Imerslund-Grasbeck Syndrome: Association with Diabetes Mellitus

Correspondence to: Dr M Vijaykumar, Flat No 4, Muktha Vandan, New No 7, Old No 4,
Ramanathan Street, Kilpauk, Chennai, India.
E-mail: [email protected] 
 

Imerslund-Grasbeck syndrome (IGS) is a rare autosomal recessive disease characterized by vitamin B₁₂ (cobalamine) deficiency due to selective malabsoprtion of this vitamin resulting in megaloblastic anemia appearing in later childhood. The anemia responds well to parenteral vitamin B₁₂ therapy. This syndrome is frequently accompanied by proteinuria and sometimes neurological symptoms(1). Associated genitourinary tract abnormalities(2), dolichocephaly(3), beta-thalassemia trait(4) and diabetes mellitus(5) have been reported. We present a case of IGS with diabetes mellitus.

A 11-year old boy, first born to second degree consanguineous parents was referred for persistent asymptomatic proteinuria since one year. There was no hematuria, oliguria, skin rash, joint pain or swelling. At the age of 2 years, during a diarrheal illness, he had periorbital puffiness, severe anemia, hyper-pigmen-tation of the hands and 2+ proteinuria. With vitamin B₁₂ injection and oral medications, he had improved.

He remained asymptomatic for 3 years but had persistent non-nephrotic proteinuria with normal hematological values. His weight increased to 44 kg. At 14 years, he was hospitalized for fever with vomiting. On this occasion, he had severe anemia, facial puffiness and loss of weight to 37 kg (25th percentile). His height was 158 cm (50th percentile)(6). There was no neurological deficit, optic atrophy, or hearing defect. Blood pressure was normal. Investigations revealed severe anemia with leucopenia and thrombocytopenia; hemoglobin was 4.9 g/dL. There were macrocytes, hypersegmented neutrophils and anisopoikilocytosis in the peripheral smear. Bone marrow revealed megaloblastic erythropoiesis with occasional megakaryocytes. Serum LDH levels were elevated. In view of megaloblastic anemia, persistent proteinuria and absence of chronic diarrhea, parasitic infestations or obvious nutritional deficiency, the possibility of IGS was considered and serum vitamin B₁₂ levels were estimated. This was low (vitamin B₁₂ 97 [211-911 pg/mL]). Injection of vitamin B₁₂ was given with advice for follow-up B₁₂ injections. At follow-up, his general condition was good with an increase in weight to 39 kg. Hemoglobin increased to 11.9g/dL. Three months later, he was admitted for severe diabetic ketoacidosis (fasting urine sugar4+, fasting plasma glucose 421 mg/dL, post prandial plasma glucose 590 mg/dL). With human insulin and four monthly injections of Vitamin B12 he remained asymptomatic with a weight gain to 42 kg.

His ten years old younger sibling, who was asymptomatic but for hyperpigmentation of the dorsum of the fingers, was administered 2 monthly injection of B₁₂ by his pediatrician in view of the elder sibling’s diagnosis. The hemogram done subsequently was normal with non-nephrotic proteinuria. His vitamin B₁₂ level was normal (444 [211-911 pg/mL]) and glucose tolerance test was normal. We plan to stop vitamin B₁₂ injections for him and recheck his serum B₁₂ values after 6 months.

In the absence of history of exposure to nitrous oxide, vegetarian diet, parasitic infestation or chronic gastroenterstinal malabsorption syndromes, the cause of macrocytic and megaloblastic anemia is likely to be due to an inherited disorder of folate or vitamin B₁₂. In clinical practice, diagnosis can be nearly reached by observing the response to treatment with oral dose of folate or injection vitamin B₁₂. The response in this child favours the diagnosis of a B₁₂ deficiency state. The presence of proteinuria favors the diagnosis of IGS, which is present in about 70% of the patients(7).

The selective malabsorption of vitamin B₁₂ and proteinuria involves a mutation in one of two genes, cubulin (CUBN) on chromosome 10 or amnionless (AMN) on chromosome 14. Both proteins are components of the ileal enterocyte receptor for the vitamin B₁₂ intrinsic factor complex and the receptor mediating the tubular reabsorption of protein from urine(9). Life long treatment with injection B₁₂ leads to complete recovery. Proteinuria persists with normal renal function. Schroder, et al.(5), reported two siblings with IGS and in one of them type 1 diabetes mellitus (DM) preceded the diagnosis of IGS by 7 years(5). Our child developed DM with ketoacidosis later on. This presentation is because of the rare association and unexplainable common etiological factor.

9. Grasbeck R. Imerslund-Gräsbeck syndrome (selective vitamin B₁₂ malabsorption with proteinuria). Orphanet Rare Dis 2006; 1: 17.