Hereditary phosphate-diabetes (vitamin-D-resistant, hypophosphatemic, rickets)

Hereditary phosphate-diabetes is a heterogeneous group of hereditary diseases with a disruption of the metabolism of phosphates and vitamin D. Hypophosphatemic rickets is a disease characterized by hypophosphatemia, a violation of calcium absorption and rickets or osteomalacia that are not sensitive to vitamin D. Symptoms include bone pain, fractures and disorders growth. The diagnosis is based on the determination of phosphate, alkaline phosphatase and 1,25-dihydroxyvitamin D3 levels in the serum. Treatment includes oral administration of phosphates and calcitriol.

[1], [2], [3], [4], [5], [6]

Causes and pathogenesis of phosphate-diabetes

Family hypophosphatemic rickets are inherited in X-linked dominant type. Cases of sporadic acquired hyposphotemic rickets are sometimes associated with benign mesenchymal tumors (oncogenic rickets).

At the heart of the disease is a decrease in the reabsorption of phosphates in the proximal tubules, which leads to hypophosphatemia. This defect develops due to circulating factor and is associated with primary anomalies of osteoblast function. There is also a decrease in absorption in the intestine of calcium and phosphate. Disturbance of bone mineralization is largely due to low phosphate levels and osteoblast dysfunction than due to low calcium levels and increased parathyroid hormone levels with calcium-deficient rickets. Since the level of 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D) is normal or slightly decreased, it is possible to assume the presence of a defect in the formation of active forms of vitamin D; in normal hypophosphatemia should cause an increase in the level of 1,25-dihydroxyvitamin D.

Hypophosphatemic rickets (phosphate-diabetes) develops as a result of reduced reabsorption of phosphates in the proximal tubules. This tubular dysfunction is observed in isolation, the type of inheritance is dominant, linked to the X-chromosome. In addition, phosphate-diabetes is one of the components of the Fanconi syndrome.

Paraneoplastic phosphate-diabetes is caused by the production of the parathyroid-like factor by tumor cells.

[7], [8], [9], [10], [11], [12]

Symptoms of phosphate-diabetes

Hypophosphatemic rickets are manifested as a number of disorders, from asymptomatic hypophosphataemia to delayed physical development and low growth up to the clinic of severe rickets or osteomalacia. Manifestations in children, as a rule, differ after they begin to walk, they develop O-shaped curvature of the legs and other bone deformities, pseudo-fractures, bone pain and low growth. Bony growths in places of attachment of muscles can limit movement. With hypophosphatemic rickets, ricket changes in the spine or pelvic bones, dental enamel defects and spasmophilia, which develop with vitamin D deficiency rickets, are rarely observed.

Patients should determine the level of calcium, phosphate, alkaline phosphatase and 1,25-dihydroxyvitamin D and GPT in blood serum, as well as excretion of phosphate in the urine. In hypophosphatemic rickets, the serum phosphate levels are lower, but excretion in urine is high. The level of calcium and PTH in the serum is normal, and alkaline phosphatase is often elevated. With calcium-deficient rickets, hypocalcemia is observed, there is no hypophosphataemia or it is mild, urinary excretion of phosphate is not increased.

Hypophosphatemia is already detected in a newborn. On the 1-2-st year of life the clinical symptoms of the disease develop: growth retardation, pronounced deformities of the lower limbs. Muscle weakness is moderately or absent. Disproportionately short extremities are characteristic. In adults, osteomalacia is gradually developing.

To date, 4 types of inherited disorders have been described in hypophosphatemic rickets.

I type - X-linked X-linked hypophosphatemia - vitamin D-resistant rickets (hypophosphatemic tubulopathy, familial hypophosphatemia, hereditary phosphate kidney diabetes, renal phosphate diabetes, familial persistent phosphate diabetes, renal tubular rickets, Albright-Butler-Bloomberg syndrome) caused by a decrease in the reabsorption of phosphates in the proximal part of the tubule of the kidney and manifested by hyperphosphaturia, hypophosphatemia and the development of ricket-like changes resistant to normal doses of vitamin D.

