Introduction
Fanconi-Bickel Syndrome (FBS; OMIM 227,810), is a rare autosomal recessive disorder of carbohydrate metabolism which was first described by Fanconi and Bickel in 1949 when they identified a combination of tubular nephropathy and glycogen storage disease in a Swiss boy [
1]. It is characterized by hepato-renal accumulation of glycogen, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose due to defect in the glucose transporter GLUT2 encoded by
SLC2A2 [
2]. Common features at presentation include failure to thrive, protuberant abdomen & hepatomegaly secondary to glycogen accumulation, glucose, and galactose intolerance, fasting hypoglycaemia and postprandial hyperglycemia, proximal tubular nephropathy as evidenced by glycosuria, phosphaturia, aminoaciduria and hypophosphatemia leading to subsequent features of rickets [
3]. Presentation is heterogeneous making a clinical diagnosis challenging, especially where healthcare resources are scarce. As presentation is varied, a high index of suspicion is needed to diagnose these cases. It is mainly based on the clinical symptoms, radiological and biochemical features of rickets, laboratory data of renal tubular dysfunction, and resultant metabolic acidosis and accumulation of glycogen on the liver or renal biopsy. The clinical diagnosis is confirmed by the presence of a pathogenic variant in
SLC2A2. Treatment is largely supportive and pointed towards the management of rickets, acid-base disturbances, and glucose metabolism.
Many scattered cases have been reported worldwide from different ethnic groups, but little is known about cases from Sub-Saharan Africa [
4]. This is the first series to be reported from Sudan since the first case with neonatal diabetes was published [
5]. In this series, we aimed to describe the clinical and biochemical features of FBS at presentation as well as genetic mutations.
Patients and methods
This was a cross-sectional, descriptive hospital-based study. Records of all patients who were diagnosed as having FBS in the paediatric endocrinology and gastroenterology units at Gaafar Ibn Auf Children Teaching Hospital in Khartoum, the capital city, were reviewed. This is the main tertiary care centre for Sudan which gets referrals from all over the country. Data including age, sex, ethnic group, clinical presentation, laboratory, and radiological findings as well as liver biopsy findings to confirm the pathological diagnosis were obtained in addition to the management. Genetic testing was done in the University of Exeter UK Genomic laboratory for all patients except one who had a suggestive clinical and biochemical features supported by characteristic findings on liver biopsy. The study was approved by the hospital’s ethical committee and written consent was obtained from the parents.
Genetic testing
Genetic testing was undertaken on purified whole blood-derived DNA either by Sanger sequencing of all coding and flanking intronic regions of
SLC2A2 (NM_000340), or by targeted Next-Generation Sequencing of all coding and flanking intronic regions of
SLC2A2 as part of a panel of genes causing monogenic diabetes (full information available at
www.diabetesgenes.org).
SLC2A2 variants identified were assessed against the American College of Medical Genetics guidelines for variant interpretation.
Discussion
FBS is a rare clinical syndrome caused by recessively inherited pathogenic variants in
SLC2A2 encoding GLUT2 (SLC2A2). The exact incidence and prevalence is not known but many pathogenic variants in
SLC2A2 from different ethnic groups have been identified, of which around half are novel. Data from Sub-Saharan Africa (apart from one case of neonatal DM, reported from Sudan), are not available [
2,
4,
5].
Since the first case of FBS was reported, many additional cases have been observed with variable clinical presentations and many attempts have been made to explain the pathophysiology of this syndrome. The loss of function of GLUT2 can explain most of the characteristic clinical manifestation seen in patients with FBS. Normally, GLUT2 facilitates glucose diffusion in and out of liver cells. In patients with FBS, decreased uptake of glucose by the liver cells, leads to postprandial hyperglycemia, which is further exacerbated by low insulin secretion due to defective glucose sensing in the pancreatic ß cell. Concomitantly, defective transport of glucose out of the cells leads to increase intracellular glucose and inhibits glycogen degradation that eventually leads to hypoglycemia in the fasting state and subsequent hepatomegaly. Renal loss of glucose due to defective transport of glucose and galactose across the basolateral membrane of tubular cells contributes more to hypoglycemia and renal glycogen accumulation, further disrupting other tubular functions leading to tubular nephropathy and nephromegaly. Impairment absorption of glucose from enterocytes and carbohydrate accumulation leads to the malabsorption and gastroenteritis symptoms seen in some patients with FBS [
3,
6].
