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Primary Fanconi renotubular syndrome
A rare generalized, genetic disorder of proximal tubular transport characterized by excessive urine output with loss of low molecular weight solutes (amino acids, glucose, low-molecular weight proteins, organic acids, carnitine, calcium, phosphate, potassium, bicarbonate) and water, and which can be life threatening.
ORPHA:3337Classification level: Disorder
The prevalence of the condition is not known.
Onset is typically between infancy and childhood with symptoms related to tubular loss of nutrients, water and electrolytes. Typical clinical features include failure to thrive and rickets, normoglycemic glycosuria and polyuria with bicarbonaturia leading to hyperchloremic metabolic acidosis. Nephrocalcinosis and kidney stones are less common.
The genetic etiology has been identified in a handful of families, and includes mutations in either GATM (15q21.1), involved in mitochondrial function, EHHADH (3q27.2), due to a specific mutation (c.7G>A) that introduces a mitochondrial targeting motif, or SLC34A1 (5q35.3) which encodes the proximal tubular sodium-phosphate transporter, NaPi-IIa. However, the disease may be due to unidentified mutations. Of note, the gene SLC34A1 is also associated with two other diseases: autosomal recessive infantile hypercalcemia and dominant hypophosphatemia with nephrolithiasis or osteoporosis.
Diagnosis is based on clinical presentation as well as plasma electrolytes levels and evaluation of urinary solute excretion (aminoaciduria, proteinuria, phosphaturia, calciuria, uricosuria, glycosuria).
Before the diagnosis of primary Fanconi renotubular syndrome is made all causes of secondary Fanconi syndrome must be ruled out, including both inherited (cystinosis, tyrosinemia type I, fructosemia, Wilson's disease, galactosemia, glycogen storage disease, Dent disease, Oculocerebrorenal syndrome of Lowe, arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, mitochondrial cytopathies) and acquired disorders (drug or heavy metal poisoning, malignancies).
The majority of reported cases are sporadic and may be associated with de novo mutations. However, hereditary forms have been reported. The pattern of inheritance is autosomal dominant for EHHADH and GATM, and autosomal recessive for SLC34A1. The risk of transmission to offspring is 50% for autosomal dominant disease and, where both parents are heterozygous for the pathogenic mutation, 25% in autosomal recessive disease.
Management and treatment
Treatment is symptomatic. Kidney transplantation is curative.
With adequate fluid, electrolyte and nutrient supplementation, adequate physical and neurocognitive development is usually possible. Mutations in GATM are associated with progressive chronic kidney disease, whereas this has not been observed with EHHADH-associated disease.