It is assumed that with X-linked hypophosphatemic rickets, regulation of 1-a-hydroxylase activity by phosphate is disturbed, which indicates a defect in the synthesis of the vitamin D metabolite 1,25 (OH) 2D3. The concentration of l, 25 (OH) 2D3 in patients is inadequately reduced for the present degree of hypophosphatemia.

The disease manifests itself up to 2 years of life. The most characteristic features:

• stunting, squat, large muscular strength; There is no hypoplasia of the enamel of permanent teeth, but there are extensions of the pulp space; alopecia;
• hypophosphatemia and hyperphosphaturia with normal calcium content in the blood and increased activity of alkaline phosphatase;
• pronounced deformities of the legs (with the onset of walking);
• Rhenological rachitis-like changes in bones - wide diaphysis with thickening of the cortical layer, coarse trabeculation, osteoporosis, vagal deformity of the lower limbs, delay in the formation of the skeleton; the total calcium content in the skeleton is increased.

There are no violations of CBS and the content of electrolytes in plasma. The level of parathyroid hormone in the blood is normal. The level of inorganic phosphorus serum is reduced to 0.64 mmol / l and less (at a rate of 1.29-2.26 mol / l). The calcium content in the blood serum is normal.

The phosphate reabsorption in the kidneys is reduced to 20-30% or less, the excretion of phosphorus in the urine is increased to 5 g / day; activity of alkaline phosphatase increased (2-4 times compared with the norm). Hyperaminoaciduria and glucosuria are not characteristic. Calcium excretion is not changed.

There are 4 clinical and biochemical variants of phosphate-diabetes on the reaction to the introduction of vitamin D. In the first variant, an increase in the content of inorganic phosphates in the blood on the background of therapy is associated with an increase in their reabsorption in the renal tubules, while the second increases the reabsorption of phosphates in the kidneys and intestines, - Increased reabsorption occurs only in the intestine, with the fourth - significantly increases the sensitivity to vitamin D, so that even relatively small doses of vitamin D cause the appearance of signs of intoxication.

II type - a form of hypophosphatemic rickets - is an autosomal dominant, not linked to an X-chromosome disease. The disease is characterized by:

• beginning of the disease at the age of 1-2 years;
• curvature of the legs with the beginning of walking, but without changing the growth, sturdy physique, deformations of the skeleton;
• hypophosphatemia and hyperphosphaturia at a normal level of calcium and a moderate increase in the activity of alkaline phosphatase;
• X-ray: light signs of rickets, but with severe osteomalacia.

There are no changes in the composition of electrolytes, CBS, parathyroid hormone concentration, blood amino acid composition, creatinine level, residual nitrogen in the serum. Changes in the urine are uncharacteristic.

III type - autosomal recessive dependence on vitamin D (hypocalcemic rickets, osteomalacia, hypophosphatemic vitamin-D-dependent rickets with aminoaciduria). The cause of the disease in violation of education in the kidneys is 1.25 (OH) 2D3, which leads to a violation of calcium absorption in the intestine and a violation of the direct influence of vitamin D on specific bone receptors, hypocalcemia, hyperaminoaciduria, secondary hyperparathyroidism, disruption of phosphorus reabsorption and hypophosphatemia.

The onset of the disease refers to the age of 6 months. Up to 2 years. The most characteristic features:

• excitability, hypotension, convulsions;
• hypocalcemia, hypophosphatemia, hyperphosphaturia and increased activity of alkaline phosphatase in the blood. Increased the concentration of parathyroid hormone in the plasma, and also observed generalized aminoaciduria and defect, sometimes - a defect urinary acidification;
• late onset of walking, short stature, severe rapidly developing deformities, muscle weakness, enamel hypoplasia, tooth anomalies;
• X-ray revealed severe rhechotic changes in the areas of growth of long tubular bones, thinning of the cortical layer, a tendency to osteoporosis. There is no change in CBS, the content of residual nitrogen, but the concentration of l, 25 (OH) 2D3 in blood is sharply reduced.

