Fanconi syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vahid Eidkhani, M.D.

Fanconi syndrome is a disorder in which the proximal tubular function of the kidney is impaired, resulting in decreased reabsorption of electrolytes and nutrients back into the bloodstream. Compounds involved include glucose, amino acids, uric acid, phosphate, and bicarbonate.

The reduced reabsorption of bicarbonate results in type 2 or proximal renal tubular acidosis, which may in some cases exist on its own, or more usually in combination with the Fanconi syndrome.

In many cases, the disease is developed in the context of multi-system genetic diseases(e.g Cystinosis, Galactosemia). And in many others, high exposure to toxic substances(e.g heavy metals, drugs) is discovered as the main risk factor. The disease can also develop as a consequence of other acquired diseases(e.g multiple myeloma, PNH)^[1].

Patients mainly present with dehydration, growth failure, rickets(children) and osteomalacia(adults)^[2][3].

It is named after Guido Fanconi, a Swiss pediatrician; this may be a misnomer since Fanconi himself never identified it as a syndrome^[2].

It should not be confused with Fanconi anemia, a separate disease^[4].

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vahid Eidkhani, M.D.

Fanconi syndrome is nominated after the name of professor Guido Fanconi, who first explained the detailed characteristics of the disease in 1931^[1]. He investigated and proposed the possible links between dwarfing and hypophosphataemic rickets to renal glycosuria in children suffering from the disease^[2][1]. 

• Simultaneous rickets and albuminuria due to kidney disease were first described in 1881 referred ‘disorder of adolescence’, but the precise mechanism remained unknown^[3].

• Fanconi syndrome was first explained as a renal proximal tubule defect with details by Guido Fanconi, a Swiss pediatrician, in 1931^[1].
• Besides Dr. Fanconi, the clinical characteristics of the disease were further studied by Debre and De Toni, that’s why the disease is also called Debre-De Toni-Fanconi syndrome^[4][5].
• In 1949 Professor Fanconi and his assistant Dr. Horst Bickel described a rare type of Glycogen storage disease characterized by GLUT2 glucose transporter mutations which leads to liver, pancreas and kidney failure. The disease was further named Fanconi-Bickel syndrome, Although the renal involvement of this syndrome is mostly the renal Fanconi syndrome, these two syndromes are separate diseases^[6].
• Later on, the syndrome clinical characteristics were studied by many other scientists. As the Fanconi syndrome can result from many genetic disorders with various etiologies, drugs and substances effect on the kidneys, and also is one of the characteristics included in many complicated syndromes, the details of pathophysiology and genetic perspective of the disease is becoming more evident gradually from 40s decade^[7]. 
• Even now in 2017, there are novel mutations and genetic loci discussed leading to the disease^[8].

• • in 1950s, Mianstay treatment approach to the disease(replacement therapy) was first discussed and is still remains as the main therapeutic approach^[9].
  • Specific therapies modifying the underlying diseases continued to be introduced with the progression of disease comprehension. 

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vahid Eidkhani, M.D.

