Three phosphate-wasting lesions in the proximal tubule have been identified. Type I, first described by Albright, is seen most frequently. It is transmitted as a sex-linked dominant trait and the reabsorptive defect is confined to phosphate only. In type II, the defect is broader and involves both phosphate and glucose. In type III, the proximal Fanconi syndrome, the reabsorptive defect is for phosphate, glucose, and various amino acids.

VITAMIN D–RESISTANT RICKETS AND OSTEOMALACIA DUE TO PROXIMAL AND DISTAL RENAL TUBULAR DEFECTS

In another group of vitamin D–resistant rachitic and osteomalacic syndromes, the range of renal tubular defects is considerably broader and may interfere more severely with normal metabolism (see Plate 3-17). Reabsorption of phosphate, glucose, and amino acids in the proximal tubule is impaired, and, in addition, the functions of the distal tubule are significantly altered. Consequently, in patients with type I syndrome, known as the proximal and distal Fanconi syndrome, or the Debré-de Toni-Fanconi syndrome, the kidney’s ability to reabsorb water, bicarbonate, proteins, and fixed base is to some degree impaired. This represents a severe challenge to the patient, particularly the newborn, and requires major replacement therapy.

Typically, the patient is a very ill child, often dehydrated and hypoproteinemic, with rachitic changes in the bones. The rachitic and osteomalacic patterns in these patients result from the failure of tubular reabsorption of phosphate coupled with the loss of fixed base, including calcium. This unfortunate combination results in both rachitic changes and a mild-to-moderate secondary hyperparathyroidism (which worsens the bone lesions and intensifies the hypophosphatemia). These conditions have little relationship to vitamin D; in fact, treatment with even high doses of the sterol vitamin has little effect.

Biochemical changes in type I disease include hypocalcemia, hypophosphatemia, increased serum alkaline phosphatase level, and normal serum levels of 25(OH)D and 1,25(OH)₂D. The patient is likely to have signs of renal tubular acidosis (hyperchloremia, hyponatremia, and hypokalemia in association with an alkaline urine). Urinalysis reveals a low fixed specific gravity and the presence of excessive concentrations of metabolites, including calcium, sodium, and potassium ions; phosphate (as a result of a greatly lowered %TRP); uric acid; amino acids; and proteins.

Three other less common types of the severe form of vitamin D–resistant rickets and osteomalacia are often included under the proximal and distal Fanconi syndrome. (1) Type II, Lignac-Fanconi syndrome, is almost identical to type I but has an additional defect in the metabolism of cystine. This defect leads to the deposition of crystals of the amino acid in the viscera, bone marrow, and eyes (the diagnosis may be made by slit-lamp examination). As a result of the deposits, cirrhosis of the liver and renal failure frequently supervene by puberty. (2) Type III disease is known as oculocerebrorenal, or Lowe, syndrome. Patients with this condition have many of the manifestations of type I disease but may also have a broad range of ocular and neurologic abnormalities, which include congenital glaucoma, nystagmus, mental retardation, muscular hypotonia, and weakness. (3) Type IV, the superglycine syndrome, is rare. It is less severe than the other types and usually has a later onset. Presenting symptoms are profound motor weakness and very high urinary concentrations of glycine and glycylproline.