Research

Clinical comparison between patients with selective immunoglobulin A deficiency and other primary immunodeficiencies.

Arch Argent Pediatr. 2015 Apr;113(2):141-5

Authors: Lozano NA, Lozano A, Sasia LV, Saranz RJ, Agresta MF, del Pilar Bovina Martijena M, Ianiero L, Grenat AR

Abstract
Primary immunodeficiencies (PID) are low-prevalence diseases. There are warning signs that may raise clinical suspicion. The objectives of this study were to describe the clinical characteristics and warning signs of patients with PID and to compare the clinical differences between selective immunoglobulin A (IgA) deficiency and other PIDs. Eighty-nine patients were studied; their median age at the time of diagnosis was 6 years old (4.08-11.67). Fifty-three (59.5%) patients were male. Fifty-four (60.7%) patients had selective IgA deficiency, and 35 (39.3%) had other PIDs. The main clinical manifestations were rhinopharyngitis in 65 (73.03%) patients and atopy in 39 (43.82%). Twenty- four (26.97%) patients showed warning signs, and none had selective IgA deficiency. Patients with other PIDs had a higher incidence of lower respiratory tract infection, sepsis, skin infections, mucocutaneous candidiasis, dental alterations, cardiovascular malformations, angioedema, hospitalizations and death. Ten (28.57%) patients received intravenous gammaglobulin, 15 (42.85%) antibiotic prophylaxis, and 2 (2.24%) antifungal prophylaxis.

PMID: 25727826 [PubMed – indexed for MEDLINE]

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Hematopoietic stem cell transplantation corrects osteopetrosis in a child carrying a novel homozygous mutation in the FERMT3 gene.

Bone. 2017 Jan 14;:

Authors: Palagano E, Slatter MA, Uva P, Menale C, Villa A, Abinun M, Sobacchi C

Abstract
Osteopetrosis (OPT) is a rare skeletal disorder with phenotypic and genotypic heterogeneity: a variety of clinical features besides the bony defect may be present, and at least ten different genes are known to be involved in the disease pathogenesis. In the framework of this heterogeneity, we report the clinical description of a neonate, first child of consanguineous parents, who had osteoclast-rich osteopetrosis and bone marrow failure in early life, but no other usual classical features of infantile malignant OPT, such as visual or hearing impairments. Because of the severe presentation at birth, the patient received Hematopoietic Stem Cell Transplantation (HSCT) at 2months of age with successful outcome. Post-HSCT genetic investigation by means of exome sequencing identified a novel homozygous mutation in the Fermitin Family Member 3 (FERMT3) gene, which was predicted to disrupt the functionality of its protein product kindlin 3. Our report provides information relevant to physicians for recognizing patients with one of the rarest forms of infantile malignant OPT, and clearly demonstrates that HSCT cures kindlin 3 deficiency with severe phenotype.

PMID: 28095295 [PubMed – as supplied by publisher]

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Germline IKAROS mutation associated with primary immunodeficiency that progressed to T-cell acute lymphoblastic leukemia.

Leukemia. 2017 Jan 18;:

Authors: Yoshida N, Sakaguchi H, Muramatsu H, Okuno Y, Song C, Dovat S, Shimada A, Ozeki M, Ohnishi H, Teramoto T, Fukao T, Kondo N, Takahashi Y, Matsumoto K, Kato K, Kojima S

Abstract
Leukemia accepted article preview online, 18 January 2017. doi:10.1038/leu.2017.25.

PMID: 28096536 [PubMed – as supplied by publisher]

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Comprehensive assessment of peripheral blood TCRβ repertoire in infectious mononucleosis and chronic active EBV infection patients.

Ann Hematol. 2017 Jan 14;:

Authors: Liu S, Zhang Q, Huang D, Zhang W, Zhong F, Feng J, Chen X, Meng Q, Chen X, Zhang W, Zhang H

