Novel biallelic TRNT1 mutations resulting in sideroblastic anemia, combined B and T cell defects, hypogammaglobulinemia, recurrent infections, hypertrophic cardiomyopathy and developmental delay

2018 ◽  
Vol 188 ◽  
pp. 20-22 ◽  
Author(s):  
Vassilios Lougaris ◽  
Janet Chou ◽  
Manuela Baronio ◽  
Luisa Gazzurelli ◽  
Tiziana Lorenzini ◽  
...  
Keyword(s):  
T Cell ◽  
Hypertrophic Cardiomyopathy ◽  
Developmental Delay ◽  
Recurrent Infections ◽  
Sideroblastic Anemia

scholarly journals Autoimmunity and immunodeficiency at the crossroad: autoimmune disorders as the presenting feature of selective IgM deficiency

2019 ◽  
Vol 12 (1) ◽  
pp. e223180
Author(s):  
Corrado Campochiaro ◽  
Sirin Atay ◽  
Kristina E N Clark ◽  
Voon Ong ◽  
Christopher P Denton
Keyword(s):  
T Cell ◽  
Literature Review ◽  
Autoimmune Diseases ◽  
European Society ◽  
Immunoglobulin M ◽  
External Factors ◽  
Recurrent Infections ◽  
Serum Iga ◽  
History Of ◽  
Igm Deficiency

Selective immunoglobulin M deficiency (sIgMD) is an immunodeficiency with undefined pathogenesis and commonly presenting with recurrent infections.1The European Society for Immunodeficiencies Registry defines sIgMD as a serum IgM level repeatedly below 2 SD of normal with normal levels of serum IgA, IgG and IgG subclasses, normal vaccination responses, absence of T-cell defects and absence of causative external factors. Rarely it can also be associated with autoimmune diseases.2–7Here we describe a patient with primary sIgMD; who presented with multiple autoimmune diseases without a history of recurrent infections and we provide a short literature review on sIgMD and autoimmune diseases.

scholarly journals P.133 Expanding the phenotype of TRNT1 mutations to include Leigh syndrome

2018 ◽  
Vol 45 (s2) ◽  
pp. S51-S51
Author(s):  
C Gorodetsky ◽  
CF Morel ◽  
I Tein
Keyword(s):  
Developmental Delay ◽  
Early Adulthood ◽  
Leigh Syndrome ◽  
Global Developmental Delay ◽  
High Dose ◽  
Sideroblastic Anemia ◽  
Whole Exome ◽  
Mitochondrial Transfer ◽  
Neurological Phenotype ◽  
Biallelic Mutations

Background: Children with biallelic mutations in TRNT1 have multi-organ involvement with congenital sideroblastic anemia, -B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) as well as seizures, ataxia and sensorineural hearing loss. The TRNT1 gene encodes the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs accounting for phenotypic pleitropy. Neurodegenerative Leigh syndrome has not been previously reported. Methods:Case summary: A Portuguese boy presented with global developmental delay, 2 episodes of infantile Leigh encephalopathy at 8 mo and 4 yr responsive to high-dose steroids, slow neurodegeneration of cognitive, language and motor functions with optic atrophy, pigmentary retinopathy, spasticity, dystonia, and focal dyscognitive seizures, pancytopenia, transfusion dependent sideroblastic anemia, recurrent febrile infections (pulmonary, gastrointestinal), hypernatremia, with tracheostomy dependence at age 5 yr, malabsorption and TPN dependence at 9 yr, and survival to early adulthood. Neuroimaging showed symmetric hemorrhagic lesions in the thalamus, brain stem (periaqueductal grey) and cerebellum consistent with Leigh syndrome but no lactate peak on MRS. Results: Whole exome sequencing identified a homozygous missense pathogenic variant in TRNT1, c.668T>C (p.I223T) in the affected individual. Conclusions: This report expands the neurological phenotype of TRNT1 mutations and highlights the importance of considering this gene in the evaluation of Leigh syndrome.

