Imad Mohammad Dweikat

Issa Shaher Alawneh

Mutaz Idrees Sultan

Sami Fares Bahar

BMC Research Notes

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Dweikat et al. BMC Res Notes  (2016) 9:387 
DOI 10.1186/s13104-016-2184-2
CASE REPORT
Fanconi-Bickel syndrome in two 
Palestinian children: marked phenotypic 
variability with identical mutation
Imad Mohammad Dweikat1*, Issa Shaher Alawneh1, Sami Fares Bahar1 and Mutaz Idrees Sultan2
Abstract 
Background: Fanconi-Bickel syndrome (FBS, OMIM 227810) is a rare autosomal recessive disease caused by a defi-
ciency of glucose transporter 2 (GLUT2), a member of the facilitative glucose transporter family (Santer et al. J Inherit 
Metab Dis 21:191–194, 1998). The typical clinical picture is characterized by hepatorenal glycogen accumulation 
resulting in hepato- and nephromegaly, impaired utilization of glucose and galactose, proximal renal tubular dysfunc-
tion, rickets and severe short stature.
Case presentation: We report 2 Palestinian patients from 2 families who were homozygous for the mutation 
p.R301X (C>T) in exon 7of GLUT2 gene. Patient 1 showed clinical and laboratory improvement with age characterized 
by normal growth and resolution of rickets. Patient 2 had severe phenotype characterized by progressive weight loss, 
persistent metabolic acidosis, marked polyuria and clinical and laboratory findings of rickets progressing to death at 
age 10 months.
Conclusion: This report further expands the clinical spectrum of FBS even with identical mutations. Other yet 
unknown genetic, environmental or stochastic factors may be responsible for phenotypic variability
Keywords: FBS, Hepatomegaly, Rickets, Short stature, Hypoglycemia
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Background
A functional loss of GLUT2 is compatible with the clini-
cal symptoms observed in FBS patients [1]. GLUT2 is 
expressed in hepatocytes, enterocytes and pancreatic 
β-cell membranes and is involved in the transcellular 
monosaccharide transport of renal tubular cells and 
enterocytes [1, 2]. The main features of this disorder 
are hepatorenal glycogen accumulation, proximal renal 
tubular dysfunction, impaired utilization of glucose and 
galactose, rickets and severe short stature [3]. Biochemi-
cally, the disease is characterized by a general renal 
proximal tubular defect (glucosuria, bicarbonate wast-
ing, aminoaciduria, renal tubular acidosis, hyperphos-
phaturia) and carbohydrate abnormalities that include 
postprandial hyperglycemia, fasting hypoglycemia and 
hypergalactosemia [3, 4]. Mutations of GLUT2 (SLC2A2) 
are the basic defect in FBS patients with characteristic 
clinical features and also in patients with atypical clinical 
signs such as intestinal malabsorption, failure to thrive, 
the absence of hepatomegaly or renal hyperfiltration [5]. 
These mutations are scattered over the whole coding 
sequence of the SLC2A2 gene and none of these muta-
tions is particularly frequent which makes molecular 
genetic diagnosis laborious [5, 6]. FBS is generally con-
sidered a well-defined clinical condition and the overall 
prognosis seems to be favorable [2, 7]. Phenotypic varia-
bility in FBS has been reported and includes atypical phe-
notype, unusually mild clinical course, severe phenotype 
and also variable clinical severity in patients with identi-
cal mutations [2–8].
We report the first 2 Palestinian patients with FBS 
from 2 different families who are unrelated and from 
different geographic location. They are homozygous for 
the mutation p.R301X in exon 7 of the GLUT2 gene. 
Open Access
BMC Research Notes
*Correspondence:  i.dweikat@najah.edu 
1 Pediatric Department, Faculty of Medicine and Health Sciences,  
An-Najah National University, P.O.Box 7, 44839 Nablus, Palestine, Israel
Full list of author information is available at the end of the article
Page 2 of 5Dweikat et al. BMC Res Notes  (2016) 9:387 
Both presented with the typical phenotype of FBS but 
showed marked variation in the clinical progression of 
the disease.
Case presentation
Case 1
The 6 year old female was born at term to consanguine-
ous parents after uneventful pregnancy. Birth weight was 
