Infantile Tremor Syndrome: A Case Report with Review of Current Evidence

Vitamin B12 deficiency in childhood and adolescence

Infantile tremor syndrome (ITS) affects children aged 6-18 months, and is characterized by tremors, pallor, developmental regression, skin pigmentation changes, and sparse hypopigmented hair. This case report highlights an ITS presentation in a 16-month-old exclusively breastfed male, emphasizing the significance of complementary feeding. The patient presented with abnormal body movements, loss of developmental milestones, hyperpigmented skin changes, hypopigmented scalp hairs, pallor, and microcephaly. Born to a vegetarian mother with inadequate prenatal care, the child's exclusive breastfeeding till 16 months of age without complementary feeding led to severe developmental delay and moderate malnutrition. Diagnostic workup revealed vitamin B12 deficiency, anaemia, and neurologic abnormalities. ITS is associated with various manifestations, including pallor, hyperpigmentation, and tremors, commonly linked to vitamin B12 deficiency. In this case, developmental delays and malnutrition underscored the importance of early recognition. Despite neurological improvement with vitamin B12 supplementation, ITS's long-term impact on cognitive functions necessitates vigilance and appropriate nutritional interventions. Early recognition of ITS is vital for the prevention of long-term neurodevelopmental sequelae. Injectable vitamin B12 supplementation and nutritional interventions have demonstrated significant developmental gains. Increased awareness among mothers about nutritional intake during pregnancy and lactation is crucial, especially among vegetarians.

Objective: The objective of this study was to assess the clinical profile of infantile tremor syndrome (ITS) and to correlate serum Vitamin B12 level with ITS. Materials and Methods: This prospective study was done in the Department of Pediatrics of a Medical College of Kota. A total of 40 children, presenting with clinical features of ITS, were included in the study. A detailed history was taken. Investigations including complete blood count with blood indices (mean corpuscular volume, mean corpuscular hemoglobin [MCH], and MCH concentration), peripheral smear, and serum Vitamin B12 level were done in accordance with the WHO guidelines. Vitamin B12 deficiency was defined as serum Vitamin B12 concentration <150 pmol/L or 203 pg/mL. Results: All patients with ITS had pallor (100%) and skin hyperpigmentation (100%). Psychomotor changes in the form of apathy and/or developmental regression/stasis were found in 40 (100%) cases. Regression of developmental milestones was found in 26 (65%) and 10 (25%) patients had stasis of milestones. Tremor was present in 14 (35%) cases. Hepatomegaly was present in the majority 25 (62.5%) of these children, whereas splenomegaly was present in only 8 (20%) patients. Hypopigmented hair was found in only 12 (30%) cases. Twenty-five (62.5%) children were exclusively breastfed (p<0.05). Of the 40 cases, 26 (65%) presented in prodromal phase and 14 (35%) presented in the tremor phase. Among 26 patients of prodromal phase, 22 (84.62%) had Vitamin B12 deficiency while among 14 cases of tremor phase, 9 (64.28%) had Vitamin B12 deficiency. The majority of ITS children had macrocytic anemia (65%) followed by dimorphic anemia (25%). A significant number of ITS patients (21, 80.77%), having macrocytic anemia, had Vitamin B12 deficient. Conclusion: We conclude that children of ITS presented with anemia, skin hyperpigmentation, psychomotor changes, apathetic look, and developmental abnormality. The majority of children were on faulty feeding in the form of prolonged exclusive breastfeeding. Vitamin B12 deficiency was present in a significant number of patients with ITS

