History

A thorough history is required to determine if Fanconi syndrome is inherited. The majority of medical disorders associated with Fanconi syndrome are inherited in an autosomal recessive pattern. Hence with two heterozygous parents, the child of either gender has a ¼ chance of being homozygous for the disorder. Patients who develop Fanconi syndrome may present with the following history:

• Extreme thirst and frequent urination are often the most common complaints. The patient will claim that he/she is thirsty all the time, which is primarily due to loss of solutes in the urine.
• Even though there is excess amount of urine produced with dehydration, the patient will have hypokalemia. This indicates that the ability of the proximal tubules to concentrate the urine is now defective.
• The resulting hypokalemia may lead to constipation, muscle weakness and arrhythmias.
• Infants who have Fanconi syndrome will usually also develop a fever with the dehydration and polyuria.
• The excess urinary loss of phosphate, calcium and a defect in the renal conversion of 25-hydroxyvitamin D3 into 1, 25-dihydroxyvitamin D3 can result in rickets in children.
• Almost all children and infants with Fanconi syndrome develop growth failure or failure to thrive. This is primarily due to the numerous metabolic derangements that occur in Fanconi syndrome. Besides defective vitamin D metabolism there are also alterations in pH.
• Mild to moderate degree of proteinuria may be seen in patients who develop a variation of nephrotic syndrome. The proteins that appear in urine may be albumin or of tubular origin. In some cases, small enzymes, immunoglobulin fragments and peptide hormones may also appear in urine.
• The renal dysfunction also leads to impairment in phosphate reabsorption. The phosphate excretion is often seen in the initial phase of the disease and then plateaus once a steady state has been reached.
• When damage occurs to the proximal tubules, systemic acidosis occurs, and consequently urine pH is high because of the high amount of bicarbonate.

Physical

The physical findings depend on the type of Fanconi syndrome. For example some patients may have presence of cysteine crystals in the cornea which is pathognomonic for cystinosis. Other nonspecific findings include presence of hepatomegaly, which can be found in glycogenesis, galactosemia, and tyrosinemia.

• In children with inherited forms of Fanconi syndrome, failure to thrive is the most obvious feature. These children tend to have a short stature, are hypotonic and frail. Examination of the extremities will reveal features of severe rickets open link like leg bowing, frontal bossing, rosaries and widening of the ankles, wrists and, knees. The children are often hyper-reflexic because of hypocalcemia.
• Slit lamp exam may reveal presence of needle-shaped refractile bodies in the cornea, which are pathognomonic of cystinosis. These crystals are always found in children older than 2 years but may be observed during the first year of life.

• Fatigue

  We report a unique case of Sjögren's syndrome complicated with Fanconi syndrome and Hashimoto's thyroiditis in a 53-year-old Chinese woman, initially found to have proteinuria, fatigue and multiple old costal fractures. [ncbi.nlm.nih.gov]

  Clinical features include poor growth, fatigue, dehydration, polyuria, muscle weakness, and bone pain. Features on a basic blood panel include hypokalemia, hypophosphatemia and metabolic acidosis. [radiopaedia.org]

  She was fatigued and confused after the event and complained of pain in her wrist. On review of systems, she endorsed polyuria and polydipsia. Relevant medications included valproic acid, started 6 months ago, for her epilepsy. [step1.medbullets.com]

• Easy Bruising

  They may exhibit symptoms such as: Unexplained fatigue Recurrent colds or viral infections Recurrent nosebleeds Easy bruising Blood in the stool or urine Shortness of breath Poor growth / short stature In rare cases, symptoms do not occur until early [cincinnatichildrens.org]

  Early signs and symptoms may include the following: Extreme fatigue Shortness of breath Pale skin Feeling dizzy Headaches Chest pain Frequent infections Easy bruising Nosebleeds About 60 percent of children with Fanconi anemia are born with at least one [stjude.org]

