Fanconi Renotubular Syndrome 1

Description

Fanconi renotubular syndrome is a consequence of decreased solute and water reabsorption in the proximal tubule of the kidney. Patients have polydipsia and polyuria with phosphaturia, glycosuria, and aminoaciduria. They may develop hypophosphatemic rickets or osteomalacia, acidosis, and a tendency toward dehydration. Some will eventually develop renal insufficiency. Common laboratory abnormalities include glucosuria with a normal serum glucose, hyperaminoaciduria, hypophosphatemia, progressive renal insufficiency, renal sodium and potassium wasting, acidosis, uricosuria, and low-molecular-weight proteinuria (summary by Lichter-Konecki et al., 2001).

Genetic Heterogeneity of Fanconi Renotubular Syndrome

Fanconi renotubular syndrome-1 has been mapped to chromosome 15q15.3. See also FRTS2 (613388), caused by mutation in the SLC34A1 gene (182309) on chromosome 5q35; FRTS3 (615605), caused by mutation in the EHHADH gene (607037) on chromosome 3q27; and FRTS4 (616026), which is associated with maturity-onset diabetes of the young (MODY), caused by mutation in the HNF4A gene (600281) on chromosome 20q13.

Clinical Features

Ben-Ishay et al. (1961) and Hunt et al. (1966) reported pedigrees consistent with autosomal dominant inheritance of the Fanconi renotubular syndrome. In the family of Hunt et al. (1966), a mother and son had retarded growth, rickets, hypophosphatemia, hypokalemia, acidosis, amino aciduria, proteinuria, and glycosuria, whereas 6 relatives had amino aciduria but no bone disturbance. Autopsy and biopsies showed no cystine deposits in tissues. Smith et al. (1976) described a kindred in which the syndrome appeared in 4 successive generations and was possibly associated with diabetes mellitus. The proposita had hypophosphatemia, renal glycosuria, proteinuria, and generalized amino aciduria. At the age of 22 she developed symptoms of osteomalacia which responded to treatment with oral phosphate. Her father, who died from diabetes mellitus, had been similarly affected. A sister was affected and at least 7 persons in 3 preceding generations had crippling bone disease and profound muscle weakness of early adult onset. Friedman et al. (1978) observed the Fanconi syndrome in father and son; a unique feature was progression to early renal failure, requiring renal transplant in the father.

Brenton et al. (1981) restudied the original family of Dent and Harris (1951, 1956) in which 4 of 5 sibs had Fanconi renotubular syndrome, suggesting autosomal recessive inheritance, and concluded that the inheritance was undoubtedly autosomal dominant. The 30-year follow-up also showed that lactic aciduria and tubular proteinuria were probably the earliest manifestations of the disorder in childhood, with glycosuria and amino aciduria developing in the second decade and osteomalacia from the start of the fourth decade. Glomerular function deteriorates slowly but is compatible with a normal life span. Brenton et al. (1981) concluded that there is no good example of recessive inheritance in the literature.

Luder and Sheldon (1955) and Sheldon et al. (1961) described cases of generalized amino aciduria with loss of glucose and phosphate as well. Mild rickets with late onset or with no bone disease occurred. Three generations were affected. Dominant inheritance is unusual for a defect of this type. The affected persons were female twins, their father and his father. A follow-up by Patrick et al. (1981) showed that 3 members had developed renal failure with renal transplant in 1.

Tolaymat et al. (1992) stated that 10 families with Fanconi syndrome had been described, of which 6 had an autosomal dominant mode of transmission.

Wen et al. (1989) reported a large family from central Wisconsin with autosomal dominant renal Fanconi syndrome. Affected individuals had variable expressivity of tubular reabsorptive defects. Most of the affected family members developed polyuria and loss of proximal tubular function during the second decade of life and demonstrated significant renal insufficiency by the third decade. The 10 affected family members whose genomes were analyzed had been diagnosed with renal Fanconi syndrome by the following diagnostic criteria: a tubular reabsorption of phosphorus (calculated as maximum rate of tubular absorption of phosphate/glomerular filtration rate) less than 2.5 mg/dl and amino aciduria and glucosuria in patients with normal serum glucose.

Inheritance

The transmission pattern of renal Fanconi syndrome in the family reported by Wen et al. (1989) was consistent with autosomal dominant inheritance.

Mapping

By a genomewide screen of 24 members of the family with renal Fanconi syndrome reported by Wen et al. (1989), Lichter-Konecki et al. (2001) demonstrated linkage of the disorder to chromosome 15q15.3.

Animal Model

Bovee et al. (1978) demonstrated a presumably hereditary Fanconi syndrome in dogs.