megaloblastic anemia is an important morbidity in children and adolescents especially in developing countries and with poor socioeconomic status .
imerslund grasbeck syndrome ( igs ) is a rare autosomal recessive megaloblastic anemia characterized by selective vitamin ( vit ) b12 deficiency and asymptomatic proteinuria .
it is the most common cause of cobalamin deficiency in certain communities like lapps in scandinavia , north african jews , few families in norway and finland .
about 300 cases have been reported worldwide with new cases appearing in eastern mediterranean countries .
it has varying manifestations like failure to thrive , insidious onset of infections , hematological and neurological symptoms .
igs is resistant for oral vit b12 supplements , but responds very well for parenteral therapy.[27 ] we report a case of young female who presented with pancytopenia and proteinuria , evaluated in local hospitals as chronic hemolytic anemia ( autoimmune cause ) , finally diagnosed as igs on complete evaluation .
an 18-year - old unmarried female hailing from north karnataka , came with history of generalized weakness and easy fatigability since 1 month .
there was no history of of pain abdomen , melaena , hematemesis , hematuria , chest pain or cough .
past history revealed that she had similar complaints since childhood and was evaluated in local hospitals as chronic hemolytic anemia ( autoimmune etiology ) and treated with oral vitamin supplements ( vit b12 of 150 g ) and multiple blood transfusions . family history and menstrual history were unremarkable . she was moderately built and moderately nourished on mixed diet had severe pallor ( + + + ) and mild icterus ( + ) .
complete hemogram at the time of admission showed hemoglobin of 4 g / dl , erythrocyte count of 2.4 millions / dl , total leucocyte count of 3700 cells / mm , platelet count of 1,17,000 cells/ mm , mean corpuscular volume of 114 fl , mean corpuscular hemoglobin of 33 pg , mean corpuscular hemoglobin concentration of 30% , reticulocyte count of 1.2% and erythrocyte sedimentation rate of 45 mm at the end of 1 hour .
her total protein was 7 g / dl , albumin was 4.8 g / dl , globulin was 2.2 g / dl , total bilirubin of 2.5 g / dl , direct of 0.6 g / dl and indirect was 1.9 g / dl .
urine analysis showed moderate proteinuria ( + + ) with 24-hour urine protein of 0.9 g / dl ( non - nephrotic range ) .
peripheral smear showed predominantly macrocytic erythrocytes , few elliptocytes , tear drop cells and macroovalocytes .
serum vit b12 was 42.14 pg / ml ( normal range 211 - 946pg / ml ) .
serum ferritin , iron , folate and total iron binding capacity were within normal limits .
on reviewing previous records , she had similar complaints since childhood and was evaluated in various local hospitals as chronic hemolytic anemia ( autoimmune etiology ) and proteinuria with suspicious of vasculitic disorder .
ham test , sucrose lysis test , sickling test , urine porphyrin and antinuclear antibodies were negative .
erythropoiesis was hyperplastic and showed megaloblastic change with many binuleated forms and frequent mitotic figures[figure 1 ] .
perl 's stain showed grade 1 iron store . in view of the above findings ,
oral administration of intrinsic factor also failed to show improvement in radioactive vit b12 excretion .
patient was treated with loading dose of vit b12 1000 g ( cyanocobalamin ) i m and 100 g i m weekly for 3 months , showed good response with reticulocyte count ( 9% ) , hemoglobin raised to 9.2 g / dl and erythrocyte count of 3.8 millions / dl . drastic recovery with parenteral vit b12 and
hence , an adolescent female with pancytopenia , persisting asymptomatic proteinuria , bone marrow showing megaloblastic anemia with defective absorption of vit b12 in schilling test , intact intrinsic factor and good response to parenteral vit b12 , a final diagnosis of igs was made .
patient symptomatically improved with regular parenteral vit b12 therapy and was followed up for 8 months . at her last follow - up hemoglobin was 10.8 g / dl and erythrocyte count of 4.1 millions / dl .
igs , also termed as familial selective malabsorption of vit b12 associated with proteinuria was first described by imerslund and grasbeck et al,.[246 ] estimated prevalence of this disorder is < 6:1,000,000 people .
the diagnosis of igs should be considered when three typical features are present like macrocytic anemia , decreased serum vit b12 level and proteinuria in absence structural renal pathology .
igs is caused by selective incapacity to transport the vit b12 across the intestinal wall . in most cases , the molecular basis of the selective malabsorbtion and proteinuria involves mutation in one or both of the two genes , cubulin on chromosome 10 or amnionless on chromosome 14.[2578 ] both the proteins are components of the intestinal receptor for the vit b12-intrinsic factor complex and receptor mediating the tubular reabsorption of protein from the urine .
the diagnosis of igs is made by detecting the presence of cobalamin deficiency , then demonstrating it is poorly absorbed , then excluding other causes of vit b12 malabsorbption and finally by showing the response to parenteral vit b12 . in our case ,
serum vit b12 was low ( 42.14 pg / ml ) and schilling test revealed low urinary radioactive vit b12 excretion . patient was treated with loading dose of vit b12 1000 g ( cyanocobalamin ) i m and 100 g i m weekly for 3 months . after therapy , repeat hb improved to 9.2 g / dl , reticulocyte count to 9% and erythrocyte count to 3.8 millions / dl .
few cases may be managed with 1 mg of vitamin b12 oral therapy administered at 2-week interval with varied clinical outcome .
although schilling test was the gold standard method for detecting cobalamin absorption , it is now outdated due to constraints like reduced availability of test components , cost , radioactive waste disposal and concern about the animal derived tissues for human use ( intrinsic factor ) .
replacement for it is under development like measurement of change in holotranscobalamin following oral administration of non - radio - labeled cobalamin and accelerated mass spectrometry .
both these methods show promise but not yet in routine practice . this disease is transmitted as an autosomal recessive trait ; hence , early detection of this disorder would enable screening and genetic counselling for asymptomatic family members .
the patient should be warned not to stop the treatment eventhough symptoms seen not to reappear immediately following cessation of therapy .
 imerslund grasbeck syndrome ( igs ) is a rare autosomal recessive childhood disorder characterized by selective vitamin ( vit ) b 12 malabsorption with asymptomatic proteinuria without any structural renal pathology . 
 the patients stay healthy for decades with life - long parenteral vit b12 . 
 we report a case of young female who presented with pancytopenia and proteinuria , evaluated in local hospitals as chronic hemolytic anemia ( autoimmune cause ) , finally diagnosed as igs on complete evaluation . 
 she was treated with injectable vit b12 ( 1000 g cyanocobalalmin ) and showed drastic recovery . 
 igs should be considered in patients with megaloblastic anemia not responding to oral vit b12 and associated proteinuria . 
INTRODUCTION
CASE REPORT
DISCUSSION