Fanconi-Bickel syndrome versus osteogenesis imperfeeta: An Iranian case with a novel mutation in glucose transporter 2 gene, and review of literature
AA is a 3.5-year-old Iranian girl, referred to the genetic clinic for cyclic pamidronate therapy with the diagnosis of osteogenesis imperfecta. She was the first and the only child of the family, product of an uneventful normal pregnancy and was delivered by C/S. BW was 2600 g and height 49 cm. Main symptoms was growth failure, severe bone pain, inability to stand and walk, and history of several bone fractures from about age 2 year. In the second admission for pamidronate treatment, her clinical and radiologic findings were re-evaluated. All the findings were in favor of hypo-phosphatemic resistant rickets. Ca 9.3 mg/dl, P 2.5 mg/dl, Alk. Phosphatase was markedly elevated 1100 IU/L, PTH was 72 pg/mL (mildly elevated) and 25(OH) vitamin D 180 ng/mL (normal range 7.5-75). We were not able to test 1,25 (OH) 2 vitamin D. There was not any clue for hepatic or renal involvement at that time. Cyclic pamidronate therapy was discontinued, and we administered rocartrol, Ca syrup, phosphate as jouli solution. She began to stand and walk after 3 month treatment. In the age of 4 years and 2 month we noticed on enlarged liver, confirmed by sonography, however, the size and shape of spleen, kidneys, and pancreas were reported as normal. Biochemical analysis for thyroid and renal functions, as well as routine analyses and serum electrolytes all were within normal limits. CBC was normal, but SGOT 155 IU/L (NL 0-46) and SGPT 206 IU/L (NL 0-49) respectively (they were strongly elevated). Serum total protein was 7.5 g, 65% of it was albumin, α1 and β-globulins were normal, g-globulin was decreased, but α2 globulin was increased. Because of progressive liver enlargement we checked again liver function tests along with biochemical markers for Tyrosinemia, Wilson's disease, Galactosemia, and α-1-antitrypsin deficiency, all of the results were WNL. Ophthalmologic evaluation did not show cataract. Liver biopsy has been done and showed marked glycogen storage in hepatocytes (GSD).\nOne year later (when she was 4.5-years-old), we detected 4+ glucosuria, and trace protein in the urine. Measurement of abnormal metabolites excretion in the urine showed glycosuria, phosphaturia, calciuria, uricosuria, and aminoaciduria. In renal ultrasound both of the were enlarged. Fasting hypoglycemia was (51 mg/dL), and on GTT, blood glucoses were 157, 199, and 248 respectively. Arterial blood gasses analysis revealed metabolic acidosis (pH, 7.318; bicarbonate 12.7 mmol/L). Urine pH was 5.0 (normal: 4.5-8), we put the cardinal findings together;\nHypophosphatemic resistant rickets, Hepatomegaly due to glycogen storage and, Renal tubulopathy with the finding for Fanconi syndrome, FBS instead of osteogenesis imperfecta was suggested strongly.\nWith this impression, all coding exons, including flanking introns in the GLUT2 gene, were amplified by polymerase chain reaction (PCR) from genomic DNA. The PCR products were directly sequenced, and we found a novel mutation in GIUT2 gene, (c. 685_70l del GCCATCCTTCAGTCTCT ins CAGAAAA). It was a homozygous deletion-insertion mutation in exon 5. This mutation has not been reported before, however, due to the fact that it results in a frameshift mutation and premature termination of translation (p.A229 QfsX19), this indeed is a disease causing mutation.