Presentation of FBS usually occurs in early infancy but the late presentation has also been reported [
7]. We found wide variability and severity even in patients within the same family or with the same pathogenic variant in
SLC2A2, in keeping with other reports suggesting other factors that may underlie this that necessitate further studies [
8,
9]. Six patients (60%) from ten unrelated families harbored the same p.(Arg53Ter) variant, suggesting this may be a founder variant in the Sudanese population and could be screened by genotyping before sequencing of the whole gene in Sudanese patients. Our patients presented late in the disease course with strong features of rickets, abdominal distention, and growth impairment. Many patients had a history of recurrent tachypnea and dehydration which were wrongly diagnosed as pneumonia or gastroenteritis at their first presentation to their local health facility, and six families reported that they had other children who died with a similar clinical picture without being diagnosed. Features of growth failure, hepatomegaly, signs of rickets, and tubulopathy are typical in FBS, but some other rare features have been described [
10]. Though our patients had typical clinical features of FBS at presentation, abdominal distension remained the main concern that brought our patients to medical attention, while rickets or high blood glucose were incidentally discovered during the examination and investigations. One of our patients reported delayed dentition at the age of 16 months. This highlights the importance of careful dental assessment in patients with FBS where many abnormalities have been described and are explained by the presence of hypophosphatemic rickets and chronic acidosis [
11]. Skeletal deformities in patients with FBS were not uncommon and severe chest deformity was seen in three of our patients. This may be explained by bone disease seen in patients with hypophosphatemic rickets as was proposed in similar reports [
12].
The birth weight of patients with FBS has been found to be low in some reports, similar to our cases which may suggest low insulin in utero. This has not been widely discussed in the literature and further researches are needed to explain this observation [
13]. Polyuria was documented as early as 40 days in eight patients of whom three proved to have neonatal diabetes.
SLC2A2 has been documented to be the cause of neonatal diabetes (NDM) in different reports suggesting the role of GLUT2 in insulin secretion [
5]. Our patients with NDM were the outcome of consanguineous marriage, homozygous for the same
SLC2A2 mutation (c.157C > T) and had low birth weight suggesting reduced insulin secretion in utero, though normal birth weight has been reported before in patients with FBS and NDM [
14]. Diabetes in this group tends to be transient suggesting low pancreatic B cell mass in the neonatal period that increases during development in infancy. Transient hyperglycemia is less severe suggesting that glycosuria frequently seen in FBS patients may help in decreasing the blood glucose level, however permanent NDM has also been reported [
15]. It is not known why some patients of FBS who share the same mutations develop NDM while others do not, but it has been proposed that relatively late presentation and milder diabetes seen in FBS cases might be implicated as patients’ diabetes might have resolved by the time of the diagnosis [
5].
Growth is greatly affected in patients with FBS and that was obvious in our patients at presentation. Delayed presentation and management with some patients having repeated episodes of chest infections and gastroenteritis could contribute to this. Other factors include proximal tubular dysfunction and glucose hemostasis disturbances. It has been proposed that nocturnal enteral nutrition (NEN) might improve the growth failure seen in patients with FBS [
16]. We attempted corn starch feeding at night (at a dose of 1.6 g/kg) to our patients at diagnosis to prevent early morning hypoglycemia for which they showed good response [
17].
Glycosuria, as seen in most of our tested patients, is moderate to severe at the time of diagnosis, however mild glycosuria in a milder phenotype of this syndrome has been reported [
18]. The fasting blood glucose is found to be low in patients with FBS while they have a higher post prandial level. Interestingly, our patients showed a much lower values of fasting blood glucose and higher post prandial glucose levels compared to a previous study done to evaluate the blood glucose level in FBS patients. However, it may be that our patients were younger at presentation (0.9
\(\pm\)0.8 years) than the other study (7.3 ± 4.8 years) and this could be explained by improving glucose levels over time [
19]. Genetic diagnosis has decreased the need for a liver biopsy to confirm FBS diagnosis and such an invasive procedure can be avoided if genetic testing is available. Features on liver biopsy include deposition of glycogen in the hepatocytes, steatosis and fibrosis which were similar to our findings. Liver carcinoma is not known to be an association but a case of a liver carcinoma with FBS has been reported and the mechanism of this remains unknown [
20].
Management is largely supportive and focused on the treatment of rickets and acid-base disturbance. In many developing countries medications such as phosphate, vitamin D analogs, or even solutions to correct acid-base balance are difficult to access and thus should be secured even at the local level. Some patients showed good response after treatment, with improvement of acidosis and features of rickets, but long term follow up is needed for further evaluation of their growth and puberty. Most of our patients came from remote areas with very limited access to tertiary facilities therefore follow up is usually interrupted. Survival to adulthood is favorable with normal fertility documented in one case report [
21]. Early recognition and appropriate management may lead to a better prognosis while late diagnosis complicates the picture and increases the mortality usually because of respiratory infections or liver failure as seen in some reported cases including ours [
22,
23].
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