Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency

Abstract

Genetic deficiency of adenosine deaminase (ADA) can cause profound lymphopenia and result in the clinical presentation of severe combined immune deficiency (SCID). However, because of the ubiquitous expression of ADA, ADA-deficient patients often present also with nonimmunologic clinical problems, affecting the skeletal, central nervous, endocrine, and gastrointestinal systems. We now report that myeloid dysplasia features and bone marrow hypocellularity are often found in patients with ADA-SCID. As a clinical correlate to this finding, we have observed vulnerability to antibiotic-induced myelotoxicity and prolonged neutropenia after nonmyeloablative chemotherapy. We have also noted that, in the absence of enzyme replacement therapy, absolute neutrophil counts of patients with ADA deficiency vary inversely with the accumulation of deoxynucleotides. These data have significant implications for the application of standard and investigational therapies to patients with ADA-SCID and support further studies to investigate the possibility that ADA deficiency is associated with a stem cell defect. These trials were registered at www.clinicaltrials.gov as #NCT00018018 and #NCT00006319.

Figures

Figure 1

Peripheral blood abnormalities in patients with ADA-SCID. (A) Trilobed eosinophil from patient ADA1. (B) Hyperlobular neutrophil from patient ADA14. (C) Pyknotic neutrophil from patient ADA3. (D) Giant platelet from patient ADA14. (E) Pseudo-Pelger-Hüet cell from patient ADA16. (F) Atypical lymphocyte from patient ADA10. Slides were stained with Wright-Giemsa. Images were obtained via digital microscopy using an Olympus BX-51 microscope equipped with a DPlan 40×/0.65 numeric aperture objective and captured using an Olympus DP70 digital camera system. Microsoft PowerPoint was used to assemble the panels into 1 figure. (A-F) Original magnification ×1000.

Figure 2

Bone marrow abnormalities in patients with ADA-SCID. (A) Hypocellular biopsy from patient ADA1 at 21 years of age. (B) Left-shifted eosinophilia in patient ADA6. (C) Atypical, mononuclear megakaryocytes in a clot section from patient ADA16. (D) Dysplastic megakaryocyte with separated nuclear lobes in patient ADA6. (E) Area of atypical fibrosis in the marrow biopsy of patient ADA10. (F) Hypogranular granulocytic precursor and megaloblastoid erythroid precursor (arrows) in the marrow aspirate of patient ADA10. Biopsies were stained with hematoxylin and eosin and aspirates with Wright-Giemsa. Images were obtained via digital microscopy using an Olympus BX-51 microscope equipped with a DPlan 40×/0.65 numeric aperture objective and captured using an Olympus DP70 digital camera system. Adobe Photoshop CS3 was used to assemble the panels into one figure. (A,E) Original magnification ×40. (B,D,F) Original magnification ×1000. (C) Original magnification ×200.

Figure 3

Response to G-CSF after low-dose busulfan conditioning. Arrows represent G-CSF doses. (A) Patient ADA10. (B) Patient ADA14. (C) Patient ADA16.

Figure 4

Plots of dAXP percentage versus ANC. (A) Samples drawn during routine evaluation. P = .8369. (B) Samples drawn from patients who had had chemotherapy followed by gene therapy, starting from one month after gene therapy. P = .0015. Measurements were taken up to 4 years after gene therapy. (C) Samples drawn at diagnosis of ADA-SCID, before institution of PEG-ADA therapy. P = .1312.