Megaloblastic anemia in a child with central nervous system manifestations
http://www.100md.com
《美国医学杂志》
Shree Medical Research Center,Opposite Hotal Mazda, Trambak Naka, Nasik, Maharashtra, India
Vitamin B12 deficiency is encountered in malnourished infants or in offsprings of strict vegan mothers or mothers with pernicious anemia accompanied by hematological and neurological findings. Megaloblastic anemia is a common feature between 6 months - 2 years and rarely occurs after 5 years of age, especially in a child consuming non-vegeterian diet. B12 deficiency may occur after 5 years of age because of chronic diarrhea, malabsorption syndrome, or intestinal surgical causes. Pernicious anemia causes B12 deficiency, but nutritional B12 deficiency, causing recurrent diarrhea, recurrent stomatitis with subacute combined degeneration causing ataxia in a 9- year-old child, is rare.
A 9-year-old male child was first born of a 2nd degree consanguineous marriage, with repeated attacks of diarrhea (about 10 to 15 attacks in last the 3 years lasting for 5-7 days), vomiting, glossitis since the age of 3 and scholastic backwardness since last the 6 months. His developmental milestones were normal and achieved till age. He was breast-fed till the age of 9 months and started on supplementary feeds at the age of 6 months. The child was non-vegetarian and he was fond of junk food all the time and rarely had home made food and vegetables. His daily calorie consumption was 2000 kcal/day. Because of junk food and non-vegetarian items he was getting adequate proteins (38-40 gms/day) but insufficient vitamins. On examination, the weight was 24 kg (50th percentile); height, 130 cm (50th percentile); there was no icterus, moderate pallor, no lymphadenopathy and no pigmentation anywhere on the body. CNS examination revealed normal higher centers and normal cranial nerves. Motor system was normal. There was hypotonia in extensor and flexor group of muscles of knee and ankle joints. The child was unable to walk in a straight line. Romberg's sign was positive. Other systemic examinations were normal.
He was investigated and complete blood count (CBC) showed : Hb-8.2 g/dl, hematocrit (Ht)-36.4, WBC-7800/cumm, mean corpuscular volume (MCV)-74.8 fl, mean corpuscular hemoglobin (MCH) 28.6 pg, (mean corpuscular hemoglobin concentration (MCHC)-36.4% and red-cell differential width (RDW)-16.4%. He was started on hematinics, oral vitamin B12 and folic acid supplementation. Over the course of years, the child showed transient improvement in hematological and clinical parameters. All these years the child's parents refused the advice of bone marrow examination. He was pursued to make dietary changes and junk food was eliminated from his diet. On the follow-up after 2 months, clinical picture improved and complete blood count showed Hb-13 g/dl, hematocrit (Ht)-42%, WBC-9400/cumm, MCV:- 80.8 fl, (MCH)-26.2 pg, MCHC-32.4% and RDW-12.1%.
Other blood chemistry studies (Random blood sugar level, Blood Urea Nitrogen, Serum creatinine, LDH, Serum bilirubin) were normal. There was no history of any family member suffering from similar illness. Over the next 4-5 months, the child was doing well until one day he was brought to the OPD with complaints of progressive unsteadiness in standing and swaying while walking for 2 weeks duration. CBC showed Hb-11.4 g/dl, Ht-34.8%, WBC- 6300/cumm, MCV-94.1 fl, MCH-31 pg, MCHC-32.9%, and RDW-18.2%. Bone marrow examination revealed significant megaloblastic features. Work-up included G6PD activity, Direct coomb's test, Liver function tests, Renal function tests, Serum protein electrophoresis, Serum iron studies (serum iron, total iron binding capacity, transferrin saturation), Serum ferritin assay, thyroid function tests, anti-nuclear anitibodies, HIV antibody, HbsAG test and HCV, which were found to be normal. Serum vitamin B12 level was found to be 17 pg/dl (normal-200-950pg/ml). Serum folic acid level was normal. The child was further investigated for pernicious anemia, which included intrinsic factor blocking antibody test (showed value of 0.99, Negative ratio upto 1.1, Grey Zone: 1.1-1.2, Positive ratio: Greater than 1.2) and Anti parietal cell antibodies (showed value of 5.4 U/ml, Normal range 0.00-10.00) both of which showed normal values. He was started on Inj. Methycobal 1000 ug sc twice a week for 1st month, followed by once a week in 2nd month and followed by once a month for a year. His unsteadiness disappeared in a month. Hypotonia also improved and there was no neurological deficit. MRI of the dorsolumbar spine was normal. On follow-up of 6 months there were no neurological deficits, anemia had improved so also scholastic performance.