• Proximal convoluted tubule (PCT) of nephrons is responsible for most of the reabsorption capacity of the kidneys. Filtered Glucose, amino acids, proteins, albumin, Bicarbonate, sodium, chloride, phosphate, and uric acid are the main ingredients reabsorbed back to the plasma in the PCTs. And importantly PCT is the exclusive site for the absorption of glucose,amino acids, and proteins^[1].
• The absorption process through PCTs mostly involves sodium (Na+) gradient-dependent and megalin-/cubilin-mediated endocytic pathways transport systems^[2]. The electrochemical gradient of Na+ required for the transportations is produced by the function of the basolateral 3Na+-2K+-ATPase pump. Besides, the pump net function also leads to a negative intracellular potential. This renal sodium regulation is one of the major energy consuming processes in the kidneys and probably accounts for high overall renal energy demand which is more than ~10% of total body expenditure while kidneys consist only about 1% of body weight.
• The powerful electrochemical gradient of Na+ is then utilized for multiple transportation processes as they are synced with the flow of extracellular Na+ to inside the PCT cells.
• Glucose absorption is coupled to Na+ by SGLT1 and SGLT2 proteins.
• amino acids absorption is mainly mediated by members of the solute carrier families(SLC)^[3].
• Phosphate is absorbed by the NaPi2a, NaPi2c channels^[4].
• Bicarbonate absorption consists of a more complicated process; apical Na+-H+ exchanger drives H+ ions out of the cell in exchange for Na+ entrance. The extracellular hydrogen ions combine with filtered bicarbonate ions to form carbonic acid which is then converted into water and carbon dioxide by carbonic anhydrase IV^[5]. Co₂ diffuses into the proximal tubular cells via aquaporin 1, where is hydroxylated to form bicarbonate by the act of intracellular carbonic anhydrase II. Intracellular HCO3 is co-transported with Na+ at the basolateral -membrane via NBCe1 co-transporter^[6].
• Low molecular weight proteins and albumin are essentially absorbed by the Cubilin-Megalin protein complex function^[7].
• Vitamin D which is mostly attached to a carrier protein in blood is also filtered with its carrier through nephrons and reabsorbed by megalin function in PCT^[8]. 

As Fanconi syndrome affects most of the PCT’s normal function, the underlying causes mainly deteriorate the Na+ and/or megalin-/cubilin-mediated pathways or interfere with the normal vitality of PCT cells leading to inappropriately high amounts of mentioned electrolytes and metabolites excretions. According to the various mechanisms involved in each of the initial causes, here we categorize the most important causes of the disease and provide a brief review of their effect mechanisms as well.

• Cystinosis: A lysosomal storage disease due to lysosomal cystine transporter cystinosin mutation. It functions as a proton/cystine cotransporter and is driven by the high proton content within the lysosomal lumen. It is characterized by the accumulation of cystine in all organs, mainly kidney, bone marrow, cornea, thyroid, liver, lymph nodes and spleen^[9], the underlying mechanism linking cysteine accumulation in the cells and Fanconi syndrome incidence is not fully understood, however, evidence of ATP depletion, cell atrophy and reduced expression of multi-ligand megalin and cubilin receptor and NaPi2a channel are reported^[10].
• Tyrosinemia: A disease of tyrosine aminoacid metabolism caused by a mutation in the fumarylacetoacetate hydrolase (FAH) gene which codes for the last enzyme in the tyrosine catabolic chain; this enzyme catabolizes the conversion of fumarylacetoacetate (FAA) into fumarate and acetoacetate. FAH is mostly expressed in the liver and kidneys, where during its malfunction, maleylacetoacetate (MAA) and FAA and their derivative succinylacetone accumulate and lead to liver damage and renal Fanconi syndrome^[11].
• Galactosemia: A disease of the galactose metabolism caused by defective galactose-1-phosphate uridyltransferase. Patients commonly present with severe symptoms including jaundice, lethargy, liver disease cataracts, sepsis, and Fanconi syndrome in their neonatal period after the first intake of galactose^[12].
• Wilson: An inborn error of copper (Cu) metabolism. Wilson disease is caused by a mutation in the gene ATP7B that encodes a mitochondrial P-type Cu-transporting ATPase beta polypeptide enzyme^[13]. Failure the normal excretion of Cu in the biliary system and also presenting defects in the Cu-ceruloplasmin conjugation leads to multi-organ failure. The most highlighted clinical view includes liver failure and neuro-degeneration. Excessive Cu accumulation in the kidneys leads to proximal renal tubular dysfunction and Fanconi syndrome^[14].
• Lowe syndrome: Oculo Cerebro Renal Syndrome of Lowe (OCRL) is an X-linked recessive multisystem disorder resulting from loss-of-function mutations in OCRL which encodes for the phosphatidylinositol 4,5-bisphosphate 5-phosphatase enzyme^[15]. The most affected organs are kidneys, brain, and eyes^[16]. It is suggested that OCRL enzyme plays a role in intracellular trafficking, sorting, and recycling of apical membrane multi-ligand receptors megalin–cubilin^[17].
• Dent disease: A disease caused by inactivating mutations in the CLCN5 gene, which encodes for a kidney exclusive chloride channel co-expressed with vacuolar H+-ATPase^[18]. Abnormal cellular endocytosis secondary to CLCN5 malfunction disturbs normal recycling of megalin and cubilin to the luminal membrane leading to reduced luminal expression of these receptors^[19]. Dent 2 disease is renal exclusive phenotype that is believed to be a result of OCRL gene similar to Lowe syndrome and these 2 diseases are considered as 2 ends of one phenotypic spectrum^[20].
• Mitochondriopathies: The high energy demand for PCT duties,(mostly to maintain Na+ gradient) signifies mitochondria’s fundamental role in maintaining functional PCT cells. Mitochondriopathies are also multi-systemic diseases which can be the result of various mutation and molecular defects. Fanconi syndrome secondary to mitochondriopathies commonly present with complete dysfunctional PCTs and all of them present in early childhood except the A3243G mutation of the tRNA gene which is the only known mitochondrial mutation that leads to adult-onset Fanconi syndrome^[21][22].