2800 g (−1.2 SD), length and occipitofrontal circumfer-
ence at birth were not recorded. Other 3 male siblings 
are healthy with no symptoms suggestive of FBS and 
no other family member with diabetes mellitus. First 
hospitalization was at age 17  month for evaluation of 
inadequate weight gain and abdominal distension. Her 
weight was 6600 g (−5.3 SD), length 69 cm (−3.3 SD) and 
occipitofrontal circumference 43  cm (−2.6 SD). Physi-
cal examination showed hepatomegaly and doll-like face. 
Laboratory findings included high serum triglycerides, 
mildly elevated serum aspartate aminotransferase, ala-
nine aminotransferase, low phosphorous and elevated 
alkaline phosphatase. She had polyuria  >6  ml/kg/h, 
massive generalized aminoaciduria, phosphaturia and 
glucosuria. Serum ammonia, lactic acid, calcium, para-
thyroid hormone and 25-hydroxyvitamin D were normal 
(Table 1). Abdominal ultrasound revealed hepatomegaly 
and minimal calcification of both renal calyces. Radiolog-
ical findings included generalized osteopenia and rachitic 
changes. Genetic analysis showed that the patient is 
homozygous for the mutation R301X (C>T) in exon 7 of 
the GLUT2 gene. Treatment included anhydrous phos-
phate (Joulie’s) solution 5  ml given every 4  h, 5 times 
daily (0.75 g/24 h), alpha D3 drops (alphacalcidol) 1 µg/
day, galactose-restricted diet and uncooked cornstarch 
1.6  g/kg given every 6  h during night time to prevent 
hypoglycemia. Metabolic acidosis was mild and did not 
require treatment.
Table 1 Biochemical findings of the two patients during the first and the last hospitalization
Laboratory test Patient 1 Patient 2 Normal values
Initial values age 17 
months
Last values age 6 
year
Initial values age 5 
months
Last values age 8 
months
Serum Ca (mg/dl) 9.8 9.8 9.8 9.8 9–11
Serum PO4 2.3 mg/dl 3.8 mg/dl 1.3 mg/dl 1.7 mg/dl 1 month–2 year: 
3.8–6.5 g/dl
3–9 year: 3.2–5.8 mg/dl
Serum alkaline phos-
phatase (U/l)
666 206 1200 1178 150–420
Parathyroid hormone 
(ng/l)
47 49 13 83 10–65
Vitamin D3 (pg/ml) 25 24 27 16–65 
Serum triglyceride 
(mg/dl)
761 187 1200 254 27–125
Serum cholesterol 
(mg/dl)
210 186 400 153 <170
Aspartate aminotrans-
ferase (U/l)
49 37 140 117 9–80
Alanine aminotrans-
ferase (U/l)
76 32 61 56 13–46
Random blood sugar 
(mg/dl)
120 135 102 88 <126
Serum uric acid (mg/dl) 1.5 1.5 1.1 2.2–6.6 
Venous pH 7.32 7.42 7.25 7.30 7.35–7.45
HCO3 (mEq/l) 17 22 13 14 18–24
TRP (%) 59 69 32 33 >85
Urine calcium excretion 
(mg/kg/day)
7.4 5.6 3.2 <4 
Glomerular filtration 
rate (ml/min/1.73 m2)
83 226 13 98 49–165 
Urine protein excretion 
(mg/m2/h)
64 18.8 42 44  <4
Urine glucose excretion 
(g/24 h)
25.7 1.8 4.5 
Page 3 of 5Dweikat et al. BMC Res Notes  (2016) 9:387 
The clinical phenotype was characterized by improve-
ment of growth parameters with age. Rickets resolved 
with normalization of serum phosphate, alkaline phos-
phatase and triglyceride. She still shows laboratory find-
ings of renal tubular dysfunction including polyuria, 
massive aminoaciduria, glucosuria and phosphaturia.
At age 6  years, her weight was 18  kg (−0.8 SD) and 
height 107 cm (−1.6 SD) (Fig. 1). Physical exam showed 
mild hepatomegaly and renal ultrasound showed resolu-
tion of calyceal calcifications.
Case 2
The patient was the first born child to consanguineous 
parents at term after uneventful pregnancy at 36  weeks 
gestation. His birth weight was 2200 g (−2 SD). Length 
and occipitofrontal circumference at birth were not 
recorded. No other family members with symptoms sug-
gestive of FBS or other family member with diabetes mel-
litus. At age 2 months, noted to have inadequate weight 
gain and enlarged anterior fontanel. Different milk for-
mulas were tried but did not result in weight gain. Hospi-
talized at age 5 months for evaluation of severe failure to 
thrive, Hyperlipidemia and metabolic acidosis. His weight 
was 4500 g (−4.3 SD), length 50 cm (−8.8 SD). Physical 
examination showed abdominal distension, hepatomeg-
aly and doll-like face. He also had rachitic rosaries and 
wide wrist joints. Laboratory findings included very low 
serum phosphate, high serum alkaline phosphatase and 
triglycerides, mildly elevated serum cholesterol, alanine 
