Skip to main content
Download PDF

Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases

Orphanet Journal of Rare Diseases volume 18, Article number: 291 (2023) Cite this article

Abstract

Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder characterized by vitamin B12 malabsorption. Most patients present with non-specific symptoms attributed to vitamin B12 deficiency, and proteinuria. Patients may if untreated, develop severe neurocognitive manifestations. If recognized and treated with sufficient doses of vitamin B12, patients recover completely. We provide, for the first time, an overview of all previously reported cases of IGS. In addition, we provide a complete review of IGS and describe two new patients.

Background

Imerslund-Gräsbeck syndrome (IGS, OMIM 261,100/618,882) is an autosomal recessive disorder characterized by a vitamin B12 (vitB12) deficiency, caused by a selective malabsorption of vitB12, with normal secretion of intrinsic factor (IF) and hydrochloric acid into the stomach [1]. Before the diagnosis of vitB12 deficiency, patients have non-specific symptoms such as failure to thrive, paleness, fatigue, recurring viral infections and mild neurological symptoms. Laboratory examination often reveals macrocytic anemia with or without proteinuria [1]. IGS was first described in 1960 by Imerslund [2] and Gräsbeck et al. [3]. The reports included ten and two patients, respectively, although similar cases had been published since the early 19th century [4]. IGS is caused by mutations in the gene CUBN [Genbank NG_008967] encoding cubilin or AMN [Genbank NG_008276] encoding amnionless [5]. Homozygous or compound heterozygous mutations in either CUBN or AMN lead to IGS [1]. Cubilin and amnionless are the two subunits of the vitB12-IF receptor of the ileal mucosa, known as cubam. It is considered essential for intestinal absorption of vitB12, as well as for renal protein reabsorption. Most IGS patients are treated with intra-muscular vitB12, which most frequently corrects the clinical phenotype [1].

IGS is a rare disorder with an estimated prevalence to be less than 6 per 1,000,000 1. We report on two siblings with IGS, which prompted us to provide an overview of all previously reported cases and a review of IGS.

New cases

The patient was a 4-year-old girl of Turkish parents. Medical history was uneventful. Parents were consanguinous, all grandparents were interrelated. The brother of our patient had congenital adrenal deficiency due to a homozygous pathogenic deletion of exon 1–3 of CYP21A2 [Genbank NM_007941] mutation. Futhermore, a sister who was born with hydrops fetalis died three days after birth.

Our patient presented at our outpatient clinic with three days of fever and coughing. Clinical examination and laboratory analysis suggested a viral infection. Unexpectedly, a slight decrease in hemoglobin was observed, in addition to high mean corpuscular hemoglobin, high mean corpuscular volume, thrombocytopenia, and leukopenia (Table 1). Furthermore, a high lactate dehydrogenase (LDH) and low vitB12 were observed. The peripheral blood smear showed several abnormalities and abnormal cells, with tear drop cells as the most apparent. Teardrop cells are described in a wide range of diseases that are associated with bone marrow fibrosis, such as myelodysplastic syndromes, leukemia, metabolic disorders, hemolytic anemia, iron deficits, thalassemia, but have also been described in macrocytic anemia [6]. There was no evidence of hemolytic anemia, ferritin was in the normal range and hemoglobin electrophoresis showed no evidence of a hemoglobinopathy such as thalassemia.

Table 1 Laboratory examination of patient 1
Full size table

Because high LDH and pancytopenia may be signs of myelodysplastic syndrome and leukemia, the bone marrow was examined. The bone marrow contained an increase in erythroblasts, but no other abnormalities.

Urinalysis revealed proteinuria (1.04 g/L, normal range: <0.12). Due to the combination of megaloblastic anemia, vitB12 deficiency and proteinuria, screening for abnormalities in the AMN and CUBN gene was performed. A homozygous variant in AMN, c.208-2 A > G, was identified. The variant was previously reported in the literature and considered pathogenic.

Oral supplementation with vitB12 was initiated, correcting the vitB12 deficiency, anemia, and related symptoms.

The brother of patient 1 was tested for IGS and the same homozygous pathogenic variant c.208-2 A > G mutation in AMN was detected at 8 months of age, in addition to the homozygous partial deletion of CYP21A2. He had an adrenal crisis at the age of 12 days, for which resuscitation and therapeutic hypothermia had been necessary. He was treated with steroids. At the age of 18 months, he was suffering from proteinuria and low levels of vitB12, without anemia or other clinical manifestations. Oral supplementation of vitB12 (cyanocobalamin 1 mg daily) was started, and vitB12 deficiency was corrected.

We describe two siblings with IGS, who presented with vitamin B12 deficiency and proteinuria. The rare occurrence of this syndrome motivated us to provide an overview of all previously published cases and to discuss all aspects of IGS.

Materials and methods

Inclusion criteria

This is a retrospective study with no restriction on the publication date or language. The data were gathered using a Pubmed and Google Scholar search, using the keywords “Imerslund-Grasbeck” and/or “Imerslund Grasbeck”. All relevant articles, such as case reports, case series, and reviews, were reviewed. Additional cases were identified by consulting cited references of the identified articles. The included articles were selected based on title and abstract.

Data collection

The following data were collected, if available: gender, consanguinity, origin, mutation analysis, age at onset and diagnosis, clinical manifestations at onset and diagnosis, laboratory examination (presence of pernicious anemia, vitB12 deficiency, proteinuria, Schilling tests, IF), examination of the renal system (including kidney biopsy and/or imaging, if applicable) and treatment. If the molecular analysis was not performed, information on IF analysis was included.

Statistical analysis

We used descriptive statistics to summarize the data.

Results

Demographics

In total, 111 articles were included [2, 3, 5, 7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108]. 22 additional articles were not accessible. A total of 456 patients were included, of which 2 were described in this report.

Origin

In 349/456 patients, ethnicity was documented. 22% were Turkish, 15% Finnish, 7% Norwegian, 6% Tunisian, 5% Bedouin and 6% were from the United States of America. All other origins occurred in less than 3%. Consanguinity of the parents was reported in 160/456 patients, of which 73% were consanguineous.

Gender

Gender was reported in 278/456 patients of which 55% were male and 45% female.

Age

The median age of onset of the symptoms was 2,3 years old (mean 4,2, SD ± 5,3 years, ranging from 0 months to 38 years old). The median age at diagnosis was 7,2 years old (mean 7,7, SD ± 7,9 years, range from 8 months to 48 years old).

Gene and mutation analysis

The genetic analysis had been performed in 252/456 patients, 49% had a genetic variation in AMN and 51% in CUBN. In total, 119 different homozygous and compound heterozygous variants were detected, of which 34 were in AMN and 85 were in CUBN.

The most common variants in AMN were c.208-2 A > G (n = 78), c.14del6 (n = 22), c.1006 + 34_48del15bp (n = 18).

The most common CUBN mutations were c.3890 C > T (n = 36), c.434G > A (n = 22), c.2614_2615delGA (n = 14) and c.9053 A > C (n = 14).

Diagnosis

In 52% of cases (235/456 patients), the diagnosis of IGS was confirmed by genetic analysis. In 22% (99/456 patients) the diagnosis was confirmed using a Schilling test and in 2% (9/456 patients), the diagnosis of the patient was suspected due to negative IF antibodies.