Vitamin B12 causing megaloblastic anemia with stomatitis, diarrhea in a child, aged 5-10 years, is uncommon, especially when he is a non- vegetarian. Almost all vitamin B12 in plasma is bound to Transcobalamine (TC) I and TC III, and thus measurement of serum B12 concentration relects storage of this vitamin. TC II deficiency is a rare cause of megaloblastic anemia due to decreased utilization of cobalamine. A congenital deficiency is inherited as autosomal recessive condition, with failure to absorb and transport vitamin B12.[1] Dastur et al[2] reported 5 cases with neurological manifestations of vitamin B12 deficiency over several years in Mumbai. Jeejeebhoy et al[3] found 8 cases and showed that they were mostly due to malabsorption. All the cases described by Dastur et al and Jeejeebhoy et al were adults and vegetarians. Junk food does not give any supplementation of vitamin B12 and folic acid. Pernicious anemia is also known to cause vitamin B12 deficiency which is ruled out in our case by negative Intrinsic Factor Blocking Antibodies and Negative Anti Parietal cell Antibodies. CNS signs are common with vitamin B12 deficiency, in infants clinically presenting as infantile tremor syndrome. In India, infantile tremor syndrome was described in 1950. This syndrome was first thought to be due to vitamin B12 deficiency by Jadhav et al[4], based on 6 cases with megaloblastic anemia and improved with B12. These findings were reproduced by Garewal et al[5] who found megaloblastic anemia in 20 and low B12 levels (below 100 pg/m) in 88% of cases. Neurological manifestations of B12 and folic acid deficiency are varied. Wadia et al have collected data of 99 cases of true deficiency (serum B12 level less than 200 pg/ml and folate less than 3 ng/ml) and 68 cases of borderline deficiency ( B12 200-300 pg/ml and folate 3-4 ng/ml). In these 167 cases, neuropathy was detected in 42 cases. Half of these had sensory neuropathy. Evidence of spinal cord involvement was found in 12, and 7 of these had evidence of involvement of peripheral nerves. Posterior columns and pyramidal tracts, cognitive and behavioral signs were present in 10.3%.[6] The neuropathy in cobalamine deficiency is characterized by demyelination of posterolateral columns of spinal cord (subacute combined degeneration).[7]
Contributors: SSK and PSK did the literature search. GMK prepared the manuscript. SSK conceived the idea, revised the manuscript and will act as the guarantor for the paper.
References
1. Bertil Glader. Megaloblastic anemias. In Bertil Glader, Richard E, Behrman, Robert M, Kuegman, Hal B Jenson, eds. Nelson Textbook of Pediatrics, New Delhi; Elsevier, 2004; 1611-1613.
2. Dastur DK, Quaddros EV, Wadia NH et al. Effect of vegetarianism and smoking on vitamin B 12, thiocynate, and folate levels in the blood of normal subjects. BMJ 1972; 3 : 260-264.
3. Jeejeebhoy KN, Wadia NH, Desai HG et al. Role of vitamin B12 deficiency in Tropical nutritional Neuromyelopathy. J Neurol Neurosurg Psychiatry 1967; 30 : 7.
4. Jadhan M, Webbs JKG, Vaishnava et al. Vitamin B12 deficiency in Indian infants. A Clinical Syndrome. Lancet 1962; 2; 903-906
5. Garewal G, Narang A, Das KC. Infantile tremor syndrome: A vitamin B12 deficiency in infants. J Trop Pediat 1988; 34; 174-178
6. Wadia RS, Bandishti SS, Kharche MM, B12 and folate deficiency: incidence and clinical features. Neurol India 2000; 48 : 302-304.
