A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD)

Abstract

Congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders identified by pathological erythroid precursors with perinuclear mitochondrial iron deposition in bone marrow. An international collaborative group of physicians and laboratory scientists collated clinical information on cases of CSA lacking known causative mutations, identifying a clinical subgroup of CSA associated with B immunodeficiency, periodic fevers, and development delay. Twelve cases from 10 families were identified. Median age at presentation was 2 months. Anemia at diagnosis was sideroblastic, typically severe (median hemoglobin, 7.1 g/dL) and markedly microcytic (median mean corpuscular volume, 62.0 fL). Clinical course involved recurrent febrile illness and gastrointestinal disturbance, lacking an infective cause. Investigation revealed B-cell lymphopenia (CD19⁺ range, 0.016-0.22 × 10⁹/L) and panhypogammaglobulinemia in most cases. Children displayed developmental delay alongside variable neurodegeneration, seizures, cerebellar abnormalities, sensorineural deafness, and other multisystem features. Most required regular blood transfusion, iron chelation, and intravenous immunoglobulin replacement. Median survival was 48 months, with 7 deaths caused by cardiac or multiorgan failure. One child underwent bone marrow transplantation aged 9 months, with apparent cure of the hematologic and immunologic manifestations. We describe and define a novel CSA and B-cell immunodeficiency syndrome with additional features resembling a mitochondrial cytopathy. The molecular etiology is under investigation.

Figure 1

Pedigree for cases 1 and 2 with descriptions of phenotypes displayed. The other siblings unaffected by SA and immunodeficiency exhibited a different cluster of features consistent with the Cenani-Lenz syndrome.

Figure 2

Photomicrographs of BM smears, demonstrating presence of ringed sideroblasts and erythroid hyperplasia with dyserythropoietic features. (A) Case 1 (Perl stain). (B) Case 11 (H&E). (C) Case 11 (Perl stain).

Figure 3

Graph showing decline in circulating B-, NK-, and T-cell numbers in case 1 with increasing age. This child died during the 15th year of life, at which point she displayed profound lymphocytopenia of all 3 lymphocyte classes (units are in cells per microliter).

Figure 4

Detailed B-cell maturation analysis performed on BM from case 11. (A) Bar chart displays proportion of B cells at different stages of maturation within the BM compartment as determined by flow cytometric analysis. The bottom bar is from child 11 aged 8 months, demonstrating a leaky maturation block before the cytoplasmic Igμ-positive pre-B-II cell stage. The middle bar shows repeat analysis in the same patient 10 months after BMT, at which time the pattern had reverted to that observed in age-matched normal controls (top bar). (B) Relative proportions of B cells at different maturation stages in BM samples before and after BMT (analysis performed by M. van der Burg and J. J. M. van Dongen [Erasmus Medical Center, Rotterdam, The Netherlands]).

Figure 5

Graphical representation of selected clinical events in child 11’s early disease course. Line graph traces serial C-reactive protein levels, illustrating recurrent inflammatory episodes occurring with periodicity of 4- to 6-week intervals; red lines represent periods of hospitalization. Other than a single early episode of Enterobacter septicemia, BMT appears to have effectively cured the immunologic and fever components of the disease as well as the SA.