Clinical manifestations

Information on clinical manifestations before diagnosis was provided in 325 of 456 patients (71%).

Gastrointestinal manifestations occurred in 103 patients (32%), including non-specific symptoms (diarrhea, vomiting, failure to thrive, n = 67, 51%), hepato(spleno)megaly (n = 38, 37%), and jaundice (n = 6, 6%). Mucosal lesions in the mouth, such as a sore tongue, recurrent oral ulcers and gingivitis were present in 54/325 patients (17%).

Respiratory symptoms were present in 9/325 (3%) patients, including recurrent respiratory infection, bronchopneumonia, and exertional dyspnea. Other symptoms included hypopigmented hair in 6 patients (1.8%) and local skin hyperpigmentation (n = 5, 1.5%). Other symptoms were present in only 1 or 2 patients (Additional file 1).

Neurological manifestations were observed in 52 patients (16%). Most frequently, patients showed lethargy (n = 13, 25%), ataxia (n = 10, 19%), and motor or sensory deficits (n = 7, 13%). More severe clinical manifestations were present in 4% of IGS patients, which included funicular myelosis (subacute combined degeneration of the cord, n = 5, 10%), seizures (n = 3, 6%), focal cortical atrophy of the left insular region on MRI (n = 2; 3.8%) and progressive dementia (n = 1, 2%). For the other neurological manifestations, we refer to Additional file 1.

In 247 patients, vitB12 levels were described, which were decreased in 94% of the patients. 89% of these patients had pernicious anemia.

In 239/456 patients, urinalysis was documented. Of these patients, 212 (89%) had proteinuria. Only in Finland, the fraction of patients with proteinuria was lower than in other countries (20% had proteinuria, 18% had no proteinuria, 62% had no urinalysis).

Comorbidities

Of the 325 patients with reported clinical circumstances, 48 (15%) had associated comorbidities in addition to IGS (Table 2). Abnormalities in the urogenital tract were most often observed, which included anatomic nephrogenic or urinary tract abnormalities (n = 10, 3%) and vesicoureteral reflux or IgA nephropathy (both n = 1, 0.3%).

Table 2 Comorbidities in IGS patients, expressed in number of patients n and percentage % (of the total amount of patients in which clinical characteristics were described in the article; 325 patients)
Full size table

In 19 patients, a kidney biopsy was performed. Most patients exhibited glomerular abnormalities (n = 17, 5.2% of 325 patients) including 4 cases of focal segmental glomerulosclerosis. Some patients exhibited tubular abnormalities (n = 2, 0.6% of 325 patients). No deterioration of kidney function has been reported in any IGS patients, to the authors’ knowledge.

The other most common comorbidities were thalassemia (n = 7, 2.2%), IgA deficiency and defective neutrophil function (both n = 3, 0.9%). Other comorbidities occurred in only 1 or 2 patients.

Therapy

The method of vitB12 therapy was described in 240/456 cases. VitB12 was administered intramuscularly in 88%, parenteral (either intravenous or intramuscular, but not further specified) in 2%, and orally in 9% (including in our patients).

Discussion

Vitamin B12 physiology

VitB12 is a water-soluble vitamin most commonly found in animal products. It serves as a cofactor for enzymes involved in metabolism. Upon entry into the stomach, vitB12 is released from dietary proteins and bound to haptocorrin. The complex consisting of vitB12 and haptocorrin is broken down in the intestine and a complex consisting of vitB12 and IF is formed [109]. In the terminal ileum, it binds to the cubam receptor located on the ileal apical brush border, and the cubam complex is internalized by endocytosis. In the endosome, the IF-vitB12 complex is released from the cubam receptor. VitB12 is released from IF in the lysosome and exported to blood [109,110,111]. In the blood, it is transported bound by transcobalamin II, which also enables vitB12 to enter target cells. In the target cells, vitB12 is released into the lysosome, enabling it to serve as a cofactor in metabolic processes [109, 111]. VitB12 deficiency can lead to the deficiency of the cofactors adenosylcobalamin and methylcobalamin. Adenosylcobalamin is a cofactor of the enzyme methylmalonyl-coenzyme A mutase which enables the degradation of methylmalonyl-CoA into succinyl-CoA, which is a Kreb cycle intermediate. This is the final step in the degradation of the aminoacids isoleucine/valine/threonine and odd-chain fatty acids [112]. Methylcobalamin is a cofactor of methionine synthase, which is responsible for converting homocysteine into methionine. Methionine is then converted to S-adenosylmethionine, which is essential for the methylation of several compounds such as creatine, epinephrine, DNA, RNA and proteins [113].

Pathophysiology

IGS is an autosomal recessive disorder caused by pathogenic variants in either CUBN or AMN, which encode the 2 subcomplexes of the cubam receptor: cubilin and amnionless. Cubilin is a large protein that can bind several ligands and is responsible for the uptake of vitB12, but also for renal tubular reabsorption of other proteins after glomerular ultrafiltration [106]. As it has no transmembrane region, it is bound to the transmembrane protein amnionless, which also mediates internalization of the IF-vitB12-cubam complex [83, 106].

It has been demonstrated that the binding of amnionless to cubilin occurs very early in its biogenesis. After that, cubilin undergoes a posttranslational modification in the endoplasmatic reticulum (ER), after which the complex is packed in the vesicles of the Golgi apparatus and transported to the plasma membrane [114]. Studies have shown that cubilin and amnionless are mutually dependent on each other and that none of the two proteins can reach the plasma membrane if the other is deficient [106]. Udagawa et al. [106] described several mechanisms underlying impairment in renal and intestinal absorption in IGS patients. Variants in either CUBN or AMN caused defects in intracellular trafficking, accumulation in the ER and therefore decreased membrane expression in vitro. This was confirmed in vivo by a kidney biopsy of an IGS patient with a CUBN mutation. There was an expression of cubilin and amnionless in the ER of proximal tubular cells but not in the brush border of proximal tubular cells, where cubilin and amnionless should be present. Furthermore, AMN variants result in defective binding of cubilin to amnionless, which was not observed in CUBN variants. Finally, both AMN and CUBN variants cause disrupted glycosylation of cubilin. N-glycosylation is a posttranslational modification process that regulates protein folding, protein stability, protein complex formation and intracellular trafficking. Specific N-glycosylation in cubilin domains is be essential for cubam complex maturation and surface localization [106].

Clinical manifestations

Patients may develop symptoms once fetal hepatic vitB12 is exhausted, generally between the ages of 1 and 5 years [112]. Patients may present with non-specific symptoms such as failure to thrive, general weakness, and recurrent gastro-intestinal and/or respiratory infections. In addition to non-specific symptoms, we observed a relatively high amount of oral mucosal lesions in 17% of the patients. We did not observe any relations between these non-specific symptoms and genotype.

Neurocognitive symptoms have been attributed to several pathophysiological mechanisms, including decreased myelinization as a result of impaired methylation due to vitB12 shortage and the direct toxic effects of homocysteine and methylmalonic acid [109]. Neurological symptoms are reported to be generally mild and non-specific such as developmental delay, learning difficulties, and psychological symptoms due to vitB12 deficiency [1, 5]. In our review, we observed a surprisingly high incidence of moderate (ataxia in 4% of IGS patients) and even severe neurological manifestations including patients with convulsions, degeneration of the spinal cord, focal cortical brain atrophy, and progressive dementia (3.5% of IGS patients) [48, 71, 72, 74]. The numbers of these severe neurological manifestations were, however, too small to draw conclusions about phenotype-genotype correlations.

