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Imerslund-Gräsbeck syndrome in a 15-year-old German girl caused by compound heterozygous mutations in CUBN

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Abstract

Imerslund-Gräsbeck syndrome (IGS) is a recessive disorder of intestinal cobalamin (Cbl) absorption and renal tubular protein reabsorption sometimes accompanied by urinary tract malformation. Mutations in the cubilin (CUBN) and amnionless (AMN) genes have been described as causal defects. CUBN and AMN proteins form the cubam complex that functions as the receptor for the intrinsic factor-Cbl (IF-Cbl) complex in the ileum and for proteins found in the primary urine in the kidney. We report the case of a 15-year-old German girl who presented with megaloblastic anaemia and funicular myelosis due to Cbl-deficiency and selective proteinuria. We clinically diagnosed- and for the first time in a patient of German ancestry-genetically confirmed IGS by detecting a compound heterozygous gene deletion and missense mutation in the CUBN gene. In conclusion IGS should be considered in paediatric patients presenting with symptoms like megaloblastic anaemia, funicular myelosis and benign proteinuria. Diagnosis should be confirmed genetically to avoid further invasive diagnostics, administer proper lifelong treatment and offer genetic counselling.

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Abbreviations

AMN :

amnionless gene

Cbl:

cobalamin (vitamin B12)

CUBN :

cubilin gene

EGF:

epidermal growth factor

GIF :

gastric intrinsic factor gene

IF:

intrinsic factor

IFD:

intrinsic factor deficiency

IGS:

Imerslund-Gräsbeck syndrome

MGA:

megaloblastic anaemia

References

  1. Abdelaal MA, Ahmed AF (1991) Imerslund-Gräsbeck syndrome in a Saudi family. Acta Paediatr Scand 80:1109–1112

    Article  PubMed  CAS  Google Scholar 

  2. Altay C, Cetin M, Gumruk F, Irken G, Yetgin S (1995) Familial selective vitamin B12 malabsorption (Imerslund-Gräsbeck syndrome) in a pool of Turkish patients. Pediatr Hematol Oncol 12:19–28

    Article  PubMed  CAS  Google Scholar 

  3. Aminoff M, Carter JE, Chadwick RB, Johnson C, Gräsbeck R, Abdelaal MA, Broch H, Jenner LB, Verroust PJ, Moestrup SK, de la Chapelle A, Krahe R (1999) Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nature Genet 21:309–313

    Article  PubMed  CAS  Google Scholar 

  4. Becker M, Rotthauwe HW, Weber HP, Fischbach H (1977) Selective vitamin B12 malabsorption (Imerslund-Grasbeck syndrome). Studies on gastroenterological and nephrological problems. Eur J Pediatr 124:139–153

    Article  PubMed  CAS  Google Scholar 

  5. Ben-Bassat I, Feinstein A, Ramot B (1969) Selective vitamin B 12 malabsorption with proteinuria in Israel: clinical and genetic aspects. Isr J Med Sci 5:62–68

    PubMed  CAS  Google Scholar 

  6. Birn H, Fyfe JC, Jacobsen C, Mounier F, Verroust PJ, Orskov H, Willnov TE, Moestrup SK, Christensen EI (2000) Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. J Clin Invest 105:1353–1361

    Article  PubMed  CAS  Google Scholar 

  7. Carmel R, Green R, Rosenblatt DS, Watkins D (2003) Update on cobalamin, folate and homocysteine. In: Am Soc Hematol. Education Program Book (eds) Hematology, pp 62–81

  8. Fyfe JC, Madsen M, Hojrup P, Christensen EI, Tanner SM, de la Chapelle A, He Q, Moestrup SK (2004) The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood 103:1573–1579

    Article  PubMed  CAS  Google Scholar 

  9. Gräsbeck R, Gordin R, Kantero I, Kuhlbäck B (1960) Selective vitamin B12 malabsorption and proteinuria in young people. Acta Med Scand 167:289–296

    Article  PubMed  Google Scholar 

  10. Gräsbeck R, Kvist G (1967) Congenital and selective malabsorption of vitamin B12 with proteinuria. Cah Coll Med Hop Paris 8:935–944

    PubMed  Google Scholar 

  11. Gräsbeck R (2006) Imerslund-Gräsbeck syndrome (selective vitamin B12 malabsorption with proteinuria). J Rare Dis 1:17

    Article  Google Scholar 

  12. Imerslund O (1960) Idiopathic chronic megaloblastic anemia in children. Acta Paediat Scand (Suppl) 1:1–115

    Google Scholar 

  13. Ismail EA, Al Saleh Q, Sabry MA, Al Ghanim M, Zaki M (1997) Genotypic/phenotypic heterogeneity of selective vitamin B12 malabsorption (Gräsbeck-Imerslund syndrome) in two Bedouin families. Acta Paediatr 86:424–425