Biallelic TRNT1 variants in a child with B cell immunodeficiency, periodic fever and developmental delay without sideroblastic anemia (SIFD variant)

2020 ◽  
Vol 225 ◽  
pp. 64-65
Author(s):  
Donato Rigante ◽  
Emilia Stellacci ◽  
Chiara Leoni ◽  
Roberta Onesimo ◽  
Francesca Clementina Radio ◽  
...  
Keyword(s):  
B Cell ◽  
Developmental Delay ◽  
Periodic Fever ◽  
Sideroblastic Anemia

Familial and Acquired SH2B3 mutations in ALL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1326-1326
Author(s):  
Arianne Perez-Garcia ◽  
Charles A. LeDuc ◽  
Kara A. Kelly ◽  
Chaim Jalas ◽  
Wendy K Chung ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Growth ◽  
Tumor Suppressor ◽  
Developmental Delay ◽  
Genetic Defect ◽  
Adaptor Protein ◽  
Genetic Alterations ◽  
Ashkenazi Jewish ◽  
Wild Type ◽  
Stat Signaling

Abstract Abstract 1326 Acute lymphoblastic leukemia (ALL) is a heterogeneous disease in which multiple genetic alterations contribute to the malignant transformation of lymphoid progenitor cells. Although the pathogenesis of ALL is considered to be multifactorial, few environmental factors have been conclusively associated with increased risk. In addition, although recent genome-wide association studies of childhood ALL have suggested that common variation at some genetic loci may predispose to ALL, the risk associated with these variants seems to be modest. Here we hypothesized that leukemia development in the context of rare familial inherited disorders may indicate a tumor suppressor activity for the underlying genetic defect present in these kindreds. In this context, we studied a pediatric B precursor ALL female patient of Eastern European Ashkenazi Jewish background with a history of remote consanguinity, short stature and mild developmental delay. Her family history is significant for a brother with similar growth retardation and mild developmental defects, neonatal anemia, thrombocytopenia and elevated white cell count, who was diagnosed with chronic hepatitis of probable autoimmune origin and Hashimoto's autoimmune thyroiditis. A second male sibling was healthy. We proposed that an underlying autosomal recessive genetic defect resulting in dysregulation of the development and function of the immune system could contribute to the concurrence of a lymphoid neoplasia and an autoimmune disorder in two siblings in this family. We performed homozygosity mapping and linkage analysis in the family. Whole exome sequencing of each of the two affected siblings identified a homozygous frameshift c.671insGGCCCCG p.Asp231fs mutation in the SH2B3 gene. Dideoxynucleotide sequencing of SH2B3 confirmed that both affected siblings were homozygous for this mutation, while the unaffected brother and both parents were carriers. Analysis of 2,000 normal Ashkenazi Jewish adults identified 1 SH2B3 c.671insGGCCCCG p.Asp231fs carrier and no homozygous individuals. The SH2B adaptor protein gene 3 (SH2B3) encodes an adaptor protein involved in the negative regulation of the JAK STAT signaling pathway. Western Blot analysis of immortalized lymphoblastoid cell lines from the two affected siblings and an unrelated normal control showed complete loss of SH2B3 protein expression in SH2B3 mutant cells. Consistently, analysis of JAK STAT signaling in these cells showed increased JAK2 and STAT3 phosphorylation compared with controls. Moreover, SH2B3 mutant lymphoblastoid cells showed increased proliferation and accelerated cell cycle kinetics, which was particularly pronounced in low serum conditions. Consistently, expression of wild type SH2B3 in these cells impaired cell growth and decreased JAK-STAT signaling. Analysis of a cohort of 167 additional ALLs including 119 B-precursor ALLs and 48 T-ALLs identified a homozygous c.1279insCTGTTGCCGTGTGC p.Val426fs SH2B3 mutation in a B-precursor ALL sample and a homozygous nonsense c.908C>A p.Ser303* SH2B3 mutation in a pediatric T-cell ALL. Notably, analysis of normal (remission) DNA demonstrated the somatic origin of the c.908C>A p.Ser303* SH2B3 mutation. In addition, our sequence analysis of SH2B3 in ALL identified two additional heterozygous germline single nucleotide variants resulting in amino acid substitutions (c.557G>T p.Ser186Ile and c.232G>A p.Glu78Lys). Expression of each of these variants in SH2B3 null cells resulted in partial correction of the increased cell growth phenotype and JAK-STAT signaling associated with SH2B3 loss compared with wild type controls. Notably, heterozygous somatic mutations in SH2B3 have been observed in patients with myeloproliferative neoplasms and heterozygous germline SH2B3 alleles have been linked to essential erythrocytosis, suggesting that the hypomorphic SH2B3 p.Ser186Ile and p.Glu78Lys variants found in our analysis may represent rare leukemia predisposing SH2B3 alleles. Overall these results link the loss of SH2B3 with the pathogenesis of a familial developmental delay, autoimmunity and leukemia predisposition syndrome and demonstrate a tumor suppressor role for SH2B3 in the pathogenesis of B-precursor and T-cell ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD)

