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Hereditary phosphate diabetes (vitamin-D-resistant, hypophosphatemic, rickets)
Last reviewed: 05.07.2025
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Hereditary phosphate diabetes is a heterogeneous group of inherited disorders involving phosphate and vitamin D metabolism. Hypophosphatemic rickets is a disorder characterized by hypophosphatemia, calcium malabsorption, and vitamin D-resistant rickets or osteomalacia. Symptoms include bone pain, fractures, and growth failure. Diagnosis is by measuring serum phosphate, alkaline phosphatase, and 1,25-dihydroxyvitamin D3. Treatment includes oral phosphate and calcitriol.
[ Causes and pathogenesis of phosphate diabetes
Familial hypophosphatemic rickets is inherited in an X-linked dominant manner. Cases of sporadic acquired hypophosphatemic rickets are sometimes associated with benign mesenchymal tumors (oncogenic rickets).
The disease is based on decreased proximal tubular phosphate reabsorption, resulting in hypophosphatemia. This defect is due to factor circulation and is associated with primary abnormalities in osteoblast function. There is also decreased intestinal absorption of calcium and phosphate. The impairment of bone mineralization is due more to low phosphate levels and osteoblast dysfunction than to low calcium and elevated parathyroid hormone levels in calcium-deficiency rickets. Since 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D) levels are normal or slightly decreased, a defect in the formation of active forms of vitamin D may be suspected; hypophosphatemia should normally cause elevated 1,25-dihydroxyvitamin D levels.
Hypophosphatemic rickets (phosphate diabetes) develops due to decreased phosphate reabsorption in the proximal tubules. This tubular dysfunction is observed in isolation, the inheritance type is dominant, linked to the X chromosome. In addition, phosphate diabetes is one of the components of Fanconi syndrome.
Paraneoplastic phosphate diabetes is caused by the production of parathyroid hormone-like factor by tumor cells.
Symptoms of Phosphate Diabetes
Hypophosphatemic rickets manifests as a range of disorders, from asymptomatic hypophosphatemia to failure to thrive and short stature, to clinical features of severe rickets or osteomalacia. Manifestations in children are usually different after they begin to walk, with bow legs and other bone deformities, pseudofractures, bone pain, and short stature. Bone growths at muscle attachment sites may limit movement. Rachitic changes in the spine or pelvic bones, enamel defects, and spasmophilia, which develop in vitamin D-deficiency rickets, are rarely observed in hypophosphatemic rickets.
Patients should have serum calcium, phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D, and GPT levels, as well as urinary phosphate excretion. In hypophosphatemic rickets, serum phosphate levels are low, but urinary excretion is high. Serum calcium and PTH levels are normal, but alkaline phosphatase is often elevated. In calcium-deficiency rickets, hypocalcemia is present, hypophosphatemia is absent or mild, and urinary phosphate excretion is not elevated.
Hypophosphatemia is detected already in a newborn. In the 1st-2nd year of life, clinical symptoms of the disease develop: growth retardation, pronounced deformations of the lower extremities. Muscle weakness is moderate or absent. Disproportionately short extremities are characteristic. Osteomalacia gradually develops in adults.
To date, 4 types of inherited disorders in hypophosphatemic rickets have been described.
Type I - X-linked hypophosphatemia - vitamin D-resistant rickets (hypophosphatemic tubulopathy, familial hypophosphatemia, hereditary phosphate renal diabetes, renal phosphate diabetes, familial persistent phosphate diabetes, renal tubular rickets, Albright-Butler-Bloomberg syndrome) - a disease caused by decreased phosphate reabsorption in the proximal tubules of the kidney and manifested by hyperphosphaturia, hypophosphatemia and the development of rickets-like changes resistant to normal doses of vitamin D.
It is assumed that in X-linked hypophosphatemic rickets, the regulation of 1-a-hydroxylase activity by phosphate is impaired, which indicates a defect in the synthesis of the vitamin D metabolite 1,25(OH)2D3. The concentration of 1,25(OH)2D3 in patients is inadequately reduced for the existing degree of hypophosphatemia.
The disease manifests itself before the age of 2. The most characteristic signs are:
- growth retardation, squatness, high muscle strength; no enamel hypoplasia in permanent teeth, but expansion of the pulp space occurs; alopecia;
- hypophosphatemia and hyperphosphaturia with normal blood calcium levels and increased alkaline phosphatase activity;
- pronounced deformations of the legs (with the onset of walking);
- X-ray rickets-like changes in bones - wide diaphyses with thickening of the cortical layer, coarse trabecular pattern, osteoporosis, vagal deformity of the lower extremities, delayed skeletal formation; the total calcium content in the skeleton is increased.
No violations of acid-base balance and electrolyte content in plasma are observed. The level of parathyroid hormone in the blood is normal. The level of inorganic phosphorus in the blood serum is reduced to 0.64 mmol/l and less (with the norm being 1.29-2.26 mol/l). The calcium content in the blood serum is normal.
Phosphate reabsorption in the kidneys decreases to 20-30% or less, phosphorus excretion in urine increases to 5 g/day; alkaline phosphatase activity is increased (2-4 times compared to the norm). Hyperaminoaciduria and glucosuria are not typical. Calcium excretion is unchanged.
There are 4 clinical and biochemical variants of phosphate diabetes based on the reaction to the introduction of vitamin D. In the first variant, the increase in the content of inorganic phosphates in the blood during therapy is associated with increased reabsorption in the renal tubules, in the second, the reabsorption of phosphates in the kidneys and intestines increases, in the third, increased reabsorption occurs only in the intestines, and in the fourth, sensitivity to vitamin D increases significantly, so that even relatively small doses of vitamin D cause signs of intoxication.