  Seek immediate medical attention if any of these rare but serious side effects occur: extreme tiredness, slow/fast/irregular heartbeat, easy bruising/bleeding, new fever, bloody/dark urine, severe stomach/abdominal pain, yellowing eyes/skin, sudden vision [barnardandfifth.com]

  In addition, affected individuals may develop bleeding (hemorrhages) within skin (dermal) layers or layers below the mucous membranes (submucosal), resulting in easy bruising (ecchymoses) and/or the appearance of pinpoint-sized, purplish or reddish spots [rarediseases.org]

• Failure to Thrive

  Recurrent episodes of dehydration, rickets, and failure to thrive are the most common. Prognosis varies. Some patients develop renal failure in late childhood or early adulthood. [emedicine.medscape.com]

  At a Glance The clinical findings of (renal) Fanconi syndrome are that of polyuria, polydipsia, failure to thrive and risk of dehydration in infancy and/or early child hood. [clinicaladvisor.com]

  Main clinical findings are polyuria, failure to thrive, rickets/osteomalacia, metabolic acidosis, bone deformities, and, occasionally, nephrocalcinosis. [ncbi.nlm.nih.gov]

  Impaired growth and failure to thrive. Differential diagnosis Other causes of polyuria and polydipsia - eg, diabetes mellitus, diabetes insipidus. Other causes of rickets and osteomalacia. Other causes of failure to thrive and short stature. [patient.info]

  When Fanconi syndrome occurs because of cystinosis, failure to thrive and growth retardation are common. The retinas show patchy depigmentation. [msdmanuals.com]

• Hypertension

  Author information 1 Division of Hypertension and Nephrology, National Kyushu Medical Center, Fukuoka, Japan. [email protected] Abstract A 60-year-old woman was admitted because of multiple bone pain. [ncbi.nlm.nih.gov]

  Authors+Show Affiliations Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [unboundmedicine.com]

  […] a patient history, ask about symptoms that pertain specifically to the pathology of the renal and urologic systems, such as frequency or urgency, and about the presence of any systemic diseases that can produce renal or urologic dysfunction, such as hypertension [checkorphan.org]

  Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected] Abstract Proximal renal tubular acidosis (RTA) is caused by a defect in bicarbonate [koreamed.org]

• Corneal Opacity

  Fig. 1 Corneal opacities in cystinosis. Tinsel-like refractile opacities in the cornea of a patient with cystinosis under slit-lamp examination. [pediatric.theclinics.com]

• Hearing Impairment

  Although other clinical variations such as liver dysfunction have been associated with HNF4A mutations, hearing impairment has not previously been associated. [ncbi.nlm.nih.gov]

  impairment, Obesity, Visual impairment Biology Miss Press (2012-01-05) - ISBN-13: 978-620-0-24573-1 29.00 € Impingement Syndrome Syndrome, Rotator cuff, Acromion, Arthrogram, Medical ultrasonography Biology Crypt Publishing (2012-03-08) - ISBN-13: 978 [morebooks.de]

  impairment Deafness Hearing defect [ more ] 0000365 Infantile onset Onset in first year of life Onset in infancy [ more ] 0003593 Leukocytosis Elevated white blood count High white blood count Increased blood leukocyte number [ more ] 0001974 Recurrent [rarediseases.info.nih.gov]

  Case presentation We report the case of an 18-year-old Romanian man with short stature, external ophthalmoplegia, palpebral ptosis, myopathy, sensorineural hearing impairment, cerebellar ataxia, cardiac conduction defect, diabetes mellitus, hypoparathyroidism [jmedicalcasereports.biomedcentral.com]

  In pedigrees with associated sensorineural deafness, heterozygous female subjects have been found with gout and hearing impairment [ 22 ]. [doi.org]

• Polyuria

  Furthermore, she had polyuria, with a mean urine output of 6.1 L/day. Despite ICU admission on the 11 th day, she died after 12 days of hospitalization. [scielo.br]

  We discuss in this article the atypical electrolytes losses found in our patient, as well as the possible mechanisms of severe polyuria. [ncbi.nlm.nih.gov]

