Fanconi-Bickel syndrome (FBS) is caused by biallelic pathogenic variants in the SLC2A2 gene, which encodes the glucose transporter protein 2 (GLUT2), leading to a rare disorder that affects glucose homeostasis. The exact mechanisms by which FBS leads to dysglycaemia are not clearly understood. The clinical manifestations are those related to dysglycaemia, proximal tubulopathy (glycosuria, galactosuria, aminoaciduria, proteinuria, phosphaturia), hepatomegaly, galactose intolerance, rickets and short stature.We report a teenage girl with persistent glycosuria and short stature. Laboratory findings revealed glycosuria, proteinuria, aminoaciduria, hypercalciuria and hypouricaemia indicating a proximal tubulopathy. Whole exome sequencing identified two variants, c.218C>G p.(Ser73*) and c.371+5G>A, likely in trans in the SLC2A2 gene, establishing the diagnosis of FBS. She was asymptomatic, and the treatment consisted of vitamin D supplementation and dietary changes.FBS may have a wide range of clinical manifestations and severity. Abnormal laboratory results indicating glucose metabolism issues are crucial diagnostic clues for mild forms of FBS. Indeed, the diagnosis of mild forms of FBS is challenging due to the lack of specific clinical and analytical features.

The kidneys play a critical role in maintaining glucose homeostasis. Under normal renal tubular function, most of the glucose filtered from the glomeruli is reabsorbed in the proximal tubules, leaving only trace amounts in the urine. Glycosuria can occur as a symptom of generalized proximal tubular dysfunction or when the reabsorption threshold is exceeded or the glucose threshold is reduced, as seen in familial renal glycosuria (FRG). FRG is characterized by persistent glycosuria despite normal blood glucose levels and tubular function and is primarily associated with mutations in the sodium/glucose cotransporter 5A2 gene, which encodes the sodium-glucose cotransporter (SGLT) 2. Inhibiting SGLTs has been proposed as a novel treatment strategy for diabetes, and since FRG is often considered an asymptomatic and benign condition, it has inspired preclinical and clinical studies using SGLT2 inhibitors in type 2 diabetes. However, patients with FRG may exhibit clinical features such as lower body weight or height, altered systemic blood pressure, diaper dermatitis, aminoaciduria, decreased serum uric acid levels, and hypercalciuria. Further research is needed to fully understand the pathophysiology, molecular genetics, and clinical manifestations of renal glucosuria.

This study aims to investigate the clinical, biochemical, and genetic characteristics of Fanconi-Bickel syndrome (FBS) in a cohort of 20 individuals from Palestine and to identify novel pathogenic variants. A retrospective analysis was conducted on medical records from Al-Makassed Hospital's pediatric department spanning 2015 to 2023. Individuals diagnosed with FBS via molecular genetic testing were included in the study. Among the 20 genetically confirmed FBS patients, hepatomegaly was prevalent in 95%, whereas 70% exhibited both developmental delay and hypophosphatemic rickets, and 68.4% experienced growth retardation. Hypertriglyceridemia (HTG) was universal. Elevated liver enzymes and alkaline phosphatase were common, along with hypophosphatemia (95%) and urinary abnormalities. Genetic analysis revealed five distinct SLC2A2 pathogenic variants, including three previously unreported variants: p.Gln23Arg (c.68A > G), p.Thr353Arg (c.1058_1059delinsGG), and an exon 7 deletion. This study presents the largest single-center cohort of FBS patients, expanding our understanding of the disorder's phenotypic and genotypic spectrum. Despite FBS generally carrying a favorable prognosis, timely diagnosis remains crucial to prevent severe complications.

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by a spectrum of clinical manifestations, the association of this syndrome with cytomegalovirus (CMV) infection makes this condition very rare. We reported a 3-month-old infant with cytomegalovirus infection with presenting hepatosplenomegaly, doll-like face, microcephaly, metabolic hyperchloremic acidosis with a normal anion gap, rachitis, hyperglycosuria, proteinuria, elevated levels of alanine aminotransferase and aspartate aminotransferase, and growth retardation. After the prescription of ganciclovir, the levels of bilirubin and alanine aminotransferase decreased to normal, and the splenomegaly regressed. However, hepatomegaly and hyperglycosuria remained aggravating. The co-occurrence of FBS and CMV infection in infants presents a complex clinical scenario, demonstrating significant challenges in diagnosis and management. Further research is needed to elucidate the interplay between genetic disorders like FBS and viral infections and facilitate the development of targeted therapeutic interventions and preventive strategies.

Increased urinary tetraglucoside (Glc4) excretions are associated with abnormal glycogen metabolism. While Glc4 is an established biomarker for glycogen storage disease (GSD) type II, a traditional muscle GSD, little data is available on excretions in liver GSD. A single-center retrospective analysis was conducted on urinary Glc4 samples obtained during routine clinical care of 99 individuals with liver GSD, including 9 patients with Glc4 samples taken as part of the diagnostic work-up (i.e., before treatment) and 5 patients with Glc4 samples after liver transplantation. Glc4 excretions were increased at time of diagnosis in 1/1 GSD IIIa, 3/3 GSD IXa, 1/2 GSD IXa female carrier, 0/1 GSD IXb and 2/2 Fanconi-Bickel syndrome patients. In 8/9 of these patients with samples in the diagnostic work-up, subsequent follow-up samples were available, displaying that Glc4 excretions decreased after initiation of GSD management in 8/8 patients, and in 6/8 patients Glc4 excretions were within the reference range on last follow-up. Analysis of Glc4 samples in the monitoring phase revealed that, despite management, Glc4 excretions were elevated in the majority of GSD Ia (17/27) and Ib (6/10), and all GSD IIIa (19/19), GSD IIIb (4/4), and IXc (1/1) patients. In contrast, increased Glc4 excretions were less frequently observed in GSD IV (1/6), GSD VI (1/2), IXa (4/19), IXa female carrier (0/1), IXb (0/2), and Fanconi-Bickel syndrome (2/4) patients during clinical follow-up. After liver transplantation in a GSD Ia and a GSD Ib patient, Glc4 excretions normalized. Urinary Glc4 may be a useful additional biomarker in liver GSD patients, both in the diagnostic work-up and in the monitoring phase. Future studies could additionally assess the role of Glc4 as response biomarker in drug development. Urinary Glc4 may be a useful additional biomarker in liver GSD patients, both in the diagnostic work-up and in the monitoring phase.