7. Metz J. Cobalamin deficiency and the pathogenesis of nervous system disease. Annu Rev Nutr 1992; 12 : 59-79.(Kashyape SS, Kashyape PS,)
Vitamin B12 deficiency is encountered in malnourished infants or in offsprings of strict vegan mothers or mothers with pernicious anemia accompanied by hematological and neurological findings. Megaloblastic anemia is a common feature between 6 months - 2 years and rarely occurs after 5 years of age, especially in a child consuming non-vegeterian diet. B12 deficiency may occur after 5 years of age because of chronic diarrhea, malabsorption syndrome, or intestinal surgical causes. Pernicious anemia causes B12 deficiency, but nutritional B12 deficiency, causing recurrent diarrhea, recurrent stomatitis with subacute combined degeneration causing ataxia in a 9- year-old child, is rare.
A 9-year-old male child was first born of a 2nd degree consanguineous marriage, with repeated attacks of diarrhea (about 10 to 15 attacks in last the 3 years lasting for 5-7 days), vomiting, glossitis since the age of 3 and scholastic backwardness since last the 6 months. His developmental milestones were normal and achieved till age. He was breast-fed till the age of 9 months and started on supplementary feeds at the age of 6 months. The child was non-vegetarian and he was fond of junk food all the time and rarely had home made food and vegetables. His daily calorie consumption was 2000 kcal/day. Because of junk food and non-vegetarian items he was getting adequate proteins (38-40 gms/day) but insufficient vitamins. On examination, the weight was 24 kg (50th percentile); height, 130 cm (50th percentile); there was no icterus, moderate pallor, no lymphadenopathy and no pigmentation anywhere on the body. CNS examination revealed normal higher centers and normal cranial nerves. Motor system was normal. There was hypotonia in extensor and flexor group of muscles of knee and ankle joints. The child was unable to walk in a straight line. Romberg's sign was positive. Other systemic examinations were normal.
He was investigated and complete blood count (CBC) showed : Hb-8.2 g/dl, hematocrit (Ht)-36.4, WBC-7800/cumm, mean corpuscular volume (MCV)-74.8 fl, mean corpuscular hemoglobin (MCH) 28.6 pg, (mean corpuscular hemoglobin concentration (MCHC)-36.4% and red-cell differential width (RDW)-16.4%. He was started on hematinics, oral vitamin B12 and folic acid supplementation. Over the course of years, the child showed transient improvement in hematological and clinical parameters. All these years the child's parents refused the advice of bone marrow examination. He was pursued to make dietary changes and junk food was eliminated from his diet. On the follow-up after 2 months, clinical picture improved and complete blood count showed Hb-13 g/dl, hematocrit (Ht)-42%, WBC-9400/cumm, MCV:- 80.8 fl, (MCH)-26.2 pg, MCHC-32.4% and RDW-12.1%.
Other blood chemistry studies (Random blood sugar level, Blood Urea Nitrogen, Serum creatinine, LDH, Serum bilirubin) were normal. There was no history of any family member suffering from similar illness. Over the next 4-5 months, the child was doing well until one day he was brought to the OPD with complaints of progressive unsteadiness in standing and swaying while walking for 2 weeks duration. CBC showed Hb-11.4 g/dl, Ht-34.8%, WBC- 6300/cumm, MCV-94.1 fl, MCH-31 pg, MCHC-32.9%, and RDW-18.2%. Bone marrow examination revealed significant megaloblastic features. Work-up included G6PD activity, Direct coomb's test, Liver function tests, Renal function tests, Serum protein electrophoresis, Serum iron studies (serum iron, total iron binding capacity, transferrin saturation), Serum ferritin assay, thyroid function tests, anti-nuclear anitibodies, HIV antibody, HbsAG test and HCV, which were found to be normal. Serum vitamin B12 level was found to be 17 pg/dl (normal-200-950pg/ml). Serum folic acid level was normal. The child was further investigated for pernicious anemia, which included intrinsic factor blocking antibody test (showed value of 0.99, Negative ratio upto 1.1, Grey Zone: 1.1-1.2, Positive ratio: Greater than 1.2) and Anti parietal cell antibodies (showed value of 5.4 U/ml, Normal range 0.00-10.00) both of which showed normal values. He was started on Inj. Methycobal 1000 ug sc twice a week for 1st month, followed by once a week in 2nd month and followed by once a month for a year. His unsteadiness disappeared in a month. Hypotonia also improved and there was no neurological deficit. MRI of the dorsolumbar spine was normal. On follow-up of 6 months there were no neurological deficits, anemia had improved so also scholastic performance.