  The presenting symptoms are polyuria, polydipsia, and dehydration. [accessanesthesiology.mhmedical.com]

  Clinical features include poor growth, fatigue, dehydration, polyuria, muscle weakness, and bone pain. Features on a basic blood panel include hypokalemia, hypophosphatemia and metabolic acidosis. [radiopaedia.org]

  Dehydration due to polyuria: prevent by ensuring adequate fluid intake; episodes of dehydration require either oral or intravenous fluid replacement. [patient.info]

• Renal Injury

  Renal injury from valproic acid: case report and literature review. Pediatr Neurol. 18. Laube G, Haq M, Hoff W. Exfoliated human proximal tubular cells: a model of cystinosis and Fanconi syndrome. Pediatr Nephrol. 2005;20:136. 19. [uspharmacist.com]

  Urinary beta 2-microglobulin as a possible sensitive marker for renal injury caused by tenofovir disoproxil fumarate. AIDS Res Hum Retroviruses. 2006;22(8):744-8. http://dx.doi.org/10.1089/aid.2006.22.744 Hall AM. [portalnepas.org.br]

  The renal prognosis seems favorable after corticosteroid therapy, even in case of severe renal injury. Nonetheless mild tubular defects may persist after treatment or spontaneous remission. [bmcnephrol.biomedcentral.com]

  The presence of FS and NDI in this particular patient suggests the probability of multiple sites of renal injury including proximal tubule and collecting duct, indicating that probably, it is not mediated by hOAT1 only, since hOAT1 is not found in collecting [jpgmonline.com]

• Uremia

  Charles Thomas, Springfield, IL1973: 1418 Friis T Hahnemann S Weeke E Serum calcium and serum phosphorus in uremia during administration of sodium phytate and aluminum hydroxide. [ajkd.org]

  What is uremia? Retention versus oxidation. Blood Purif 24 : 33–38, 2006. Crossref PubMed ISI Google Scholar 56 Wang Y, Holmes E, Nicholson JK, Cloarec O, Chollet J, Tanner M, Singer BH, Utzinger J. [doi.org]

The test for diagnosis of Fanconi syndrome depends on what cause is suspected [9]. For the inherited disorder, genetic testing is done. For the acquire Fanconi syndrome, the following studies are needed:

• Urine and blood levels of drugs and heavy metals
• Urine exam for glucose, amino acids, bicarbonate and phosphate
• If cystinosis is suspected, the content of cysteine in white blood cells or fibroblasts should be obtained
• If an inborn error of metabolism is suspected, levels of enzymes should be measured.

Imaging

• In general images are not important in evaluating patients with Fanconi syndrome. However, sometimes a child may present with rickets and then X-rays may be obtained to determine the extent of the bone defect.
• A renal biopsy is not performed in Fanconi syndrome because there is no specific feature that is characteristic of Fanconi syndrome. During microscopy exam, distortion of the proximal tubules may be observed but this is not a specific feature of the disorder.

• Glycosuria

  Defects in proximal tubular function can be isolated (e.g. isolated renal glycosuria, aminoacidurias, or hypophosphataemic rickets) or generalized. [oxfordmedicine.com]

  Analysis of the urine reveals a low specific gravity (despite evidence of dehydration), amino aciduria (seen as a "positive" dip stick for protein), glycosuria and, if measured, phosphaturia. [clinicaladvisor.com]

  The new studies about the tubular defect for aminoaciduria, phosphaturia and glycosuria are reported and discussed. For the de Toni-Debré-Fanconi syndrome primary and on genetic basis, the name "de Toni-Debré-Fanconi disease" is appropriate. [ncbi.nlm.nih.gov]

  Clinical presentation is with variable chronic kidney disease, low molecular weight proteinuria, aminoaciduria, hyperphosphaturia, uricosuria, bicarbonaturia, and non-diabetic glycosuria. [orpha.net]

  Creatinine clearance, microalbuminuria, tubular reabsorption of phosphate and glycosuria [revistanefrologia.com]

