Immunoglobulin and Lymphocyte Subset Abnormalities in Patients with Fanconi Anemia and Dyskeratosis Congenita.

Abstract

Fanconi anemia (FA) and dyskeratosis congenita (DC) are genetic disorders characterized by bone marrow failure and an increased risk of acute myeloid leukemia, myelodysplastic syndrome (MDS) and epithelial cancers. While immunological abnormalities have been reported in small numbers of FA and DC patients, their correlation with the evolution of hematologic and neoplastic complications is unclear. To investigate these associations in a prospective cohort we evaluated serum immunoglobulins (IgG, IgA, IgM) and lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+ ratio, B, and NK cells) in 17 FA and 18 DC patients enrolled in the National Cancer Institute's Inherited Bone Marrow Failure Syndrome (IBMFS) study. All patients were seen at the NIH Clinical Center and had not undergone bone marrow transplantation or received immunosuppressive treatment including corticosteroids in the past 2 years. Their clinical, hematological, immunological and neoplastic features at study entry are summarized in the table. Abnormal values were defined as below the normal range (95% CI).ParameterFA (n=17)DC (n=18)Median age in years (range)18 (5–42)17 (3–47)Any hematological abnormality12 (71%)16 (89%)Any cytopenia9 (53%)16 (89%)MDS3 (18%)0Low absolute lymphocyte count1 (16%)0Low IgG, IgA, or IgM6 (35%)5 (28%)High IgG, IgA, or IgM07 (38%)Low lymphocyte subset4/6 (67%)4/10 (40%)Low immunoglobulins and/or lymphocytes8 (47%)9 (50%)Neoplasm52Fanconi Anemia: 6/17 patients had low immunoglobulin levels. All 5 with normal complete blood counts (CBC) had normal immunoglobulin levels. Among 3 with MDS, 1 had low IgG, IgA and IgM. Among 9 with cytopenias 1 had low IgG, IgA and IgM and 4 had low IgM. Thus 0/5 with normal CBC versus 6/12 with abnormal CBC had at least one low immunoglobulin level (p=0.1). 4/6 patients had abnormal lymphocyte subset numbers; all 4 had decreased CD4+, CD19+ cells and an abnormal CD4+/CD8+ ratio (<1) and 2 had low NK cells. 2/4 with abnormal lymphocyte subset numbers had neoplasms (1 head and neck squamous cell carcinoma [HNSCC], 1 liver adenoma). Taken together, 1/5 with normal CBC (this patient had HNSCC) had abnormal immune parameters (decreased CD4+, CD19+ cells and an abnormal CD4+/CD8+ ratio), compared with 7/12 with abnormal CBC (p=0.15). 2/9 FA patients with normal and 3/8 with abnormal immune parameters had neoplasms (1 lymphoma and vulvar SCC in the former; 1 liver adenoma, 1 HNSCC + MDS, 1 HNSCC in the latter) (p=0.6).Dyskeratosis congenita: 5/18 patients had low immunoglobulin levels (2 IgA, 2 IgG, 1 IgM), and 7 had high levels (2 IgG and IgA, 5 IgA; 1 patient had low IgM and high IgA). 4/10 also had reduced lymphocyte subset numbers (3 low NK cells; 1 low CD19+, CD3+, CD4+ and abnormal CD4+/CD8+ ratio). 9/16 patients with abnormal CBC had abnormal immune studies versus 0/2 with normal CBC (p=1). 1/2 DC patients with SCC had low IgM.Our preliminary screening identified decreased immunoglobulins and/or lymphocytes in ~50% of the FA and DC patients. The decreases were associated with hematological and/or neoplastic complications in all cases. Since CD4+ cells participate in regulation of myeloid hematopoiesis, abnormal numbers of CD4+ cells may contribute to bone marrow failure. Defects in T-helper and NK cell differentiation may increase the risk of neoplasms. Further and larger studies are required to determine the functional importance of these preliminary observations and their correlation with bone marrow failure, MDS, leukemia, or solid tumors.