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A 2-year-old with Congenital Intrinsic Factor Deficiency Presenting with Methylmalonic Acidemia and Megaloblastic Anemia

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A 2-year-old with Congenital Intrinsic Factor Deficiency Presenting with Methylmalonic Acidemia and Megaloblastic Anemia. Joanna Robles, MD; Amarilis Sanchez-Valle, MD. Department of Pediatrics. University of South Florida Morsani College of Medicine


Pediatric causes of vitamin B12 deficiency include decreased intake, abnormal absorption, and inborn errors of B12 transport and metabolism. Rare causes of abnormal cobalamin absorption include Imerslund-Grasbeck syndrome (IGS) and mutations in or absence of gastric intrinsic factor. IGS, in which cobalamin absorption is interrupted and not corrected by intrinsic factor has been associated with defects in genes CUBN and AMN [1]. 


A 2 year old male (Figure 1) presented with daily persistent emesis, pallor and perioral cyanosis. Past medical history was significant for 2 prior episodes of pneumonia and wheezing. Initial evaluation revealed severe megaloblastic anemia.  He had extensive work-up by hematology including a bone marrow biopsy which led to initial suspicion for myelodysplastic syndrome (Figure 2).  Further laboratory work-up revealed markedly elevated methylmalonic acid prompting a referral to our metabolic clinic. Homocysteine levels were increased while vitamin B12 levels were decreased, and methylmalonic acid levels were elevated. He was found to have a GIF heterozygous mutation c.79+1G>A associated with congenital gastric intrinsic factor deficiency and a novel variant c.960C>A in trans position. The patient was started on weekly 1mg cobalamin injections. His hemoglobin, methylmalonic acid, homocysteine, and cobalamin  levels normalized. He was given a trial off of the injections and his vitamin B12 levels started to decline; cobalamin injections were resumed.  


•Complete blood count- hemoglobin 5.3g/dL (ref. 10.2-12.7), MCV 105fL (ref.71-85), RDW 26.8 (12-14.9), and platelet count 115,000th/cumm.  WBC was 6.4th/cumm (ref. 4.86-13.38).
•LDH 9574 IU/L(ref.500-920)
•Fanconi’s DNA- no mutation detected
•Bone marrow cytogenetics- 46, XY
•Methylmalonic acid level- 25,920nmol/L (ref 87 to 318nmol/L).
•Urine organic acids- marked elevation of methylmalonate. Methylcitrate and 3-OH propionate were also present but not in elevated amounts
•Serum amino acids- normal
•Acylcarnitine profile- C3 of 5.84umol/L (ref 0.14-0.85) and elevated C3/C2 ratio
•Homocysteine- 56.2 umol/L (ref 0-15)
•Vitamin B12- 53 pg/ml (ref range 211-946).
•GIF heterozygous mutation c.79+1G>A and a novel variant c.960C>A in trans position. 


Congenital intrinsic factor deficiency has been reported as a rare cause of megaloblastic anemia. The genetic testing of the CUBN, GIF, and AMN genes were solely available through a genetic laboratory in Germany. The GIF mutation (c.79+1G>A) has been described as a loss of function mutation in a French family clinically diagnosed with Imerslund-Grasbeck syndrome [1]. In the family described, the patients were diagnosed at 1.5 and 6 years of age with proteinuria, decreased cobalamin levels, and megaloblastic anemia. The GIF splice site mutation (c.79+1G>A) was also found in a 15 year old boy with megaloblastic anemia with pancytopenia, slight proteinuria and slightly elevated methylmalonate [2].

 The patients with this GIF mutation presented with megaloblastic anemia similarly to the patient discussed. While one had a slightly elevated methylmalonic acid, the methylmalonic acid in our patient was significantly elevated over 80 times the upper limit of normal. The methylmalonic acidemia was initially concerning for an inborn error of metabolism. This was considered in our patient until his laboratory results indicated vitamin B12 deficiency as a cause of his megaloblastic anemia, thrombocytopenia, and methylmalonic acidemia. Elevation of methylmalonic acid and homocysteine are expected and highly sensitive in vitamin B12 deficiency [4].

  His initial working diagnosis was myelodysplastic syndrome due his megaloblastic anemia and the appearance of his bone marrow. In children presenting with macrocytic anemia, the differential diagnosis does include myelodysplastic syndrome and bone marrow failure, yet cobalamin and folate deficiency should be considered even in the absence of an obvious explanation. In any child presenting with a possible vitamin B12 deficiency, the vitamin B12, methylmalonic acid and homocysteine levels should be evaluated [5].

  Genetic testing for congenital intrinsic factor, specifically for the CUBN, GIF, and AMN genes, should be considered in pediatric patients without a clear etiology of vitamin B12 deficiency or in patients dependent on supplemental hydroxocobalamin injections. 


[1] Tanner SM, Li Z, Perko JD, et al. Proceedings of the National Academy of Sciences of the United States of America. Mar 15 2005;102(11):4130-4133.

[2] Overgaard UM, Tanner SM, Birgens HS. Br J Haematol. Aug 2010;150(3):369-371.

[3] Manoli I, Venditti CP. Methylmalonic Acidemia. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews(R). Seattle (WA):1993.

[4] Savage DG, Lindenbaum J, Stabler SP, Allen RH.The American journal of medicine. Mar 1994;96(3):239-246.

[5] Rasmussen SA, Fernhoff PM, Scanlon KS. The Journal of pediatrics. Jan 2001;138(1):10-1.


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