Fanconi-Bickel Syndrome

Mendelian MONDO:0009216 Pathograph 15 Show in embeddings browser Disorder of Glycogen Metabolism Inherited Renal Tubulopathy

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder of carbohydrate metabolism caused by biallelic loss-of-function variants in SLC2A2, which encodes the facilitative glucose transporter GLUT2. GLUT2 is expressed on the basolateral membrane of hepatocytes, the basolateral membrane of renal proximal tubular epithelial cells, pancreatic beta cells, and the basolateral membrane of intestinal enterocytes, where it mediates bidirectional, insulin-independent transport of glucose (and galactose) down their concentration gradient. Loss of GLUT2 function traps glucose intracellularly in hepatocytes and renal tubular cells, driving hepatorenal glycogen accumulation, a generalized (Fanconi-type) proximal renal tubulopathy, and impaired hepatic glucose release with fasting hypoglycemia with glucose and galactose intolerance. Clinically, FBS presents in infancy with hepatomegaly, failure to thrive, rickets/growth failure, and a characteristic "doll-like" facies, and carries a generally favorable long-term prognosis with dietary and supportive management.

Ask OpenScientist

Ask a research question about Fanconi-Bickel Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
4
Pathophys.
11
Phenotypes
15
Pathograph
1
Genes
3
Medical Actions
1
References
👪

Inheritance

1
Autosomal Recessive HP:0000007
Fanconi-Bickel syndrome is inherited in an autosomal recessive manner, requiring biallelic pathogenic variants in SLC2A2. Affected individuals are homozygous or compound heterozygous for loss-of-function variants; parents of affected individuals are typically unaffected heterozygous carriers, and consanguinity is common in reported families.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:9354798 SUPPORT Human Clinical
"Homozygous mutations were found in affected individuals, whereas all parents tested were heterozygous for the respective mutation."
The original gene-discovery study demonstrates the autosomal recessive segregation pattern of SLC2A2 mutations in Fanconi-Bickel syndrome families.
⚙

Pathophysiology

4
SLC2A2 (GLUT2) Loss-of-Function Variants
Biallelic pathogenic variants in SLC2A2, the gene encoding the facilitative glucose transporter GLUT2, predict truncated or non-functional translation products lacking monosaccharide transport activity. Reported variants include frameshift, nonsense, splice-site, and missense changes, as well as exonic deletions, distributed throughout the gene.
SLC2A2 hgnc:11006 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC2A2 (hgnc:11006). hgnc:11006 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of GLUT2 Transporter Function Truncating and other loss-of-function SLC2A2 variants abolish GLUT2 monosaccharide transport activity.
Show evidence (2 references)
PMID:9354798 SUPPORT Human Clinical
"Here we report mutations in the gene encoding the facilitative glucose transporter 2 (GLUT2) in three FBS families, including the original patient described in 1949 by Fanconi and Bickel."
The seminal gene-discovery study identifies SLC2A2/GLUT2 mutations as the molecular cause of Fanconi-Bickel syndrome, including in the original 1949 patient.
PMID:39548873 SUPPORT Human Clinical
"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."
A large Palestinian cohort study expands the SLC2A2 pathogenic variant spectrum, including novel missense variants and an exonic deletion.
Loss of GLUT2 Transporter Function
GLUT2 is a high-capacity, low-affinity facilitative glucose transporter normally expressed on the basolateral membrane of hepatocytes and renal proximal tubular epithelial cells, on pancreatic beta cells, and on the basolateral membrane of intestinal enterocytes, where it mediates bidirectional, insulin-independent glucose (and galactose) flux down the concentration gradient. Loss of GLUT2 activity uncouples intracellular glucose handling from these tissues' normal transport function, impairing both glucose uptake/release across the basolateral membrane and pancreatic beta-cell glucose sensing.
SLC2A2 hgnc:11006 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC2A2 (hgnc:11006). hgnc:11006 is a gene from the HUGO Gene Nomenclature Committee.
D-glucose transmembrane transport GO:1904659 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased D-glucose transmembrane transport (GO:1904659). GO:1904659 is a biological process from the Gene Ontology. ↓ DECREASED Glucose homeostasis GO:0042593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Glucose homeostasis (GO:0042593). GO:0042593 is a biological process from the Gene Ontology. ↓ DECREASED
D-glucose transmembrane transporter activity GO:0055056 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased D-glucose transmembrane transporter activity (GO:0055056). GO:0055056 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Hepatocyte Glucose Transport Loss of hepatocyte basolateral GLUT2 function traps glucose within hepatocytes, shifting it toward glycogen synthesis rather than release into the circulation.
Impaired Renal Proximal Tubular Glucose Transport Loss of basolateral GLUT2 in renal proximal tubular epithelial cells impairs glucose exit from the reabsorbing cell back into the bloodstream, causing intracellular glucose and glycogen accumulation and secondary generalized proximal tubular dysfunction.
Dysregulated Beta-Cell and Intestinal Glucose Handling Loss of GLUT2 in pancreatic beta cells and intestinal enterocytes impairs normal glucose sensing/insulin secretion coupling and transepithelial glucose absorption, contributing to glucose and galactose intolerance.
Show evidence (2 references)
PMID:9809815 SUPPORT Human Clinical
"Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder of carbohydrate metabolism recently demonstrated to be caused by mutations in Glut2, the gene for the glucose transporter protein 2 expressed in liver, pancreas, intestine and kidney."
Describes GLUT2 expression across the four tissues (liver, pancreas, intestine, kidney) whose dysfunction defines the disease.
PMID:38802119 SUPPORT Human Clinical
"Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen."
Directly links impaired basolateral GLUT2-mediated glucose transport to intracellular glucose/glycogen accumulation in renal proximal tubular cells.
Impaired Hepatocyte Glucose Transport
With hepatocyte GLUT2 nonfunctional, glucose entering via other routes (e.g., during feeding) cannot be efficiently released back into the circulation during fasting, and instead accumulates intracellularly where it drives excessive glycogen synthesis. This produces massive hepatic glycogen accumulation and hepatomegaly, with impaired hepatic glucose output during fasting.
Hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Glycogen biosynthetic process GO:0005978 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Glycogen biosynthetic process (GO:0005978). GO:0005978 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hepatic Glycogen Accumulation and Hepatomegaly Intracellular glucose trapping in hepatocytes drives excess glycogen synthesis, producing progressive hepatomegaly.
Fasting Hypoglycemia and Glucose/Galactose Intolerance Impaired hepatic glucose release during fasting and altered GLUT2-mediated handling of glucose and galactose produce fasting hypoglycemia with glucose and galactose intolerance.
Show evidence (1 reference)
PMID:9354798 SUPPORT Human Clinical
"Fanconi-Bickel syndrome (FBS) is a rare autosomal-recessive inborn error of metabolism characterized by hepatorenal glycogen accumulation, Fanconi nephropathy and impaired utilization of glucose and galactose."
Establishes hepatorenal glycogen accumulation as a defining biochemical feature linked to the GLUT2 transport defect.
Impaired Renal Proximal Tubular Glucose Transport
Failure of basolateral GLUT2-mediated glucose efflux in the proximal tubule causes intracellular glucose and glycogen accumulation in tubular epithelial cells, producing a generalized (Fanconi-type) proximal tubulopathy characterized by glucosuria, generalized aminoaciduria, phosphaturia, and bicarbonaturia, despite normal or low blood glucose.
Epithelial cell of proximal tubule CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
D-glucose transmembrane transport GO:1904659 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased D-glucose transmembrane transport (GO:1904659). GO:1904659 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Renal Fanconi Syndrome Intracellular glucose/glycogen accumulation and consequent tubular cell dysfunction produce the generalized proximal reabsorptive defect characteristic of renal Fanconi syndrome.
Rickets and Growth Failure Chronic renal phosphate and bicarbonate wasting from the proximal tubulopathy produces hypophosphatemic rickets and contributes to growth failure.
Show evidence (1 reference)
PMID:38802119 SUPPORT Human Clinical
"Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen."
Directly links the renal Fanconi-type tubulopathy to impaired basolateral GLUT2-mediated glucose transport.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Referential integrity issues (5):
  • Target 'Dysregulated Beta-Cell and Intestinal Glucose Handling' (from 'Loss of GLUT2 Transporter Function') not found in named elements
  • Target 'Hepatic Glycogen Accumulation and Hepatomegaly' (from 'Impaired Hepatocyte Glucose Transport') not found in named elements
  • Target 'Fasting Hypoglycemia and Glucose/Galactose Intolerance' (from 'Impaired Hepatocyte Glucose Transport') not found in named elements
  • Target 'Rickets and Growth Failure' (from 'Impaired Renal Proximal Tubular Glucose Transport') not found in named elements
  • Target 'Fasting Hypoglycemia and Glucose/Galactose Intolerance' (from 'Dietary Management (Frequent Feeding and Uncooked Cornstarch)') not found in named elements
Pathograph: causal mechanism network for Fanconi-Bickel Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

