Amaryan, Gayane

Leumann, Ernst

Santer, René

Sarkissian, Ashot

Steinmann, Beat

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Nephrol Dial Transplant (2004) 19: 1319–1320DOI: 10.1093/ndt/gfh088Teaching Point(Section Editor: K. Ku¨hn)Supported by an educational grant fromThe boy with massive glucosuriaAshot Sarkissian1, Rene´ Santer2, Beat Steinmann3, Gayane Amaryan1 and Ernst Leumann31Medical Centre Arabkir, Yerevan, Armenia, 2University Children’s Hospital, Hamburg, Germany and3University Children’s Hospital, Zurich, SwitzerlandKeywords: Fanconi–Bickel syndrome; glucose trans-port; GLUT2; renal glucosuria; tubular dysfunctionCaseA 3.5-year-old boy living in a remote Armenian villagewas admitted to the hospital in Yerevan in March 2002with a history of polydipsia since the age of 6 months,bowed legs since he started to walk at the age of 1 yearand an increasingly large abdomen. The child was verysmall [height: 74 cm (5.9 SDS)] but alert, had amoonlike face, a grossly enlarged liver (10 cm below thecostal margin) and a waddling gait due to severe ricketswith genua vara (Figure 1). Psychomotor developmentwas adequate for age. The liver was markedly enlargedat ultrasonography, but of homogeneous structure. Thekidneys were large (length: 76mm; normal for height:45–70mm).Laboratory examination showed proximal tubulardysfunction with generalized amino aciduria, but gluco-suria was excessive with 213mmol¼ 38.4 g per 24 h or133 g/1.73m2/day (normal: 0.13–0.32 g/1.73m2/day) atblood glucose levels of 4.9mmol/l fasting (normal:3.8–6.4mmol/l) and of 9.4mmol/l after feeding(normal: <7.8mmol/l). Tubular reabsorption of glu-cose was only 13% (normal: 100%) of the ﬁltered loadat normal blood glucose. Serum sodiumwas 128mmol/l(normal: 134–144mmol/l), phosphorus 0.74mmol/l(normal: 1.2–2.1mmol/l) and uric acid 79 mmol/l(normal: 110–350 mmol/l). Elevated values were foundfor liver enzymes; cholesterol was 7.12mmol/l (normal:1.6–4.9mmol/l) and triglycerides were 3.15mmol/l(normal: 0.4–1.8mmol/l).We suspected Fanconi–Bickel syndrome (MIM227810), which is characterized by generalized renaltubular dysfunction with massive glucosuria and byhepatorenal glycogen accumulation [1,2]. Geneticanalysis conﬁrmed this diagnosis and revealed homo-zygosity for a novel missense mutation (GLUT2 c.887A!G) leading to the substitution of histidine atposition 192 by arginine (H192R) and heterozygosityin the parents. The patient markedly improved ontreatment with vitamin D2 (16 000 U/day), frequentfeedings and a generous intake of ﬂuid and electrolytes.DiscussionThe ﬁrst description of Fanconi–Bickel syndrome datesback >50 years [1] and more than 100 cases have beenreported since, mainly from Europe, but also fromTurkey, Israel, the Arab Countries, Japan and theUnited States. There are no reports on cases fromChina, Central Africa or among blacks in the USA [3].In 1998 this disease was shown to result from a defect ofthe facilitative glucose transporter GLUT2 [4]. So far,10 missense, seven non-sense, 10 frameshift and sevensplice-site mutations have been reported in 64 patientswith Fanconi–Bickel syndrome [5,6].Monosaccharide transporters can be assigned to twomajor groups, the SGLTs (‘active’ sodium-dependentglucose transporters) and the GLUTs (‘passive’ glucosetransporters) [7]. GLUT2, like all GLUT proteins,has 12 transmembrane domains. Patients with theFanconi–Bickel syndrome demonstrate the importantrole of GLUT2. The metabolic consequences of thedefective GLUT2 protein are primarily related toaltered glucose equilibrium at the liver cell [3,6].Elevated intracellular glucose concentrations, despitefasting hypoglycaemia, lead to glycogen storagethrough impaired glycogen degradation. Conversely,glucose and galactose concentrations in blood areelevated in the fed state due to decreased hepaticCorrespondence and offprint requests to: Dr Ashot Sarkissian, MD,‘Arabkir’ Medical Centre, Head of the Division of Nephrology, 30Mamikoniants Street, 375014 Yerevan, Armenia. Email: ashsark@arminco.comNephrol Dial Transplant Vol. 19 No. 5  ERA–EDTA 2004; all rights reservedmonosaccharide uptake and inappropriately low insu-lin secretion. The proximal tubular