Transcobalamin II deficiency in twins with a novel variant in the TCN2 gene: case report and review of literature

J Pediatr Endocrinol Metab. 2020 Nov 26;33(11):1487-1499. doi: 10.1515/jpem-2020-0096.


Objectives Transcobalamin II (TC) is an essential plasma protein for the absorption, transportation, and cellular uptake of cobalamin. TC deficiency presents in the first year of life with failure to thrive, hypotonia, lethargy, diarrhea, pallor, mucosal ulceration, anemia, pancytopenia, and agammaglobulinemia. Herein, we present TC deficiency diagnosed in two cases (twin siblings) with a novel variant in the TCN2 gene. Case presentation 4-month-old twins were admitted with fever, respiratory distress, vomiting, diarrhea, and failure to thrive. Physical examination findings revealed developmental delay and hypotonia with no head control, and laboratory findings were severe anemia, neutropenia, and hypogammaglobulinemia. Despite normal vitamin B12 and folate levels, homocysteine and urine methylmalonic acid levels were elevated in both patients. Bone marrow examinations revealed hypocellular bone marrow in both cases. The patients had novel pathogenic homozygous c.241C>T (p.Gln81Ter) variant in the TCN2 gene. In both cases, with intramuscular hydroxycobalamin therapy, laboratory parameters improved, and a successful clinical response was achieved. Conclusions In infants with pancytopenia, growth retardation, gastrointestinal manifestations, and immunodeficiency, the inborn error of cobalamin metabolism should be kept in mind. Early diagnosis and treatment are crucial for better clinical outcomes. What is new? In literature, to date, less than 50 cases with TC deficiency were identified. In this report, we presented twins with TCN2 gene mutation. Both patients emphasized that early and aggressive treatment is crucial for achieving optimal outcomes. In this report, we identified a novel variation in TCN2 gene.

Keywords: TCN2 gene; homocysteine; hypogammaglobulinemia; pancytopenia; vitamin B12.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / diagnosis
  • Amino Acid Metabolism, Inborn Errors / drug therapy
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Codon, Nonsense / genetics
  • Consanguinity
  • Diseases in Twins / diagnosis
  • Diseases in Twins / drug therapy
  • Diseases in Twins / genetics*
  • Female
  • Homozygote
  • Humans
  • Hydroxocobalamin / administration & dosage
  • Infant
  • Injections, Intramuscular
  • Male
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Transcobalamins / deficiency
  • Transcobalamins / genetics*
  • Turkey
  • Twins, Dizygotic


  • Codon, Nonsense
  • TCN2 protein, human
  • Transcobalamins
  • Hydroxocobalamin