11
Digestive 1
Hepatomegaly VERY_FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39548873 SUPPORT Human Clinical
"Among the 20 genetically confirmed FBS patients, hepatomegaly was prevalent in 95%"
A large genetically confirmed cohort quantifies hepatomegaly frequency at 95%, mapping to VERY_FREQUENT.
Genitourinary 2
Renal Fanconi Syndrome VERY_FREQUENT HP:0001994 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal Fanconi syndrome (HP:0001994). HP:0001994 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9809815 SUPPORT Human Clinical
"a characteristic proximal tubular nephropathy"
Long-term natural history study identifies the characteristic proximal tubular (Fanconi-type) nephropathy as persisting into adulthood.
Glucosuria Glycosuria HP:0003076 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glycosuria (HP:0003076). HP:0003076 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38802119 SUPPORT Human Clinical
"Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen."
Impaired basolateral tubular glucose transport in FBS results in urinary glucose loss despite normal-to-low serum glucose, the classic diagnostic biochemical clue.
Metabolism 3
Fasting Hypoglycemia VERY_FREQUENT HP:0003162 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fasting hypoglycemia (HP:0003162). HP:0003162 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9809815 SUPPORT Human Clinical
"the typical clinical and laboratory findings of FBS (hepatomegaly secondary to glycogen accumulation, glucose and galactose intolerance, fasting hypoglycaemia, a characteristic proximal tubular nephropathy and severe short stature) persist into adulthood"
Long-term follow-up identifies fasting hypoglycemia as one of the typical, persistent clinical/laboratory findings of FBS.
Hypophosphatemia VERY_FREQUENT HP:0002148 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypophosphatemia (HP:0002148). HP:0002148 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39548873 SUPPORT Human Clinical
"hypophosphatemia (95%)"
A large genetically confirmed cohort quantifies hypophosphatemia frequency at 95%, mapping to VERY_FREQUENT.
Hypertriglyceridemia VERY_FREQUENT HP:0002155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertriglyceridemia (HP:0002155). HP:0002155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39548873 SUPPORT Human Clinical
"Hypertriglyceridemia (HTG) was universal."
A large genetically confirmed cohort reports hypertriglyceridemia as universal (100%), mapping to VERY_FREQUENT.
Musculoskeletal 1
Hypophosphatemic Rickets FREQUENT HP:0002748 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rickets (HP:0002748). HP:0002748 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39548873 SUPPORT Human Clinical
"70% exhibited both developmental delay and hypophosphatemic rickets"
A large genetically confirmed cohort quantifies hypophosphatemic rickets at 70%, mapping to FREQUENT.
Growth 1
Growth Failure / Short Stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:9809815 SUPPORT Human Clinical
"severe short stature) persist into adulthood"
Long-term follow-up of the original patient over more than 50 years documents severe short stature persisting into adulthood.
PMID:39548873 SUPPORT Human Clinical
"68.4% experienced growth retardation"
A large genetically confirmed cohort quantifies growth retardation at 68.4%, mapping to FREQUENT.
Other 3
Increased Hepatic Glycogen Content HP:0006568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased hepatic glycogen content (HP:0006568). HP:0006568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9354798 SUPPORT Human Clinical
"Fanconi-Bickel syndrome (FBS) is a rare autosomal-recessive inborn error of metabolism characterized by hepatorenal glycogen accumulation, Fanconi nephropathy and impaired utilization of glucose and galactose."
Defines hepatorenal glycogen accumulation as a core defining feature of the disorder.
Doll-like Facies HP:0000295 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Doll-like facies (HP:0000295). HP:0000295 is a phenotype from the Human Phenotype Ontology.
Classically described in clinical summaries of Fanconi-Bickel syndrome, but the cited abstract/full-text cache available in this PR did not contain an exact quotable phrase for doll-like facies; no evidence block is attached.
Galactose Intolerance HP:0004919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Galactose intolerance (HP:0004919). HP:0004919 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9809815 SUPPORT Human Clinical
"glucose and galactose intolerance"
Long-term natural history study documents glucose and galactose intolerance as a typical, persistent clinical/laboratory finding of FBS.
🧬