Abstract
Epstein-Barr virus (EBV) primary infection is usually asymptomatic, but it sometimes progresses to infectious mononucleosis (IM). Occasionally, some people develop chronic active EBV infection (CAEBV) with underlying immunodeficiency, which belongs to a continuous spectrum of EBV-associated lymphoproliferative disorders (EBV(+) LPD) with heterogeneous clinical presentations and high mortality. It has been well established that T cell-mediated immune response plays a critical role in the disease evolution of EBV infection. Recently, high-throughput sequencing of the hypervariable complementarity-determining region 3 (CDR3) segments of the T cell receptor (T cell receptor β (TCRβ)) has emerged as a sensitive approach to assess the T cell repertoire. In this study, we fully characterized the diversity of peripheral blood TCRβ repertoire in IM (n = 6) and CAEBV patients (n = 5) and EBV-seropositive controls (n = 5). Compared with the healthy EBV-seropositive controls, both IM and CAEBV patients demonstrate a significant decrease in peripheral blood TCRβ repertoire diversity, basically, including narrowed repertoire breadth, highly expanded clones, and skewed CDR3 length distribution. However, there is no significant difference between IM and CAEBV patients. Furthermore, we observed some disease-related preferences in TRBV/TRBJ usage and combinations, as well as lots of T cell clones shared by different groups (unique or overlapped) involved in public T cell responses, which provide more detailed insights into the divergent disease evolution.

PMID: 28091735 [PubMed – as supplied by publisher]

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[Recurrent meningitis and inherited complement deficiency].

Epidemiol Mikrobiol Imunol. 2016;65(4):238-242

Authors: Šrotová A, Litzman J, Rumlarová Š, Drahošová M, Bartoňková D, Krčmová I, Roberts A, Jolles S, Králíčková P

Abstract
Complement deficiency represents 5% of primary immunodeficiencies worldwide. A total of seven patients with deficiencies of the classical complement pathway were reported in the Czech Republic by the end of 2015. Typical manifestations of complement deficiency are recurrent meningitis, other bacterial infections, autoimmunity and kidney disease.Two case reports are presented of patients with molecularly confirmed C7 (compound heterozygote, c.663_644del in exon 6 and c.2350+2T:>C in intron 16) and C8 (homozygous c.1282C>T in exon 9) deficiency. The first patient had four attacks of meningococcal meningitis and an episode of pneumonia of unknown aetiology in childhood. The second had six attacks of meningitis. He also suffered from recurrent infections (otitis media, tonsillitis, chronic mucopurulent rhinitis and subsequent pansinusitis complicated by nasal polyposis) since childhood. No autoimmune disease was documented in either patient. They both received meningococcal and pneumococcal vaccines. Antibiotic prophylaxis was used only in the second patient, leading to a decline in the number of ENT infections.Complement deficiency should be suspected in patients with recurrent meningococcal infections, especially if combined with other infections caused by encapsulated bacteria or autoimmunity diseases. Prophylaxis with conjugate polysaccharide vaccines is recommended and antibiotic prophylaxis should be considered in individual cases.

PMID: 28078901 [PubMed – in process]

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Intravenous Immunoglobulin in the Treatment of Primary Immunodeficiency Diseases.

Pediatr Ann. 2017 Jan 01;46(1):e8-e12

Authors: De Ranieri D, Fenny NS

Abstract
Intravenous immunoglobulin (IVIG) has been used as antibody replacement therapy in primary immunodeficiency diseases (PIDDs) for more than 50 years. Its role as a therapeutic agent has expanded over the past couple of decades as its anti-inflammatory and immune-modulatory mechanisms of action have been elucidated. It is now used “off-label” to treat other autoimmune diseases. This article focuses on the role of IVIG in the treatment of PIDDs characterized by absent or deficient antibody production. Replacement doses are given on a monthly basis in these conditions as a prophylactic measure to prevent acute and serious bacterial infections. [Pediatr Ann. 2017;46(1):e8-e12.].

PMID: 28079912 [PubMed – in process]

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Low immunoglobulin E flags two distinct types of immune dysregulation.

Clin Exp Immunol. 2017 Jan 11;:

Authors: Elkuch M, Greiff V, Berger CT, Bouchenaki M, Daikeler T, Bircher A, Navarini AA, Heijnen I, Recher M

Abstract
During the last two decades, hyper-immunoglobulin (Ig)E syndromes have been characterized clinically and molecularly in patients with genetically determined primary immunodeficiencies. However, the detection of low IgE levels, defined here as below detection limit in the routine clinical immunology laboratory, has received little attention. We analysed the association of serum IgA, IgM and IgG levels (including IgG subclasses) with low, normal or high serum IgE levels in patients evaluated in a single-centre out-patient immunodeficiency and allergy clinic. The correlation of serum IgE levels with IgG subclasses depended on the clinical phenotype. In patients with immunodeficiencies, IgE correlated with IgG2 and IgG4 but not with IgG3. In contrast, in patients referred for signs of allergy, IgE correlated with IgG3 but not with IgG2. A low IgE result was associated with low IgG3 and IgG4 in allergy referrals, while immunodeficiency referrals with a low IgE result had significantly lower IgG1, IgG2 and IgG4 levels. Hierarchical clustering of non-IgE immunoglobulin profiles (IgM, IgA, IgG, IgG1-4) validated that non-IgE immunoglobulin levels predict the clinic referral, i.e. phenotype, of low-IgE patients. These results suggesto guide the clinical management of patients with low serum IgE levels.

