The majority of genes that could explain variation in vitamin B12 concentrations are reported from Caucasian population studies (14).
TC deficiency is a rare and potentially lethal autosomal recessive disease with an early infantile onset and the following clinical and laboratory features: failure to thrive, weakness, diarrhoea, pallor, anemia, pancytopenia, agammaglobulinemia.
This syndrome may resemble a neonatal leukemia or a severe combined immunodeficiency disease (15, 16). Differential diagnosis with these two disease should be warranted because TC deficiency, when treated aggressively, appears to be associated with an overall favorable outcome.
TC deficiency patients usually present with megaloblastic anemia of variable severity. A delay in diagnosis and treatment are associated with life threatening neurological and hematopoietic complications, which can also be fatal (16, 17).
Patients might show isolated elevation in methylmalonic aciduria (MMA), whereas others show combined increase in circulating MMA and homocysteine (18).
In our patient there was a family history of a similar syndrome that included pancytopenia. The blood concentrations of folate and cobalamin were normal excluding the kinds of deficits where they are low (deficiency of the absorption of B12, malabsorption of folate). Aminoaciduria highlighted the presence of homocysteine and the absence of methylmalonic acid, leading to the exclusion of a deficiency of methylmalonyl-CoA mutase. These findings and the presence of anemia lead us to hypothesize the diagnostic suspicion of TC deficiency initially described in 1971 (19).
Our hypothesis was confirmed genetically only at the age of 29 years of age when we found a c.115_116delCA homozigous mutation in TCN2 gene, further confirmed by the parents’genetic analysis that showed the same mutation in the heterozygous status.
About 50 cases have been reported in the literature of TCN2 variants (20), our mutation c.115_116delCA in exon 8 was cited among these, indeed it was reported in only one patient in which this mutation was present in association with c.501_503delCCA in exon 4. In silico analysis demonstrate that exon 8 is the region involved in cobalamin binding site, whereas mutation in exon 4 should affect TC-TC receptor interaction (15).
For the first time we report the clinical significance of the c.115_116delCA homozigous mutation alone and not in association with other TCN2 mutations.
The TC deficiency suspicion before genetic screening was indirectly confirmed by the clear response to empiric treatment with IM hydroxycobalamin: disappearance of vomiting, diarrhea and normalization of the hematological picture.
At present there are no guidelines on the treatment of TC deficiency regarding the form of B12 supplement to use (i.e. hydroxocobalamin vs cyanocobalamin), the dose, the administration method (IM vs oral), the frequency (weekly vs monthly) and the duration of administration, the treatment monitoring period and follow-up.
IM administration of 1 mg of hydroxocobalamin or cyanocobalamin once a week for a lifetime appears to be the most suitable treatment regime according to the observational data reported in a series of 30 patients (16).
The working hypothesis that such a treatment regime can be correct is confirmed ex adiuvantibus in our patient by the observed reappearance of megaloblastic anemia following the attempted suspension of IM hydroxycobalamin at 8 years of age. The timely resumption of treatment (3 mg in the first week, 2 mg in the second week and subsequently 1 mg per week sine die) normalized the hematological picture.
In conclusion our case report highlights that early detection of TC deficiency and early initiation of aggressive IM treatment is likely associated with disease control and an overall favorable outcome.
Genetic counseling should be provided to affected families. Neonatal screening could be useful in the early diagnosis of the syndrome: some studies suggest that prenatal diagnosis of TC deficiency is possible by means of measuring TC production in amniotic-fluid cells (21–24).
The treatment is easily administered, does not give adverse events and overall is well tolerated and safe.