Infantile tremor syndrome (ITS) is a rare but significant clinical condition characterized by a tetrad of pallor, developmental delay or regression, skin pigmentation abnormalities, and sparse brown scalp hair, often accompanied by involuntary tremors. ITS primarily affects children aged 5 months to 3 years, with a higher prevalence in males, especially in regions like the Indian subcontinent, Southeast Asia, and Africa. The exact cause of ITS remains uncertain, but a strong association with vitamin B12 deficiency has been observed in numerous studies. Malnutrition, including deficiencies of zinc, magnesium, iron, calcium, and hypoalbuminemia, is common among affected infants, who often come from lower socioeconomic backgrounds with vegetarian mothers lacking animal food in their diets. In this case report, an 8-month-old female child presented with progressive tremors, poor feeding, and developmental delay. The child had been exclusively breastfed by a vegetarian mother and lacked proper complementary feeding. Clinical examination revealed pallor, hypopigmented hair, hyperpigmented knuckles, and generalized hypotonia. Laboratory tests confirmed vitamin B12 deficiency, anemia and other nutritional deficiencies. Neuroimaging showed cerebral atrophy. Treatment involved addressing the nutritional deficiencies, primarily through vitamin B12 supplementation, iron, magnesium, calcium, and a protein-rich diet. Tremors were managed with propranolol and phenobarbitone. Within a month of treatment, the child exhibited significant improvement in tremors, developmental milestones, and overall well-being. This case emphasizes the importance of considering ITS in infants with specific clinical features and highlights the role of healthcare providers in educating parents about proper nutrition during pregnancy and infancy. Early diagnosis and management, including nutritional interventions and symptom control, can lead to substantial improvements in affected children's health and development. Further research is necessary to better understand the etiology and optimal management strategies for ITS.

Vitamin B12 deficiency in childhood presents with a wide variety of symptoms including anemia, failure to thrive and developmental delays. It is a diagnostic consideration in children who are exclusively breastfed or have minimal solid intake, especially if their mother is vegetarian or has underlying vitamin B12 deficiency. Infantile tremor syndrome (ITS) has been associated with vitamin B12 deficiency. ITS presents with neurological symptoms such as developmental delays and tremors. The tremors seen in ITS can be profound and interfere with daily functioning. Different therapies have been tried for those tremors without much evidence or information regarding their efficacy and dosing regimens. We present the case of a 13-month-old girl with vitamin B12 deficiency who developed ITS with significant tremors after initiation of vitamin B12 therapy. She was treated with propranolol which resulted in significant improvement in her tremors. This case highlights the efficacy and safety of propranolol for the treatment of ITS in the context of vitamin B12 deficiency.

Anemia in children is a significant public health problem in our country. Comprehensive National Nutrition Survey 2016-18 provides evidence that more than 50% of childhood anemia is due to an underlying nutritional deficiency. The National Family Health Survey-5 has reported an increase in the prevalence of anemia in the under-five age group from 59% to 67.1% over the last 5 years. Clearly, the existing public health programs to decrease the prevalence of anemia have not shown the desired results. Hence, there is a need to develop nationally acceptable guidelines for the diagnosis, treatment and prevention of nutritional anemia. To review the available literature and collate evidence-based observations to formulate guidelines for diagnosis, treatment and prevention of nutritional anemia in children. These guidelines have been developed by the experts from the Pediatric Hematology-Oncology Chapter and the Pediatric and Adolescent Nutrition (PAN) Society of the Indian Academy of Pediatrics (IAP). Key areas were identified as: epidemiology, nomenclature and definitions, etiology and diagnosis of iron deficiency anemia (IDA), treatment of IDA, etiology and diagnosis of vitamin B12 and/or folic acid deficiency, treatment of vitamin B12 and/or folic acid deficiency anemia and prevention of nutritional anemia. Each of these key areas were reviewed by at least 2 to 3 experts. Four virtual meetings were held in November, 2021 and all the key issues were deliberated upon. Based on review and inputs received during meetings, draft recommendations were prepared. After this, a writing group was constituted which prepared the draft guidelines. The draft was circulated and approved by all the expert group members. We recommend use of World Health Organization (WHO) cut-off hemoglobin levels to define anemia in children and adolescents. Most cases suspected to have IDA can be started on treatment based on a compatible history, physical examination and hemogram report. Serum ferritin assay is recommended for the confirmation of the diagnosis of IDA. Most cases of IDA can be managed with oral iron therapy using 2-3 mg/kg elemental iron daily. The presence of macro-ovalocytes and hypersegmented neutrophils, along with an elevated mean corpuscular volume (MCV), should raise the suspicion of underlying vitamin B12 (cobalamin) or folic acid deficiency. Estimation of serum vitamin B12 and folate level are advisable in children with macrocytic anemia prior to starting treatment. When serum vitamin B12 and folate levels are unavailable, patients should be treated using both drugs. Vitamin B12 should preferably be started 10-14 days ahead of oral folic acid to avoid precipitating neurological symptoms. Children with macrocytic anemia in whom a quick response to treatment is required, such as those with pancytopenia, severe anemia, developmental delay and infantile tremor syndrome, should be managed using parenteral vitamin B12. Children with vitamin B12 deficiency having mild or moderate anemia may be managed using oral vitamin B12 preparations. After completing therapy for nutritional anemia, all infants and children should be advised to continue prophylactic iron-folic acid (IFA) supplementation as prescribed under Anemia Mukt Bharat guidelines. For prevention of anemia, in addition to age-appropriate IFA prophylaxis, routine screening of infants for anemia at 9 months during immunization visit is recommended.