Genetic Associations

1
SLC2A2 (Causative)
Gene: SLC2A2 hgnc:11006 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC2A2 (hgnc:11006). hgnc:11006 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:9354798 SUPPORT Human Clinical
"Here we report mutations in the gene encoding the facilitative glucose transporter 2 (GLUT2) in three FBS families, including the original patient described in 1949 by Fanconi and Bickel."
The seminal gene-discovery study establishes SLC2A2/GLUT2 as the causative gene for Fanconi-Bickel syndrome.
PMID:39548873 SUPPORT Human Clinical
"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."
A large cohort study confirms and expands the SLC2A2 pathogenic variant spectrum causative for Fanconi-Bickel syndrome.
💊

Medical Actions

3
Dietary Management (Frequent Feeding and Uncooked Cornstarch)
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Frequent small meals and uncooked cornstarch supplementation provide a sustained-release glucose source to reduce the amplitude of fasting hypoglycemia and glucose/galactose intolerance characteristic of Fanconi-Bickel syndrome; galactose restriction is also used given the shared GLUT2-dependent transport defect.
Mechanism Target:
MODULATES Fasting Hypoglycemia and Glucose/Galactose Intolerance — Frequent feeding and sustained-release cornstarch reduce the amplitude of glycemic instability resulting from impaired GLUT2-mediated hepatic glucose buffering and glucose/galactose intolerance.
Show evidence (1 reference)
PMID:9809815 SUPPORT Human Clinical
"fasting hypoglycaemia"
Long-term natural history study documents persistent fasting hypoglycemia, the target abnormality that frequent feeding/cornstarch dietary management addresses.
Phosphate, Alkali, and Alfacalcidol Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: alfacalcidol CHEBI:31186 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses alfacalcidol (CHEBI:31186). CHEBI:31186 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral phosphate, alkali, and active vitamin D (alfacalcidol) replacement address the renal phosphate and bicarbonate wasting from the proximal tubulopathy and support treatment of hypophosphatemic rickets.
Mechanism Target:
MODULATES Impaired Renal Proximal Tubular Glucose Transport — Supplementation replaces phosphate and bicarbonate lost through the Fanconi-type proximal tubulopathy and supports bone mineralization.
Show evidence (1 reference)
PMID:38802119 SUPPORT Human Clinical
"supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children"
Documents standard supplementation regimen (phosphate, alkali, carnitine, alfacalcidol) used to manage the renal tubulopathy prior to empagliflozin repurposing.
Empagliflozin (SGLT2 Inhibitor, Off-Label)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: empagliflozin CHEBI:82720 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses empagliflozin (CHEBI:82720). CHEBI:82720 is a therapeutic agent from Chemical Entities of Biological Interest. SGLT2 Inhibitor NCIT:C98083 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses SGLT2 Inhibitor (NCIT:C98083). NCIT:C98083 is a therapeutic agent from the NCI Thesaurus.
Off-label repurposing of the SGLT2 inhibitor empagliflozin blocks apical glucose reabsorption in renal proximal tubular cells, reducing the intracellular glucose/glycogen burden created by the basolateral GLUT2 defect and improving biochemical markers of tubular integrity and function; in a case series, phosphate/alkali/carnitine/alfacalcidol supplementation could be discontinued in treated children.
Mechanism Target:
MODULATES Impaired Renal Proximal Tubular Glucose Transport — SGLT2 inhibition blocks apical glucose reabsorption in the proximal tubule, shifting the metabolic block and reducing the intracellular glucose/glycogen accumulation caused by the basolateral GLUT2 defect.
Show evidence (2 references)
PMID:38802119 SUPPORT Human Clinical
"SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi-Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood."
A case series of seven genetically confirmed FBS patients demonstrates that empagliflozin, by blocking apical tubular glucose reabsorption, specifically targets the underlying basolateral GLUT2 transport defect and improves biochemical markers of tubular function.
PMID:38802119 SUPPORT Human Clinical
"biochemical parameters of tubular cell integrity (urinary N-acetyl-glucosaminidase) and/or tubular functions (including urinary α1-microglobulin) improved in all persons with Fanconi-Bickel syndrome, albeit to varying degrees"
Demonstrates measurable improvement in tubular cell integrity and function biomarkers under empagliflozin treatment across all seven treated patients.
🔬