dysfunction mightbe the result of the storage of glycogen and of theelevation of free glucose within the cell; the exactmechanism, however, is not well understood. Theenormous glucosuria is associated with osmotic diur-esis, resulting in polyuria and electrolyte loss. However,unlike the situation in diabetics where the amount ofﬁltered glucose is strongly elevated, glomerular hyper-ﬁltration and glomerular damage are exceptional. Life-long treatment is directed to compensate for lossesof water, electrolytes, phosphate and bicarbonate.Frequent feeds and the use of slowly absorbedcarbohydrates are recommended to avoid hypoglycae-mia and to suppress futile gluconeogenesis. Prognosis isfairly good; only few patients have died because of anacute metabolic derangement with severe acidosis. Theoriginal patient of Fanconi and Bickel is now 58 yearsold [3]. Short stature is the main subjective problem.Three additional clinical conditions have been linkedso far to a defect of a glucose transporter, (i) the glucosetransporter protein syndrome due to mutations ofGLUT1 (De Vivo syndrome; MIM 138140) with lowglucose in the cerebrospinal ﬂuid, (ii) congenitalintestinal glucose/galactose malabsorption, which canbe accompanied by mild glucosuria, due to mutationsof SGLT1 (MIM 182380) and (iii) isolated benign renalglucosuria (MIM 182381) [7]. The latter condition,which is not uncommon, is caused by mutations ofSGLT2 [8]. Glucosuria in this condition may also bemassive. However, in contrast to the situation inFanconi–Bickel syndrome, there is no secondaryimpairment of other tubular transport systems.Teaching pointsRenal glucosuria may occur as an isolated ﬁnding or aspart of a more widespread tubular dysfunction that iseither genetically determined (e.g. Fanconi–Bickelsyndrome or cystinosis) or is acquired (e.g. malignantfocal segmental sclerosis or tubulointerstitial nephritiswith uveitis).Patients with Fanconi–Bickel syndrome exhibitgeneralized tubular dysfunction, but glucosuria isexcessive. These ﬁndings, although present from birth,seem to be compatible with a nearly normal life span.Defects of the monosaccharide transporters GLUT2,SGLT1 and SGLT2 have been identiﬁed as underlyingmechanisms of renal glucosuria.Acknowledgements. A.S. and G.A. were in charge of the patient inArmenia, E.L. coordinated the examinations, B.S. performed themetabolic investigations and R.S. did the molecular analysis.Conﬂict of interest statement. None declared.References1. Fanconi G, Bickel H. Die chronische Aminoacidurie(Aminosa¨urediabetes oder nephrotisch-glukosurischerZwergwuchs) bei der Glykogenose und der Cystinkrankheit.Helv Paediatr Acta 1949; 4: 359–3962. Manz F, Bickel H, Brodehl J et al. Fanconi–Bickel syndrome.Pediatr Nephrol 1987; 1: 509–5183. Santer R, Schneppenheim R, Suter D, Schaub J, Steinmann B.Fanconi–Bickel syndrome – the original patient and his history,historical steps leading to the primary defect, and a review ofthe literature. Eur J Pediatr 1998; 157: 783–7974. Santer R, Schneppenheim R, Dombrowski A, Go¨tze H,Steinmann B, Schaub J. Mutations in GLUT2, the gene forthe liver-type glucose transporter, in patients with Fanconi–Bickel syndrome. Nat Genet 1997; 17: 324–3265. Santer R, Groth S, Kinner M et al. The mutation spectrum ofthe facilitative glucose transporter gene SLC2A2 (GLUT2) inpatients with Fanconi–Bickel syndrome. Hum Genet 2002; 110:21–296. Santer R, Steinmann B, Schaub J. Fanconi–Bickel syndrome –a congenital defect of facilitative glucose transport. Curr MolMed 2002; 2: 213–2277. Santer R. Disorders of glucose transport. In: Blau N, DuranM, Blaskovics ME, Gibson KM, eds. Physicians’ Guide to theLaboratory Diagnosis of Inherited Metabolic Diseases, 2nd edn.Springer, Heidelberg: 2003; 357–3678. Santer R, Kinner M, Lassen CL et al. Molecular analysis of theSGLT2 gene in patients with renal glucosuria. J Am SocNephrol 2003; 14: 2873–2882Fig. 1. The patient at the age of 3.5 years. Note the small stature(height: 74 cm), the moonlike face, the grossly enlarged liver and thegenua vara due to severe rickets.1320 A. Sarkissian et al.

The boy with massive glucosuria

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