Infantile tremor syndrome and laryngomalacia: A novel association?

Objective: The aim of the study was to determine the percentage of Vitamin B12 deficiency in mothers of children suffering from infantile tremor syndrome (ITS). Other objectives were to determine the percentage of Vitamin B12 deficiency in children and to look for percentage of children having neurological changes in contrast enhanced computed tomography (CT) scan of brain. Methods: Data of children between 1 and 60 months admitted between April 2019 and December 2019 with ITS in a tertiary care hospital were collected. Serum Vitamin B12 levels of both mother and child were determined. Vitamin B12 deficiency and insufficiency were defined as levels <200 pg/ mL and 200–350 pg/mL, respectively. The primary outcome was percentage of mother with Vitamin B12 deficiency and the secondary outcomes were percentage of children with Vitamin B12 deficiency and percentage of children with cerebral atrophy on contrast-enhanced CT of brain. Results: Forty-five children were enrolled in our study. Vitamin B12 deficiency was found in 29 (64.4%) children and 22 (55%) of their mothers. Cerebral atrophy in CT scan was found in 29 (70%) out of 41 children. Conclusion: The most of the mothers of children with ITS are also Vitamin B12 deficient. ITS occurs in infants and toddler with underlying Vitamin B12 deficiency and causes early cerebral atrophy in children, which is crucial period of brain growth. Hence, screening and supplementing anemic pregnant women with vitamin B12 can be one of the primary prevention in India.

Infantile tremor syndrome (ITS) is usually present in purely breastfed babies of vegetarian mothers with acute regression of developmental milestones, pallor with megaloblastic anemia, bleating goat like cry, knuckle, and other body site hyperpigmentation, apathy, listlessness, and brown scanty hair. This is usually due to Vitamin B12 deficiency and symptoms can be reversed with Vitamin B12 supplementation. There are only a few anecdotal case reports of seizure in children with ITS. Hereby, we are presenting a case of a child having epileptic spasms associated with ITS along with megaloblastic anemia with hypersegmented neutrophils in peripheral smear and high mean corpuscular volume. The child was successfully treated with Vitamin B12 supplementation and oral corticosteroids. This case report underscores the importance of considering the possibility of Vitamin B12 deficiency in any child presenting with megaloblastic anemia with either generalized tremulousness with or without seizures.

Infantile Tremor Syndrome (ITS) is a disorder of infancy, and characterized by developmental delay and/or regression, pallor, skin hyperpigmentation and hypopigmented hair. It is commonly seen in infants in whom exclusive breastfeeding is given inappropriately for longer durations than recommended. ITS is predominantly reported from the Indian subcontinent and in children from a lower socioeconomic background. It is a clinical diagnosis and vitamin B12 deficiency is the most commonly accepted etiology of this entity. The primary objectives of study were to compare the plasma and urine amino acid levels among children with ITS spectrum with those of healthy children. The secondary objectives were to compare the plasma and urine amino acid levels among children with ITS and Pre-ITS. This cross-sectional, observational study was carried out at a tertiary care hospital in North India. A total of 50 children aged < 36 months with ITS/Pre-ITS were enrolled. Children with Pre-ITS and ITS were compared with healthy age-matched study subjects. Thirty-nine (78%) cases and twelve (24%) healthy children had low serum vitamin B12 levels. Folate levels were normal in all the controls, while only one case had folate deficiency. There were significant differences (p < 0.05) in the values of 32 amino acids in plasma. Among 44 urinary amino acids, levels of 30 amino acids were significantly different in the cases compared with the controls (p < 0.05). Several changes in amino acids in the children suffering from ITS were observed. These changes may be a reflection of the metabolic derangements in ITS.