Biochemical Markers

2
Fasting Hypoglycemia with Glucose/Galactose Intolerance (Abnormal)
Context: Fasting hypoglycemia with glucose and galactose intolerance is a distinctive biochemical signature of Fanconi-Bickel syndrome, reflecting combined hepatic, pancreatic beta-cell, and intestinal GLUT2 dysfunction.
Pathograph Readouts
Readout Of Impaired Hepatocyte Glucose Transport Negative Diagnostic
Fasting hypoglycemia reports the failure of hepatic glucose release caused by loss of hepatocyte GLUT2 function.
Show evidence (1 reference)
PMID:9809815 SUPPORT Human Clinical
"fasting hypoglycaemia"
Long-term natural history study documents fasting hypoglycemia as a persistent laboratory finding directly tied to the hepatic transport defect.
Show evidence (1 reference)
PMID:9809815 SUPPORT Human Clinical
"glucose and galactose intolerance, fasting hypoglycaemia"
Long-term follow-up study documents glucose/galactose intolerance and fasting hypoglycemia as core, persistent biochemical features of Fanconi-Bickel syndrome.
Glucosuria with Normal-to-Low Blood Glucose (Abnormal)
Context: Urinary glucose loss occurring despite normal or low blood glucose concentration is the classic diagnostic biochemical clue distinguishing the renal tubular glucose-transport defect from ordinary diabetic glucosuria.
Pathograph Readouts
Readout Of Impaired Renal Proximal Tubular Glucose Transport Positive Diagnostic
Urinary glucose loss despite normal-to-low serum glucose reports failure of basolateral GLUT2-mediated tubular glucose reabsorption.
Show evidence (1 reference)
PMID:38802119 SUPPORT Human Clinical
"Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen."
Directly links the renal glucosuria of FBS to impaired basolateral tubular GLUT2 transport rather than a filtered-load excess.
Show evidence (1 reference)
PMID:9354798 SUPPORT Human Clinical
"hepatorenal glycogen accumulation, Fanconi nephropathy and impaired utilization of glucose and galactose"
Founding gene-discovery paper documents the Fanconi nephropathy and impaired glucose/galactose utilization underlying the diagnostic glucosuria.
🔬

Diagnosis

1
Molecular Genetic Testing of SLC2A2
Diagnosis is suggested by the characteristic clinical triad of hepatomegaly, growth failure/rickets, and a generalized (Fanconi-type) proximal renal tubulopathy in the setting of fasting hypoglycemia, glucose and galactose intolerance, glucosuria despite normal-to-low blood glucose, and hypertriglyceridemia, and is confirmed by molecular genetic testing identifying biallelic pathogenic SLC2A2 variants.
Show evidence (1 reference)
PMID:39548873 SUPPORT Human Clinical
"Individuals diagnosed with FBS via molecular genetic testing were included in the study."
Confirms molecular genetic testing of SLC2A2 as the diagnostic standard used to confirm FBS cases in a large clinical cohort.
📊

Prevalence

2
Worldwide
Cases In Literature Ultra Rare
Approximately 150 cases from over 100 families have been reported worldwide; an early literature review summarized 82 cases from 70 families.
Show evidence (1 reference)
PMID:9809815 SUPPORT Human Clinical
"give an overview of the 82 cases from 70 families in the published literature and from personal communications"
The 1998 literature review documents 82 published/personally-communicated cases from 70 families, an early quantification of the ultra-rare global case burden.
Palestinian population (Al-Makassed Hospital cohort)
Cases In Literature Not yet documented
A single-center Palestinian cohort of 20 genetically confirmed cases is the largest reported single-center series, suggesting possible local enrichment or ascertainment bias from a consanguineous population; formal regional prevalence has not been established.
Show evidence (1 reference)
PMID:39548873 SUPPORT Human Clinical
"This study presents the largest single-center cohort of FBS patients, expanding our understanding of the disorder's phenotypic and genotypic spectrum."
Documents the largest single-center FBS cohort (20 patients) reported to date, from a Palestinian population.
{ }