IV type - insufficiency of vitamin D3 - is inherited by autosomal recessive type or occurs sporadically, mostly sick 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 anomaly of teeth;
• Radiologically, rhechotic changes of different degree are detected radiological.

Diagnosis of phosphate-diabetes

One of the markers that allow suspected phosphate-diabetes is the ineffectiveness of standard dosages of vitamin D (2000-5000 IU / day) in a child suffering from rickets. However, the term "vitamin D-resistant rickets", previously used to refer to phosphate-diabetes, is not entirely correct.

[13], [14], [15], [16], [17]

Laboratory diagnostics of phosphate-diabetes

In patients with hypophosphatemic rickets, hyperphosphaturia and hypophosphatemia are detected. The content of parathyroid hormone in the blood is not changed or increased. In some patients the sensitivity of tubular epitheliocytes to parathyroid hormone is reduced. Sometimes the activity of alkaline phosphatase is increased. Hypocalcemia is observed in patients treated with inadequate dosages of phosphorus preparations.

Instrumental diagnosis of phosphate-diabetes

Radiologic examination of bones reveals a wide metaphysis, thickening of the cortical layer of tubular bones. The calcium content in the bones is usually increased.

Differential diagnosis of phosphate-diabetes

To differentiate hereditary phosphate-diabetes is necessary with vitamin-D-deficient rickets, which is well amenable to complex treatment, de Toni-Debreu-Fanconi syndrome, and osteopathy in chronic renal failure.

If you have symptoms of phosphate-diabetes for the first time in an adult, you should assume oncogenic hypophosphatemic osteomalacia. This variant of paraneoplastic syndrome is observed in many tumors, including the skin (multiple dysplastic nevuses).

[18], [19]

Treatment of phosphate-diabetes

Treatment includes ingestion of phosphate 10 mg / kg 4 times a day as a neutral solution of phosphate or tablets. Since phosphate can cause hyperparathyroidism, vitamin D is prescribed as calcitriol, starting at a dose of 0.005-0.01 μg / kg orally once a day, then 0.015-0.03 μg / kg orally once a day as a maintenance dose. There is an increase in phosphate levels and a decrease in the level of alkaline phosphatase, the disappearance of symptoms of rickets and an increase in the rate of growth. Hypercalcemia, hypercalciuria and nephrocalcinosis with decreased renal function may complicate treatment. In adult patients with oncogenic rickets, a sharp improvement occurs after the removal of a small-cell mesenchymal tumor that produces a humoral factor that reduces the reabsorption of phosphates in the proximal tubule of the kidneys.

Treatment of phosphate-diabetes is recommended starting with the introduction of phosphorus drugs (1-2 g / day), and then proceed with the use of vitamin D. This technique allows you to achieve an effect with the introduction of vitamin D in moderate doses. Its initial dose is 20000-30000 ME per day. In 4-6 weeks. It is increased by 10,000-15,000 IU daily until the level of phosphorus in the blood normalizes, alkaline phosphatase activity decreases, pain in the bones of the lower extremities disappears, and the structure of bone tissue does not return. It is necessary to monitor the release of calcium in the urine (Sulkovich test). The absence of symptoms of intoxication, a slight excretion of calcium in the urine are indications for an increase in the dose of vitamin D. In most cases, the optimal dose of vitamin D is 100,000-150000 IU / day. Combinations of vitamin D with diphosphonate (xidiphon) or with a mixture of Albright (80 ml of a mixture-solution in 1 day in 5 receptions) are shown. The presence of gross deformations of the osseous system serves as an indication for orthopedic treatment (immobilization of the limbs).

Phosphate-diabetes for I and II forms has a favorable prognosis for life. In adults with II form, there is practically no deformation of the skeleton. With a constant, lifelong, vitamin D treatment, the prognosis for life and normalization of minal metabolism in forms III and IV is favorable.