Introduction
Fankoni-Bickel syndrome is a rare disorder in the metabolism of carbohydrates. This disease is transmitted with autosomal recessive heredity. Characteristics of this disease include hepatorenal glycogenosis, proximal tumor acidosis, glucose and galactose disorder, treatment-resistant hypophosphatemic rashitism and the resulting delayed growth [1-3]. Until now, no specific enzyme deficiency has been detected in carbohydrate metabolism disorders, and it seems that the main defect is in the transfer of monosaccharides from the cell membrane [3-5]. Some have classified this disease as glycogenosis, which does not seem to be right, because the cause of this disorder is not glycogen metabolism, but rather the transfer of sugars from the mucous membrane channel GLUT2. Fankoni-Bikel syndrome is a monocytic disease. The gene encodes the GLUT2 protein or SLC2A2(facilitated glucose transporter  member 2), which is one of the largest protein family members responsible for the transfer of sugars from the cell membrane.
The position of this gene has been identified in the long arm of chromosome 3 at 3q26.1-26.3 [6]. The gene structure consists of 11 exon and 10 introns and is 30 kilobytes long [7]. The GLUT2 gene encodes the glucose transporter protein number 2.
The gene is expressed in gastric mucosal cells, liver, kidney tubules, and beta cells of the pancreatic langerhans [1, 8]. Since the detection of this gene, more than 30 mutations have been reported, most of which are new and specific mutations. The observed gene mutatin in this study is new and specific and has not yet been mentioned in medical sources. In this patient, the non-typical  signs were wrongly attributed to osteogenesis Imperfecta. It is essential in the differential diagnosis that the treatment-resistant rhiztitis in the disease treatment also be added to the list.
 
Patient and methods
A, 3.5 years old girl, was diagnosed with osteogenesis imperfecta for treatment with periodic pamidronate. The patient was the first and only child of the family. Her mother did not have any problems during pregnancy and her delivery was a cesarean section. The weight of the girl at birth was 2600 grams and her height was 49 centimeters. The main symptoms in the patient were severe growth retardation, bone pain, inability to stand up, and a history of bone fractures several times spontaneously, from the age of two years.
With the diagnosis of osteogenic disease, the first dose of pamidronate was injected to the patient. In the second visit, the patient was carefully and accurately evaluated clinically and laboratoryly. P = 2.5, and Ca= 0.63. The level of alkaline phosphatase increased significantly and 1100 units per deciliter, parathormone and 25-hydroxyvitamin D3 were slightly increased and it was not possible to measure 1-25 dehydroxyvitamin D3. Also, kidney, liver and hormonal tests were normal at this stage. With the diagnosis of hypophosphatemic resistant rickets, treatment with pamidronate was discontinued and the patient was treated with Roquartolle (a new derivative of vitamin D3), and calcium and phosphate containing syrup were also prescribed as supplement (Fig. 1).

Figure 1) Image of the patient at the start of treatment

 
Three months after the start of this treatment, the patient showed a clear improvement in motion and was able to stand up and walk, and the gradual improvement continued. At the age of 5, we noticed the magnitude of the abdomen and the size of the liver in the patient, which was confirmed by ultrasound. The size of the spleen, the kidneys and the pancreas was normal at this stage, and increased liver enzymes, total serum protein and normal albumin, CBC, electrolytes, and kidney and thyroid function tests were all normal. Due to the progression of the liver, a study was conducted to detect chronic diseases such as tyrosinemia, Wilson's disease, galactosaemia, and alpha-1-anti-tripsin deficiency, all of which were normal and the patient did not have cataract disease. Liver biopsy was performed to show glycogen stores in liver cells. From the middle of the 5th year, signs of severe renal impairment such as severe glycosyroidism, mild proteinuria, phosphorus, calcium, occipiozuria, and amino acids (symptoms of Fanconi syndrome) were emerged. The kidneys were reported in ultrasound larger than normal. In the glucose tolerance test, hypoglycemia was shown in fasting state and hyperglycemia at a later stage (fasting blood glucose 51, half an hour later 157, one hour later 199, and two hours later 248). Blood gases in the arterial blood sample showed metabolic acidosis, and the pH of the urine was acidic. Considering the symptoms, a) resistance to treatment-induced hypophosphatemia (Fig. 2), b) hepatomegaly and liver glycogenosis, and c) kidney tubulopathy and Fanconi syndrome, the clinical diagnosis of Fanconi-Bichel syndrome was presented in the patient. To confirm the diagnosis, a molecular study of the gene responsible for the disease (GLUT2) was performed.