Exogenous

• Aminoglycoside^[23] antibiotics are Cationic particles that can electrostatically attach to anionic phospholipids membrane and cause swelling with phospholipid material and impair generation of ATP which results in reduced cell energy formation, destroyed normal cellular trafficking and disrupted apical membrane function^[24].
• Valproic acid^[25] therapy has been reported to cause an increase in kidney reactive oxygen species (ROS) concentration and induce lipid peroxidation. This drug leads to depletion of Renal glutathione (GSH) reservoirs and tissue antioxidant capacity reduction in the treated animals^[26]; Besides, it is suggested that valproic acid might directly harm the mitochondria function in PCTs^[27].
• Chinese herbs^[28] containing aristolochic acids specifically induce proximal tubular renal damage with Tubular proteinuria and decreased megalin expression.Na-K-ATPase activity is probably affected^[29].
•  Reverse transcriptase inhibitors^[30] Including adefovir and cidofovir which are used as anti-human immunodeficiency virus (HIV) therapies enter into PCT cells by activated organic anion transporters(OAT) in the basolateral membrane and notably their efflux to the tubular lumen continues in a slower pace, hence their gradual accumulation in the proximal tubule cells leads to tubular toxicity and mitochondrial damage^[31].
• Ifosfamide^[32] leads to decreased total carnitine, intra-mitochondrial CoA-SH, ATP and ATP/ADP ratio, and most prominently reduced glutathione (GSH) in kidney tissues. It is suggested that preservation of the glutathione synthetase peroxidase or antioxidase system can partially protect against ifosfamide-induced Fanconi syndrome in rats^[33].
• Cisplatin^[34] inhibits peroxisome proliferator-activated receptor-alpha (PPAR-α) in PCT cells which leads to impaired fatty acid oxidation and also down-regulates the gene transcription of glucose and amino acids transporters^[35].

• Sjögren syndrome leads to chronic interstitial nephritis, with diffuse or focal plasmacytoid lymphocytic infiltration that damages PCT cells^[36].
• Multiple myeloma causes gammaglobulin light chains slowly accumulate in the PCT epithelial cells, forming crystals resistant to proteolysis by several enzymes such as cathepsin, damaging the PCT cells^[37].
• Paroxysmal nocturnal hemoglobinuria (PNH) results in iron and hemosiderin deposits accumulation occur mainly in proximal tubules leading to extensive tubular damage and interstitial nephritis^[38].  

• The following table depicts different underlying genetic disorders which can lead to Fanconi syndrome during their course. Corresponding genes and proteins are also showed.