Source YAML

click to show 
name: Fanconi-Bickel Syndrome
creation_date: "2026-07-06T00:00:00Z"
category: Mendelian
synonyms:
- Bickel-Fanconi Glycogenosis
- GSD due to GLUT2 Deficiency
- Glycogen Storage Disease due to GLUT2 Deficiency
- Glycogen Storage Disease Type XI
- Hepatorenal Glycogenosis with Renal Fanconi Syndrome
description: >-
  Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder of
  carbohydrate metabolism caused by biallelic loss-of-function variants in
  SLC2A2, which encodes the facilitative glucose transporter GLUT2. GLUT2 is
  expressed on the basolateral membrane of hepatocytes, the basolateral
  membrane of renal proximal tubular epithelial cells, pancreatic beta cells,
  and the basolateral membrane of intestinal enterocytes, where it mediates
  bidirectional, insulin-independent transport of glucose (and galactose)
  down their concentration gradient. Loss of GLUT2 function traps glucose
  intracellularly in hepatocytes and renal tubular cells, driving hepatorenal
  glycogen accumulation, a generalized (Fanconi-type) proximal renal
  tubulopathy, and impaired hepatic glucose release with fasting hypoglycemia
  with glucose and galactose intolerance.
  Clinically, FBS presents in infancy with hepatomegaly, failure to thrive,
  rickets/growth failure, and a characteristic "doll-like" facies, and carries
  a generally favorable long-term prognosis with dietary and supportive
  management.
disease_term:
  preferred_term: glycogen storage disease due to GLUT2 deficiency
  term:
    id: MONDO:0009216
    label: glycogen storage disease due to GLUT2 deficiency
references:
- reference: PMID:9809815
  title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
  findings: []
parents:
- Disorder of Glycogen Metabolism
- Inherited Renal Tubulopathy
inheritance:
- name: Autosomal Recessive
  description: >-
    Fanconi-Bickel syndrome is inherited in an autosomal recessive manner,
    requiring biallelic pathogenic variants in SLC2A2. Affected individuals
    are homozygous or compound heterozygous for loss-of-function variants;
    parents of affected individuals are typically unaffected heterozygous
    carriers, and consanguinity is common in reported families.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:9354798
    reference_title: "Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous mutations were found in affected individuals, whereas all parents tested were heterozygous for the respective mutation."
    explanation: The original gene-discovery study demonstrates the autosomal recessive segregation pattern of SLC2A2 mutations in Fanconi-Bickel syndrome families.
pathophysiology:
- name: SLC2A2 (GLUT2) Loss-of-Function Variants
  description: >-
    Biallelic pathogenic variants in SLC2A2, the gene encoding the
    facilitative glucose transporter GLUT2, predict truncated or
    non-functional translation products lacking monosaccharide transport
    activity. Reported variants include frameshift, nonsense, splice-site,
    and missense changes, as well as exonic deletions, distributed
    throughout the gene.
  gene:
    preferred_term: SLC2A2
    term:
      id: hgnc:11006
      label: SLC2A2
  evidence:
  - reference: PMID:9354798
    reference_title: "Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report mutations in the gene encoding the facilitative glucose transporter 2 (GLUT2) in three FBS families, including the original patient described in 1949 by Fanconi and Bickel."
    explanation: The seminal gene-discovery study identifies SLC2A2/GLUT2 mutations as the molecular cause of Fanconi-Bickel syndrome, including in the original 1949 patient.
  - reference: PMID:39548873
    reference_title: "Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: A large Palestinian cohort study expands the SLC2A2 pathogenic variant spectrum, including novel missense variants and an exonic deletion.
  downstream:
  - target: Loss of GLUT2 Transporter Function
    causal_link_type: DIRECT
    description: >-
      Truncating and other loss-of-function SLC2A2 variants abolish GLUT2
      monosaccharide transport activity.
    evidence:
    - reference: PMID:9354798
      reference_title: "Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Because all detected mutations (delta T446-449, C1251T and C1405T) predict truncated translation products that cannot be expected to have functional monosaccharide transport activity, GLUT2 mutations are probably the cause of FBS."
      explanation: The gene-discovery study directly links the identified truncating mutations to loss of functional GLUT2 monosaccharide transport activity.
- name: Loss of GLUT2 Transporter Function
  description: >-
    GLUT2 is a high-capacity, low-affinity facilitative glucose transporter
    normally expressed on the basolateral membrane of hepatocytes and renal
    proximal tubular epithelial cells, on pancreatic beta cells, and on the
    basolateral membrane of intestinal enterocytes, where it mediates
    bidirectional, insulin-independent glucose (and galactose) flux down
    the concentration gradient. Loss of GLUT2 activity uncouples
    intracellular glucose handling from these tissues' normal transport
    function, impairing both glucose uptake/release across the basolateral
    membrane and pancreatic beta-cell glucose sensing.
  gene:
    preferred_term: SLC2A2
    term:
      id: hgnc:11006
      label: SLC2A2
  molecular_functions:
  - preferred_term: D-glucose transmembrane transporter activity
    term:
      id: GO:0055056
      label: D-glucose transmembrane transporter activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: D-glucose transmembrane transport
    term:
      id: GO:1904659
      label: D-glucose transmembrane transport
    modifier: DECREASED
  - preferred_term: Glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:9809815
    reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder of carbohydrate metabolism recently demonstrated to be caused by mutations in Glut2, the gene for the glucose transporter protein 2 expressed in liver, pancreas, intestine and kidney."
    explanation: Describes GLUT2 expression across the four tissues (liver, pancreas, intestine, kidney) whose dysfunction defines the disease.
  - reference: PMID:38802119
    reference_title: "Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen."
    explanation: Directly links impaired basolateral GLUT2-mediated glucose transport to intracellular glucose/glycogen accumulation in renal proximal tubular cells.
  downstream:
  - target: Impaired Hepatocyte Glucose Transport
    causal_link_type: DIRECT
    description: >-
      Loss of hepatocyte basolateral GLUT2 function traps glucose within
      hepatocytes, shifting it toward glycogen synthesis rather than release
      into the circulation.
    evidence:
    - reference: PMID:9809815
      reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hepatomegaly secondary to glycogen accumulation, glucose and galactose intolerance, fasting hypoglycaemia, a characteristic proximal tubular nephropathy and severe short stature"
      explanation: Long-term natural history study links hepatomegaly and glycogen accumulation to the underlying glucose transport defect.
  - target: Impaired Renal Proximal Tubular Glucose Transport
    causal_link_type: DIRECT
    description: >-
      Loss of basolateral GLUT2 in renal proximal tubular epithelial cells
      impairs glucose exit from the reabsorbing cell back into the
      bloodstream, causing intracellular glucose and glycogen accumulation
      and secondary generalized proximal tubular dysfunction.
    evidence:
