Fanconi Bickel syndrome: clinical phenotypes and genetics in a cohort of Sudanese children

Abstract

Background Fanconi-Bickel syndrome (FBS) is a rare condition of carbohydrate metabolism, caused by a recessive defect in the facilitative glucose transporter GLUT2 encoded by the SLC2A2 gene and characterized by a wide spectrum of phenotypical features. There is a paucity of reported data on FBS from Sub-Saharan Africa. Here, we describe the clinical, biochemical and genetic characteristics of our patients with FBS from Sudan, a country with a high consanguinity rate. Patients & methods Eleven patients from ten unrelated Sudanese families were included. Clinical & biochemical data were documented and imaging studies done including bone survey and abdominal ultrasound. Liver biopsy was done to confirm the pathological diagnosis in 45% of cases and molecular genetics was performed through contribution with the Exeter genomics laboratory for ten patients. Results Reported consanguinity was 70% among our patients. Growth was significantly impaired at presentation with mean weights of (-5.3 ± 1.8) SD and heights (-5.4 ± 2.5) SD. Severe chest deformity was present in (27%) and all patients showed features of rickets at presentation. Three patients had neonatal diabetes requiring insulin therapy of which one has been reported before. Six families lost undiagnosed siblings with similar clinical presentations. We identified a total of four homozygous pathogenic SLC2A2 variants in our patients, one of whom had a novel mutation. Conclusions FBS is not uncommon in Sudan where there is a high rate of consanguinity. Many cases are likely missed because of variable presentation and lack of public and professionals’ awareness. This is the first series to describe this condition from Sub-Saharan Africa.

Understanding the Mechanism of Dysglycemia in a Fanconi-Bickel Syndrome Patient

“…GLUT2 mutations were first described in three FBS patients, including the original patient in 1997 ( 2 ). More than 100 FBS cases with different SLC2A2 mutations; nonsense, missense, Fs/InDel, intronic, and compound heterozygous variants have been reported so far ( 3 – 8 ). SLC2A2 gene consists of 11 exons and 10 introns and encodes for the GLUT2 transmembrane protein (524 amino acids) (SLC2A2-201 ENST00000314251.8) ( 9 ).…”

“…Furthermore, GLUT2 is the major glucose transporter in the rat beta cells and is suggested to play a role in glucose uptake and insulin secretion. However, GLUT2 is expressed at low levels in human beta cells, and its role is not well studied and is still controversial ( 3 , 14 , 15 ). FBS patients develop dysglycemia (glucose intolerance, post-prandial hyperglycemia, fasting hypoglycemia, transient neonatal diabetes, frank diabetes mellitus, and gestational diabetes) with different severity regardless of the type of mutation.…”

Case Report: Fanconi-Bickel Syndrome in a Chinese Girl With Diabetes and Severe Hypokalemia

“…In her clinical symptoms, diabetes and hypokalemia are rare. In this patient, transient or permanent neonatal diabetes is an unusual feature of Fanconi–Bickel syndrome, reported in 15 patients with homozygous SLC2A2 mutations ( 3 , 6 , 12 – 17 ). Furthermore, SLC2A2 mutation has been shown to increase the risk of developing type 2 diabetes (T2D) ( 18 , 19 ).…”

“…Taha et al ( 26 ) reported that the use of insulin should be avoided in patients with FBS to decrease the risk of hypoglycemia. In contrast, insulin was used in some patients with hyperglycemia or neonatal diabetes, and all of them did not have symptomatic hypoglycemia ( 6 , 17 , 20 , 27 ). In our patient, we use a small dosage of insulin to control postprandial blood sugar and CGMS to monitor for 24 h. The CGMS played an important role not only in diagnosis but also in the prevention of hypoglycemia.…”

“…A high index of suspicion is needed for diagnosis due to its varied clinical presentations. It is mainly based on the clinical symptoms, radiological and biochemical features of rickets, laboratory data on renal tubular dysfunction, resultant metabolic acidosis, accumulation of glycogen on the liver or renal biopsy ( 6 ), and whole-exome sequencing (WES).…”