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Fulltext Severe combined immunodeficiency in a Malaysian child

Noh LM, Amir HL, Hung LC, Zulkifli I, Nasuruddin BA

Med J Malaysia, 1997 Mar;52(1):88-91.
PMID: 10968061

A 3-month-old Malay male infant presented with multiple infections (candidiasis, Pseudomonas aeruginosa, Cytomegalovirus), persistent pneumonia, intractable diarrhoea and failure to thrive. There was lymphopaenia affecting both T and B subsets. He developed Graft versus Host disease weeks following transfusion with non irradiated blood. In spite of aggressive microbicidal and supportive therapy including regular immunoglobulin infusions, the child succumbed to infection before a bone marrow transplant could be instituted.

Matched MeSH terms: Severe Combined Immunodeficiency/complications; Severe Combined Immunodeficiency/immunology*
Long-Term Health Outcome and Quality of Life Post-HSCT for IL7Rα-, Artemis-, RAG1- and RAG2-Deficient Severe Combined Immunodeficiency: a Single Center Report

Abd Hamid IJ, Slatter MA, McKendrick F, Pearce MS, Gennery AR

J Clin Immunol, 2018 08;38(6):727-732.
PMID: 30105620 DOI: 10.1007/s10875-018-0540-9

Hematopoietic stem cell transplantation (HSCT) is curative for severe combined immunodeficiency (SCID), but data on long-term impact of pre-HSCT chemotherapy, immune reconstitution and quality of life (QoL) of specific SCID genotypes are limited. We evaluated the long-term immune-reconstitution, health outcome and QoL in IL7Rα SCID, Artemis and RAG1 and 2 SCID survivors > 2 years post-HSCT in our center. Clinical data and immune reconstitution parameters were collated, and patients/families answered PedsQL generic core scale v4.0 questionnaires. Thirty-nine patients with a diagnosis of IL7Rα SCID (17 patients), Artemis SCID (8 patients) and RAG1/2 SCID (13 patients) had undergone HSCT with median age at last follow up for IL7Rα SCID, 14 years (range 4-27) and Artemis and RAG1/2 SCID, 10 years (range 2-18). Many patients have ongoing medical issues at latest follow-up [IL7Rα (73%), Artemis (85%), RAG1/2 (55%)]. Artemis SCID patients experienced more sequela than RAG1/2 SCID. Conditioned recipients with Artemis and RAG SCID had more CD4+ naïve lymphocytes compared to unconditioned recipients. All patients except those of IL7Rα SCID reported lower QoL; further subset group analysis showed parents and Artemis and RAG1/2 survivors without ongoing medical issues reported normal QoL. Conditioned recipients have superior long-term thymopoiesis, chimerism and immunoglobulin-independence. QoL was normal in those who did not have medical issues at long-term follow-up.

Matched MeSH terms: Severe Combined Immunodeficiency/diagnosis; Severe Combined Immunodeficiency/etiology*; Severe Combined Immunodeficiency/epidemiology*; Severe Combined Immunodeficiency/therapy
Fulltext Spectrum of Viral Infections Among Primary Immunodeficient Children: Report From a National Registry

Al-Herz W, Essa S

Front Immunol, 2019;10:1231.
PMID: 31191561 DOI: 10.3389/fimmu.2019.01231

Objective: To present the frequency and spectrum of viral infections in primary immunodeficient children. Methods: The data was obtained from the Kuwait National Primary Immunodeficiency Disorders (PIDs) Registry during the period of 2004-2018. Results: A total of 274 PID children were registered in KNPIDR during the study period with predominance of immunodeficiencies affecting cellular and humoral immunity, followed by combined immunodeficiencies with associated syndromic features and diseases of immune dysregulation. Overall infectious complications affected 82.4% of the patients, and viral infections affected 31.7% of the registered patients. Forty-five patients (16.4%) developed viral infections caused by at least 2 organisms, among those 20 patients were affected by three or more viral infections. There was a statistically significant association between viral infections and PID category. However, there was no statistically significant association between viral infections and gender or the patients' onset age. There was a total of 170 viral infections during the study period and the causes of these infections were predominated by CMV (22.2%), adenovirus (11.7%), EBV (11.1%), and enteroviruses (7.4%). CMV and parainfluenza infections were more common in the group of immunodeficiencies affecting cellular and humoral immunity while EBV and human papilloma virus (HPV) were more common in the immune dysregulation group and combined immunodeficiencies with associated syndromic features, respectively. The most common presentation was viremia (28.8%) followed by pneumonia (28.2%) and skin infections (17.6%). The most common causes of viremia were CMV followed by adenovirus and EBV, while the most common organisms causing pneumonia were CMV followed by rhinovirus and parainfluenza. There were 80 deaths among the registered patients, 10% were caused by viral infections. Conclusions: Viral infections are common in PIDs and result into a wide-range of clinical manifestations causing significant morbidity and mortality.

Matched MeSH terms: Severe Combined Immunodeficiency/immunology; Severe Combined Immunodeficiency/epidemiology
Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency

Yang W, Lee PP, Thong MK, Ramanujam TM, Shanmugam A, Koh MT, et al.