Figure 2) Radiological image indicating rickets

With the clinical diagnosis of Fankoni-Bickel syndrome, all exons, introns, and the attachment of exons to introns in the GLUT2 gene were performed by polymerase chain reaction amplification and sequencing. A new mutation (Novel Mutation) of the type of add-remove was discovered. In exon 5 of this gene, 17 nucleotides were removed and instead replaced them with 7 new nucleotides. This mutation had not previously been reported in any other patient. The mutation in the patient is homozygote, meaning that the parents are both carriers of the mutation.
The result of the mutation is the Frameshift Mutation, which produces a shorter protein with the following characteristics:
C.685_701del GCCATCCTTCAGTCTCT ins CAGAAAA; p.A229 QfsX19 which is unmistakable pathogenic mutation.
 

Discussion
Fanconi-Bickel`s specification is a combination of treatment-resistant hypophosphatemic rachitis, renal tubular tuberculosis and liver enlargement due to accumulation of glycogen in hepatocytes.
The patient was introduced due to motor retardation and repeated fractures with diagnosis of osteogenic imperfecta. In fact, the main symptoms of the disease (osteoporosis and fractures) are due to severe and resistant to rachitis, and despite the classic treatment of rickets, it has not been resolved. By following the patient's physical condition for a long time, signs of liver and kidney were gradually revealed, and finally, the diagnosis of FBS was made. The main pathological mechanism in this disease, is the mutation in the GLUT2 gene and the alteration of the protein structure of the membrane canal which is responsible for glucose and galactose transmission (Fig. 3). GLUT2, is a member of the gene family and facilitates the transfer of sugars from the cell membrane (Fig. 3).

Figure 3) Main pathologic mechanism in patient with mutation in GLUT2 gene

The gene is made up of 11 exons and 10 introns and has a length of 30 kilobytes [7]. In the past 15 years, several mutations have been identified and reported in the FBS syndrome gene. The largest available study is the study of the gene in the FBS disease by Santer in Germany, which has been surveyed in 88 families with 109 patients and reported the disease mutations. Patients` nationalities were Turkey, European countries, the Middle East, North Africa and the United States [9]. Unfortunately, there is no special point and important point for the release of mutations, so it is inevitable that in each patient all the gene building should be examined by sequencing method, and most of the reported mutations are of a specific and specific type of family and not replicated. Our patient mutation also had the same characteristics and had not previously been reported to any other family.
The obvious characteristic of the patient was that the signs appear gradual and over time. The initial symptom was a severe generalized osteoporosis, and it became clear in further investigation and follow-up that the cause of fractures was resistance to rachitis. The patient under study is now 11 years old. (Figure 4).

Figure 4) The patient's image under further treatment at the age of 11

After definitive diagnosis, the patient was treated with corn starch, rochartrol and growth hormone. Signs of disease were significantly inhibited. The liver is small and the patient has an acceptable progress in terms of growth. Due to the mutation being detected, accurate genetic counseling was performed and the information was provided to the family. In the next pregnancies, diagnosis can be done before the birth to be aware of the fetal health or illness.

Conclusion
Fancoli-Bickel's syndrome should be considered in the differential diagnosis of the causes of resistant rachitis, severe growth retardation, liver enlargement and tubular disease and renal acidosis. It should also be considered in the differential diagnosis of osteogenic imperfecta. After confirmation of clinical and molecular diagnosis, the patient was treated with corn starch, rochartrol, and growth hormone injections. The response to treatment was excellent, the symptoms of disease were controlled and developmental status was significantly corrected. The risk of recurrence of illness in later pregnancies was explained to parents and the possibility of prenatal diagnosis by the molecular method in subsequent pregnancies was also explained.

Acknowledgments
The authors are grateful to the patient's family in close cooperation in studying and tracking the patient.
Ethical permissions
The case was not found by the authors.
Conflict of Interest
The case was not found by the authors.
Financial support
This study was supported by Sarem Fertility and Infertility Research Center.
Contribution of Authors
Yousef Shafeghati (First author), author of the article/main author/author of discussion (%30); Peymaneh Sarkheil (Second author), author of the article/main author/author of discussion (%30); Taghi Baghdadi (Third author), author of the article/methodology/helper author (%10); Fatemeh Hadipour (Fourth author), author of the article/helper author (%10); Zahra Hadipour (Fifth author), author of the article/helper author (%10); Mehrdad Noruzinia (Sixth author), author of the article/helper author (%10).