Abstract
INTRODUCTION/BACKGROUND: Transcobalamin-II Deficiency (TCII-Deficiency) is a rare autosomal-recessive metabolic condition, resulting in ineffective transport and uptake of Vitamin B12. Clinical features of pancytopenia, failure to thrive, diarrhea, and developmental delay typically present between 1-12 months of age(1). CASE DESCRIPTION: A 10-month-old term, previously well male with a normal newborn screen, presented with a one-month history of decreased energy, failure to thrive, and diarrhea. He had a two-week history of gross motor regression with lower limb and periorbital edema. Examination was notable for perioral rash, severe diaper dermatitis, buccal ulcerations, pallor, and generalised edema including ascites. There was no organomegaly or any dysmorphic features. Investigations revealed macrocytic anemia, thrombocytopenia, worsening neutropenia, hypoalbuminemia, hypertriglyceridemia, and hypogammaglobulinemia (Table 1). Vitamin B12 and B9 levels were normal. Bone marrow biopsy was hypocellular, and ruled out aplastic anemia and leukemia. Intestinal biopsy showed generalized edema from duodenum to rectum with GVHD-like injury pattern, and evidence for protein-losing enteropathy (PLE). Required therapy included numerous RBC, platelet, and albumin transfusions and enteral feeding. A disorder of vitamin B12 metabolism, specifically TCII-Deficiency, was suspected based on clinical presentation with no other clear explanation. Serum MMA was highly elevated at 24,154 nmol/L (0-500 nmol/L) as was homocysteine at 27.3 umol/L (4.7-10.3 umol/L). Whole-exome sequencing identified two mutations in TCN2. Treatment with intramuscular vitamin B12 resulted in reduction of urinary MMA level to 5.6 umol/mmol Cr (< 2 umol/mmol Cr) in 10 days. DISCUSSION: Over the next months of treatment with intramuscular hydroxocobalamin, the MMA, homocysteine, albumin and CBC normalized and all clinical complications were resolved. Gross motor skills returned to normal, with only mild persistent speech delay. TCII-Deficiency often presents with a heterogeneous constellation of symptoms. In this case, the differential included several hematologic and gastrointestinal pathologies, including DGAT1 deficiency (due to hypertriglyceridemia, diarrhea, and PLE) and CHAPLE syndrome (due to low immunoglobulins and PLE). MMA and homocysteine levels are often markedly elevated in B12 metabolism defects, and can justify initiation of treatment with cyanocobalamin/hydroxocobalamin (Vitamin B12) while awaiting confirmatory genetic testing(2). CONCLUSION: TCII-Deficiency is a rare cause of macrocytic anemia; early consideration and treatment with intramuscular vitamin B12 leads to dramatic symptom improvement and is important for paediatricians to recognize. Clinical Pearls: • Clinicians should consider B12 metabolism defects on their differential in a young child who has macrocytic anemia with normal B12 levels. • Paediatricians can use MMA and homocysteine levels to assess for B12 metabolism defects while awaiting genetic testing. REFERENCES: 1.Schiff M, Ogier de Baulny H, Bard G, et al. Should transcobalamin deficiency be treated aggressively?. J Inherit Metab Dis. 2010;33(3):223-229. doi:10.1007/s10545-010-9074-x 2.Aslinia F, Mazza JJ, Yale SH. Megaloblastic anemia and other causes of macrocytosis [published correction appears in Clin Med Res. 2006 Dec;4(4):342]. Clin Med Res. 2006;4(3):236-241