AR: Autosomal recessive/AD: Autosomal dominant /Sources: Wilmer MJ, Schoeber JP, van den Heuvel LP, Levtchenko EN (2011). “Cystinosis: practical tools for diagnosis and treatment.”. Pediatr Nephrol. 26 (2): 205–15. PMC 3016220 Freely accessible. PMID 20734088. doi:10.1007/s00467-010-1627-6./ Enriko Klootwijk, Stephanie Dufek, Naomi Issler, Detlef Bockenhauer & Robert Kleta (2016)Pathophysiology, current treatments and future targets in hereditary forms of renal Fanconi syndrome,Expert Opinion on Orphan Drugs, 5:1, 45-54, DOI: 10.1080/21678707.2017.1259560

Commonly associated conditions found in almost all Fanconi syndrome patients regardless of the underlying cause include^[39][40]:

• Bone deformities & Osteomalacia
• Systemic acidosis
• Electrolyte disturbances

• On gross pathology, osteomalacic bones, and musculoskeletal  features of rickets are characteristic findings of Fanconi syndrome^[39][40].

• Due to the molecular and cellular nature of the Fanconi syndrome, usually, there are no evident common characteristics found in routine microscopic investigations of the patients’ kidneys. And specific characteristics are found (usually via electron microscopy) only based on the underlying cause of the disease (but not Fanconi syndrome itself), for example, cysteine, light chain crystals and abnormal mitochondria in PCT cells plasma found in cystinosis, multiple myeloma and mitochondriopathies respectively^[10][37].  

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vahid Eidkhani, M.D.

Fanconi syndrome could be the result or complication of various causes affecting the normal function of Proximal convoluted tubule (PCT); in a simple and useful classification method, the causes could be classified as^[1][2]:

• Genetic causes
  • Accumulation of a toxic substance (e.g. Cystinosis, Tyrosinemia, Lysinuric Protein Intolerance, Glycogen Storage Diseases, Galactosemia, Wilson, Fructose Intolerance)
  • Energy provision failure (e.g. Mitochondriopathies)
  • Disruption of endocytosis and intracellular transport mechanisms (e.g. ARC syndrome, Lowe syndrome and Dent disease).
• Exogenous causes (e.g. Heavy metals exposure, Drugs, Chemotherapy)
• Acquired causes (e.g. Multiple myeloma, Amyloidosis, Paroxysmal nocturnal hemoglobinuria)

• Accumulation of a toxic substance
  • Cystinosis
    • The most common inherited cause of Fanconi syndrome in children
  • Tyrosinemia
  • Lysinuric Protein Intolerance
  • Glycogen Storage Disease type I
  • Galactosemia
  • Wilson
  • Fructose intolerance
  • Fanconi-Bickel syndrome
• Energy provision failure
  • Mitochondriopathies
• Disruption of endocytosis and intracellular transport
  • Lowe syndrome
  • NaPi-IIa gene mutation
  • EHHADH gene mutations
  • Dent disease

• Drugs
  • Antiviral & Anti-retroviral drugs
    • Adefovir
    • Tenofovir
    • Didanosine
    • Cidofovir
    • Lamivudine
    • Stavudine

• • Antibacterial Drugs
    • Tetracyclines
    • Aminoglycosides

• • Anticonvulsants
    • Valproic acid

• Heavy metals
  • Lead
  • Cadmium
  • Mercury
  • Copper
• Chemotherapy

• • Alkylating & Platinating Agents
    • Cisplatin
    • Streptozocin
    • Carboplatin
    • Ifosfamide
    • Oxaplatin

• • Mercaptopurine

• Nephrotic syndrome
• Multiple myeloma
• Amyloidosis
• Paroxysmal nocturnal hemoglobinuria(PNH)
• Sjögren syndrome
• Renal transplantation
• Acute tubulointerstitial nephritis with uveitis (TINU) syndrome
• Autoimmune interstitial nephritis and membranous nephropathy
• Anorexia nervosa
• Untreated condition of distal renal tubular acidosis

Less common causes of Fanconi syndrome mostly found on case reports include:

• Other drugs such as: Fumaric Acid, Ranitidine, Salicylate, Methyl-3-Chromone in high doses and for long periods
• Chronic Alcohol abuse
• Crude Chinese herbal drugs (sometimes called Boui-ougi-tou)
• L-Lysine
• Glue Sniffing
• Autosomal dominant Fanconi syndrome with macrosomia and young-onset diabetes mellitus
• Arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome
• Idiopathic Fanconi syndrome

List the causes of the disease in alphabetical order.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vahid Eidkhani, M.D.