Type II - a form of hypophosphatemic rickets - is an autosomal dominant, non-X-linked disease. The disease is characterized by:
- onset of the disease at the age of 1-2 years;
- curvature of the legs with the onset of walking, but without change in height, strong physique, skeletal deformities;
- hypophosphatemia and hyperphosphaturia with normal calcium levels and moderate increase in alkaline phosphatase activity;
- Radiologically: mild signs of rickets, but with pronounced osteomalacia.
No changes in the composition of electrolytes, acid-base balance, parathyroid hormone concentration, blood amino acid composition, creatinine level, or residual nitrogen in the serum are observed. Changes in urine are not typical.
Type III - autosomal recessive dependence on vitamin D (hypocalcemic rickets, osteomalacia, hypophosphatemic vitamin D-dependent rickets with aminoaciduria). The cause of the disease is a violation of the formation of 1,25 (OH) 2 D3 in the kidneys, which leads to a violation of calcium absorption in the intestine and a violation of the direct effect of vitamin D on specific bone receptors, hypocalcemia, hyperaminoaciduria, secondary hyperparathyroidism, impaired phosphorus reabsorption and hypophosphatemia.
The onset of the disease occurs between the ages of 6 months and 2 years. The most characteristic signs are:
- excitability, hypotension, convulsions;
- hypocalcemia, hypophosphatemia, hyperphosphaturia and increased activity of alkaline phosphatase in the blood. Increased concentrations of parathyroid hormone in plasma, and generalized aminoaciduria and a defect, sometimes a defect in urine acidification, are also observed;
- late onset of walking, short stature, severe rapidly developing deformities, muscle weakness, enamel hypoplasia, dental anomalies;
- X-ray examination reveals severe rachitic changes in the growth zones of long tubular bones, thinning of the cortical layer, and a tendency to osteoporosis. There is no change in the acid-base balance or residual nitrogen content, but the concentration of l,25(OH)2D3 in the blood is sharply reduced.
Type IV - vitamin D3 deficiency - is inherited in an autosomal recessive manner or occurs sporadically, and predominantly affects girls. The onset of the disease is noted in early childhood; it is characterized by:
- curvature of the legs, deformation of the skeleton, convulsions;
- frequent alopecia and sometimes dental anomalies;
- Radiologically, rachitic changes of varying degrees are revealed.
Diagnosis of phosphate diabetes
One of the markers that allows one to suspect phosphate diabetes is the ineffectiveness of standard doses of vitamin D (2000-5000 IU/day) in a child suffering from rickets. At the same time, the term "vitamin D-resistant rickets", previously used to designate phosphate diabetes, is not entirely correct.
Laboratory diagnostics of phosphate diabetes
In patients with hypophosphatemic rickets, hyperphosphaturia and hypophosphatemia are detected. The content of parathyroid hormone in the blood is unchanged or increased. In some patients, the sensitivity of tubular epithelial cells to parathyroid hormone is reduced. Sometimes, the activity of alkaline phosphatase is increased. Hypocalcemia is observed in patients treated with inadequate doses of phosphorus preparations.
Instrumental diagnostics of phosphate diabetes
X-ray examination of bones reveals a wide metaphysis, thickening of the cortical layer of tubular bones. The calcium content in bones is usually elevated.
Differential diagnosis of phosphate diabetes
It is necessary to differentiate hereditary phosphate diabetes from vitamin D-deficiency rickets, which responds well to complex treatment, de Toni-Debre-Fanconi syndrome, and osteopathy in chronic renal failure.
If symptoms of phosphate diabetes occur for the first time in an adult, oncogenic hypophosphatemic osteomalacia should be suspected. This variant of paraneoplastic syndrome is observed in many tumors, including skin tumors (multiple dysplastic nevi).
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Treatment of phosphate diabetes
Treatment involves oral administration of phosphate 10 mg/kg 4 times daily as neutral phosphate solution or tablets. Because phosphate can cause hyperparathyroidism, vitamin D is given as calcitriol, starting with 0.005-0.01 mcg/kg orally once daily, then 0.015-0.03 mcg/kg orally once daily as a maintenance dose. Phosphate levels increase and alkaline phosphatase levels decrease, symptoms of rickets disappear, and growth rate increases. Hypercalcemia, hypercalciuria, and nephrocalcinosis with decreased renal function may complicate treatment. In adult patients with oncogenic rickets, dramatic improvement occurs after removal of a small cell mesenchymal tumor that produces a humoral factor that reduces phosphate reabsorption in the proximal tubules of the kidneys.
Treatment of phosphate diabetes is recommended to begin with the introduction of phosphorus preparations (1-2 g/day), and then proceed to the use of vitamin D. This method allows achieving the effect with the introduction of vitamin D in moderate doses. Its initial dose is 20,000-30,000 IU per day. After 4-6 weeks, it is increased by 10,000-15,000 IU daily until the level of phosphorus in the blood is normalized, the activity of alkaline phosphatase decreases, pain in the bones of the lower extremities disappears and the structure of bone tissue is restored. Monitoring the excretion of calcium in the urine (Sulkovich test) is mandatory. The absence of intoxication symptoms and a small excretion of calcium in the urine are indications for increasing the dose of vitamin D. In most cases, the optimal dose of vitamin D is 100,000-150,000 IU/day. Combinations of vitamin D with diphosphonate (xydiphone) or with Albright's mixture (80 ml of the mixture-solution per day in 5 doses) are indicated. The presence of gross deformations of the skeletal system serves as an indication for orthopedic treatment (immobilization of the limbs).
Phosphate diabetes in forms I and II has a favorable prognosis for life. In adults with form II, there are practically no skeletal deformities. With constant, lifelong treatment with vitamin D, the prognosis for life and normalization of mineral metabolism in forms III and IV is favorable.