• Hyperchloremia

  Failure to thrive Acidosis Low blood potassium (hypokalemia) High blood chloride (hyperchloremia) Symptoms of the generalized proximal renal tubule dysfunction seen in Fanconi syndrome include the following: Low blood phosphate (hypophosphatemia) Increased [news-medical.net]

  […] bone metabolism in adults.[3] Presentation[edit] The clinical features of proximal renal tubular acidosis are: Polyuria, polydipsia and dehydration Hypophosphatemic rickets (in children) and osteomalacia (in adults) Growth failure Acidosis Hypokalemia Hyperchloremia [en.wikipedia.org]

  Clinical features of Fanconi Syndrome Developmental delay Slow growth Polyuria Polydipsia Dehydration Osteomalacia in adults Hypophosphatemic rickets in children Acidosis Growth failure Hyperchloremia Hypokalemia Glycosuria Aminoaciduria Hyperuricosuria [lecturio.com]

• Alkaline Phosphatase Increased

  phosphatase Greatly elevated alkaline phosphatase High serum alkaline phosphatase Increased alkaline phosphatase Increased serum alkaline phosphatase [ more ] 0003155 Failure to thrive Faltering weight Weight faltering [ more ] 0001508 Generalized aminoaciduria [rarediseases.info.nih.gov]

The treatment of Fanconi syndrome irrespective of the cause involves the following [10]:

• Reverse the dehydration with fluids. In mild cases, oral hydration may help but in severe cases, IV hydration may be required until the patient is stabilized.
• Replace electrolytes.
• Correct the metabolic acidosis by administering sodium bicarbonate. The dose of sodium bicarbonate varies from 5-10 mg/kg and is usually administered in divided doses over many days/weeks. Reversing acidosis alone is not sufficient to correct the bone breakdown and hence patients must also receive vitamin D supplements and phosphate. Supplements of phosphate should be started at a low dose (1 g/day) and increased very slowly over several weeks to prevent gastrointestinal symptoms of nausea, bloating and constipation.
• To avoid excess volume intake or pulmonary edema, some elderly patients may require low doses of hydrochlorothiazide. However, since this diuretic can also worsen the hypokalemia, the dose needs to be carefully titrated. Most patients will also need supplements of potassium citrate or potassium bicarbonate.
• When vitamin D is administered, it should be the 1, 25 dihydroxyvitamin D3 formula because patients with Fanconi syndrome have defective synthesis in the liver and or kidney.
• Even though some patients with Fanconi syndrome have losses of amino acids, proteins, uric acid and glucose, these substances do not require supplementation. The goal is to reduce their loss in the kidneys. Carnitine supplementation has been advocated but the evidence for its benefits seem to be lacking.

Surgical care

• In patients with Wilson disease who have end stage liver disease, liver transplantation may be an option if a donor is available. The liver transplantation has been shown to reverse the renal dysfunction of Fanconi syndrome.
• In patients with cystinosis and end stage renal disease, kidney transplants have been performed. While cysteine continues to accumulate in the interstitial cells of the transplanted kidney, it does not occur in the proximal tubules. Hence, the symptoms of Fanconi syndrome do not occur.
• If cystinosis is suspected, the patient should be referred to an ophthalmologist for a slit lamp exam. These patients may have needle shaped refractile bodies in the cornea. In patients with Wilson disease the slit lamp exam may reveal presence of kayser Fleischer rings. Similarly patients with Lowe syndrome and galactosemia also need to be seen by the ophthalmologist because a variety of ocular features may be present.

Diet

Fanconi syndrome is also caused by accumulation of nutrients like phenylalanine, fructose, galactose and fructose because of deficiency in certain biochemical enzymes. Thus, elimination of these substances from the diet may help reverse the renal manifestation of Fanconi syndrome. Thus a dietary consult is necessary and patients should be educated about what foods they can and cannot eat. Unfortunately these disorders have other systemic manifestations like growth retardation, developmental delay, ovarian dysfunction, speech impairment or liver cirrhosis, which are not affected by restricting the diet of these substances. Individuals with Wilson disease may benefit from treatment with D-penicillamine and a low copper diet.

