Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular ...genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.05 × 109 autologous T cells/L on repetitive testing, with either pathogenic variant(s) in a SCID-associated gene, very low/undetectable T-cell receptor excision circles or less than 20% of CD4 T cells expressing naive markers, and/or transplacental maternally engrafted T cells. Patients with less profoundly impaired autologous T-cell differentiation are designated as having leaky/atypical SCID, with 2 or more of these: low T-cell numbers, oligoclonal T cells, low T-cell receptor excision circles, and less than 20% of CD4 T cells expressing naive markers. These patients must also have either pathogenic variant(s) in a SCID-associated gene or reduced T-cell proliferation to certain mitogens. Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly. Thymic stromal defects and other causes of secondary T-cell deficiency are excluded from the definition of SCID. Application of these revised Primary Immune Deficiency Treatment Consortium 2022 Definitions permits precise categorization of patients with T-cell defects but does not imply a preferred treatment strategy.
Newly diagnosed immune thrombocytopenia (ITP) is a relatively common disorder of childhood that does not require an exhaustive laboratory workup for diagnosis. A history and physical exam with a ...review of the peripheral smear are crucial for excluding secondary causes of thrombocytopenia. Several guidelines have been published to guide physicians in the management of ITP. However, the decision for treatment can be arduous. The management strategy should not be focussed on the platelet count but the severity of bleeding symptoms. Agents for treating acute ITP, including corticosteroids, immunoglobulin and anti-D immunoglobulin, do not seem to have a significant impact on the natural history of the disease. The majority of children with ITP do not need therapy and have a spontaneous resolution of the disease. Some children can develop chronic ITP that is not commonly life-threatening but can lead to impaired quality of life. Traditional therapies such as rituximab and splenectomy for chronic ITP are not without significant adverse effects. Thrombopoietin receptor agonists are newer agents for the treatment of chronic ITP and hold promise, however, their cost currently precludes use in most of the patients in low-middle-income countries. This review compares and contrasts the specific treatments available for the treatment of ITP to help the reader make a balanced choice. This review, based on a series of case examples, will help physicians in making decisions about choosing a practical management strategy for patients with newly diagnosed as well as chronic ITP.
Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)–B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)–MALT1 paracaspase (MALT1) (CBM) complex are ...associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation. However, the impact of CARD11 deficiency on human B-cell development, signaling, and function is incompletely understood.
This study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis.
Patients underwent next-generation sequencing, immunophenotyping by flow cytometry, signaling assays by immunoblot, and transcriptome profiling by RNA-sequencing.
Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression. This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cTFH) development, which was associated with impaired antibody responses and absent germinal center structures on lymph node histology. Transcriptomics indicated that CARD11-dependent signaling is essential for immune signaling pathways involved in the development of these cells. Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization.
Complete human CARD11 deficiency causes profound CID by impairing naive/type 1 B-cell and cTFH cell development and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. Hematopoietic stem cell transplantation functionally restores impaired signaling pathways.
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In April 2019, the Alberta Newborn Screening Program expanded to include screening for classic galactosemia using a two-tier screening approach. This approach secondarily identifies infants with ...glucose-6-phosphate dehydrogenase (G6PD) deficiency. The goals of this study were (i) to evaluate the performance of a two-tier galactosemia screening protocol, (ii) to explore the impact on and acceptability to families of reporting G6PD deficiency as a secondary finding, and (iii) assess the communication and follow-up process for positive G6PD deficiency screening results. The two-tiered galactosemia approach increased the positive predictive value (PPV) for galactosemia from 8% to 79%. An additional 119 positive newborn screen results were reported for G6PD deficiency with a PPV of 92%. The results show that there may be utility in reporting G6PD deficiency results. Most parents who participated in the study reported having some residual worry around the unexpected diagnosis; however, all thought it was helpful to know of their child's diagnosis of G6PD deficiency. Finally, the communication process for reporting G6PD deficiency newborn screen results was determined to result in appropriate follow up of infants.
Ataxia-telangiectasia (AT) is a complex neurodegenerative disease with an increased risk for bone marrow failure and malignancy. AT is caused by biallelic loss of function variants in
, which encodes ...a phosphatidylinositol 3-kinase that responds to DNA damage. Herein, we report a child with progressive ataxia, chorea, and genome instability, highly suggestive of AT. The clinical ataxia gene panel identified a maternal heterozygous synonymous variant (NM_000051.3: c.2250G > A), previously described to result in exon 14 skipping. Subsequently, trio genome sequencing led to the identification of a novel deep intronic variant NG_009830.1(NM_000051.3): c.1803-270T > G inherited from the father. Transcript analyses revealed that c.1803-270T > G results in aberrant inclusion of 56 base pairs of intron 11.
tests predicted a premature stop codon as a consequence, suggesting non-functional ATM; and DNA repair analyses confirmed functional loss of ATM. Our findings highlight the power of genome sequencing, considering deep intronic variants in undiagnosed rare disease patients.
Childhood cancer and its treatment often impact the haematopoietic and lymphatic systems, with immunological consequences. Immunological assessments are not routinely included in surveillance ...guidelines for most survivors of childhood cancer, although a robust body of literature describes immunological outcomes, testing recommendations, and revaccination guidelines after allogeneic haematopoietic cell transplantation. Survivorship care providers might not fully consider the impaired recovery of a child's immune system after cancer treatment if the child has not undergone haematopoietic cell transplantation. We did a scoping review to collate the existing literature describing immune function after childhood cancer therapy, including both standard-dose chemotherapy and high-dose chemotherapy with haematopoietic cell rescue. This Review aims to summarise: the principles of immunology and testing of immune function; the body of literature describing immunological outcomes after childhood cancer therapy, with an emphasis on the risk of infection, when is testing indicated, and preventive strategies; and knowledge gaps and opportunities for future research.
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous non-Hodgkin lymphoma involving CD8+ T cells, the genetic underpinnings of which remain incompletely understood. Here ...we report two unrelated patients with B cell Expansion with NF-κB and T cell Anergy (BENTA) disease and a novel presentation of SPTCL. Patient 1 presented early in life with recurrent infections and B cell lymphocytosis, linked to a novel gain-of-function (GOF) CARD11 mutation (p.Lys238del). He developed SPTCL-like lesions and membranoproliferative glomerulonephritis by age 2, treated successfully with cyclosporine. Patient 2 presented at 13 months with splenomegaly, lymphadenopathy, and SPTCL with evidence of hemophagocytic lymphohistiocytosis. Genetic analysis revealed two in cis germline GOF CARD11 variants (p.Glu121Asp/p.Gly126Ser). Autologous bone marrow transplant resulted in SPTCL remission despite persistent B cell lymphocytosis. These cases illuminate an unusual pathological manifestation for BENTA disease, suggesting that CARD11 GOF mutations can manifest in cutaneous CD4+and CD8+ T cell malignancies.
•We describe 2 patients with BENTA disease and a novel presentation of SPTCL/ALLP.•Though unusual, SPTCL noted in BENTA may require aggressive treatment if severe.•CARD11 GOF variants can occur in both CD4+ and CD8+ T cell dyscrasias.
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