Rare Disease Highlight: Congenital disorder of glycosylation type IIc (CDGIIc)

Leukocyte Adhesion Deficiencies (LAD) are autosomal recessive immunodeficiencies characterized by severe and recurrent bacterial infections, impaired wound healing, and neutrophilia (Cagdas et al., 2014). Congenital disorder of glycosylation type IIc (CDGIIc) is an ultra-rare LAD in which patients exhibit these general LAD phenotypes, but are sometimes further characterized by two additional potential symptoms including moderate to severe psychomotor retardation and mild dysmorphism (OMIM, 2014). In CDGIIc patients, the body is unable to sufficiently add fucose sugars to the surface of certain cells (hypo-fucosylation), which causes leukocytosis, persistent and recurrent infections, severely reduced selectin activity, Bombay blood group, hypotonia, poor feeding, short stature, coarse facial features and neurological deficits. This is mainly because the leukocytes in the body are unable to adhere to cell surfaces which would normally be marked with fucose sugars to fight off infections (Marquardt et al., 1999). In some cases, patients died because of clinical manifestations of the disease (confirmed after death), demonstrating the severe and life-threatening nature of CDGIIc (Cagdas et al., 2014; Karsan et al., 1998).

Immune defects are the direct result of a lack of cluster of differentiation (CD) 15, a fucose-containing, cell surface glycoprotein that serves as a ligand for certain cell adhesion molecules called E- and P‑selectins (Frydman et al., 1996). In addition, CDGIIc patients’ red blood cells lack the H antigen, a fucosylated glycoprotein, which is the precursor molecule of the A, B, and O blood groups, and consequently manifests as the Bombay blood type. Recurrent bacterial infections occur in almost all patients during the first years of life, although periodontitis has been reported at later ages (A. Etzioni et al., 1992). Biochemical analysis confirms global hypo-fucosylation of proteoglycans, suggesting an inborn error of fucose metabolism. CDGIIc is a serious and potentially life-threatening disease, particularly for infants and young children (Dauber et al., 2014; A. Etzioni et al., 1992; Amos Etzioni et al., 2002; Frydman et al., 1992; Karsan et al., 1998; Marquardt et al., 1999; Sturla et al., 1998). The onset of clinical symptoms is typically during infancy and almost always within the first year of life. Without medical intervention, clinical manifestations of CDGIIc, in most cases, persist through development or result in patient mortality during early childhood (Dauber et al., 2014; A. Etzioni et al., 1992; Amos Etzioni et al., 2002; Frydman et al., 1992; Marquardt et al., 1999; Sturla et al., 1998)


Cagdas, D., Yilmaz, M., Kandemir, N., Tezcan, I., Etzioni, A., & Sanal, Ö. (2014). A novel mutation in leukocyte adhesion deficiency type II/CDGIIc. Journal of clinical immunology, 34(8), 1009–1014. doi:10.1007/s10875-014-0091-7

Dauber, A., Ercan, A., Lee, J., James, P., Jacobs, P. P., Ashline, D. J., . . . Sackstein, R. (2014). Congenital disorder of fucosylation type 2c (LADII) presenting with short stature and developmental delay with minimal adhesion defect. Human molecular genetics, 23(11), 2880–2887. doi:10.1093/hmg/ddu001

Etzioni, A., Frydman, M., Pollack, S., Avidor, I., Phillips, M. L., Paulson, J. C., & Gershoni-Baruch, R. (1992). Brief report: Recurrent severe infections caused by a novel leukocyte adhesion deficiency. N Engl.J Med, 327(25), 1789–1792. doi:10.1056/nejm199212173272505

Etzioni, A., Sturla, L., Antonellis, A., Green, E. D., Gershoni-Baruch, R., Berninsone, P. M., . . . Tonetti, M. (2002). Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc founder effect and genotype/phenotype correlation. Am J Med Genet, 110(2), 131–135. doi:10.1002/ajmg.10423

Frydman, M., Etzioni, A., Eidlitz-Markus, T., Avidor, I., Varsano, I., Shechter, Y., . . . Gershoni-Baruch, R. (1992). Rambam-Hasharon syndrome of psychomotor retardation, short stature, defective neutrophil motility, and Bombay phenotype. Am J Med Genet, 44(3), 297–302. doi:10.1002/ajmg.1320440307

Frydman, M., Vardimon, D., Shalev, E., & Orlin, J. B. (1996). Prenatal diagnosis of Rambam-Hasharon syndrome. Prenat Diagn, 16(3), 266-269. doi:10.1002/(sici)1097-0223(199603)16:3<266::Aid-pd845>3.0.Co;2-#

Karsan, A., Cornejo, C. J., Winn, R. K., Schwartz, B. R., Way, W., Lannir, N., . . . Harlan, J. M. (1998). Leukocyte Adhesion Deficiency Type II is a generalized defect of de novo GDP-fucose biosynthesis. Endothelial cell fucosylation is not required for neutrophil rolling on human nonlymphoid endothelium. J Clin Invest, 101(11), 2438–2445. doi:10.1172/jci905

Marquardt, T., Brune, T., Lühn, K., Zimmer, K. P., Körner, C., Fabritz, L., . . . Koch, H. G. (1999). Leukocyte adhesion deficiency II syndrome, a generalized defect in fucose metabolism. J Pediatr, 134(6), 681–688.

OMIM. (2014). Online Mendelian Inheritance in Man: MIM Number: 266265. Retrieved from https://omim.org

Sturla, L., Etzioni, A., Bisso, A., Zanardi, D., Flora, G. d., Silengo, L., . . . Tonetti, M. (1998). Defective intracellular activity of GDP-D-mannose-4,6-dehydratase in leukocyte adhesion deficiency type II syndrome. FEBS Lett, 429(3), 274–278.

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