Medications

Over the years, several drugs have been developed that can lower levels of cysteine in the laboratory but unfortunately most have not been found to be effective clinically. The one agent that is used clinically is cysteamine bitartrate. It has been shown to lower tissue levels of cysteine, improve linear growth and delay progression of kidney disease when started early in children. However, most studies show that it does not affect progression of Fanconi syndrome.

Patients with Wilson disease are often treated with D penicillamine, which helps remove excess level of copper from the body. High doses of the drug are required for it to function well but unfortunately it does not work in all patients with Wilson disease. Patients who are not able to tolerate D-penicillamine may be treated with Trientine, but clinical experience with this agent is limited.

The prognosis of Fanconi syndrome depends on the cause and clinical presentation. The majority of patients who have inherited Fanconi syndrome have a guarded or poor prognosis [8].These individuals often have involvement of multiple organ systems. Those who have acquired disorder have a much improved prognosis as the primary condition can be reversed and the symptoms will improve.

• Patients with Fanconi syndrome who develop renal failure tend to have a poor prognosis as they remain dialysis dependent. Those patients who undergo liver or renal transplant do fare better in the short term but then have to deal with adverse reactions of chemotherapeutic drugs that are used to prevent rejection.
• Patients with cystinosis often develop end stage renal disease, hypothyroidism, visual impairment, generalized myopathy and progressive neurological deficits. While treatment with cysteamine may help a few patients, the majority continue to have progression of symptoms.
• Despite omission of galactose from the diet, the symptoms of galactosemia progress with significant development delay, ovarian dysfunction and speech impairment.
• Patients with tyrosinemia usually develop end stage liver disease and development of hepatomas. Liver transplantation can help a few patients, but the surgery is complex and post complications are significant. The cost of chemotherapy can also be prohibitive for some patients.
• Wilson disease is generally progressive in nature with most patients developing neuropsychiatric features, hemolytic crises and end stage liver disease. Liver transplant is an option for some patients but only when done early.
  Patients with Lowe syndrome may present with systemic features of glaucoma, congenital cataracts, renal failure, mental retardation and failure to thrive.

Fanconi syndrome may be inherited or be acquired. In rare cases, the disorder may be idiopathic. In these patients despite exhaustive work up no identifiable cause is ever identified. In addition, individuals with idiopathic fanconi syndrome do not always present with all the features of the disorder, thus making the diagnosis difficult.

• Inborn errors of metabolism known to cause Fanconi syndrome include cystinosis, tyrosinemia and galactosemia. They all have an autosomal recessive genetic trait [4].
• Disorders of glycogen storage are also known to cause Fanconi syndrome. The most common disorder includes Fanconi-Bickel syndrome, which is characterized by impairment in utilization of galactose use and deposition of glycogen in the proximal tubule cells.
• Systemic disorders associated with dysproteinemias like amyloidosis, multiple myeloma, benign monoclonal gammopathy and light-chain nephropathy are known to cause Fanconi syndrome in adults.
• Immunological injury to the proximal renal tubules may be observed in kidney transplant and many other malignancies
• Other rare disorders known to cause Fanconi syndrome include Wilson disease, Lowe syndrome, paroxysmal nocturnal hemoglobinuria and mitochondrial cytopathies.