Proteinuria and renal manifestations

Proteins that are found in the urine are predominantly middle molecular weights proteins with a high fraction of albumin (61–100%) [2, 27]. Aminoaciduria has been described by some authors [2, 27, 100, 115]. Only very small amounts of high molecular weight proteins, such as IgG, were found [27].

The pathophysiology of proteinuria has not been fully elucidated. The proteinuria is not of the classical glomerular or tubular type, but probably results from the lack of cubilin function that is needed for tubular reabsorption of some, but not all, urinary proteins [52]. Both cubilin and amnionless are highly expressed in the proximal tubules of the kidney. In the proximal tubule, but not in the intestine, they interact with the endocytic receptor megalin, which leads to the internalization of the cubilin-amnionless complex (cubam) and thus enables the reabsorption of filtered plasma proteins [83, 106]. In the case of a mutation in CUBN or AMN, retention of cubilin and amnionless in the ER of proximal tubular cells can occur, leading to the absence of cubam on the cell surface and deficient reabsorption of albumin in the proximal tubule, resulting in proteinuria [106]. There have been some observations of tubular abnormalities in patients who had a kidney biopsy, including tubular atrophy and the presence of giant mitochondria in epithelial cells of the proximal tubule [25, 106].

There is, however, also some evidence of a glomerular origin of proteinuria and several authors described glomerular abnormalities in patients who had a kidney biopsy. This included pathological changes in podocytes (cubilin is also expressed in podocytes), which may contribute to proteinuria [3, 5, 10, 22, 25, 27, 38, 68, 102, 104]. Evidence of focal segmental glomerulosclerosis with glomerular mesangial cell proliferation, interstitial fibrosis, and structural abnormalities of podocytes including effacement of foot processes and podocyte microvillation, has also been observed [10]. Other authors have found similar abnormalities of slight chronic glomerulopathy or glomerulonephritis [3, 10, 27, 104].

The pathophysiology of these renal manifestations remains poorly understood. The involvement of megalin, has been suggested in the pathophysiology of renal abnormalities [106]. Megalin can bind albumin, while cubilin is thought to have a higher binding affinity to albumin as compared to megalin. Some authors hypothesized that in the absence of normal cubilin, a higher amount of albumin is bound to megalin, promoting a pathological cascade resulting in podocyte apoptosis via the PI-3 K/PKB pathway, resulting in changes in glomerular basement membrane abnormalities and focal segmental glomerulosclerosis [10].

Kidney biopsy has been performed only rarely, because in the last years, it has become clear that although proteinuria persists, renal abnormalities do not progress in IGS patients that are treated with vitB12 1. The reason for this observation is unknown, but it has been suggested that unlike proteinuria, there may be small changes in kidney ultrastructure that respond to vitB12 supplementation [112].

In our series, 89% of IGS patients had proteinuria. Smaller numbers have been reported earlier [1, but these were small series within one region. There are several reasons for overestimation.

Firstly, urinanalysis was documented in 232 patients, but clinical features were documented in 325 patients. It may be possible that 89% proteinuria is an overestimation and that the number of patients with proteinuria may be closer to 62% (203 patients with proteinuria among 325 patients in which clinical characteristics were described). Secondly, given that only 92 of those patients had genetically confirmed IGS (40%), some of the patients may strictly not be IGS. However, due to the combination of vitB12 deficiency and proteinuria, IGS is very likely. Thirdly, there may be an overestimation because patients without proteinuria may not all be diagnosed. A combination of vitB12 deficiency and proteinuria prompts further diagnostic testing for IGS. An absence of proteinuria, however, may not lead to diagnostic testing for IGS. Fourthly, we observed that Finnish patients less frequently exhibited proteinuria. As Finland is one of the countries in which IGS is more common as compared to other countries, there may be a large number of unreported cases.

Tanner et al. [5] previously hypothesized that proteinuria may only be observed in patients harboring AMN or CUBN variants that encode the cubilin-amnionless interaction domain, but not in patients with variants in CUBN in the IF-binding site [5]. However, we also observed patients with AMN variants without proteinuria.

Urinary tract abnormalities were observed in 10 patients (3.1% of IGS patients), of which 6 patients had genetic testing. In all cases, AMN variants were identified. CUBN variants were not identified in this specific cohort. Urinary tract abnormalities have indeed, been previously associated with AMN-related IGS, reflecting the role of AMN during embryonic development [1, 116]. The absence of CUBN variants in patients with urinary tract anomalies suggests a difference in the phenotypic spectrum with potential genotype-phenotype correlation. However, the numbers are too small to draw definitive conclusions. Also, congenital anomalies of the kidney and urinary tract are not rare. They represent approximately 20–30% of all anomalies identified in the prenatal period [117].

Diagnosis

As described above, the observation of macrocytic anemia, vitB12 deficiency, and permanent proteinuria is highly suggestive of IGS. Because we observed that 92% of patients with IGS had proteinuria, we recommend health care providers to examine the urine in any child with a vitB12 deficiency.

Other clinical diagnostic findings may include thrombocytopenia, moderate leukopenia and neutropenia, and high levels of homocysteine and methylmalonic acid in serum or urine [2, 3, 5].

IGS is diagnosed by detecting vitB12 deficiency and the molecular analysis of the CUBN and AMN genes to confirm IGS, and the CBLIF [Genbank NG_008120] gene to exclude IF-deficiency. If a molecular analysis is unavailable, serum vitB12, folate, methylmalonyl acid (accumulates in vitB12 deficiency but not in folate deficiency), homocysteine, and a myelogram (to rule out malignant conditions) may be helpful [1]. Antibodies against IF can be investigated to exclude deficiency of IF as a cause of megaloblastic anemia [5]. IF assays in the gastric fluid may be used to differentiate between IGS and IF deficiency [1].

In addition, a test to demonstrate that vitB12 is poorly absorbed, such as the Schilling test, a radiolabeled vitB12 absorption test to confirm vitB12 malabsorption [1, has been used. However, this test does not distinguish between IGS and congenital IF deficiency (absence or production of inert IF) [27]. In the two-stage Schilling test, IF was added to one of the steps, which resulted in the correction of IF deficiency, but not of IGS. Another limitation of the Schilling test is that vitB12 deficiency may affect the enterocyte function, leading to secondary malabsorption and an abnormal Schilling test [5]. Currently, the Schilling test is not available in most countries due to the difficulty to obtain labeled cobalamine. Other tests using, for example cyano-vitB12 to measure the fraction of transcobalamin bound to cyano-vitB12, are proposed by previous authors, who however, also expressed concerns about its sensitivity [5]. No replacement test has been validated. A therapeutic test with vitB12 or folate can be useful.

Mutations

In 1999, CUBN mutations were first described in a group of Finnish patients with vitB12 deficiency and proteinuria, followed by AMN mutations observed in Norwegian and Jewish patients [51, 81]. Because CUBN and AMN were not recognized until after 1999 as the genes responsible for IGS, many of the previously published cases of IGS were found not to be due to IGS but rather to defects in IF [1]. Tanner et al. [5] carried out genetic screening in 154 cases of suspected inherited vitB12 malabsorption. Of these patients, 64% of patients had either a CUBN or AMN mutation, 18% of patients had a CBLIF mutation, and 18% had no mutation that could be identified. The authors suggested several other candidate genes based on their role in vitB12 transport, but none of these mutations could be confirmed in their patients [5].