aminotransferase, aspartate aminotransferase and meta-
bolic acidosis. He had massive generalized aminoaci-
duria, phosphaturia, proteinuria and glucosuria. Serum 
calcium, parathyroid hormone and 25-hydroxyvitamin 
D3 were normal as well as urinary excretion of calcium. 
Other normal laboratory findings included coagulation 
studies, serum ammonia and lactic acid (Table 1).
Radiological findings showed generalized osteopenia 
and rachitic changes in the wrist and knee joints. Genetic 
analysis also showed that the patient is homozygous for 
the mutation R301X (C>T) in exon 7 of the GLUT2 gene.
The clinical course was characterized by severe polyu-
ria, inability to gain weight, metabolic acidosis despite 
treatment with uncooked cornstarch 1.6 g/kg given every 
5  h during night time, lactose-free infant formula, oral 
phosphate supplement at initial dose 0.5  g/24  h given 
every 4 h, 5 times daily, 1,25-hydroxyvitamin D3 0.5 µg/
day and oral sodium bicarbonate supplement 1  mEq/kg 
given 4 times daily. The medications were given appropri-
ately in terms of both dosage and frequency. Rehospital-
ized at age 8 months for weight loss, persistent metabolic 
acidosis and polyuria. Weight was 3.5 kg (−8.9 SD). Indo-
methacin was added to reduce polyuria but urine output 
remained persistently elevated >8 ml/kg/h.
The patient died at age 10 months.
Discussion
The clinical picture of FBS has been thought to be rather 
homogenous and characterized as a combination of hepa-
tomegaly secondary to glycogen accumulation, galactose 
intolerance, impaired glucose homeostasis with fasting 
hypoglycemia and postprandial hyperglycemia, proximal 
tubular nephropathy and, very typically, severely stunted 
growth [2, 4, 7].
Our patients presented with the typical phenotype 
described in the introduction. However, a distinctive fea-
ture is the wide variability of clinical course showing nor-
mal stature and normal physical exam at age 6  years in 
patient 1 and a rapidly progressive course characterized 
by weight loss, massive polyuria, metabolic acidosis and 
persistence of radiological and biochemical signs of rick-
ets progressing to death in patient 2.
Phenotypic variability has been reported in eight 
patients from a single Bedouin sibship, all were homozy-
gous for the p.R301X mutation. All had failure to thrive 
and/or hepatomegaly, fluctuations in blood glucose 
levels and proximal tubular dysfunction evidenced 
by massive glucosuria, generalized aminoaciduria, 
Fig. 1 Showing normal growth of case 1 at age 6 years
Page 4 of 5Dweikat et al. BMC Res Notes  (2016) 9:387 
hypercalciuria and hyperphosphaturia. Skeletal involve-
ment ranged from none to radiological and/or clinical 
signs of rickets and osteopenia. A spectrum of diseases 
severity was evident during follow up regarding the 
growth parameters, hospitalizations for disease exacerba-
tions, mean amount of electrolyte replacement therapy, 
and skeletal and renal complications [4]. 3 patients had 
mild phenotype; two needed small amounts of replace-
ment therapy and one patient did not require replace-
ment therapy since he was under the authors’ follow up at 
age 16 years. On the other hand, two patients had severe 
phenotype characterized by hypocalcemic titanic events 
in one patient and recurrent symptomatic nocturnal 
hypoglycemia necessitating gastrostomy for continuous 
night feedings until age 3 years in the other patient.
Our patients had similar phenotype initially and both 
had clinical and radiological signs of rickets and osteo-
penia. The main distinction was the rapidly progressive 
deterioration in patient 2 in our report despite adequate 
replacement therapy.
The R301X mutation has also been reported in four 
unrelated families among 33 different SLC2A2 mutations 
in 49 patients with a clinical diagnosis of FBS [5]. No spe-
cific case descriptions was provided and the diagnosis 
was based on the combination of typical clinical and lab-
oratory signs. The authors postulated that it is premature 
to discuss a genotype–phenotype correlation in FBS and 
there is no indication that FBS having missense muta-
tions show a milder clinical course when compared with 