Fanconi syndrome is characterized by freely losses of water, HCO3-, Na+ and K+, all classes of amino acids, uric acid, LMW nutrients, and glucose in line with evidence of proximal renal tubular acidosis(P-RTA). It has been mentioned that one or two of the above substances can have normal renal excretion and the disease still be called (however incomplete) Fanconi syndrome.

The differential diagnosis(DDx) of the syndrome is mainly done on the basis of clinical and laboratory findings. Hence the disease must be differentiated with all of the other conditions which partly present its characteristics and clinical findings (and so cannot be called Fanconi syndrome yet) or just have some limited features in common. The most important DDxs are:

• Glomerular defects
• Diuretic use
• Nephrotic syndrome
• Gitelman syndrome
• Bartter’s syndrome
• Proximal RTA
• Distal RTA
• RTA Type IV

The table below describe the characteristics of these DDx in more details:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vahid Eidkhani, M.D.

• Fanconi syndrome is a rare condition with potential various etiologies, many of which are still being studied and has not gone further of case reports, the approximation of the disease incidence/prevalence is not available at the present time due to the low incidence/prevalence of these underlying diseases.

• Inherited forms of the Fanconi syndrome, mostly found in the context of genetic disorders with many other clinical presentations are generally first diagnosed in early infancy (Lowe syndrome, Cystinosis, Tyrosinemia, Hereditary Fructose Intolerance) or childhood (Glycogen storage diseases, Wilson disease, Galactosemia). Except for rare instances like the A3243G mutation of the mitochondrial tRNA gene which is a genetic and adult-onset form of the disease^[1][2].
• Fanconi syndrome due to Acquired and Exogenous causes can be seen in any age group depending on the underlying cause and exposure to toxic substances.

• No race preference is indicated for Fanconi syndrome overall. An exception is when cystinosis is the etiology and is almost exclusively seen in Caucasians although there are case reports of Black race affected infants^[3].

• Among Genetic causes of Fanconi syndrome, “Lowe syndrome“, and “Dent I & II” diseases have X-linked inheritance so the clinical signs and symptoms are mostly seen in boys. Other etiologies engage both genders equally^[1].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vahid Eidkhani, M.D.

The symptomatic onset of Fanconi syndrome could occur at any age depending on the underlying etiology. Fanconi syndrome due to exogenous compounds toxicity usually develops gradually and during long-term exposures and probably occur most commonly in adults age group. Inherited forms of the disease mainly become symptomatic in childhood. Cystinosis is the most common genetic disease accompanying Fanconi syndrome and in almost 95% of cases develops clinical symptoms in the first year of life^[1][2].

• The symptomatic onset of Fanconi syndrome could occur at any age depending on the underlying etiology.
• Inherited forms of the disease, prominently cystinosis,Tyrosinemia, and Wilson disease are mainly presented in infancy and childhood.
• Fanconi syndrome due to exogenous compounds(e.g drugs, heavy metals) toxicity usually develops gradually and during long-term exposures and probably occur most commonly in adults age group.

• Common complications of Fanconi syndrome include^[3][4]:
  • Osteomalacia, Rickets, and musculoskeletal deformities.
  • Growth failure & short stature
  • Weakness, walking problems, and immobility

• Prognosis essentially varies according to the underlying cause, its severity, time of diagnosis and treatment start and follow-up of the patient.
• Overall, renal disease per se in patients of Fanconi syndrome with adequate and precise management is interpreted “might be controllable” from the literature^[5][1][3].
• In patients with tyrosinemia, earlier presentation of the symptoms correlates with poorer survival rate^[6].
• In Cystinosis, treatment with cysteamine vastly improves the overall prognosis of the patients and should start as soon as possible^[1].

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