We found 119 different mutations in either CUBN or AMN genes. In 48% of cases that have been classified as IGS, genetic testing has not been performed. In 24% of these patients, other diagnostic tests were carried out suggesting IGS, including in 22% a Schilling test and in 2% a test to rule out an IF deficiency.

Most of the patients have proteinuria, and therefore probably IGS. But some of the patients may have another cause of vitB12 deficiency, as suggested by Tanner et al. [5]. However, due to the limitations described in the previous section, these cases should be (if possible) reassessed using molecular analysis to either confirm or reject the diagnosis of IGS.

Comorbidity

In 15% of IGS patients, other diseases in addition to IGS were present, such as congenital adrenal hyperplasia in patient 2. As previously mentioned, patients with IGS probably have a high rate of comorbidity due to the high rate of consanguinity [1]. Urinary tract abnormalities are observed relatively frequently, the pathophysiology of which is described in more detail earlier in this report.

Treatment

Initially, vitB12 deficiency in IGS patients was corrected with monthly intramuscular injections of vitB12. One would expect a lack of effect of oral vitB12 since IGS is caused by malabsorption of vitB12 2. However, as with our patient, effective oral treatment with vitB12 has been previously described. Oral treatment is based on the assumption that if the dose is high enough, a small but still sufficient part is absorbed [118]. Because approximately 1% of oral vitB12 is absorbed by passive diffusion in its free form, high doses can effectively treat vitB12 deficiency, also in patients with IGS [119]. VitB12 needs to be administered throughout life in IGS [1].

Prognosis

IGS patients treated with vitB12 are clinically and hematologically normal. The proteinuria persists but does not increase in severity The kidney function does not deteriorate [1, 27]. However, to the authors’ knowledge, the long-term studies only described patients up to the age of 46 years [27].

Limitations

Firstly, the clinical details of the IGS patients described above are limited. Secondly, due to the lack of genetic testing in 48% of the patients included in this study, the diagnosis of IGS cannot be completely certain. Thirdly, particularly in relatively high-prevalence countries such as Norway and Finland, many cases may not have been reported. Finally, IGS may be grossly under-diagnosed as most patients present with non-specific symptoms. While a combination of vitB12 deficiency and proteinuria leads to additional diagnostic tests to diagnose IGS, in the absence of proteinuria, IGS may not be recognized. We also observed a high rate of oral mucosal lesions and neurological symptoms such as ataxia, all of which can lead to further diagnostic testing. Therefore, we expect that IGS will be significantly underdiagnosed and that we observed an overestimation of some clinical manifestations.

Conclusions

IGS is a rare autosomal recessive disorder characterized by vitB12 deficiency and in most patients, proteinuria. We reviewed the literature on IGS and, for the first time, all previously published cases of IGS. In addition, we describe two new patients. Most patients present with non-specific symptoms. If untreated, patients may develop severe (neurological) manifestations. Patients may be treated with oral vitB12 supplementations but may need higher doses. Because 92% of patients with IGS had proteinuria, we advise health-care providers to examine the urine of any child with vitB12 deficiency.

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Abbreviations

AMN :

Amnionless/amnion-associated transmembrane protein

CBLIF:

Cobalamin binding intrinsic factor

CUBN :

Cubilin

CYP21A2 :

cytochrome P450 family 21 subfamily A member 2

ER:

Endoplasmatic reticulum

IF:

Intrinsic factor

IGS:

Imerslund-Grasbeck syndrome

LDH:

Lactate dehydrogenase

VitB12:

Vitamin B12

References

  1. Gräsbeck R. Imerslund-Gräsbeck syndrome (selective vitamin B12 malabsorption with proteinuria). Orphanet J Rare Dis. 2006;1(1):1–6.

    Google Scholar 

  2. Imerslund O. Idiopathic chronic megaloblastic anemia in children. Acta Paediatr. 1960;49(Suppl):208–9.

    Google Scholar 

  3. Grasbeck R, Gordin R, Kantero I, Kuhlback B. Selective vitamin B12 malabsorption and proteinuria in young people. A syndrome. Acta Med Scand. 1960;167:289–96.

    CAS  PubMed  Google Scholar 

  4. Stieglitz EJ. Disturbances of renal function in pernicious Anemia. Arch Intern Med. 1924;33(1):58–70.

    CAS  Google Scholar 

  5. Tanner SM, Sturm AC, Baack EC, Liyanarachchi S, De La Chapelle A. Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. Orphanet J Rare Dis. 2012;7(1):1–15.

    Google Scholar 

  6. Gütgemann I, Heimpel H, Nebe CT. Significance of teardrop cells in peripheral blood smears. LaboratoriumsMedizin. 2014;38(1):1–5.

    Google Scholar 

  7. Sievers CJ. Megaloblastaer anaemi hos ett nicieuse de I’enfant avec activitt ‘facteur in- 3-lrs barn. Ugeskr Laeg. 1963;125:1744–7.

    CAS  PubMed  Google Scholar 

  8. Eslamiyeh H. Acute cerebellar ataxia as the first manifestation of Imerslund-Gräsbeck. Iran J Child Neurol. 2021;15(4):105–8.

    PubMed  PubMed Central  Google Scholar 

  9. Li J, Gao MH, Gao XJ, Lau K. A child with megaloblastic anemia and proteinuria: answers. Pediatr Nephrol. 2022;(0123456789):10–2.

  10. Yang J, Xu Y, Deng L, Zhou L, Qiu L, Zhang Y, et al. CUBN gene mutations may cause focal segmental glomerulosclerosis (FSGS) in children. BMC Nephrol. 2022;23(1):1–8.

    Google Scholar 

  11. Baker KM, Parikh NS, Salsbery KT, Shaw GR, Steiner RD, Oelstrom MJ, et al. A 17-Month-old boy with Pancytopenia caused by a rare genetic defect of vitamin B12 malabsorption. J Pediatr Hematol Oncol. 2021;00(00):1–3.

    Google Scholar 

  12. Tanner SM, Li Z, Perko JD, Öner C, Çetin M, Altay Ç, et al. Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc Natl Acad Sci U S A. 2005;102(11):4130–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Spurling CL, Sacks MS, Jiji RM. Juvenile pernicious Anemia. N Engl J Med. 1964;271:995–1003.

    CAS  PubMed  Google Scholar 

  14. Chavelet F, Najean Y, Ravailleau J, Grenet P, Bernard J. Study of a case of pernicious anemia in a child with normal intrinsic factor activity in its gastric juice. Nouv Rev Fr Hematol. 1964;4:311–5.

    CAS  PubMed  Google Scholar 

  15. Mohamed SD, McKay E, Galloway WH. Juvenile familial megaloblastic anaemia due to selective malabsorption of vitamin B-12. A family study and a review of the literature. Q J Med. 1966;35(139):433–53.

    CAS  PubMed  Google Scholar 

  16. Hippe E. Malabsorption of vitamin B12. Report of a case in a 1-year-old boy, including studies of the absorption of B12. Acta Paediatr Scand. 1966;55(5):510–6.

