Case Report: Profound newborn leukopenia related to a novel RAC2 variant.

Abstract

We report the case of a 1-week-old male born full-term, who had two inconclusive severe combined immunodeficiency (SCID) newborn screens and developed scalp cellulitis and Escherichia coli bacteremia. He did not pass early confirmatory hearing screens. Initial blood counts and lymphocyte flow cytometry revealed profound neutropenia and lymphopenia with a T-/B-/NK- phenotype. Red blood cell adenosine deaminase 1 activity was within normal limits. A presumptive diagnosis of reticular dysgenesis was considered. Granulocyte colony-stimulating factor was started, but there was no improvement in neutrophil counts. Subsequent lymphocyte flow cytometry at around 4 weeks of age demonstrated an increase in T-, B- and NK-cell numbers, eliminating suspicion for SCID and raising concern for congenital neutropenia and bone marrow failure syndromes. Genetic testing revealed a novel variant in RAC2 [c.181C>A (p.Gln61Lys)] (Q61K). RAC2, a Ras-related GTPase, is the dominant RAC protein expressed in hematopoietic cells and is involved with various downstream immune-mediated responses. Pathogenic RAC2 variants show significant phenotypic heterogeneity (spanning from neutrophil defects to combined immunodeficiency) across dominant, constitutively activating, dominant activating, dominant negative, and autosomal recessive subtypes. Given the identification of a novel variant, functional testing was pursued to evaluate aberrant pathways described in other RAC2 pathogenic variants. In comparison to wild-type RAC2, the Q61K variant supported elevated superoxide production under both basal and PMA-stimulated conditions, increased PAK1 binding, and enhanced plasma membrane ruffling, consistent with other dominant, constitutively active mutations. This case highlights the diagnostic challenge associated with genetic variants identified via next-generation sequencing panels and the importance of functional assays to confirm variant pathogenicity.

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Citation

Published Version (Please cite this version)

10.3389/fped.2024.1365187

Publication Info

Hall, Geoffrey, Ágnes Donkó, Cristina Pratt, Julie J Kim-Chang, Paul L Martin, Amy P Stallings, John W Sleasman, Steven M Holland, et al. (2024). Case Report: Profound newborn leukopenia related to a novel RAC2 variant. Frontiers in pediatrics, 12. p. 1365187. 10.3389/fped.2024.1365187 Retrieved from https://hdl.handle.net/10161/30419.

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Scholars@Duke

Kim-Chang

Julie Joo Yeon Kim-Chang

Assistant Professor of Pediatrics
Martin

Paul Langlie Martin

Professor of Pediatrics

For most of my career in Pediatric Hematology/Oncology I have focused on the use of stem cell transplant for the treatment of pediatric leukemias (ALL, AML, CML and JMML) and other non-malignant blood disorders, such as sickle cell disease, hemaphagocytic disorders, Wiskott-Aldrich, aplastic anemia, Diamond-Blackfan Anemia, as well as inherited metabolic diseases. In addition to focusing on determining the best use of stem cell transplants for these disorders, I have also been involved in clinical research investigating the prevention and treatment of transplant related morbidity, particularly veno-occlusive disease of the liver, infections and diffuse alveolar hemorrhage. As study chair for the Children's Oncology Group protocol 9904, I was involved in the development, implementation and analysis of a large, international frontline study of childhood acute lymphoblastic leukemia. Results from this study show that a significant number of children with certain favorable cytogenetic abnormalities in their leukemic cells and who have a rapid response to their initial chemotherapy can expect to have a >95% chance of cure when treated with relatively low intensity chemotherapy.  

I have concentrated on providing high quality care for high risk leukemia patients who require high intensity therapies, such as stem cell transplant and immunotherapy.  As a member of the Pediatric Transplant and Cellular Therapy Division I provide clinical care for these patients.  As a member of various cooperative groups and local PI for several drug trials, I have worked to provide better care and more specific therapies for the toxicities associated with stem cell transplant.  

I have also collaborated with the Pediatric Immunology Division to provide a life-saving therapy for a small group of patients with thymic dysfunction, which causes severe immunodeficiency.  Our clinical team now provides support during these patients hospital admissions for donor thymus tissue implantation.  We once again achieved a new record for the number of implanted patients during the 2022-2023 academic year.

Stallings

Amy Stallings

Associate Professor of Pediatrics

I am a Clinician Educator with a primary interest in Pediatric food allergy, allergic rhinitis, and eczema. I am also the Allergy and Immunology Fellowship Training Director. I conduct clinical research in food allergy and asthma.

Sleasman

John William Sleasman

Dr. Glenn A. Kiser and Eltha Muriel Kiser Professor of Pediatrics
Mousallem

Talal Imad Mousallem

Associate Professor of Pediatrics

I am an allergist and immunologist who cares for children. I manage patients with primary immunodeficiency and different allergic diseases. This includes managing patients with recurrent infections, allergic rhinitis, asthma, food allergy, drug allergy, stinging insect hypersensitivity, urticaria/ angioedema, and allergic skin disease. I also see patients with abnormal severe combined immunodeficiency newborn screen results.


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