Imerslund–Grasbeck Syndrome – A Rare Encounter!

Rare clinical conditions often are last to be excluded in real scenarios and sometimes produce surprising results. We would like to present a clinical case which presented a diagnostic dilemma due to confusing laboratory findings and finally turned out to be a rare genetic syndrome. A 3-year-old male child from Maharashtra was brought with a short history of fever and generalized weakness for the past 1 week. On examination, the child was well developed for age but showed pallor. The rest of the general and systemic examination was within normal limits. Baseline investigations showed hemoglobin (Hb) of 4.5 g/dL, total leukocyte count – 19.7 × 103/μL, and platelet count of 60 × 103/μL with a reticulocyte count of 2.5% (corrected reticulocyte count of 0.7%, mean corpuscular volume – 81.2 fL, mean corpuscular hemoglobin – 19.3 pg, mean corpuscular hemoglobin concentration 29 g/dL, and total red blood cell – 1.65 × 106/μL). Peripheral smear showed a marked leukoerythroblastic picture with 35 nucleated red blood cells/100 white blood cells and differential of polymorphs - 21% Lymphocytes- 55% Monocytes -08% Eosinophils - 02% myelocytes- 06% Metamyelocytes- 08% along with many activated lymphocytes. The red cells were microcytic hypochromic with severe anisopoikilocytosis, teardrops, target cells, Howell–Jolly bodies [Figure 1a and b], and basophilic stippling. Platelets recovered to normal after 2 days with large and giant platelets. On further evaluation, he was found to have persistent proteinuria (2+) on urine examination with a high protein creatinine ratio of 248. No signs of kidney damage was seen – serum urea and creatinine were persistently normal. The patient's serum sample was markedly chylous [Figure 1c] and showed hypertriglyceridemia (790 mg/dL) with high very low-density lipoprotein levels (120 mg/dL). Lactate dehydrogenase was found to be raised 7180 IU/L. A study for Vitamin B12 levels showed low B12 (45 pg/ml) and high homocysteine levels (>50 μmol/L). The rest of the biochemistry and electrolytes were essentially within the normal range. High-performance liquid chromatography performed on the patient sample showed HbF – 14.9%, HbA2 – 6.8%, and HbA – 0%–65% suggestive of heterozygous beta-thalassemia. Since thalassemia trait alone does not explain this severe anemia, further workup was taken up. Bone marrow examination revealed hypercellular marrow with marked megaloblastic changes [Figure 1d]. Whole clinical exome sequencing was done which confirmed heterozygosity of beta-thalassemia (exon 1 HBB mutation – C27dup variant) and additionally showed homozygosity of AMN + mutation (exon 12 C1312-1313del) suggestive of Imerslund–Grasbeck syndrome.Figure 1: LG stained peripheral smear in 100x oil field - Composite figure showing; (a) PBS picture showing microcytic hypochromic RBC and leucoerythroblastic reaction, (b) Inset shows prominent Howell jolly bodies, (c) serum sample showing marked chylous appearance, (d) Hypercellular bone marrow with marked megaloblastic changesImerslund–Grasbeck syndrome is an autosomal recessive congenital disorder (1 in 10 million) due to a pathogenic mutation in the CUBN or AMN gene which leads to malabsorption of Vitamin B12.[1] Distinct entities such as beta-thalassemia trait, triglyceridemia, proteinuria, and megaloblastic anemia are common associations/manifestations of this syndrome which, when seen in isolation, are difficult to put together and present a diagnostic quandary.[2] Vague clinical presentation may lead to a delay in diagnosis. Our patient responded well to injectable cobalamin replacement and his hemoglobin recovered slowly (10.4 g/dL). He is under follow-up, and the plan is to continue injectable Vitamin B12 lifelong. This patient is a learning case as to how a syndromic presentation usually results in rare diagnosis which can be managed clinically by simple interventions. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.