    CAS  PubMed  Google Scholar 

  17. Castel Y, Najean Y, Pacrean B, Chapuis G, Saleun G, Mollaret J, et al. La malabsorption specifique de la vitamine B 12 avec proteinurie: Anemie pernicieuse d’imerslund-Najman-Grasbeck. Trois observations dans la meme fratrie. Ouest mtd. 1966;19:573–90.

    Google Scholar 

  18. Anttila R, Salmi HA. Selective malabsorption of vitamin B12 with proteinuria in children. Acta Paediatr Scand. Suppl 1967;177:90–1.

    Google Scholar 

  19. Aminoff M, Tahvanainen E, Grasbeck R, Weissenbach J, Broch H, De la Chapelle A. Selective intestinal malabsorption of vitamin B12 displays recessive mendelian inheritance: assignment of a locus to chromosome 10 by linkage. Am J Hum Genet. 1995;57(4):824–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Lillibridge CB, Brandborg LL, Rubin CE. Childhood pernicious Anemia: gastrointestinal secretory, histological, and electron microscopic aspects. Gastroenterology. 1967;52(5):792–809.

    CAS  PubMed  Google Scholar 

  21. Gorin R, Salama C, Guillien F. Apropos of a new case of anemia due to specific malaborsorption of vitamin B12 with proteinuria: study of the megaloblastic anemias of infants due to primary B12 avitaminosis. Ann Pediatr (Paris). 1967;14(5):1383–97.

    CAS  PubMed  Google Scholar 

  22. Becker M, Rotthauwe HW, Weber H-P, Fischbach H. Selective vitamin Bl2 malabsorption (Imerslund-Graisbeck syndrome) studies on gastroenterological and nephrological problems. Eur J Med Genet. 1977;124:139–53.

    CAS  Google Scholar 

  23. Attock B, Marsh G, Rossiter M, Hoffbrand A. Selective malabsorption of vitamin B12without proteinuria or structural renal tract anomaly. Br Med J. 1977;2(6090):807.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Marsden KA, Newman NM, Marsden DE. Imerslund’s Syndrome A Case from Australia and Review of the literature. J Paediatr Child Health. 1979;15(1):49–52.

    CAS  Google Scholar 

  25. Collan Y, Lähdevirta J, Jokinen EJ. Selective vitamin B12 malabsorption with Proteinuria. Nephron. 1979;23(6):297–303.

    CAS  PubMed  Google Scholar 

  26. Campbell AN, Inglis J, Paynter AS. Failure to thrive associated with the Imerslund-Grasbeck syndrome. Postgrad Med J. 1981;57(670):509–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Broch H, Imerslund O, Monn E, Hovig T, Seip M. Imerslund-Grasbeck Anemia. A long-term follow-up study. Acta Paediatr. 1984;73:248–53.

    CAS  Google Scholar 

  28. Burman JF, Jenkins WJ, Walker-Smith JA, Phillips AD, Sourial NA, Williams CB, et al. Absent ileal uptake of IF-bound vitamin B12 in vivo in the Imerslund-Grasbeck syndrome (familial vitamin B12 malabsorption with proteinuria). Gut. 1985;26(3):311–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Auchterlonie I, Thom H, Campbell A. Selective vitamin B12 malabsorption without anaemia but with profound failure to Thrive. Acta Pædiatrica. 1985;74(3):469–71.

    CAS  Google Scholar 

  30. Chisholm JC. Selective malabsorption of vitamin B12 and vitamin B12- intrinsic factor with megaloblastic anemia in an adult. J Natl Med Assoc. 1985;77(10):835–8.

    PubMed  PubMed Central  Google Scholar 

  31. Russo C, Hyman P, Oseas R. Megaloblastic Anemia characterized by microcytosis: Imerslund-Grasbeck Syndrome with Coexistent a-thalassemia. Pediatrics. 1988;81(6):875–6.

    CAS  PubMed  Google Scholar 

  32. Reisner EHJ, Wolff JA, McKay RJJ, Doyle EF. Juvenile pernicious anemia. Pediatrics. 1951;8(1):88–106.

    PubMed  Google Scholar 

  33. Smith C. Selective cobalamin (vitamin B 12) malabsorption in adolescence. SAMJ. 1988;73:607.

    CAS  PubMed  Google Scholar 

  34. el Mauhoub M, Sudarshan G, Aggarwal V, Banerjee G. Imerslund-Grasbeck syndrome in a lybian boy. Ann Trop Paediatr. 1989;3:180–1.

    Google Scholar 

  35. Ben-Ami M, Katzuni E, Koren A. Imerslund syndrome with dolichocephaly. Pediatr Hematol Oncol. 1990;7(2):177–81.

    CAS  PubMed  Google Scholar 

  36. Abdelaal MA, Ahmed AF. Imerslund-Grasbeck syndrome in a saudi family. Acta Paediatr Scand. 1991;80(11):1109–12.

    CAS  PubMed  Google Scholar 

  37. Salameh MM, Banda RW, Mohdi AA. Reversal of severe neurological abnormalities after vitamin B12 replacement in the Imerslund-Grasbeck syndrome. J Neurol. 1991;238(6):349–50.

    CAS  PubMed  Google Scholar 

  38. Liang DC, Hsu HC, Huang FY, Wei KN. Imerslund-gräsbeck syndrome in two brothers: renal biopsy and ultrastructural findings. Pediatr Hematol Oncol. 1991;8(4):361–5.

    PubMed  Google Scholar 

  39. Lin SH, Sourial NA, Lu KC, Hsueh EJ. Imerslund-Grasbeck syndrome in a chinese family with distinct skin lesions refractory to vitamin B12. J Clin Pathol. 1994;47(10):956–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Altay C, Cetin M, Gümrük F, Irken G, Yetgin S, Laleli Y. Familial selective vitamin b12 malabsorption (imerslund-grasbeck syndrome) in a pool of turkish patients. Pediatr Hematol Oncol. 1995;12(1):19–28.

    CAS  PubMed  Google Scholar 

  41. Gangarossa S, Romano V, Schiliro G. Efficacy of oral administration of high-dose cobalamide in a patient with Imerslund-Grasbeck syndrome. Pediatri. 1996;13:387–9.

    CAS  Google Scholar 

  42. Guéant JL, Saunier M, Gastin I, Safi A, Lamireau T, Duclos B, et al. Decreased activity of intestinal and urinary intrinsic factor in Gräsbeck-Imerslund disease. Gastroenterology. 1995;108(6):1622–8.

    PubMed  Google Scholar 

  43. Mackenzie IL, Donaldson RMJ, Trier JS, Mathan VI. Ileal mucosa in familial selective vitamin B 12 malabsorption. N Engl J Med. 1972;286(19):1021–5.

    CAS  PubMed  Google Scholar 

  44. Celep F, Karagüzel A, Aynaci FM, Erduran E. A case report of 46,XX,del (21)(q22) de novo deletion associated with Imerslund-Grasbeck syndrome. Clin Genet. 1996;50(4):248–50.

    CAS  PubMed  Google Scholar 

  45. Ismail EAR, Al Saleh Q, Sabry MA, Al Ghanim M, Zaki M. Genotypic/phenotypic heterogeneity of selective vitamin B12 malabsorption (Grasbeck-Imerslund syndrome) in two Bedouin families. Acta Paediatr Int J Paediatr. 1997;86(4):424–5.