Background: Infantile tremor syndrome (ITS) is a condition reported from many areas of Indian subcontinent due to lack of proper nutrition, improper weaning or delayed introduction of complementary feeding. There is no proven macro or micro nutrient deficiency responsible for it but relation with vitamin B12 deficiency has been identified in some studies. The aim of this study was to study the clinical profile of patients with ITS.Methods: It is a prospective observational study including total 30 patients, from 6 months to 3-year age group, admitted to pediatric wards and nutritional rehabilitation centre, civil hospital, Ahmedabad, from June 2018 to December 2019.Results: Out of 30 patients studied, 69% had pre-ITS and rest had ITS, 61.5% were males and 38.4% were females, 69.2% had severe acute malnutrition, 84.6% had severe anemia and 23% of them presented with CCF, 15.4% patients had microcephaly and 23% had hypotonia. 23% had motor and speech delay. 61.5% belonged to lower socio-economic group. There was delayed introduction of complementary feeding in 63% of patients. 69% patients had severe vitamin B12 deficiency and 21% had moderate vitamin B12 deficiency.Conclusion: ITS, is commonly seen among male children belonging to lower socio-economic group among age group of 6 months to 24 months, presents with coarse tremors with moderate to severe anemia with moderate to severe acute malnutrition and is associated with deficiency of vitamin B12. Early diagnosis and treatment including nutritional rehabilitation grossly improved the outcome.

Neuro-developmental outcomes in infants with vitamin B12-deficiency and neurologic features.

Background: Infantile tremor syndrome (ITS) is a clinical syndrome of infants and young children characterized by acute or gradual onset with mental and psychomotor changes, pigmentary disturbances of hair and skin, pallor and tremors. Methods: The study was conducted on 50 children of age group 6 – 24 months with clinical diagnosis of infantile tremor syndrome. The demographic profile and relevant information of individual patient were collected by using structured proforma and an informed consent was taken for enrolling the children into the study. Serum ferritin, folate and vitamin B12 levels were estimated to assess iron, folic acid and vitamin B12 status by electrochemiluminiscence (ECL) method. Results: Significantly higher numbers of patients (68%) were exclusively breastfed. All children had dark skin pigmentation and regression (82%)/delayed (18%) developmental milestones; while most of children had palmer pallor (98%), hypopigmented hair (92%) and majority of the patients (52%) had tremors. Significant number of patients had vitamin B12 deficiency (P=0.005) whereas none of the child was found to be having folate and ferritin deficiency. There was significant association between vitamin B12 deficiency with severity of anemia (P=0.011) and thrombocytopenia (P=0.002). Conclusions: Vitamin B12 deficiency was present in 70% of children with ITS while none of them had iron or folate deficiency.

Megaloblastic wobbliness: A reversible neurological condition.