    - reference: PMID:38802119
      reference_title: "Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen."
      explanation: Directly attributes the renal Fanconi-type tubulopathy to impaired basolateral GLUT2 transport and consequent intracellular glucose/glycogen accumulation.
  - target: Dysregulated Beta-Cell and Intestinal Glucose Handling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of GLUT2 in pancreatic beta cells and intestinal enterocytes
      impairs normal glucose sensing/insulin secretion coupling and
      transepithelial glucose absorption, contributing to glucose and
      galactose intolerance.
    evidence:
    - reference: PMID:9354798
      reference_title: "Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "impaired utilization of glucose and galactose"
      explanation: The gene-discovery paper documents impaired glucose and galactose utilization consistent with disrupted GLUT2-dependent handling in beta cells and intestine.
- name: Impaired Hepatocyte Glucose Transport
  description: >-
    With hepatocyte GLUT2 nonfunctional, glucose entering via other routes
    (e.g., during feeding) cannot be efficiently released back into the
    circulation during fasting, and instead accumulates intracellularly
    where it drives excessive glycogen synthesis. This produces massive
    hepatic glycogen accumulation and hepatomegaly, with impaired hepatic
    glucose output during fasting.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: Glycogen biosynthetic process
    term:
      id: GO:0005978
      label: glycogen biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:9354798
    reference_title: "Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fanconi-Bickel syndrome (FBS) is a rare autosomal-recessive inborn error of metabolism characterized by hepatorenal glycogen accumulation, Fanconi nephropathy and impaired utilization of glucose and galactose."
    explanation: Establishes hepatorenal glycogen accumulation as a defining biochemical feature linked to the GLUT2 transport defect.
  downstream:
  - target: Hepatic Glycogen Accumulation and Hepatomegaly
    causal_link_type: DIRECT
    description: >-
      Intracellular glucose trapping in hepatocytes drives excess glycogen
      synthesis, producing progressive hepatomegaly.
    evidence:
    - reference: PMID:9809815
      reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hepatomegaly secondary to glycogen accumulation"
      explanation: Long-term follow-up of the original patient links hepatomegaly directly to glycogen accumulation from the underlying transport defect.
  - target: Fasting Hypoglycemia and Glucose/Galactose Intolerance
    causal_link_type: DIRECT
    description: >-
      Impaired hepatic glucose release during fasting and altered
      GLUT2-mediated handling of glucose and galactose produce fasting
      hypoglycemia with glucose and galactose intolerance.
    evidence:
    - reference: PMID:9809815
      reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "glucose and galactose intolerance, fasting hypoglycaemia"
      explanation: Long-term natural history study documents glucose/galactose intolerance and fasting hypoglycemia as persistent clinical/laboratory findings in Fanconi-Bickel syndrome.
- name: Impaired Renal Proximal Tubular Glucose Transport
  conforms_to: "defective_skeletal_mineralization#Phosphopenic Substrate Deficiency"
  description: >-
    Failure of basolateral GLUT2-mediated glucose efflux in the proximal
    tubule causes intracellular glucose and glycogen accumulation in tubular
    epithelial cells, producing a generalized (Fanconi-type) proximal
    tubulopathy characterized by glucosuria, generalized aminoaciduria,
    phosphaturia, and bicarbonaturia, despite normal or low blood glucose.
  cell_types:
  - preferred_term: Epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  biological_processes:
  - preferred_term: D-glucose transmembrane transport
    term:
      id: GO:1904659
      label: D-glucose transmembrane transport
    modifier: DECREASED
  evidence:
  - reference: PMID:38802119
    reference_title: "Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen."
    explanation: Directly links the renal Fanconi-type tubulopathy to impaired basolateral GLUT2-mediated glucose transport.
  downstream:
  - target: Renal Fanconi Syndrome
    causal_link_type: DIRECT
    description: >-
      Intracellular glucose/glycogen accumulation and consequent tubular
      cell dysfunction produce the generalized proximal reabsorptive defect
      characteristic of renal Fanconi syndrome.
    evidence:
    - reference: PMID:9809815
      reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a characteristic proximal tubular nephropathy"
      explanation: Long-term natural history study identifies the characteristic proximal tubular nephropathy persisting into adulthood.
  - target: Rickets and Growth Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Chronic renal phosphate and bicarbonate wasting from the proximal
      tubulopathy produces hypophosphatemic rickets and contributes to
      growth failure.
    evidence:
    - reference: PMID:39548873
      reference_title: "Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "70% exhibited both developmental delay and hypophosphatemic rickets, and 68.4% experienced growth retardation."
      explanation: A large cohort study documents hypophosphatemic rickets and growth retardation as frequent consequences of the renal tubulopathy.
phenotypes:
- name: Hepatomegaly
  description: >-
    Enlargement of the liver secondary to massive hepatic glycogen
    accumulation; typically present from infancy and persisting into
    adulthood.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39548873
    reference_title: "Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the 20 genetically confirmed FBS patients, hepatomegaly was prevalent in 95%"
    explanation: A large genetically confirmed cohort quantifies hepatomegaly frequency at 95%, mapping to VERY_FREQUENT.
- name: Increased Hepatic Glycogen Content
  description: >-
    Hepatorenal glycogen accumulation is the hallmark histopathologic and
    biochemical feature of Fanconi-Bickel syndrome, resulting from trapped
    intracellular glucose being diverted into glycogen synthesis.
  phenotype_term:
    preferred_term: Increased hepatic glycogen content
    term:
      id: HP:0006568
      label: Increased hepatic glycogen content
  evidence:
  - reference: PMID:9354798
    reference_title: "Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fanconi-Bickel syndrome (FBS) is a rare autosomal-recessive inborn error of metabolism characterized by hepatorenal glycogen accumulation, Fanconi nephropathy and impaired utilization of glucose and galactose."
    explanation: Defines hepatorenal glycogen accumulation as a core defining feature of the disorder.
- name: Fasting Hypoglycemia
  description: >-
    Low blood glucose during fasting periods, reflecting impaired hepatic
    glucose release due to loss of GLUT2-mediated hepatocyte glucose efflux.
  phenotype_term:
    preferred_term: Fasting hypoglycemia
    term:
      id: HP:0003162
      label: Fasting hypoglycemia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:9809815
    reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the typical clinical and laboratory findings of FBS (hepatomegaly secondary to glycogen accumulation, glucose and galactose intolerance, fasting hypoglycaemia, a characteristic proximal tubular nephropathy and severe short stature) persist into adulthood"