    CAS  Google Scholar 

  46. Flechelles O, Schneider P, Lesesve JF, Baruchel A, Vannier JP, Tron P, et al. Maladie d’ Imerslund. Aspects cliniques et biologiques. A propos de six cas. Arch Pediatr. 1997;4:862–6.

    CAS  PubMed  Google Scholar 

  47. Eaton DM, Livingston JH, Seetharam B, Puntis JWL. Overexpression of an unstable intrinsic factor-cobalamin receptor in Imerslund-Grasbeck syndrome. Gastroenterology. 1998;115(1):173–6.

    CAS  PubMed  Google Scholar 

  48. Al Essa M, Sakati NA, Dabbagh O, Joshi S, Al Jishi EA, Rashed MS, et al. Inborn error of vitamin B12 metabolism: a treatable cause of childhood dementia/paralysis. J Child Neurol. 1998;13(5):239–43.

    CAS  PubMed  Google Scholar 

  49. Stones DK, Ferreira M. Imerslund-Gräsbeck syndrome in an african patient. J Trop Pediatr. 1999;45(2):106–7.

    CAS  PubMed  Google Scholar 

  50. Karatekin G, Sezgin B, Kayaoglu S, Nuhoglu A. Imerslund-Grasbeck Syndrome. Indian Pediatr. 1999;36:1262–4.

    CAS  PubMed  Google Scholar 

  51. Aminoff M, Carter JE, Chadwick RB, Johnson C, Gräsbeck R, Abdelaal MA, et al. Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet. 1999;21(3):309–13.

    CAS  PubMed  Google Scholar 

  52. Wahlstedt-Fröberg V, Pettersson T, Aminoff M, Dugué B, Gräsbeck R. Proteinuria in cubilin-deficient patients with selective vitamin B12 malabsorption. Pediatr Nephrol. 2003;18(5):417–21.

    PubMed  Google Scholar 

  53. Bonfin C, Strapasson E, Dellê LAB, Malvezzi M, Vaneuza A, Arthur G, et al. Imerslund-Gräsbeck-syndroom: rapport van twee gevallen. J Pediatr (Rio J). 1999;75(6):477–80.

    CAS  PubMed  Google Scholar 

  54. Walters TR, Koch HF. Generalized malabsorption, failure to thrive and megaloblastic anemia. Result of cyanocobalamin deficiency. Am J Dis Child. 1972;124(5):766–8.

    CAS  PubMed  Google Scholar 

  55. Sandoval C, Bolten P, Franco I, Freeman S, Jayabose S. Recurrent urinary tract infections and genitourinary tract abnormalities in the Imerslund-Grasbeck syndrome. Pediatr Hematol Oncol. 2000;17(4):331–4.

    CAS  PubMed  Google Scholar 

  56. Schröder A, Witt O, Eber S. Diabetes mellitus typ I, zoliakie und imerslund-Grasbeck-syndrom: Nur eine ungewohnliche kombination seltener erkrankungen? Klin Padiatr. 2000;212(1):22–5.

    PubMed  Google Scholar 

  57. Şen Ç, Aygün AD, Gürgöze MK, Kiliç H. Imerslund-Grasbeck syndrome: a Case Report. Firat Tip Derg Firat Med J. 2001;6(2):393–5.

    Google Scholar 

  58. Al-Alami JR, Tayeh MK, Al-Sheyyab MY, El-Shanti HI. Linkage analysis of a large inbred family with congenital megaloblastic anemia. Saudi Med J. 2002;23(10):1251–6.

    PubMed  Google Scholar 

  59. Rössler J, Breitenstein S, Havers W. Late onset of Imerslund-Gräsbeck syndrome without proteinuria in four children of one family from the Lebanon. Eur J Pediatr. 2003;162(11):808–9.

    PubMed  Google Scholar 

  60. Tanner SM, Li Z, Bisson R, Acar C, Öner C, Öner R, et al. Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder Effects, Consanguinity, and high clinical awareness explain Aggregations in Scandinavia and the Middle East. Hum Mutat. 2004;23(4):327–33.

    CAS  PubMed  Google Scholar 

  61. Bor MV, Çetin M, Aytaç S, Altay Ç, Nexo E. Nonradioactive vitamin B12 absorption test evaluated in controls and in patients with inherited malabsorption of vitamin B12. Clin Chem. 2005;51(11):2151–5.

    CAS  PubMed  Google Scholar 

  62. Al-Alami JR, Tanner SM, Tayeh MK, de la Chapelle A, El-Shanti H. Homozygous AMN mutation in hereditary selective intestinal malabsorption of vitamin B12 in Jordan. Saudi Med J. 2005;26(7):1061–4.

    PubMed  Google Scholar 

  63. Broides A, Yerushalmi B, Levy R, Hadad N, Kaplun N, Tanner SM, et al. Imerslund-Grasbeck syndrome associated with recurrent aphthous stomatitis and defective neutrophil function. J Pediatr Hematol Oncol. 2006;28(11):715–9.

    CAS  PubMed  Google Scholar 

  64. Bouchlaka C, Maktouf C, Mahjoub B, Ayadi A, Sfar MT, Sioud M, et al. Genetic heterogeneity of megaloblastic anaemia type 1 in tunisian patients. J Hum Genet. 2007;52(3):262–70.

    PubMed  Google Scholar 

  65. Buchanan N, Geefhuysen J, Cassel R, Green R. Selective malabsorption of vitamin B12 in a Negro boy. Scand J Haematol. 1973;11(2):153–7.

    CAS  PubMed  Google Scholar 

  66. Luder AS, Tanner SM, de la Chapelle A, Walter JH. Amnionless (AMN) mutations in Imerslund–Gräsbeck syndrome may be associated with disturbed vitamin B12 transport into the CNS. J Inherit Metab Dis. 2008;31(Suppl 3):493–6.

    PubMed  Google Scholar 

  67. Hauck FH, Tanner SM, Henker J, Laass MW. Imerslund-Gräsbeck syndrome in a 15-year-old german girl caused by compound heterozygous mutations in CUBN. Eur J Pediatr. 2008;167(6):671–5.

    PubMed  Google Scholar 

  68. Madhavan S, Vijayakumar M, Rajajee S, Nammalwar BR. Imerslund-grasbeck syndrome: Association with diabetes mellitus. Indian Pediatr. 2009;46(3):251–3.

    CAS  PubMed  Google Scholar 

  69. Choquet P, Levrat V, Pondarre C, Vianney C, Guffon N. Maladie d’Imerslund-Grasbeck. Arch Pediatr. 2009;16:1559–61.

    CAS  PubMed  Google Scholar 

  70. Sayli TR, Basak AN, Cümrük F, Cürgey A, Altay Ç. Imerslund-grasbeck syndrome coexisting with p-thalassemia trait. Pediatr Hematol Oncol. 1994;11(2):223–5.

    CAS  PubMed  Google Scholar 

  71. Namour F, Dobrovoljski G, Chery C, Audonnet S, Feillet F, Sper W, et al. Luminal expression of cubilin is impaired in imerslund-gräsbeck syndrome with compound AMN mutations in intron 3 and exon 7. Haematologica. 2011;96(11):1715–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Storm T, Emma F, Verroust PJ, Hertz JM, Nielsen R, Christensen EI. A patient with Cubilin Deficiency. N Engl J Med. 2011;364(1):89–91.

