focused on the B cells and the connection with the description of representative clinical entities of primary antibody deficiencies. The aim of this manuscript is to show to the reader that the generation of scientific knowledge has a direct application in the understanding of the molecular mechanisms that are affected in these diseases.

PMID: 26943830 [PubMed – as supplied by publisher]

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X-Linked Agammagobulinemia in a Large Series of North African Patients: Frequency, Clinical Features and Novel BTK Mutations.

J Clin Immunol. 2016 Mar 1;

Authors: Aadam Z, Kechout N, Barakat A, Chan KW, Ben-Ali M, Ben-Mustapha I, Zidi F, Ailal F, Attal N, Doudou F, Abbadi MC, Kaddache C, Smati L, Touri N, Chemli J, Gargah T, Brini I, Bakhchane A, Charoute H, Jeddane L, El Atiqi S, El Hafidi N, Hida M, Saile R, Alj HS, Boukari R, Bejaoui M, Najib J, Barbouche MR, Lau YL, Mellouli F, Bousfiha AA

Abstract
PURPOSE: X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton’s tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton’s disease in 40 North African male patients.
METHODS: Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2 % peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing.
RESULTS: We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5 % vs 85 %). No strong evidence for genotype-phenotype correlation was observed.
CONCLUSIONS: This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.

PMID: 26931785 [PubMed – as supplied by publisher]

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Otologic evaluation of patients with primary antibody deficiency.

Eur Arch Otorhinolaryngol. 2016 Mar 2;

Authors: Magliulo G, Iannella G, Granata G, Ciofalo A, Pasquariello B, Angeletti D, La Marra F, Quinti I

Abstract
Common variable immunodeficiency (CVID) represents the most frequent primary immunodeficiency, often encountered in the ENT clinical practice. The clinical spectrum of CVID is quite broad, but otitis media are certainly among the most common clinical manifestations. This prospective study enrolled 60 patients (34 males, 26 females) with a previous diagnosis of CVID with the aim of performing an otologic evaluation and a more precision characterization of incidence, diagnosis, and treatment of otitis media in this group of patients. In consideration that Eustachian tube dysfunction (ETD) could be the ‘primum movens’ of otitis media, we wanted to assess whether a Eustachian tube dysfunction was present in these patients. Besides, we propose a possible diagnostic algorithm of middle ear pathologies to use in all cases of primary antibody deficiency patients. Results of our otologic examination showed that: 5 % of patients had chronic suppurative otitis media, 25 % bilateral otitis media with effusion and 10 % reported unilateral OME with associated contralateral ETD. There was bilateral isolated ETD and unilateral isolated ETD in 5 and 15 % of patients, respectively. All patients with unilateral OME had associated contralateral ETD. Finally, 40 % of patients were bilaterally negative at otoscopic examination and all otologic tests.

PMID: 26935054 [PubMed – as supplied by publisher]

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Deletion of the entire interferon-γ receptor 1 gene causing complete deficiency in three related patients.

J Clin Immunol. 2016 Mar 1;

Authors: de Vor IC, van der Meulen PM, Bekker V, Verhard EM, Breuning MH, Harnisch E, van Tol MJ, Wieringa JW, van de Vosse E, Bredius RG

Abstract
PURPOSE: Complete interferon-γ receptor 1 (IFN-γR1) deficiency is a primary immunodeficiency causing predisposition to severe infection due to intracellular pathogens. Only 36 cases have been reported worldwide. The purpose of this article is to describe a large novel deletion found in 3 related cases, which resulted in the complete removal of the IFNGR1 gene.
METHODS: Whole blood from three patients was stimulated with lipopolysaccharide (LPS) and IFN-γ to determine production of tumor necrosis factor (TNF), interleukin-12 p40 (IL-12p40) and IL-10. Expression of IFN-γR1 on the cell membrane of patients’ monocytes was assessed using flow cytometry. IFNGR1 transcript was analyzed in RNA and the gene and adjacent regions were analyzed in DNA. Finally, IL22RA2 transcript levels were analyzed in whole blood cells and dendritic cells.
RESULTS: There was no expression of the IFN-γR1 on the monocytes. Consistent with this finding, there was no IFN-γ response in the whole blood assay as measured by effect on LPS-induced IL-12p40, TNF and IL-10 production. A 119.227 nt homozygous deletion on chromosome 6q23.3 was identified, removing the IFNGR1 gene completely and ending 117 nt upstream of the transcription start of the IL22RA2 gene. Transcript levels of IL22RA2 were similar in patient and control.
CONCLUSIONS: We identified the first large genomic deletion of IFNGR1 causing complete IFN-γR1 deficiency. Despite the deletion ending very close to the IL22RA2 gene, it does not appear to affect IL22RA2 transcription and, therefore, may not have any additional clinical consequence.

PMID: 26931784 [PubMed – as supplied by publisher]

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Vici syndrome: a review.

Orphanet J Rare Dis. 2016;11(1):21

Authors: Byrne S, Dionisi-Vici C, Smith L, Gautel M, Jungbluth H

Abstract
Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency. Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal, suggesting an evolving (neuro) degenerative component. In most patients there is additional variable multisystem involvement that may affect virtually any organ system, including lungs, thyroid, liver and kidneys. A skeletal myopathy is consistently associated, and characterized by marked fibre type disproportion, increase in internal nuclei, numerous vacuoles, abnormal mitochondria and glycogen storage. Life expectancy is markedly reduced.Vici syndrome is due to recessive mutations in EPG5 on chromosome 18q12.3, encoding ectopic P granules protein 5 (EPG5), a key autophagy regulator in higher organisms. Autophagy is a fundamental cellular degradative pathway conserved throughout evolution with important roles in the removal of defective proteins and organelles, defence against infections and adaptation to changing metabolic demands. Almost 40 EPG mutations have been identified to date, most of them truncating and private to individual families.The differential diagnosis of Vici syndrome includes a number of syndromes with overlapping clinical features, neurological and metabolic disorders with shared CNS abnormalities (in particular callosal agenesis), and primary neuromuscular disorders with a similar muscle biopsy appearance. Vici syndrome is also the most typical example of a novel group of inherited neurometabolic conditions, congenital disorders of autophagy.Management is currently largely supportive and symptomatic but better understanding of the underlying autophagy defect will hopefully inform the development of targeted therapies in future.

PMID: 26927810 [PubMed – as supplied by publisher]

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Selective immunoglobulin M deficiency in an adult with miliary tuberculosis: A clinically interesting coexistence. A case report and review of the literature.

Int J Mycobacteriol. 2016 Mar;5(1):106-10

Authors: Hassanein HA, Elbadry MI

Abstract
Selective immunoglobulin M (SIgM) deficiency is a rare form of dysgammaglobulinemia. Here we are reporting a 31year old man with multiple cervical and testicular abscesses who was investigated and found to have miliary tuberculosis (MTB) with primary SIgM deficiency (Serum IgM: 17.4mg/dL) and was treated aggressively with anti-tuberculous treatment.

PMID: 26928000 [PubMed – in process]

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