Institution: Penn State Hershey Medical Center
Additional authors:Melanie Comito, M.D.
Session: Erythroleukemia and megakaryoblastic AML and mimics
HISTORY
This 39 month old Mennonite girl was referred to for cytopenias. She was in good health until 3 weeks prior when she experienced a febrile illness lasting 3 days with spontaneous resolution. Since then she has been pale and tired and has poor appetite. She was born term, 8 lbs, 13oz. She was breast feed and switched to solids at 6 months. Over the last year she has become a "picky eater" and her weight gain has fallen off. Her tongue is mildly swollen. A CBC at age 14 months was normal.
Current labs: WBC 10.5 K/uL, 10% Neutrophils, 2% Immature granulocytes, 88% lymphocytes. Hgb 4.8 g/dl, HCT 14.8%, RBC 1.31 M/uL, MCV 113.0 fl, MCH 36.6 pg, MCHC 32.4 g/dl, RDW 31.2%, PLT 86 K/uL, WBC differentitial: Reticulocytes 3%, LDH 2800 units/L, haptoglobin <15 mg/dL, Tbili =WNL, Dbili=WNL, AST=WNL.DETAILS
Peripheral blood smear:
RBC's: Macrocytosis with marked anisopoikilocytosis including macroovalocytes, dacrocytes, coarse basophilic stippling, polychromasia, and NRBC's.WBC's: Mild neutrophilic left-shift up to metamyelocytes, normal granularity and nuclear segmentation. Monocytes, eosinophils and lymphocytes have normal morphology. PLT's: Small to giant, hypogranular.Bone Marrow Aspirate and Biopsy (AZF fixed, RDO decal): Hypercellular, 100%. Differential: 1% blasts, 7% promyelocytes, 31% neutrophilic myelocytes, 9% neutrophilic metamyelocytes, 6% band and segmented neutrophils, 39% erythroblasts and 7% lymphocytes. Dysmegakaryopoiesis, multiple separate nuclei in single cells. Mild left shift of the neutrophilic lineage with no increase in blasts. Dysgranulopoiesis, nucleus to cytoplasmic dyssynchrony, giant bands and metamyelocytes. Dyserythropoiesis, marked megaloblastic change, nuclear fragmentation, asymmetric binucleation, irregular nuclear contours and budding.IMMUNOHISTOCHEMISTRY AND FLOW CYTOMETRY
N/A
MOLECULAR FINDINGS
Molecular testing of CUBN, AMN and GIF genes was offered, but the parents declined. Genetic counseling was offered to the family to identify heterozygous carriers.
INTERESTING FEATURES
IGS is a rare, incidence <1:1,000,000, autosomal recessive syndrome of congenital megaloblastic anemia unresponsive to intrinsic factor replacement, proteinuria and malformations of the urinary tract. Interestingly, it may not present until years after birth. It is due to mutations of either of the cubilin (CUBN; 10p13; Finnish-type) or amnionless (AMN; 14p32.32; Norwegian-type) genes. These two proteins normally form a complex, “cubam,” necessary for enteric absorption of B12/intrinsic factor in the terminal ileum. Several other kindreds with IGS have been identified outside of Scandanavia, particularly in the Middle-East. Most of these have CUBN or AMN mutations; however, a few appear wild-type for these genes suggesting a third, uncharacterized gene may be involved. A similar syndrome of congenital megaloblastic anemia (MGA1) has been attributed to mutaions the intrinsic factor gene (GIF; 11q12.1).
Thus, sequencing of CUBN, AMN and GIF, may be recommended for patients with congenital megaloblastic anemia. Parenteral B12 therapy will reverse the hematological abnormalities, but will not reverse neurological defects or eliminate the proteinuria. There does not appear to be any increased risk of malignancy in these patients, as in other congenital bone marrow failure syndromes.PROPOSED DIAGNOSIS
Imerslund-Grasbeck syndrome
CONSENSUS DIAGNOSIS
Congenital megaloblastic anemia (Imerslund-Grasbeck syndrome)