PMID: 28078662 [PubMed – as supplied by publisher]

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FOXN1 deficient nude severe combined immunodeficiency.

Orphanet J Rare Dis. 2017 Jan 11;12(1):6

Authors: Rota IA, Dhalla F

Abstract
Nude severe combined immunodeficiency is a rare inherited disease caused by autosomal recessive loss-of-function mutations in FOXN1. This gene encodes a transcription factor essential for the development of the thymus, the primary lymphoid organ that supports T-cell development and selection. To date nine cases have been reported presenting with the clinical triad of absent thymus resulting in severe T-cell immunodeficiency, congenital alopecia universalis and nail dystrophy. Diagnosis relies on testing for FOXN1 mutations, which allows genetic counselling and guides therapeutic management. Options for treating the underlying immune deficiency include HLA-matched genoidentical haematopoietic cell transplantation containing mature donor T-cells or thymus tissue transplantation. Experience from other severe combined immune deficiency syndromes suggests that early diagnosis, supportive care and definitive management result in better patient outcomes. Without these the prognosis is poor due to early-onset life threatening infections.

PMID: 28077132 [PubMed – in process]

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[Clinical and immunological analysis of the patient with autoimmunity due to germline STAT3 gain-of-function mutation].

Zhonghua Er Ke Za Zhi. 2017 Jan 02;55(1):30-36

Authors: Ding Y, Zhang Y, Wang YP, Zhao HY, Chen XM, Xue XH, Bai XM, An YF, Zhang ZY, Tang XM, Zhao XD

Abstract
Objective: To investigate the clinical and immunological laboratory features and gene mutation in a female patient who carried a germline gain-of-function mutation in STAT3. Method: A patient with lymphadenopathy and pancytopenia, visited the Department of Rheumatology and Immunology of Children’s Hospital of Chongqing Medical University in May 2016. The clinical and laboratory characteristics, results of immunophenotyping and exome sequencing were analyzed retrospectively and related literature was reviewed. Result: The patient was a four years old girl. The clinical manifestation consisted of autoimmune pancytopenia, lymphadenopathy and recurrent infections. Multiple exams showed that peripheral blood leukocyte count was (2.2-4.9)×10(9)/L, red blood cell count was (2.09-5.75)×10(9)/L, hemoglobin level was 64-165 g/L, platelet count was (52-138) ×10(9)/L. Percentages of lymphocyte subsets showed that CD3(+) T lymphocyte was 0.716 0 (CD4(+) T lymphocyte was 0.326 0, CD8(+) T lymphocyte was 0.323 0 and CD4(-) CD8(-)T TCRαβ(+) lymphocyte was 0.029 0), CD19(+) B lymphocyte was 0.235 0 (transitional B was 0.004 3), NK was 0.032 0. Percentages of CD4(+) T lymphocyte release IL-4, IFN-γ, IL-17 and IL-21 were 0.014 9, 0.213, 0.024 0 and 0.021 0, respectively. Lymphocyte proliferation function and TCRVβ diversity were normal. The serum immunoglobulin levels were 16.4 g/L (IgG), 1.53 g/L (IgA), 3.99 g/L (IgM) and 3.20 kU/L (IgE). The patient carried a missense variant in the 21(st) exon of STAT3, c. 1974G>C, p.K658N, which was previously described as a gain-of-function mutation. The patient was treated with methylprednisolone and prednisone intermittently. There were significant improvements of hepatosplenomegaly, lymphadenopathy and pancytopenia. We searched internal database and literature for cases with gain-of-function mutations in STAT3. A total of 19 cases were identified, all were non-Chinese. Among 16 cases who had clinical data, age of onset of 11 patients was less than 5 years. 14 cases had autoimmune hemolytic anemia, autoimmune thrombocytopenia or autoimmune neutropenia. Twelve patients had lymphadenopathy while 11 had infections and 5 had endocrine abnormalities. Conclusion: The patient with Primary immunodeficiency disease (PID) due to gain-of-function mutation in STAT3 gene often has early-onset autoimmune disorders, lymphadenopathy and recurrent infections. Since the routine immunological examination may be normal or slightly abnormal, comprehensive evaluation of immune function should be done. Genetic testing ultimately helps to confirm the diagnosis.

PMID: 28072956 [PubMed – in process]

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