    CAS  PubMed  Google Scholar 

  73. Levin-Iaina N, Dinour D, Morduchowicz G, Ganon L, Holtzman EJ. Molecular study of proteinuria in patients treated with B12 supplements: do not forget megaloblastic anemia type 1. Nephron Clin Pract. 2011;118(2):67–71.

    Google Scholar 

  74. Ovunc B, Otto EA, Vega-Warner V, Saisawat P, Ashraf S, Ramaswami G, et al. Exome sequencing reveals cubilin mutation as a single-gene cause of proteinuria. J Am Soc Nephrol. 2011;22(10):1815–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Laxminarayana KPH, Yeshvanth SK, Shetty JK, Permi HS, Rao C. Unusual cause of Childhood Anemia: Imerslund Grasbeck Syndrome. J Lab Physicians. 2011;3(02):113–5.

    PubMed  PubMed Central  Google Scholar 

  76. Furuhjelm U, Nevanlinna HR. Inheritance of selective malabsorption of vitamin B12. Scand J Haematol. 1973;11(1):27–34.

    CAS  PubMed  Google Scholar 

  77. Ghosh TN, Nayek K, Banerjee A. Imerslund-Grasbeck syndrome: a Case Report. J Nepal Paediatr Soc. 2011;31(3):249–50.

    Google Scholar 

  78. Bulut I, Mutlubas F, Mir S, Balkan C. An infant with Imerslund-Grasbeck syndrome. Saoudi J Kidney Dis Transplant. 2012;23(3):569–71.

    Google Scholar 

  79. Boina Abdallah A, Ogier de Baulny H, Kozyraki R, Passemard S, Fenneteau O, Lebon S, et al. How can cobalamin injections be spaced in long-term therapy for inborn errors of vitamin B12 absorption? Mol Genet Metab. 2012;107(1–2):66–71.

    CAS  PubMed  Google Scholar 

  80. Densupsoontorn N, Sanpakit K, Vijarnsorn C, Pattaragarn A, Kangwanpornsiri C, Jatutipsompol C, et al. Imerslund-Gräsbeck syndrome: New mutation in amnionless. Pediatr Int. 2012;54(3):19–21.

    Google Scholar 

  81. Tanner SM, Aminoff M, Wright FA, Liyanarachchi S, Kuronen M, Saarinen A, et al. Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat Genet. 2003;33(3):426–9.

    CAS  PubMed  Google Scholar 

  82. Beech CM, Liyanarachchi S, Shah NP, Sturm AC, Sadiq MF, De La Chapelle A, et al. Ancient founder mutation is responsible for Imerslund-Gräsbeck syndrome among diverse ethnicities. Orphanet J Rare Dis. 2011;6(1):74.

    PubMed  PubMed Central  Google Scholar 

  83. Storm T, Zeitz C, Cases O, Amsellem S, Verroust PJ, Madsen M et al. Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome. BMC Med Genet. 2013;14(1).

  84. Shetty GM. Pancytopenia with Proteinuria – Imerslund Grasbeck Syndrome. Int J Biomed Res. 2012;3(1):56–7.

    Google Scholar 

  85. Siddiqui AH, Ansari A, Beech CM, Shah NP, Tanner SM, Sarnaik SA. Juvenile Cobalamin Deficiency in a 17 Year Old child with autonomic dysfunction and skin changes. J Pediatr Hematol Oncol. 2012;34(2):140–2.

    PubMed  PubMed Central  Google Scholar 

  86. Ercan Z, Demir ME, Ulas T, Ingec M, Horoz M. A long-term follow-up of an imerslund-grasbeck syndrome patient with proteinuria. Nefrologia. 2013;33(1):147–8.

    PubMed  Google Scholar 

  87. Colle E, Greenberg L, Krivit W. Studies of a patient with selective deficiency in absorption of vitamin B12. Blood. 1961;18:48–60.

    CAS  PubMed  Google Scholar 

  88. De Filippo G, Rendina D, Rocco V, Esposito T, Gianfrancesco F, Strazzullo P. Imerslund-Gräsbeck syndrome in a 25-month-old italian girl caused by a homozygous mutation in AMN. Ital J Pediatr. 2013;39(1):2–5.

    Google Scholar 

  89. Shivbalan S, Srinath M. Reversible skin hyperpigmentation in Imerslund-Grasbeck syndrome. Indian Pediatr. 2013;50:973–4.

    PubMed  Google Scholar 

  90. Ho CH, Thomas M, McGuire E, Yano S. 2-year-old girl with pancytopenia due to vitamin B12 (cobalamin) deficiency. J Paediatr Child Health. 2014;50(11):926–8.

    PubMed  Google Scholar 

  91. Montgomery E, Sayer JA, Baines LA, Hynes MA, Vega-Warner V, Johnson S, et al. Novel compound heterozygous mutations in AMN cause Imerslund-Gräsbeck syndrome in two half-sisters: a case report. BMC Med Genet. 2015;16(1):2–5.

    Google Scholar 

  92. Goudarzipour K, Zavvar N, Behnam B, Ahmadi MA. Imerslund-Grasbeck syndrome in a 5-year-old iranian boy. Indian J Nephrol. 2016;26:455–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Del Baldo G, Marabini C, Albano V, Lionetti ME, Gatti S. Imerslund–Grasbeck Syndrome (selective B12 malabsorption): think about it also in Down’s syndrome! Dig Liver Dis. 2016;48(2016):e274.

    Google Scholar 

  94. Wulffraat NM, De Schryver J, Bruin M, Pinxteren-Nagler E, van Dijken PJ. Failure to thrive is an early symptom of the imerslund Gräsbeck syndrome. Am J Pediatr Hematol Oncol. 1994;16(2):177–80.

    CAS  PubMed  Google Scholar 

  95. Kamath SJ, Bhat KSA, Kandula KG. Imerslund-Gräsbeck syndrome with developmental cataract. JCRS Online Case Reports. 2017;5(4):67–8.

    Google Scholar 

  96. Agarwal P, Chand S, Pandey D. Imerslund – Grasbeck syndrome presented as pancytopenia: a rare case report. Int J Heal Allied Sci. 2017;6(4):228–9.

    Google Scholar 

  97. Faatovna AE, Dmitrievna SN. Clinical observance — of Megaloblastic Anemia with B12 Deficiency and Proteinuria in Imerslund-Grasbeck Syndrome. материалы конгресса «Здоровые дети — будущее страны». 2017;12:21–2.

  98. Lamy M, Besancon F, Loverdo A, Afifi F. 4 cases of a new infantile megaloblastic anemia: the specific malaborption of vitamin B 12 with proteinuria of Imerslund-Najman-Grasbeck. Bull Mem Soc Med Hop Paris. 1961;77:1107–11.

    CAS  PubMed  Google Scholar 

  99. Goubeaux DL, Li W. Cabot rings and marked anisopoikilocytosis in Imerslund-Gräsbeck syndrome. Blood. 2018;131(1):153.

    CAS  PubMed  Google Scholar 

  100. Ciancio JIR, Furman M, Banka S, Grunewald S. Profound vitamin D deficiency in four siblings with Imerslund-Grasbeck syndrome with homozygous CUBN mutation. JIMD Rep. 2019;49(1):43–7.