    Article  PubMed  CAS  Google Scholar 

  14. Kozyraki R, Fyfe J, Verroust PJ, Jacobsen C, Dautry-Varsat A, Gburek J, Willnow TE, Christensen EI, Moestrup SK (2001) Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. Proc Natl Acad Sci USA 98:12491–12496

    Article  PubMed  CAS  Google Scholar 

  15. Kristiansen M, Kozyraki R, Jacobsen C, Nexo E, Verroust PJ, Moestrup SK (1999) Molecular dissection of the intrinsic factor-vitamin B12 receptor, cubilin, discloses regions important for membrane association and ligand binding. J Biol Chem 274:20540–20544

    Article  PubMed  CAS  Google Scholar 

  16. Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, Verroust PJ, Aminoff M, de la Chapelle A, Moestrup SK, Ray R, Gliemann J, Willnow TE, Christensen EI (2001) Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D3. Proc Natl Acad Sci USA 98:13895–13900

    Article  PubMed  CAS  Google Scholar 

  17. Rössler J, Breitenstein S, Havers W (2003) Late onset of Imerslund-Grasbeck-syndrome without proteinuria in four children of one family from the Lebanon. Eur J Pediatr 162:808–809

    Article  PubMed  Google Scholar 

  18. Schilling RF (1953) Intrinsic factor studies II. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B12. J Lab Clin Med 42:860–866

    PubMed  CAS  Google Scholar 

  19. Seetharam B, Levine JS, Rasmaswamy M, Alpers DH (1988) Purification, properties and immunochemical localization of a receptor for intrinsic factor-cobalamin complex in the rat kidney. J Biol Chem 263:4443–4449

    PubMed  CAS  Google Scholar 

  20. Tanner SM, Aminoff M, Wright FA, Liyanarachchi S, Kuronen M, Saarinen A, Massika O, Mandel H, Broch H, de la Chapelle A (2003) Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nature Genet 33:426–429

    Article  PubMed  CAS  Google Scholar 

  21. Tanner SM, Li Z, Bisson R, Acar C, Oner C, Oner R, Cetin M, Abdelaal MA, Ismail EA, Lissens W, Krahe R, Broch H, Gräsbeck R, de la Chapelle A (2004) Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavian and Middle East. Hum Mutat 23:327–333

    Article  PubMed  CAS  Google Scholar 

  22. Tanner SM, Li Z, Perko JD, Oner C, Cetin M, Altay C, Yurtsever Z, David KL, Faivre L, Ismail EA, Gräsbeck R, de la Chapelle A (2005) Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc Nat Acad Sci 102:4130–4133

    Article  PubMed  CAS  Google Scholar 

  23. Wahlstedt-Fröberg V, Pettersson T, Aminoff M, Dugue B, Gräsbeck R (2003) Proteinuria in cubilin-deficient patients with selective vitamin B12 malabsorption. Pediatr Nephrol 18:417–421

    PubMed  Google Scholar 

  24. Xu D, Fyfe JC (2000) Cubilin expression and posttranslational modification in the canine gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 279:748–756

    Google Scholar 

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Acknowledgements

We thank Dr. med. Ilona Zapf as primary outpatient physician, Zhongyuan Li, and James D. Perko for technical assistance in the laboratory.

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Authors and Affiliations

  1. Department of Paediatrics, University Hospital Carl Gustav Carus at the Technical University Dresden, Dresden, Germany

    Fabian H. Hauck, Jobst Henker & Martin W. Laass

  2. Human Cancer Genetics Program, The Ohio State University, Columbus, OH, 43210, USA

    Stephan M. Tanner

  3. Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Fetscherstr. 74, D-01307, Dresden, Germany

    Fabian H. Hauck

Authors
  1. Fabian H. Hauck
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  2. Stephan M. Tanner
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  3. Jobst Henker
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  4. Martin W. Laass
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Corresponding author

Correspondence to Fabian H. Hauck.

Additional information

Fabian H. Hauck and Stephan M. Tanner contributed equally to this work.

This research was in part funded by The Ohio State University’s Comprehensive Cancer Center, Columbus, OH.

Accession numbers: OMIM #261100, OMIM #602997, OMIM #605799, OMIM #609342, Cubilin NP_001072

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Hauck, F.H., Tanner, S.M., Henker, J. et al. Imerslund-Gräsbeck syndrome in a 15-year-old German girl caused by compound heterozygous mutations in CUBN . Eur J Pediatr 167, 671–675 (2008). https://doi.org/10.1007/s00431-007-0571-3

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  • DOI: https://doi.org/10.1007/s00431-007-0571-3

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