Final Diagnosis -- Congenital Dyserythropoietic Anemia Type II

DIAGNOSIS

Congenital Dyserythropoietic Anemia Type II.

DISCUSSION

Congenital dyserythropoietic anemias (CDA) are a group of rare disorders that result in impaired erythropoiesis of varying severity. There are three well established subtypes, CDA I, II, and III, with other rarer variants. CDA-I is a recessive disorder characterized by moderate to severe macrocytic anemia presenting in utero or in early infancy [1]. A subset of patients may show skeletal abnormalities or dysmorphologic features [2]. A majority of patients will require transfusion support in infancy, but only a small subset with require continued transfusion support throughout childhood and adulthood [3]. Histologic examination of the bone marrow shows nuclear bridging in dividing erythroid precursors and macrocytosis. Mutations in the gene CDAN1 are diagnostic for this disorder [1].

CDA-III is also presents as a macrocytic anemia at a young age, although symptoms are generally milder than CDA-I and it has not been associated with dysmorphology. Bone marrow examination will show giant multinucleated "megakaryocyte-like" erythroid precursors. It is inherited in an autosomal dominant fashion, with mutations in the KIF23 gene being diagnostic [4].

The patient in this case was diagnosed with CDA-II, the most common form of CDA. The histologic findings in this case are classic, with numerous, small, bi- to multinucleated late stage erythroid precursors with minimal changes in the megakaryocyte or myeloid lines [4]. The anemia seen in CDA-II is normocytic, as it was in this case. The clinical presentation in this case was atypical in its severity and early presentation, as CDA-II normally presents with moderate anemia in childhood or adolescence. Patients with CDA-II can have exhibit splenomegaly due to the abnormal fragility of the mature erythrocytes. This characteristic can aid in diagnosis, as the acidified serum lysis test will be positive (this test was not performed in our patient). Additional laboratory support for this diagnosis can be gained by exposing the cells to anti-i or anti-I serum, which should also result in increased lysis. CDA-II is inherited in an autosomal recessive fashion and is caused by mutations in the SEC23B gene [5]. The function of this gene is not entirely understood, but it appears to be involved in protein transport to and from the Golgi and endoplasmic reticulum [5]. Defects in this transport are hypothesized to lead to problems in surface protein glycosylation, and result in the erythrocyte fragility seen in patients with this disease. Treatment is normally supportive, but bone marrow transplant can be considered and has been successful in patients with severe disease who are transfusion dependent.

REFERENCES

1. S.N. Wickramasinghe, W.G. Wood, Advances in the understanding of the congenital dyserythropoietic anaemias, Br J Haematol, 131 (2005) 431-446.
2. G. Tchernia, B. Bader-Meunier, A. Beauchamp-Nicoud, T. Cynober, M. Feneant-Thibault, J. Delaunay, Congenital dyserythropoietic anemias, Hematol J, 5 Suppl 3 (2004) S191-194.
3. H. Shalev, J. Kapelushnik, A. Moser, O. Dgany, T. Krasnov, H. Tamary, A comprehensive study of the neonatal manifestations of congenital dyserythropoietic anemia type I, J Pediatr Hematol Oncol, 26 (2004) 746-748.
4. A. Iolascon, H. Heimpel, A. Wahlin, H. Tamary, Congenital dyserythropoietic anemias: molecular insights and diagnostic approach, Blood, 122 (2013) 2162-2166.
5. K. Schwarz, A. Iolascon, F. Verissimo, N.S. Trede, W. Horsley, W. Chen, B.H. Paw, K.P. Hopfner, K. Holzmann, R. Russo, M.R. Esposito, D. Spano, L. De Falco, K. Heinrich, B. Joggerst, M.T. Rojewski, S. Perrotta, J. Denecke, U. Pannicke, J. Delaunay, R. Pepperkok, H. Heimpel, Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II, Nat Genet, 41 (2009) 936-940.

Contributed by Daniel Marker, MD, PhD