Esra Yucel1, Ibrahim Serhat Karakus2,3, Ana Krolo4,5,6, Ayca Kiykim7, Raul Jimenez Heredia4,5,6,8, Zeynep Tamay1, Funda Erol Cipe9, Elif Karakoc-Aydiner2,3, Ahmet Ozen2,3, Serap Karaman10, Kaan Boztug4,5,6,8,11, Safa Baris12,13. 1. Istanbul Faculty of Medicine, Division of Pediatric Allergy and Immunology, Istanbul University, Istanbul, Turkey. 2. Faculty of Medicine, Division of Pediatric Allergy/Immunology, Marmara University, Fevzi Çakmak Mah. No: 41, Pendik, Istanbul, Turkey. 3. Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey. 4. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria. 5. St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria. 6. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. 7. Faculty of Medicine, Division of Pediatric Allergy and Immunology, Istanbul Cerrahpasa University, Istanbul, Turkey. 8. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. 9. Faculty of Medicine, Department of Pediatrics, Istinye University, Istanbul, Turkey. 10. Istanbul Faculty of Medicine, Division of Pediatric Hematology and Oncology, Istanbul University, Istanbul, Turkey. 11. St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. 12. Faculty of Medicine, Division of Pediatric Allergy/Immunology, Marmara University, Fevzi Çakmak Mah. No: 41, Pendik, Istanbul, Turkey. safabaris@hotmail.com. 13. Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey. safabaris@hotmail.com.
Abstract
PURPOSE: Recently, a new form of congenital neutropenia that is caused by germline biallelic loss-of-function mutations in the SMARCD2 gene was described in four patients. Given the rarity of the condition, the clinical spectrum of the disease has remained elusive. We here report a new patient with a novel frameshift mutation and compare our patient with the previously reported SMARCD2-mutant patients, aiming to provide a more comprehensive understanding of the natural course of the disease. METHODS: Clinical and laboratory findings of all reported patients were reviewed. Next-generation sequencing was performed to identify the causative genetic defect. Data on the hematopoietic stem cell transplantation including stem cell sources, conditioning regimen, engraftment, graft-versus-host disease, and infections were also collected. RESULTS: An 11-year-old female patient had a variety of infections including sepsis, deep tissue abscesses, otitis, pneumonia, gingivitis, and diarrhea since infancy. A novel homozygous mutation in SMARCD2 (c.93delG, p.Ala32Argfs*80) was detected. Bone marrow examination showed hypocellularity and decreased neutrophils with diminished granules and myeloid dysplasia, but no blast excess as in previously reported patients. The neutropenia was non-responsive even to higher doses of granulocyte colony-stimulating factor (G-CSF); therefore, the patient was transplanted at 10 years of age from a HLA-A allele-mismatched unrelated donor using a reduced toxicity conditioning regimen and recovered successfully. Compared with the previous four cases, our patient showed longer survival before transplantation without blastic transformation. CONCLUSION: Distinctive myeloid features and long-term follow-up including therapy options are presented for the newly described case of SMARCD2 deficiency. This disorder is apparent at infancy and requires early transplantation due to the unrelenting disease course despite conventional therapy.
PURPOSE: Recently, a new form of congenital neutropenia that is caused by germline biallelic loss-of-function mutations in the SMARCD2 gene was described in four patients. Given the rarity of the condition, the clinical spectrum of the disease has remained elusive. We here report a new patient with a novel frameshift mutation and compare our patient with the previously reported SMARCD2-mutant patients, aiming to provide a more comprehensive understanding of the natural course of the disease. METHODS: Clinical and laboratory findings of all reported patients were reviewed. Next-generation sequencing was performed to identify the causative genetic defect. Data on the hematopoietic stem cell transplantation including stem cell sources, conditioning regimen, engraftment, graft-versus-host disease, and infections were also collected. RESULTS: An 11-year-old female patient had a variety of infections including sepsis, deep tissue abscesses, otitis, pneumonia, gingivitis, and diarrhea since infancy. A novel homozygous mutation in SMARCD2 (c.93delG, p.Ala32Argfs*80) was detected. Bone marrow examination showed hypocellularity and decreased neutrophils with diminished granules and myeloid dysplasia, but no blast excess as in previously reported patients. The neutropenia was non-responsive even to higher doses of granulocyte colony-stimulating factor (G-CSF); therefore, the patient was transplanted at 10 years of age from a HLA-A allele-mismatched unrelated donor using a reduced toxicity conditioning regimen and recovered successfully. Compared with the previous four cases, our patient showed longer survival before transplantation without blastic transformation. CONCLUSION: Distinctive myeloid features and long-term follow-up including therapy options are presented for the newly described case of SMARCD2 deficiency. This disorder is apparent at infancy and requires early transplantation due to the unrelenting disease course despite conventional therapy.