Abstract
Fanconi–Bickel syndrome, caused by mutations in SLC2A2 encoding the glucose transporter 2 (GLUT2), is characterized by generalized proximal renal tubular dysfunction manifesting in late infancy. We describe phenotypic heterogeneity of Fanconi–Bickel syndrome in three siblings, including early and atypical presentation with transient neonatal diabetes mellitus in one. The second-born of a non-consanguineous couple, evaluated for polyuria and growth retardation, had rickets, hepatomegaly and proximal tubular dysfunction from 4 to 6 months of age. A male sibling, who expired at 4 months, also had hepatomegaly and growth retardation. The third sibling had polyuria, glucosuria and mild proteinuria on day 3 of life. Hyperglycemia was detected 2 weeks later, which required therapy with insulin for 3 months. Mild metabolic acidosis was present at 2 weeks; hypercalciuria, phosphaturia and aminoaciduria were seen at 6 months. Sanger sequencing showed a homozygous missense mutation in SLC2A2 (exon 7, c.952G > A), causing glycine to arginine substitution; both parents were heterozygous carriers. Patients with SLC2A2 mutations may present either with isolated neonatal diabetes or with hepatomegaly and the renal Fanconi syndrome. Fanconi–Bickel syndrome shows phenotypic heterogeneity and may manifest early with subtle or atypical features, mandating a high index of suspicion.
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References
Santer R, Schneppenheim R, Dombrowski A, Gotze H, Steinmann B, Schaub J. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi–Bickel syndrome. Nat Genet. 1997;17(3):324–6.
Fridman E, Zeharia A, Markus-Eidlitz T, Haimi Cohen Y. Phenotypic variability in patients with Fanconi–Bickel Syndrome with identical mutations. JIMD Rep. 2015;15:95–104.
Santer R, Groth S, Kinner M, Dombrowski A, Berry GT, Brodehl J, et al. The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi–Bickel syndrome. Hum Genet. 2002;110(1):21–9.
Yoo HW, Shin YL, Seo EJ, Kim GH. Identification of a novel mutation in the GLUT2 gene in a patient with Fanconi–Bickel syndrome presenting with neonatal diabetes mellitus and galactosaemia. Eur J Pediatr. 2002;161(6):351–3.
Dweikat IM, Alawneh IS, Bahar SF, Sultan MI. Fanconi–Bickel syndrome in two Palestinian children: marked phenotypic variability with identical mutation. BMC Res Notes. 2016;9:387.
Setoodeh A, Rabbani A. Transient neonatal diabetes as a presentation of Fanconi–Bickel syndrome. Acta Med Iran. 2012;50(12):836–8.
De Franco E, Flanagan SE, Houghton JA, Lango Allen H, Mackay DJ, Temple IK, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. The Lancet. 2015;386(9997):957–63.
Naylor RN, Greeley SA, Bell GI, Philipson LH. Genetics and pathophysiology of neonatal diabetes mellitus. J Diabetes Investig. 2011;2(3):158–69.
Sansbury FH, Flanagan SE, Houghton JA, Shuixian Shen FL, Al-Senani AM, Habeb AM, et al. SLC2A2 mutations can cause neonatal diabetes, suggesting GLUT2 may have a role in human insulin secretion. Diabetologia. 2012;55(9):2381–5.
Riva S, Ghisalberti C, Parini R, Furlan F, Bettinelli A, Somaschini M. The Fanconi–Bickel syndrome: a case of neonatal onset. J Perinatol. 2004;24(5):322–3.
Peduto A, Spada M, Alluto A, La Dolcetta M, Ponzone A, Santer R. A novel mutation in the GLUT2 gene in a patient with Fanconi–Bickel syndrome detected by neonatal screening for galactosaemia. J Inherit Metab Dis. 2004;27(2):279–80.
Thorens B. GLUT2, glucose sensing and glucose homeostasis. Diabetologia. 2015;58(2):221 – 32.
Berry GT, Baker L, Kaplan FS, Witzleben CL. Diabetes-like renal glomerular disease in Fanconi–Bickel syndrome. Pediatr Nephrol. 1995;9(3):287–91.
Santer R, Schneppenheim R, Suter D, Schaub J, Steinmann B. Fanconi–Bickel syndrome–the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature. Eur J Pediatr. 1998;157(10):783–97.
Habeb AM, Al-Magamsi MS, Eid IM, Ali MI, Hattersley AT, Hussain K, et al. Incidence, genetics, and clinical phenotype of permanent neonatal diabetes mellitus in northwest Saudi Arabia. Pediatr Diabetes. 2012;13(6):499–505.
Jahnavi S, Poovazhagi V, Mohan V, Bodhini D, Raghupathy P, Amutha A, et al. Clinical and molecular characterization of neonatal diabetes and monogenic syndromic diabetes in Asian Indian children. Clin Genet. 2013;83(5):439–45.
Aguilar-Bryan L, Bryan J. Neonatal diabetes mellitus. Endocr Rev. 2008;29(3):265–91.
Guillam MT, Hummler E, Schaerer E, Yeh JI, Birnbaum MJ, Beermann F, et al. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat Genet. 1997;17(3):327–30.
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Khandelwal, P., Sinha, A., Jain, V. et al. Fanconi syndrome and neonatal diabetes: phenotypic heterogeneity in patients with GLUT2 defects. CEN Case Rep 7, 1–4 (2018). https://doi.org/10.1007/s13730-017-0278-x
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DOI: https://doi.org/10.1007/s13730-017-0278-x