    explanation: Long-term follow-up identifies fasting hypoglycemia as one of the typical, persistent clinical/laboratory findings of FBS.
- name: Renal Fanconi Syndrome
  description: >-
    Generalized proximal renal tubular dysfunction with glucosuria,
    generalized aminoaciduria, phosphaturia, and bicarbonaturia, caused by
    impaired basolateral renal tubular GLUT2 function.
  phenotype_term:
    preferred_term: Renal Fanconi syndrome
    term:
      id: HP:0001994
      label: Renal Fanconi syndrome
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:9809815
    reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a characteristic proximal tubular nephropathy"
    explanation: Long-term natural history study identifies the characteristic proximal tubular (Fanconi-type) nephropathy as persisting into adulthood.
- name: Glucosuria
  description: >-
    Urinary glucose loss despite normal or low blood glucose, the classic
    diagnostic clue reflecting failure of renal tubular glucose reabsorption
    secondary to loss of basolateral GLUT2 function.
  phenotype_term:
    preferred_term: Glycosuria
    term:
      id: HP:0003076
      label: Glycosuria
  evidence:
  - reference: PMID:38802119
    reference_title: "Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen."
    explanation: Impaired basolateral tubular glucose transport in FBS results in urinary glucose loss despite normal-to-low serum glucose, the classic diagnostic biochemical clue.
- name: Hypophosphatemia
  description: >-
    Low serum phosphate resulting from renal phosphate wasting due to the
    proximal tubulopathy; a near-universal biochemical finding contributing
    to rickets.
  phenotype_term:
    preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39548873
    reference_title: "Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypophosphatemia (95%)"
    explanation: A large genetically confirmed cohort quantifies hypophosphatemia frequency at 95%, mapping to VERY_FREQUENT.
- name: Hypophosphatemic Rickets
  description: >-
    Rickets resulting from chronic renal phosphate wasting secondary to the
    proximal tubulopathy, presenting with growth failure and skeletal
    deformity.
  phenotype_term:
    preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  frequency: FREQUENT
  evidence:
  - reference: PMID:39548873
    reference_title: "Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "70% exhibited both developmental delay and hypophosphatemic rickets"
    explanation: A large genetically confirmed cohort quantifies hypophosphatemic rickets at 70%, mapping to FREQUENT.
- name: Growth Failure / Short Stature
  description: >-
    Severe growth retardation and short stature resulting from the combined
    effects of chronic metabolic derangement, renal phosphate/bicarbonate
    wasting, and rickets; persists into adulthood in the original 1949
    index patient.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: FREQUENT
  evidence:
  - reference: PMID:9809815
    reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe short stature) persist into adulthood"
    explanation: Long-term follow-up of the original patient over more than 50 years documents severe short stature persisting into adulthood.
  - reference: PMID:39548873
    reference_title: "Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "68.4% experienced growth retardation"
    explanation: A large genetically confirmed cohort quantifies growth retardation at 68.4%, mapping to FREQUENT.
- name: Doll-like Facies
  description: >-
    Characteristic rounded, chubby-cheeked facial appearance (attributed to
    fat deposition in the cheeks contrasted with a protuberant abdomen from
    hepatomegaly) classically described in Fanconi-Bickel syndrome.
  phenotype_term:
    preferred_term: Doll-like facies
    term:
      id: HP:0000295
      label: Doll-like facies
  notes: >-
    Classically described in clinical summaries of Fanconi-Bickel syndrome, but
    the cited abstract/full-text cache available in this PR did not contain an
    exact quotable phrase for doll-like facies; no evidence block is attached.
- name: Hypertriglyceridemia
  description: >-
    Elevated serum triglycerides, a near-universal biochemical abnormality
    in Fanconi-Bickel syndrome cohorts, reflecting the broader metabolic
    derangement of impaired glucose homeostasis.
  phenotype_term:
    preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39548873
    reference_title: "Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertriglyceridemia (HTG) was universal."
    explanation: A large genetically confirmed cohort reports hypertriglyceridemia as universal (100%), mapping to VERY_FREQUENT.
- name: Galactose Intolerance
  description: >-
    Impaired ability to metabolize dietary galactose, reflecting the shared
    GLUT2-dependent transport pathway for glucose and galactose.
  phenotype_term:
    preferred_term: Galactose intolerance
    term:
      id: HP:0004919
      label: Galactose intolerance
  evidence:
  - reference: PMID:9809815
    reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "glucose and galactose intolerance"
    explanation: Long-term natural history study documents glucose and galactose intolerance as a typical, persistent clinical/laboratory finding of FBS.
genetic:
- name: SLC2A2
  gene_term:
    preferred_term: SLC2A2
    term:
      id: hgnc:11006
      label: SLC2A2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:9354798
    reference_title: "Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report mutations in the gene encoding the facilitative glucose transporter 2 (GLUT2) in three FBS families, including the original patient described in 1949 by Fanconi and Bickel."
    explanation: The seminal gene-discovery study establishes SLC2A2/GLUT2 as the causative gene for Fanconi-Bickel syndrome.
  - reference: PMID:39548873
    reference_title: "Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: A large cohort study confirms and expands the SLC2A2 pathogenic variant spectrum causative for Fanconi-Bickel syndrome.
biochemical:
- name: Fasting Hypoglycemia with Glucose/Galactose Intolerance
  presence: Abnormal
  context: >-
    Fasting hypoglycemia with glucose and galactose intolerance is a distinctive
    biochemical signature of Fanconi-Bickel syndrome, reflecting combined
    hepatic, pancreatic beta-cell, and intestinal GLUT2 dysfunction.
  biomarker_term:
    preferred_term: D-glucose
    term:
      id: CHEBI:17634
      label: D-glucose
  readouts:
  - target: Impaired Hepatocyte Glucose Transport
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Fasting hypoglycemia reports the failure of hepatic glucose release
      caused by loss of hepatocyte GLUT2 function.
    evidence:
    - reference: PMID:9809815
      reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "fasting hypoglycaemia"
      explanation: Long-term natural history study documents fasting hypoglycemia as a persistent laboratory finding directly tied to the hepatic transport defect.
  evidence:
  - reference: PMID:9809815
    reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "glucose and galactose intolerance, fasting hypoglycaemia"
    explanation: Long-term follow-up study documents glucose/galactose intolerance and fasting hypoglycemia as core, persistent biochemical features of Fanconi-Bickel syndrome.
- name: Glucosuria with Normal-to-Low Blood Glucose
  presence: Abnormal
  context: >-
    Urinary glucose loss occurring despite normal or low blood glucose
    concentration is the classic diagnostic biochemical clue distinguishing