Blood ◽  
2013 ◽  
Vol 122 (1) ◽  
pp. 112-123 ◽  
Author(s):  
Daniel H. Wiseman ◽  
Alison May ◽  
Stephen Jolles ◽  
Philip Connor ◽  
Colin Powell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Developmental Delay ◽  
Bone Marrow Transplant ◽  
Marrow Transplant ◽  
Clinical Syndrome ◽  
Sideroblastic Anemia ◽  
Key Points ◽  
Congenital Sideroblastic Anemia

Key Points A novel clinical syndrome of CSA, B-cell immunodeficiency, periodic fevers, and developmental delay is described. Bone marrow transplant resulted in complete and durable resolution of the hematologic and immunologic manifestations.

Hypertrophic cardiomyopathy, cataract, developmental delay, lactic acidosis: A novel subtype of 3-methylglutaconic aciduria

2006 ◽  
Vol 29 (4) ◽  
pp. 546-550 ◽  
Author(s):  
Gabriella Di Rosa ◽  
Federica Deodato ◽  
Ference J. Loupatty ◽  
Cristiano Rizzo ◽  
Rosalba Carrozzo ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Lactic Acidosis ◽  
Developmental Delay ◽  
Methylglutaconic Aciduria

Relapse of T-cell all after stem cell transplant presenting as hypertrophic cardiomyopathy: The value of non-invasive diagnostic imaging in detecting cardiac leukemia

2005 ◽  
Vol 46 (1) ◽  
pp. 108-111 ◽  
Author(s):  
Tsukasa Hori ◽  
Nobuhiro Suzuki ◽  
Nobuo Mizue ◽  
Naoki Hatakeyama ◽  
Motoki Takamuro ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hypertrophic Cardiomyopathy ◽  
Diagnostic Imaging ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Non Invasive

scholarly journals 22q11.2 deletion syndrome: 20 years of experience from two pediatric immunology units and review of clues for diagnosis and disease management

2021 ◽  
Vol 49 (1) ◽  
pp. 95-100
Author(s):  
Selime Ozen ◽  
Omer Akcal ◽  
Ilke Taskirdi ◽  
Idil Akay Haci ◽  
Neslihan Edeer Karaca ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Subset ◽  
Case Series ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Cardiac Anomaly ◽  
Recurrent Infections ◽  
Speech Impairment ◽  
22Q11.2 Deletion ◽  
T Cell Subset

Introduction and objectives: The purpose of this study was to evaluate patients diagnosed with 22q11.2 deletion syndrome and determine the clues directing to diagnosis and evaluation of immunological findings for excellent management of the disease. Material and methods: Thirty-three pediatric patients with 22q11.2 deletion syndrome diag-nosed between 1998 and 2019 at Pediatric Immunology Division of Ege University Faculty of Medicine and SBU Izmir Dr Behcet Uz Children’s Education and Research Hospital were evaluated. Results: This study includes the largest case series reported from Turkey. Congenital car-diac anomalies were the most common pathology associated with the syndrome (90.9%). Hypocalcemic symptoms were observed in 13 patients (40%). Twenty-two of the 33 (66.6%) patients were diagnosed before two years of age. Autoimmune diseases, dysmorphic facial findings, recurrent infections, growth retardation, and speech impairment were other clues for diagnosis in older patients. Clinical spectrum and immunological abnormalities of this syn-drome are quite variable. All T-cell subset counts were less than 5th percentile below median by age in one patient (3%) and 10 patients had normal all T-cell subset counts (30.3%). Overall, 69.6% of the patients had normal IgG, IgA, and IgM levels and two patients had panhypogam-maglobulinemia. Recurrent infections were revealed in 75.7% of the patients during follow-up. Conclusions: Presence of cardiac anomaly is more helpful in the diagnosis, especially under two years of age. Patients with immunologically high or standard risk did not show any differ-ence in terms of numbers and severity of infections and autoimmunity.

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