Abstract Fanconi-Bickel syndrome (FBS), or glycogenstorage disease type XI, is a rare, well-defined clinicalentity. Recently, this disease was elucidated to link muta-tions in the SLC2A2 gene in many ethnic groups, indicat-ing that FBS is a single gene disease. We report here an8-month-old Turkish girl who developed characteristicfindings of FBS. However, no mutation was detected inthe protein-coding region of the SLC2A2 gene. There-fore, we propose that further molecular analysis is need-ed to determine whether other genes are involved inFBS.

Keywords Fanconi-Bickel syndrome · SLC2A2 gene ·Glycogen storage disease · Tubulopathy

Introduction

Fanconi-Bickel syndrome (FBS), or glycogen storagedisease type XI, is a rare autosomal recessive metabolicdisorder characterized by hepatorenal glycogen accumu-lation, Fanconi nephropathy, and impaired metabolism ofglucose and galactose [1, 2]. Typical clinical findings include hepatomegaly secondary to glycogen accumula-

tion, glucose and galactose intolerance, fasting hypogly-cemia, characteristic tubular nephropathy, rickets, andmarked growth retardation [1, 2, 3]. In contrast to othertypes of glycogen storage disease caused by enzymaticdefects of glycogenolysis, FBS has recently been shownto result from a defective monosaccharide transporterprotein in the cell membranes of different tissues. In1997, Santer et al. [4] reported mutations in the glucosetransporter 2 (SLC2A2 or GLUT2) gene in this disorder.

In this paper, we report a Turkish infant who was diagnosed with FBS, and other known causes of hepaticglycogen storage in differential diagnosis were excluded.Although Santer et al. [3] have detected SLC2A2 muta-tions in many ethnic groups with FBS worldwide, in-cluding 12 Turkish patients, this is the first report of aTurkish patient with this disease who has no mutation inthe SLC2A2 gene. Thus, the purpose of this report is toprovide the basis for ongoing studies to determinewhether other genes are involved in FBS and definemore clearly the clinical spectrum.

Case report

An 8-month-old girl was admitted to the hospital because ofgrowth retardation. She was born at term weighing 3 kg after anuncomplicated pregnancy and delivery. Poor weight gain was detected at 5 months of age. Her motor skills were normal. Herparents were first cousins. Her 3-year-old brother was normal andher aunt was diagnosed with type 2 diabetes mellitus.

On admission her weight, length, and head circumferenceswere below the 3rd percentiles. There was 4 cm hepatomegaly onphysical examination. On laboratory investigation, glucosuria (4+)and phosphaturia were found. Urine amino acid chromatographyrevealed generalized massive aminoaciduria. Blood glucose levelwas 1.4 mmol/l, although there were no symptoms of hypoglyce-mia. Serum calcium level was normal, but serum phosphorus wasbelow the normal range (0.8 mmol/l). Skeletal roentgenograms revealed findings typical of rickets. Tubular phosphorus reabsorp-tion was low (51%). Histological examination of the liver biopsyrevealed periodic acid-Schiff-positive, diastase-negative materialin the hepatocytes suggestive of a glycogen storage disease.

Debranching enzyme and phosphorylase kinase enzyme activi-ties in erythrocytes and tissue fibroblasts were normal, which excluded glycogenosis type III and IX. Genomic DNA was isolat-

E. A. Ozer · N. Aksu · E. Uclar · H. Erdogan · A. R. BakilerPediatric Clinic, SSK Tepecik Teaching Hospital,Tepecik, Izmir, Turkey

M. Tsuda · E. KitasawaTsuda Children’s Clinic, Tokyo, Japan

M. CokerDepartment of Pediatrics, Medical Faculty of Ege University,Izmir, Turkey

E. OzerDepartment of Pathology,Medical Faculty of Dokuz Eylul University,Izmir, Turkey

E. A. Ozer (✉)2041 Sok, Flamingo 15, No: 113/15, Mavisehir,Karsiyaka, 35540 Izmir Turkeye-mail: eozer@deu.edu.trTel.: +90-232-3244406, Fax: +90-232-4330756

Pediatr Nephrol (2003) 18:397–398DOI 10.1007/s00467-003-1085-5

B R I E F R E P O RT

Esra Arun Ozer · Nejat Aksu · Erkan UclarHakan Erdogan · Ali Rahmi BakilerMasahiko Tsuda · Emiko Kitasawa · Mahmut CokerErdener Ozer

