Synonyms: Fanconi's renotubular syndrome

Fanconi's syndrome is a generalised inherited or acquired disturbance of renal tubular transport leading to aminoaciduria, glycosuria, phosphaturia, renal tubular acidosis (RTA) type 2 (proximal), hypophosphataemic rickets (children) or osteomalacia (adults), and renal glycosuria.¹

Epidemiology

• The incidence of each cause of Fanconi's syndrome is different, although almost all of them are rather rare.
• Fanconi's syndrome may occur at any age, again according to cause; inherited causes are usually within the first 12 months.
• Cystinosis occurs almost exclusively in Caucasians. No known racial predilections exist for other forms.

Aetiology

Renal Fanconi syndrome is caused by a variety of predominantly rare causes but cystinosis is the most common cause in children.²

• Inherited:
  • Primary idiopathic: sporadic or familial (autosomal dominant - chromosome 15). Occurs in the absence of any identifiable cause, and most cases are sporadic. Some cases are inherited, but the mode of inheritance appears to be variable (autosomal-dominant, autosomal-recessive, X-linked).
  • Secondary: cystinosis, tyrosinaemia, Wilson's disease, Lowe's syndrome (oculo-cerebro-renal syndrome: bilateral congenital cataracts, glaucoma, general hypotonia, hyporeflexia, severe mental retardation and Fanconi's syndrome), galactosaemia, fructose intolerance, glycogen storage disorders and mitochondrial cytopathies.
• Acquired:
  • Intrinsic renal disease: acute tubular necrosis, interstitial nephritis, hypokalaemic nephropathy, myeloma, amyloidosis, Sjögren's syndrome, rejected transplant.
  • Hyperparathyroidism.
  • Drugs: cisplatin, ifosfamide, gentamicin, valproate^3,4 deferasirox.⁵
  • Toxins: glue sniffing, heavy metals, bee stings.⁶

Presentation

• Polyuria, polydipsia and episodes of dehydration (sometimes associated with fever).
• Bone deformities: rickets in children or osteomalacia in adults. Results from excessive urinary losses of calcium and phosphate and of a defect in the hydroxylation of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3.
• Impaired growth and failure to thrive.

Differential diagnosis

• Other causes of polyuria and polydipsia, e.g. diabetes mellitus, diabetes insipidus.
• Other causes of rickets, osteomalacia and impaired growth.

Investigations

• The diagnosis is based on excessive loss of substances in the urine (e.g. amino acids, glucose, phosphate, bicarbonate) in the absence of high plasma concentrations.
• Further investigations are required to identify the cause.
• Proteinuria: but usually only in small quantities.
• Hypokalaemia, hypophosphataemia and hyperchloraemic metabolic acidosis.

Management

• Management mainly consists of the replacement of substances lost in the urine and specific treatment for the underlying cause.
• Treat the underlying cause if present. Alkali and potassium for renal tubular acidosis (RTA), phosphate and calcitriol for phosphate wasting.
• Dehydration due to polyuria: prevent by ensuring adequate fluid intake; episodes of dehydration require either oral or intravenous fluid replacement.
• Metabolic acidosis due to the loss of bicarbonate: corrected by the administration of alkali - usually sodium bicarbonate.
• Thiazide diuretic: may be necessary to avoid volume expansion, which increases the excretion of bicarbonate by lowering the renal threshold. However, the diuretic increases potassium loss.
• Correction of metabolic acidosis is insufficient to treat bone disease, and phosphate and vitamin D supplementation is also required.
• Phosphate supplements.
• Vitamin D, given as 1,25-dihydroxyvitamin D3 or 1a-hydroxyvitamin D3, as liver and/or renal hydroxylation may be impaired in patients with Fanconi's syndrome.
• Renal losses of glucose, amino acids, and uric acid are not usually symptomatic and do not require replacement.

Complications

• Morbidity and complications are secondary to the underlying and resulting metabolic abnormalities.
• Most abnormalities, e.g. acidosis, calciuria, and phosphaturia, affect bone development and therefore growth.
• Some forms of Fanconi's syndrome, e.g. cystinosis, lead to renal failure.

Prognosis

Prognosis depends on the cause of the syndrome and the severity of renal and extrarenal manifestations.

Prevention

• Avoiding exposure to potential toxins, e.g. outdated tetracyclines and aminoglycosides.
• Effective management of any underlying metabolic disorder, e.g. galactosaemia, tyrosinaemia.

Document references

1. Izzedine H, Launay-Vacher V, Isnard-Bagnis C, et al; Drug-induced Fanconi's syndrome.; Am J Kidney Dis. 2003 Feb;41(2):292-309. [abstract]
2. Fathallah-Shaykh S et al; Fanconi Syndrome, eMedicine, Jun 2008
3. Yoshikawa H, Watanabe T, Abe T; Fanconi syndrome caused by sodium valproate: report of three severely disabled children.; Eur J Paediatr Neurol. 2002;6(3):165-7. [abstract]
4. Endo A, Fujita Y, Fuchigami T, et al; Fanconi syndrome caused by valproic acid. Pediatr Neurol. 2010 Apr;42(4):287-90. [abstract]
5. Rafat C, Fakhouri F, Ribeil JA, et al; Fanconi syndrome due to deferasirox. Am J Kidney Dis. 2009 Nov;54(5):931-4. Epub 2009 Jun 3. [abstract]
6. Ram R, Swarnalatha G, Ashok KK, et al; Fanconi syndrome following honeybee stings. Int Urol Nephrol. 2010 Oct 16. [abstract]

Internet and further reading

• Fanconi renotubular syndrome, Online Mendelian Inheritance in Man (OMIM)
• Quigley R; Proximal renal tubular acidosis. J Nephrol. 2006 Mar-Apr;19 Suppl 9:S41-5. [abstract]

Acknowledgements