Many drugs, heavy metals and other toxins can cause Fanconi syndrome. The list includes the following:

• Heavy metals like lead (esp. in children), mercury, cadmium, uranium and platinum. When lead is suspected, a history of PICA may often be elicited from the parents and laboratory tests will reveal elevated levels of the metal.
• Chinese herbs
• Pharmaceutical antibiotics like expired aminoglycosides (Esp. gentamicin), tetracyclines.[5]
• Chemotherapeutic agents like ifosfamide, cisplatin, and 6-mercaptopurine
• Anticonvulsants like valproic acid
• The reversible nucleotide reverse transcriptase inhibitor, Tenofovir
• The nucleotide analog, adefovir dipivoxil used to treat chronic hepatitis B
• The anti-TB drug Rifampin
• Deferasirox used for treating iron overload

Fanconi syndrome is either acquired or inherited. Because there are many causes of the syndrome, the exact incidence is unknown. In general, the disorder is not common but can affect people of all ages and races. Inherited cases of Fanconi syndrome are very rare but those acquired from exposure to drugs or heavy metals are slightly more common. With increased awareness of the acquired causes of Fanconi syndrome, there does appear to be a decrease in the number of reported cases.

Even though Fanconi syndrome has been shown to occur in all races, cystinosis, which is the common presentation of Fanconi syndrome in children, occurs primarily in children. The inherited Fanconi syndrome has an autosomal recessive trait and hence 25% of children will be affected.

The presentation of symptoms of Fanconi syndrome can vary. The inherited Fanconi syndrome usually presents with cystinosis and vitamin D dependent rickets within the first 12 months of life. Other inherited forms of Fanconi syndrome like Wilson disease, glycogen storage disorders, cystinosis and galactosemia may occur at a much later age. The acquired forms of cystinosis can occur at any age but usually soon after exposure to the toxic agent.

The basic defect in Fanconi syndrome is the damage to the proximal renal tubule which leads to decreased reabsorption of a number of solutes like amino acids, glucose, phosphate, bicarbonate and uric acid [6] [7]. It is believed that the following causes may be the reason why solutes fail to be reabsorbed in the proximal renal tubule:

• Generalized alteration in permeability of the renal tubular membranes.
• Dysfunction of the active transport carriers in the renal tubular membrane
• Alteration in the energy metabolism of the cells

The transport of specific substances and solutes across the proximal tubule membrane is dependent on symporters and antiporters and energy is needed for these transport system to work. It is believed that defect(s) in cellular energy in the various transporters may be the overall cause of Fanconi syndrome. This may explain why so many solutes fail to get reabsorbed in the proximal renal tubules.

Fanconi syndrome that is inherited cannot be prevented. However, these patients should be seen early in childhood so that the disease can be monitored and treated as soon as possible. For patients who develop Fanconi syndrome from acquired causes, there are some preventive measures that can be undertaken. The public should be educated about limiting exposure to toxins and not take expired antibiotics like the tetracyclines or aminoglycosides. Individuals who have galactosemia should be told to avoid lactose in the diet. In addition patients with tyrosinemia should be told to avoid tyrosine and/or phenylalanine in diet to prevent the symptoms of Fanconi syndrome.

Fanconi syndrome is a disorder due to disease or defect of the proximal renal tubules of the kidney. When this segment of the renal tubules is damaged, there is failure to reabsorb amino acids, glucose, phosphate, uric acid and bicarbonate. The disorder may be inherited or acquired after exposure to certain drugs, toxins or heavy metals. There are many other causes of Fanconi syndrome and the manifestations depend on the cause. When there is continual loss of bicarbonate, patients often develop renal tubular acidosis. When there is loss of phosphate, bone disease develops as this mineral is essential for normal skeletal growth. It is vital not to confuse Fanconi syndrome with Fanconi anemia, which is a completely distinct and separate disorder [1] [2] [3].

Patients should be informed that Fanconi syndrome may be inherited or acquired. There are many cases of acquired Fanconi syndrome, ranging from drugs, toxins and other metabolic disorders. The predominant feature of the disease is renal defects which can lead to renal failure. The acquired form of Fanconi syndrome can be treated if the offending agent is withdrawn but the inherited forms of Fanconi syndrome usually have a poor prognosis. All patients with Fanconi syndrome need close follow up with a specialist to ensure that the disease is not progressing. A dietary consult may help some patients with Fanconi syndrome. Parents with children affected by inherited Fanconi syndrome should receive genetic counseling so that they can understand the pattern of inheritance. This may help if they want to have additional children in future.

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