those having truncated mutations.
Unusually mild phenotype has been described in a 
9-year old boy characterized by absence of hepato- and 
nephromegaly, normal growth, normal glucose toler-
ance even after glucose loading and very mild glucosu-
ria, aminoaciduria and proteinuria [2]. Another mild 
phenotype was described in a patient with FBS harbor-
ing a novel mutation in the GLUT2 gene detected by 
neonatal screening for galactosemia. He was found to 
be homozygous for a 3  bp deletion (425-7/delta) within 
exon 3. Treatment with phosphate and bicarbonate at age 
16 months resulted in marked growth improvement and 
on a Mediterraniean free diet with fractionated meals, he 
has never shown symptomatic hypoglycemia [8]. Patient 
1 in our report has a much similar phenotype showing 
improvement of growth parameters and absence of car-
bohydrate abnormalities.
A significant combined defect of the muscle respira-
tory chain complexes I, III and IV has been described in 
an 8 year old boy with FBS who had a novel homozygous 
base exchange at position IVS5+5 of the GLUT2 gene [7]. 
The authors hypothesized that FBS patients are prone to 
a severe secondary respiratory chain defect that could in 
part explain the heterogeneity of the clinical symptoms. 
Patient 2 in our report had persistent metabolic acidosis 
which may be explained by this hypothesis but muscle 
biopsy for respiratory chain complexes was not performed.
Diabetic ketoacidosis has been described in a female 
infant with FBS at age 33  days [9]. Although FBS is 
characterized by carbohydrate abnormalities including 
posprandial hyperglycemia and fasting hypoglycemia, 
our patients did not show significant hyperglycemia at 
presentation or during follow up.
Conclusion
There is an increasingly recognized evidence that FBS is 
clinically heterogenous. This report further expands the 
clinical spectrum of FBS even with identical mutations. 
Other yet unknown genetic, environmental or stochastic 
factors may be responsible for phenotypic variability.
Abbreviations
FBS: Fanconi-Bickel syndrome; GLUT2: glucose transporter 2; FTT: failure to 
thrive.
Authors’ contributions
ID carried out manuscript preparation, literature search, data acquisition and 
data analysis. IA provided data about the history of the two patients and pre-
pared the table and the figure. SB contributed to interpretation of biochemical 
data and manuscript review. MS contributed to treatment of the two patients 
and manuscript review. All authors read and approved the final manuscript.
Author details
1 Pediatric Department, Faculty of Medicine and Health Sciences, An-Najah 
National University, P.O.Box 7, 44839 Nablus, Palestine, Israel. 2 Pediatric Depart-
ment, Makassed Hospital, Mount of Olives, P.O.Box 19482, Jerusalem, Palestine, 
Israel. 
Acknowledgements
We like to thank the metabolic and nephrology staff in our hospital for taking 
care of the patients. A special thanks to the laboratory staff in our hospital for 
their efforts in the reporting of biochemical data.
Competing interests
The authors declare that they have no competing interests and have received 
no funding for this article.
Availability of data and materials
The data supporting the conclusions of this paper are included in the paper.
Consent
Written informed consent was obtained from the parents of the two patients 
for publication of this case report. Parental consent for publication of non-
covered images was also obtained.
Ethical clearance
Permission for publication of this article was obtained by An-Najah National 
University Institutional Review Board.
Funding
There was no research grant for all authors of this article.
Received: 5 February 2016   Accepted: 26 July 2016
Page 5 of 5Dweikat et al. BMC Res Notes  (2016) 9:387 
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Fanconi-Bickel syndrome in two Palestinian children: marked phenotypic variability with identical mutation

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Fanconi-Bickel syndrome in two Palestinian children: marked phenotypic variability with identical mutation

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