Vitamin B12 deficiency is a major public health problem worldwide, with the highest burden in elderly people, pregnant women, and young children. Due to its role in DNA synthesis and methylation, folate metabolism, and erythropoiesis, vitamin B12 supplementation during pregnancy may confer longer-term benefits to maternal and child health outcomes. To evaluate the benefits and harms of oral vitamin B12 supplementation during pregnancy on maternal and child health outcomes. We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) on 2 June 2023, and reference lists of retrieved studies. Randomised controlled trials (RCTs), quasi-RCTs, or cluster-RCTs evaluating the effects of oral vitamin B12 supplementation compared to placebo or no vitamin B12 supplementation during pregnancy. We used standard Cochrane methods. Four review authors independently assessed trial eligibility. Two review authors independently extracted data from included studies and conducted checks for accuracy. Three review authors independently assessed the risk of bias of the included studies using the Cochrane RoB 1 tool. We used GRADE to evaluate the certainty of evidence for primary outcomes. The review included five trials with 984 pregnant women. All trials were conducted in low- and middle-income countries, including India, Bangladesh, South Africa, and Croatia. At enrolment, 26% to 51% of pregnant women had vitamin B12 deficiency (less than 150 pmol/L), and the prevalence of anaemia (haemoglobin less than 11.0 g/dL) ranged from 30% to 46%. The dosage of vitamin B12 supplementation varied from 5 μg/day to 250 μg/day, with administration beginning at 8 to 28 weeks' gestation through to delivery or three months' postpartum, and the duration of supplementation ranged from 8 to 16 weeks to 32 to 38 weeks. Three trials, involving 609 pregnant women, contributed data for meta-analyses of the effects of vitamin B12 supplementation compared to placebo or no vitamin B12 supplementation. Maternal anaemia: there may be little to no difference for maternal anaemia by intervention group, but the evidence is very uncertain (70.9% versus 65.0%; risk ratio (RR) 1.08, 95% confidence interval (CI) 0.93 to 1.26; 2 trials, 284 women; very low-certainty evidence). Maternal vitamin B12 status: vitamin B12 supplementation during pregnancy may reduce the risk of maternal vitamin B12 deficiency compared to placebo or no vitamin B12 supplementation, but the evidence is very uncertain (25.9% versus 67.9%; RR 0.38, 95% CI 0.28 to 0.51; 2 trials, 272 women; very low-certainty evidence). Women who received vitamin B12 supplements during pregnancy may have higher total vitamin B12 concentrations compared to placebo or no vitamin B12 supplementation (mean difference (MD) 60.89 pmol/L, 95% CI 40.86 to 80.92; 3 trials, 412 women). However, there was substantial heterogeneity (I2 = 85%). Adverse pregnancy outcomes: the evidence is uncertain about the effect on adverse pregnancy outcomes, including preterm birth (RR 0.97, 95% CI 0.55 to 1.74; 2 trials, 340 women; low-certainty evidence), and low birthweight (RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 344 women; low-certainty evidence). Two trials reported data on spontaneous abortion (or miscarriage); however, the trials did not report quantitative data for meta-analysis and there was no clear definition of spontaneous abortion in the study reports. No trials evaluated the effects of vitamin B12 supplementation during pregnancy on neural tube defects. Infant vitamin B12 status: children born to women who received vitamin B12 supplementation had higher total vitamin B12 concentrations compared to placebo or no vitamin B12 supplementation (MD 71.89 pmol/L, 95% CI 20.23 to 123.54; 2 trials, 144 children). Child cognitive outcomes: three ancillary analyses of one trial reported child cognitive outcomes; however, data were not reported in a format that could be included in quantitative meta-analyses. In one study, maternal vitamin B12 supplementation did not improve neurodevelopment status (e.g. cognitive, language (receptive and expressive), motor (fine and gross), social-emotional, or adaptive (conceptual, social, practical) domains) in children compared to placebo (9 months, Bayley Scales of Infant and Toddler Development Third Edition (BSID-III); 1 trial; low-certainty evidence) or neurophysiological outcomes (72 months, event-related potential measures; 1 trial; low-certainty evidence), though children born to women who received vitamin B12 supplementation had improved expressive language domain compared to placebo (30 months, BSID-III; 1 trial; low-certainty evidence). Oral vitamin B12 supplementation during pregnancy may reduce the risk of maternal vitamin B12 deficiency and may improve maternal vitamin B12 concentrations during pregnancy or postpartum compared to placebo or no vitamin B12 supplementation, but the evidence is very uncertain. The effects of vitamin B12 supplementation on other primary outcomes assessed in this review were not reported, or were not reported in a format for inclusion in quantitative analyses. Vitamin B12 supplementation during pregnancy may improve maternal and infant vitamin B12 status, but the potential impact on longer-term clinical and functional maternal and child health outcomes has not yet been established.