Clin Genet, 2015 Dec;88(6):542-9.
PMID: 25534311 DOI: 10.1111/cge.12553

Familial multiple intestinal atresias is an autosomal recessive disease with or without combined immunodeficiency. In the last year, several reports have described mutations in the gene TTC7A as causal to the disease in different populations. However, exact correlation between different genotypes and various phenotypes are not clear. In this study, we report identification of novel compound heterozygous mutations in TTC7A gene in a Malay girl with familial multiple intestinal atresias and severe combined immunodeficiency (MIA-SCID) by whole exome sequencing. We found two mutations in TTC7A: one that destroyed a putative splicing acceptor at the junction of intron 17/exon 18 and one that introduced a stop codon that would truncate the last two amino acids of the encoded protein. Reviewing the recent reports on TTC7A mutations reveals correlation between the position and nature of the mutations with patient survival and clinical manifestations. Examination of public databases also suggests carrier status for healthy individuals, making a case for population screening on this gene, especially in populations with suspected frequent founder mutations.

Matched MeSH terms: Severe Combined Immunodeficiency
Gene therapy: An updated overview on the promising success stories

Rashid RA, Ankathil R

Malays J Pathol, 2020 Aug;42(2):171-185.
PMID: 32860369

Gene therapy is a method of treatment of disease aimed at its molecular level. The progress of gene therapy, however, was as promising as it was tardy mainly due to the limitations in the resources and financial part of its development as well as owing to the rarity of most diseases it can offer its benefits to. The methods of gene therapy can vary depending on factors such as the physiology of tissue of interest, affinity of vectors to a certain type of cells, depth and accessibility of the tissue of interest, and size of the gene to be replaced or edited. The concept behind gene therapy has inspired scientists and clinicians alike leading to a rapid expansion of its clinical utility that has become so widespread to not only include diseases of monogenic origin, but also polygenic diseases, albeit not so commonly. This article delves into notable success stories of gene therapy which has been regarded as the beacon of medical novelty expected to blossom in the near future to provide a holistic, targeted, precise, and individualistic personalised-medicine as well as laying out the future hopes of gene therapy in the treatment of debilitating diseases such as solid tumours, AIDS, Tuberculosis, Diabetes Mellitus, psychiatric illnesses, which are still at a standstill, from a gene therapy point of view.

Matched MeSH terms: Severe Combined Immunodeficiency/therapy
Fulltext Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency

Luk ADW, Lee PP, Mao H, Chan KW, Chen XY, Chen TX, et al.

Front Immunol, 2017;8:808.
PMID: 28747913 DOI: 10.3389/fimmu.2017.00808

BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless treated with hematopoietic stem cell transplant. Delay in diagnosis is common without newborn screening. Family history of infant death due to infection or known SCID (FH) has been associated with earlier diagnosis.
OBJECTIVE: The aim of this study was to identify the clinical features that affect age at diagnosis (AD) and time to the diagnosis of SCID.
METHODS: From 2005 to 2016, 147 SCID patients were referred to the Asian Primary Immunodeficiency Network. Patients with genetic diagnosis, age at presentation (AP), and AD were selected for study.
RESULTS: A total of 88 different SCID gene mutations were identified in 94 patients, including 49 IL2RG mutations, 12 RAG1 mutations, 8 RAG2 mutations, 7 JAK3 mutations, 4 DCLRE1C mutations, 4 IL7R mutations, 2 RFXANK mutations, and 2 ADA mutations. A total of 29 mutations were previously unreported. Eighty-three of the 94 patients fulfilled the selection criteria. Their median AD was 4 months, and the time to diagnosis was 2 months. The commonest SCID was X-linked (n = 57). A total of 29 patients had a positive FH. Candidiasis (n = 27) and bacillus Calmette-Guérin (BCG) vaccine infection (n = 19) were the commonest infections. The median age for candidiasis and BCG infection documented were 3 months and 4 months, respectively. The median absolute lymphocyte count (ALC) was 1.05 × 10(9)/L with over 88% patients below 3 × 10(9)/L. Positive FH was associated with earlier AP by 1 month (p = 0.002) and diagnosis by 2 months (p = 0.008), but not shorter time to diagnosis (p = 0.494). Candidiasis was associated with later AD by 2 months (p = 0.008) and longer time to diagnosis by 0.55 months (p = 0.003). BCG infections were not associated with age or time to diagnosis.
CONCLUSION: FH was useful to aid earlier diagnosis but was overlooked by clinicians and not by parents. Similarly, typical clinical features of SCID were not recognized by clinicians to shorten the time to diagnosis. We suggest that lymphocyte subset should be performed for any infant with one or more of the following four clinical features: FH, candidiasis, BCG infections, and ALC below 3 × 10(9)/L.

Matched MeSH terms: Severe Combined Immunodeficiency
Fulltext Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

Stremenova Spegarova J, Lawless D, Mohamad SMB, Engelhardt KR, Doody G, Shrimpton J, et al.

Blood, 2020 Aug 27;136(9):1055-1066.
PMID: 32518946 DOI: 10.1182/blood.2020005844

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.

Matched MeSH terms: Severe Combined Immunodeficiency/genetics*; Severe Combined Immunodeficiency/pathology