No mutation in the SLC2A2 (GLUT2 ) gene in a Turkish infant with Fanconi-Bickel syndromeReceived: 8 May 2002 / Revised: 19 November 2002 / Accepted: 19 November 2002 / Published online: 11 March 2003© IPNA 2003

ed from the liver biopsy and peripheral blood leukocytes of the patient. Amplified polymerase chain reaction (PCR) products ofexon 1–10 of the SLC2A2 gene were subjected to direct sequenceanalysis as previously described [3, 5]. The analysis was extendedto the 5′ untranslated region. No mutation was found in the exonsand their neighboring introns.

The patient was treated symptomatically with vitamin D andphosphorus, and was also given uncooked cornstarch supplement.She has been followed to date up to 2 years of age. Her weight,length, and head circumference are still below the 3rd percentilesand hepatomegaly and other findings still persist.

Discussion

FBS, or glycogen storage disease type XI, is a rare, well-defined clinical entity, which is characterized by thecombination of hepatomegaly secondary to glycogenstorage and a generalized tubulopathy. Excessive gluco-suria and short stature are hallmarks of FBS. Generalizedhyperaminoaciduria, moderate hyperphosphaturia, hy-peruricosuria, and hypercalciuria are also constant find-ings. In general, the tissue glycogen content of liver tis-sue was significantly elevated [1, 2, 3]. Clinical findingsof glycogen storage disease type III and IX are similar tothose in FBS. Hypoglycemia, hepatomegaly, and growthretardation are common findings. However, glycogenstorage disease type III and IX are caused by enzymaticdefects of glycogenolysis [1, 6]. In contrast, enzymeanalysis of the erythrocytes of this patient revealed nor-mal debranching enzyme and phosphorylase kinase en-zyme activities. Additionally, type I glycogen storagedisease may manifest with a Fanconi-like syndrome [7].However, renal disease is a late complication in this dis-ease, and lactic acidosis hyperuricemia and hyperlipide-mia that are hallmarks of the disease were absent. Thus,the patient reported here had all the characteristics of thedisease, and was clinically diagnosed as FBS.

FBS is inherited in an autosomal recessive mode [2].In 1997, Santer et al. [4] reported mutations in theSLC2A2 gene, indicating that this is a single gene dis-ease. The SLC2A2 gene has been cloned and mapped tochromosome 3q26.1–26.3 and contains 11 exons span-ning 30 kilobases [8]. The molecular genetic meta-analy-sis for this gene has been performed in 49 of the 109FBS cases that have been located worldwide since theoriginal report in 1949 by Fanconi and Bickel [3]. Inthese 49 patients, a total of 23 novel mutations of theSLC2A2 gene have been detected. Of these, 12 wereTurkish; all have a novel mutation in this gene. Thesemutations are scattered over the whole coding sequenceof the SLC2A2 gene, and with the exception of exon 1(with only 15 bp), mutations have been found in all ex-ons. None of these mutations is particularly frequent,which makes molecular genetic diagnosis laborious [3].

We report here an 8-month-old Turkish girl who hascharacteristic findings of FBS. However, no mutationwas detected in the protein-coding region of the SLC2A2gene. Likewise, Akagi et al. [9] reported two Japanese

patients with FBS, one without a mutation in this gene.In 8 of the 49 FBS cases investigated by Santer et al [3],no SLC2A2 mutation could be detected, even followingextension of the mutation analysis. An explanation couldbe that at least some of the patients carry heterozygouslong-range deletions not detectable with the appliedPCR-based methods. However, despite the typical clini-cal signs of FBS and the exclusion of other known caus-es of hepatic glycogen storage, without measuring glu-cose transport across membranes, it cannot be claimedthat facilitative glucose transport was impaired in the pa-tients with FBS. In other words, from the limited evi-dence, it cannot be concluded that FBS is a single genedisease caused by SLC2A2 mutations and how these mu-tations lead to FBS is still unclear [10]. Also, it shouldbe noted that heterozygous long-range deletions and mu-tations in the introns could not be excluded by sequenc-ing of PCR products of exons of the gene. Our resultssuggest only that no mutation has been found in exonsand their neighboring introns. Further mutation analysiscould disclose whether FBS is a single gene disease orwhether it is a syndrome derived from different gene loci.

References

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