Infantile tremor syndrome (ITS) is characterized by pallor, developmental regression, tremors, hyperpigmentation of skin, and sparse brown hair. [1]. Though considered to be a vitamin B₁₂ deficiency state by many, opinion has remained divided. We describe some children with ITS to highlight its continued occurrence and also report on its probable etiology.

A retrospective review of the medical records of the children with infantile tremor syndrome attending our center between February 2010 and August 2014 was done. We investigate all infants with ITS and their mothers for vitamin B12 deficiency. All infants are initially treated with intramuscular vitamin B₁₂ alone.

Twenty-one infants, (13 boys) aged 6 to 27 month were studied. Common presenting symptoms were tremors in 12, developmental delay in three, and developmental regression in three. All infants were exclusively breast-fed and their mothers were vegetarians, with little or no milk intake. We found low serum B₁₂ in 8 of the 16 infants. Six of the 8 infants with normal serum vitamin B₁₂ had received vitamin B₁₂ before referral. Clinical and laboratory parameters are summarized in Table I. After treatment with intramuscular vitamin B₁₂ alone, improvement in general activity, interest in surroundings, and return of social smile was seen within 48-72 hours in all except one. Tremors started to diminish by the end of first week in eight infants. Six infants showed initial worsening of tremors following treatment. Tremors were completely resolved by three to four weeks in all.

TABLE I	Clinical and Laboratory Findings in Infants With Infantile Tremor Syndrome

There is epidemiological, clinical, laboratory and therapeutic evidence to suggest that vitamin B₁₂ deficiency is causally associated with ITS [2-4]. Epidemiologically, ITS occurs in exclusively breastfed infants of mothers living on diet devoid of animal products, including milk, pointing to vitamin B12 deficiency in infant-mother pairs [3]. All the mothers tested in our series had low serum vitamin B₁₂. Moreover, the manifestations of ITS are identical to those described with infantile vitamin B₁₂ deficiency reported from West [4]. Skin hyperpigmentation seen in ITS is also a well-known sign of vitamin B₁₂ deficiency [5]. Infants with normal serum vitamin B₁₂ levels in this study had other evidence of vitamin B₁₂ deficiency such as macrocytosis and low maternal serum vitamin B₁₂. From therapeutic standpoint, unequivocal improvement in general activity was observed in all the treated infants within 48-72 hours of vitamin B12. Tremors also improved gradually, all although initial worsening of tremors, a well-documented feature of vitamin B12 deficiency [6], was encountered in six infants

Interestingly enough, first study on ITS by Dikshit [1] had provided initial evidence that the symptoms and signs could be due to vitamin B₁₂ deficiency. Later authors also reported low serum vitamin B12 and good response to vitamin B₁₂ [2,3]. Deshpande and Ingle [7] also concurred with vitamin B₁₂ deficiency in ITS. Elegant study by Garewal, et al. [8] showed unambiguous evidence of vitamin B₁₂ deficiency in ITS in the form of megaloblastic bone marrow, and low serum vitamin B₁₂, including cellular evidence of vitamin B12 deficiency was revealed by the dU suppression test. On the other hand, in the studies showing lack of evidence of vitamin B₁₂ deficiency in ITS, serum vitamin B₁₂, the current gold standard of diagnosis of vitamin B₁₂ deficiency, was not measured and results were inferred from the mere absence of peripheral blood macrocytosis and megaloblastic bone marrow [9,10]. Occurrence of neurological symptoms of vitamin B₁₂ deficiency in the absence of concomitant hematological changes is well known [8,11]. Interestingly, publication bias also seems to have played a major role in this debate on etiology of ITS. Majority of the studies [2,3,8] reporting vitamin B₁₂ deficiency in ITS were published in foreign journals and likely to have escaped scrutiny of researchers of the country.

In summary, ITS continues to exist in India in modern times and is causally associated with vitamin B₁₂ deficiency. Since long-term neuro-developmental deficits can occur if treatment is delayed, infants with ITS should be treated early with vitamin B12 for rapid reversal of neurological signs.