    PubMed  PubMed Central  Google Scholar 

  101. Pacitto A, Prontera P, Stangoni G, Stefanelli M, Ceppi S, Cerri C, et al. Imerslund-Gräsbeck syndrome in an infant with a novel intronic variant in the AMN gene: a case report. Int J Mol Sci. 2019;20(3):3–7.

    Google Scholar 

  102. Jayasinghe K, White SM, Kerr PG, MacGregor D, Stark Z, Wilkins E, et al. Isolated proteinuria due to CUBN homozygous mutation - challenging the investigative paradigm. BMC Nephrol. 2019;20(1):1–5.

    CAS  Google Scholar 

  103. Gurlek Gokcebay D, Akpinar Tekgunduz S, Cavdarli B. Imerslund-Gräsbeck Syndrome presenting with microangiopathic hemolytic anemia in a child. Eur J Med Genet. 2020;63(6):2–4.

    Google Scholar 

  104. Bedin M, Boyer O, Servais A, Li Y, Villoing-Gaudé L, Tête MJ, et al. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function. J Clin Invest. 2020;130(1):335–44.

    CAS  PubMed  Google Scholar 

  105. Bargehr C, Crazzolara R. Cabot rings and other peripheral blood features of Imerslund–Gräsbeck syndrome. Br J Haematol. 2020;191(1):11.

    PubMed  PubMed Central  Google Scholar 

  106. Udagawa T, Harita Y, Miura K, Mitsui J, Ode KL, Morishita S, et al. Amnionless-mediated glycosylation is crucial for cell surface targeting of cubilin in renal and intestinal cells. Sci Rep. 2018;8(1):1–12.

    CAS  Google Scholar 

  107. Elshinawy M, Gao HH, Al-Nabhani DM, Al-Thihli KA. Clinical and molecular characteristics of imerslund-gräsbeck syndrome: first report of a novel Frameshift variant in exon 11 of AMN gene. Int J Lab Hematol. 2021;43(5):1009–15.

    PubMed  Google Scholar 

  108. Arunath V, Hoole TJ, Rathnasri A, Muthukumarana O, Kumarasiri IM, Liyanage ND, et al. A child with Imerslund-Gräsbeck syndrome concealed by co-existing α-thalassaemia presenting with subacute combined degeneration of the spinal cord: a case report. BMC Pediatr. 2021;21(1):1–5.

    Google Scholar 

  109. Huemer M, Baumgartner MR. The clinical presentation of cobalamin-related disorders: from acquired deficiencies to inborn errors of absorption and intracellular pathways. J Inherit Metab Dis. 2019;42(4):686–705.

    CAS  PubMed  Google Scholar 

  110. Beedholm-Ebsen R, Van De Wetering K, Hardlei T, Nexø E, Borst P, Moestrup SK. Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin. Blood. 2010;115(8):1632–9.

    CAS  PubMed  Google Scholar 

  111. Hamilton MS, Blackmore S. Chapter 10 - Investigation of megaloblastic anaemia [Internet]. 11th ed. Dacie and Lewis Practical Haematology. Elsevier Ltd.; 2012. 201–228 p.

  112. Watkins D, Rosenblatt DS, Fowler B. Disorders of Cobalamin and Folate Transport and Metabolism. In: Saudubray J-M, Baumgartner MR, Walter JH, editors. Inborn Metabolic Diseases. 6th editio. Springer; 2016. p. 385–99.

  113. Froese DS, Fowler B, Baumgartner MR. Vitamin B12, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation. J Inherit Metab Dis. 2019;42(4):673–85.

    CAS  PubMed  Google Scholar 

  114. Coudroy G, Gburek J, Kozyraki R, Madsen M, Trugnan G, Moestrup SK, et al. Contribution of cubilin and amnionless to processing and membrane targeting of cubilin-amnionless complex. J Am Soc Nephrol. 2005;16(8):2330–7.

    CAS  PubMed  Google Scholar 

  115. Rubin HM, Giorgio AJ, Macdonald RR, Linarelli LG. Selective malabsorption of vitamin B12: report of a case with metabolic studies. Am J Dis Child. 1974;127(5):713–7.

    CAS  PubMed  Google Scholar 

  116. Kalantry S, Manning S, Haub O, Tomihara-Newberger C, Lee HG, Fangman J, et al. The amnionless gene, essential for mouse gastrulation, encodes a visceral-endoderm-specific protein with an extracellular cysteine-rich domain. Nat Genet. 2001;27(4):412–6.

    CAS  PubMed  Google Scholar 

  117. Queisser-Luft A, Stolz G, Wiesel A, Schlaefer K, Spranger J. Malformations in newborn: results based on 30,940 infants and fetuses from the Mainz congenital birth defect monitoring system (1990–1998). Arch Gynecol Obstet. 2002;266(3):163–7.

    CAS  PubMed  Google Scholar 

  118. Bor MV, Cetin M, Aytaç S, Altay C, Ueland PM, Nexo E. Long term biweekly 1 mg oral vitamin B12 ensures normal hematological parameters, but does not correct all other markers of vitamin B12 deficiency. A study in patients with inherited vitamin B12 deficiency. Volume 93. Haematologica. Italy; 2008. pp. 1755–8.

  119. Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency. An update. Haematologica. 2006;91(11):1506–12.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Centre for Metabolic Diseases, University Hospital Antwerp, University of Antwerp, Drie Eikenstraat 655, Edegem, Antwerp, 2650, Belgium

    Sandra D.K. Kingma

  2. Department of Pediatrics, University Hospital Antwerp, University of Antwerp, Drie Eikenstraat 655, Edegem, 2650, Belgium

    Sandra D.K. Kingma, Julie Neven & Machiel van den Akker

  3. Faculty of medicine and health sciences, University of Antwerp, Antwerp, Belgium

    Sandra D.K. Kingma, An Bael & Machiel van den Akker

  4. Department of Pediatric Nephrology, ZNA Queen Paola Children’s Hospital, Lindendreef 1, Antwerp, 2020, Belgium

    An Bael

  5. Center of Medical Genetics, University Hospital Antwerp, Drie Eikenstraat 655, Edegem, 2650, Belgium

    Marije E.C. Meuwissen

  6. Department of Pediatrics, ZNA Queen Paola Children’s Hospital, Lindendreef 1, Antwerp, 2020, Belgium

    Machiel van den Akker

  7. Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Antwerp, Drie Eikenstraat 655, Edegem, Antwerp, 2650, Belgium

    Machiel van den Akker

Authors
  1. Sandra D.K. Kingma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julie Neven
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. An Bael
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marije E.C. Meuwissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Machiel van den Akker
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SDKK: Conception and design, data acquisition, analysis and interpretation, manuscript draft and revision. JN: Data acquisition, analysis, and interpretation, manuscript revision. AB: Manuscript draft and revision. MECM: Manuscript draft and revision. MvdA: Conception and design, manuscript draft and revision.

Corresponding author

Correspondence to Machiel van den Akker.

Ethics declarations

Declarations

Not applicable.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Informed consent was obtained from the index patients included in the study.

Competing interests

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Supplementary Material 2

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kingma, S.D., Neven, J., Bael, A. et al. Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases. Orphanet J Rare Dis 18, 291 (2023). https://doi.org/10.1186/s13023-023-02889-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13023-023-02889-x

Keywords

Orphanet Journal of Rare Diseases

ISSN: 1750-1172