Vitamin B12 causing megaloblastic anemia with stomatitis, diarrhea in a child, aged 5-10 years, is uncommon, especially when he is a non- vegetarian. Almost all vitamin B12 in plasma is bound to Transcobalamine (TC) I and TC III, and thus measurement of serum B12 concentration relects storage of this vitamin. TC II deficiency is a rare cause of megaloblastic anemia due to decreased utilization of cobalamine. A congenital deficiency is inherited as autosomal recessive condition, with failure to absorb and transport vitamin B12.[1] Dastur et al[2] reported 5 cases with neurological manifestations of vitamin B12 deficiency over several years in Mumbai. Jeejeebhoy et al[3] found 8 cases and showed that they were mostly due to malabsorption. All the cases described by Dastur et al and Jeejeebhoy et al were adults and vegetarians. Junk food does not give any supplementation of vitamin B12 and folic acid. Pernicious anemia is also known to cause vitamin B12 deficiency which is ruled out in our case by negative Intrinsic Factor Blocking Antibodies and Negative Anti Parietal cell Antibodies. CNS signs are common with vitamin B12 deficiency, in infants clinically presenting as infantile tremor syndrome. In India, infantile tremor syndrome was described in 1950. This syndrome was first thought to be due to vitamin B12 deficiency by Jadhav et al[4], based on 6 cases with megaloblastic anemia and improved with B12. These findings were reproduced by Garewal et al[5] who found megaloblastic anemia in 20 and low B12 levels (below 100 pg/m) in 88% of cases. Neurological manifestations of B12 and folic acid deficiency are varied. Wadia et al have collected data of 99 cases of true deficiency (serum B12 level less than 200 pg/ml and folate less than 3 ng/ml) and 68 cases of borderline deficiency ( B12 200-300 pg/ml and folate 3-4 ng/ml). In these 167 cases, neuropathy was detected in 42 cases. Half of these had sensory neuropathy. Evidence of spinal cord involvement was found in 12, and 7 of these had evidence of involvement of peripheral nerves. Posterior columns and pyramidal tracts, cognitive and behavioral signs were present in 10.3%.[6] The neuropathy in cobalamine deficiency is characterized by demyelination of posterolateral columns of spinal cord (subacute combined degeneration).[7]
Contributors: SSK and PSK did the literature search. GMK prepared the manuscript. SSK conceived the idea, revised the manuscript and will act as the guarantor for the paper.
References
1. Bertil Glader. Megaloblastic anemias. In Bertil Glader, Richard E, Behrman, Robert M, Kuegman, Hal B Jenson, eds. Nelson Textbook of Pediatrics, New Delhi; Elsevier, 2004; 1611-1613.
2. Dastur DK, Quaddros EV, Wadia NH et al. Effect of vegetarianism and smoking on vitamin B 12, thiocynate, and folate levels in the blood of normal subjects. BMJ 1972; 3 : 260-264.
3. Jeejeebhoy KN, Wadia NH, Desai HG et al. Role of vitamin B12 deficiency in Tropical nutritional Neuromyelopathy. J Neurol Neurosurg Psychiatry 1967; 30 : 7.
4. Jadhan M, Webbs JKG, Vaishnava et al. Vitamin B12 deficiency in Indian infants. A Clinical Syndrome. Lancet 1962; 2; 903-906
5. Garewal G, Narang A, Das KC. Infantile tremor syndrome: A vitamin B12 deficiency in infants. J Trop Pediat 1988; 34; 174-178
6. Wadia RS, Bandishti SS, Kharche MM, B12 and folate deficiency: incidence and clinical features. Neurol India 2000; 48 : 302-304.
7. Metz J. Cobalamin deficiency and the pathogenesis of nervous system disease. Annu Rev Nutr 1992; 12 : 59-79.(Kashyape SS, Kashyape PS,)