    the renal tubular glucose-transport defect from ordinary diabetic
    glucosuria.
  biomarker_term:
    preferred_term: D-glucose
    term:
      id: CHEBI:17634
      label: D-glucose
  readouts:
  - target: Impaired Renal Proximal Tubular Glucose Transport
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Urinary glucose loss despite normal-to-low serum glucose reports
      failure of basolateral GLUT2-mediated tubular glucose reabsorption.
    evidence:
    - reference: PMID:38802119
      reference_title: "Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen."
      explanation: Directly links the renal glucosuria of FBS to impaired basolateral tubular GLUT2 transport rather than a filtered-load excess.
  evidence:
  - reference: PMID:9354798
    reference_title: "Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hepatorenal glycogen accumulation, Fanconi nephropathy and impaired utilization of glucose and galactose"
    explanation: Founding gene-discovery paper documents the Fanconi nephropathy and impaired glucose/galactose utilization underlying the diagnostic glucosuria.
diagnosis:
- name: Molecular Genetic Testing of SLC2A2
  description: >-
    Diagnosis is suggested by the characteristic clinical triad of
    hepatomegaly, growth failure/rickets, and a generalized (Fanconi-type)
    proximal renal tubulopathy in the setting of fasting hypoglycemia,
    glucose and galactose intolerance, glucosuria despite normal-to-low blood
    glucose, and hypertriglyceridemia, and is confirmed by molecular genetic
    testing identifying biallelic pathogenic SLC2A2 variants.
  evidence:
  - reference: PMID:39548873
    reference_title: "Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals diagnosed with FBS via molecular genetic testing were included in the study."
    explanation: Confirms molecular genetic testing of SLC2A2 as the diagnostic standard used to confirm FBS cases in a large clinical cohort.
treatments:
- name: Dietary Management (Frequent Feeding and Uncooked Cornstarch)
  description: >-
    Frequent small meals and uncooked cornstarch supplementation provide a
    sustained-release glucose source to reduce the amplitude of fasting
    hypoglycemia and glucose/galactose intolerance characteristic of
    Fanconi-Bickel syndrome; galactose restriction is also used given the
    shared GLUT2-dependent transport defect.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Fasting Hypoglycemia and Glucose/Galactose Intolerance
    treatment_effect: MODULATES
    description: >-
      Frequent feeding and sustained-release cornstarch reduce the
      amplitude of glycemic instability resulting from impaired GLUT2-mediated
      hepatic glucose buffering and glucose/galactose intolerance.
  evidence:
  - reference: PMID:9809815
    reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fasting hypoglycaemia"
    explanation: Long-term natural history study documents persistent fasting hypoglycemia, the target abnormality that frequent feeding/cornstarch dietary management addresses.
- name: Phosphate, Alkali, and Alfacalcidol Supplementation
  description: >-
    Oral phosphate, alkali, and active vitamin D (alfacalcidol) replacement
    address the renal phosphate and bicarbonate wasting from the proximal
    tubulopathy and support treatment of hypophosphatemic rickets.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: alfacalcidol
      term:
        id: CHEBI:31186
        label: alfacalcidol
  target_mechanisms:
  - target: Impaired Renal Proximal Tubular Glucose Transport
    treatment_effect: MODULATES
    description: >-
      Supplementation replaces phosphate and bicarbonate lost through the
      Fanconi-type proximal tubulopathy and supports bone mineralization.
  evidence:
  - reference: PMID:38802119
    reference_title: "Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children"
    explanation: Documents standard supplementation regimen (phosphate, alkali, carnitine, alfacalcidol) used to manage the renal tubulopathy prior to empagliflozin repurposing.
- name: Empagliflozin (SGLT2 Inhibitor, Off-Label)
  description: >-
    Off-label repurposing of the SGLT2 inhibitor empagliflozin blocks apical
    glucose reabsorption in renal proximal tubular cells, reducing the
    intracellular glucose/glycogen burden created by the basolateral GLUT2
    defect and improving biochemical markers of tubular integrity and
    function; in a case series, phosphate/alkali/carnitine/alfacalcidol
    supplementation could be discontinued in treated children.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: empagliflozin
      term:
        id: CHEBI:82720
        label: empagliflozin
    - preferred_term: SGLT2 Inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
  target_mechanisms:
  - target: Impaired Renal Proximal Tubular Glucose Transport
    treatment_effect: MODULATES
    description: >-
      SGLT2 inhibition blocks apical glucose reabsorption in the proximal
      tubule, shifting the metabolic block and reducing the intracellular
      glucose/glycogen accumulation caused by the basolateral GLUT2 defect.
  evidence:
  - reference: PMID:38802119
    reference_title: "Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi-Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood."
    explanation: A case series of seven genetically confirmed FBS patients demonstrates that empagliflozin, by blocking apical tubular glucose reabsorption, specifically targets the underlying basolateral GLUT2 transport defect and improves biochemical markers of tubular function.
  - reference: PMID:38802119
    reference_title: "Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biochemical parameters of tubular cell integrity (urinary N-acetyl-glucosaminidase) and/or tubular functions (including urinary α1-microglobulin) improved in all persons with Fanconi-Bickel syndrome, albeit to varying degrees"
    explanation: Demonstrates measurable improvement in tubular cell integrity and function biomarkers under empagliflozin treatment across all seven treated patients.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Approximately 150 cases from over 100 families have been reported
    worldwide; an early literature review summarized 82 cases from 70
    families.
  evidence:
  - reference: PMID:9809815
    reference_title: "Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "give an overview of the 82 cases from 70 families in the published literature and from personal communications"
    explanation: The 1998 literature review documents 82 published/personally-communicated cases from 70 families, an early quantification of the ultra-rare global case burden.
- population: Palestinian population (Al-Makassed Hospital cohort)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    A single-center Palestinian cohort of 20 genetically confirmed cases is
    the largest reported single-center series, suggesting possible local
    enrichment or ascertainment bias from a consanguineous population;
    formal regional prevalence has not been established.
  evidence:
  - reference: PMID:39548873
    reference_title: "Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study presents the largest single-center cohort of FBS patients, expanding our understanding of the disorder's phenotypic and genotypic spectrum."
    explanation: Documents the largest single-center FBS cohort (20 patients) reported to date, from a Palestinian population.
datasets: []
📚

References & Deep Research

References

1
PMID:9809815
Fanconi-Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature.
No top-level findings curated for this source.