Familial hypophosphatemic rickets is inherited in an X-linked dominant pattern. Cases of sporadic acquired hyposhatemic rickets are sometimes associated with benign mesenchymal tumors (oncogenic rickets).
At the heart of the disease is a decrease in phosphate reabsorption in the proximal tubules, which leads to hypophosphatemia. This defect develops due to the circulation of the factor and is associated with primary anomalies of osteoblast function. There is also a decrease in intestinal absorption of calcium and phosphates. Impaired bone mineralization is more due to low phosphate levels and osteoblast dysfunction than due to low calcium levels and increased parathyroid hormone levels in calcium-deficient rickets. Since the level of 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D) is normal or slightly reduced, it can be assumed that there is a defect in the formation of active forms of vitamin D; hypophosphatemia should normally cause an increase in 1,25-dihydroxyvitamin D levels.
Hypophosphatemic rickets (phosphate-diabetes) develops due to a decrease in phosphate reabsorption in the proximal tubules. This tubular dysfunction is observed in isolation, the mode of inheritance 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 itself as a number of disorders, from asymptomatic hypophosphatemia to delayed physical development and short stature up to the clinic of severe rickets or osteomalacia. Children tend to have different manifestations after they begin to walk, with O-shaped curvature of the legs and other bone deformities, pseudofractures, bone pain, and short stature. Bony growths at muscle attachments can restrict movement. In hypophosphatemic rickets, rickets changes in the spine or pelvic bones, defects in tooth enamel and spasmophilia, which develop with vitamin D-deficient rickets, are rarely observed.
In patients, serum levels of calcium, phosphates, alkaline phosphatase and 1,25-dihydroxyvitamin D and HPT, as well as urinary phosphate excretion, should be determined. With hypophosphatemic rickets, the level of phosphates in the blood serum is reduced, but their excretion in the urine is high. Serum calcium and PTH levels are normal, and alkaline phosphatase levels are often elevated. With calcium-deficient rickets, hypocalcemia is noted, there is no hypophosphatemia or it is mild, the excretion of phosphates in the urine is not increased.
Hypophosphatemia is already detected in a newborn. In the 1-2 year of life, clinical symptoms of the disease develop: growth retardation, pronounced deformities of the lower extremities. Muscle weakness is moderate or absent. Disproportionately short limbs are characteristic. In adults, osteomalacia gradually develops.
To date, 4 types of inherited disorders have been described in hypophosphatemic rickets.
Type I – X-linked hypophosphatemia – vitamin D-resistant rickets (hypophosphatemic tubulopathy, familial hypophosphatemia, hereditary renal phosphate diabetes, renal phosphate diabetes, familial persistent phosphate diabetes, renal tubular rickets, Bullbright’s syndrome) due to a decrease in phosphate reabsorption in the proximal renal tubules and manifested by hyperphosphaturia, hypophosphatemia and the development of rickets-like changes resistant to usual 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 l, 25 (OH) 2D3 in patients is inadequately reduced for the existing degree of hypophosphatemia.
The disease manifests itself up to 2 years of age. The most characteristic signs:
- stunted growth, squat, great muscle strength; there is no hypoplasia of the enamel of permanent teeth, but there are expansions of the pulp space; alopecia;
- hypophosphatemia and hyperphosphaturia with normal blood calcium levels and increased alkaline phosphatase activity;
- pronounced deformities of the legs (with the beginning of walking);
- X-ray rickets-like changes in bones – wide diaphysis with thickening of the cortical layer, rough trabeculae pattern, osteoporosis, vagal deformity of the lower extremities, delayed skeletal formation; 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 in the blood serum is reduced to 0.64 mmol / l and less (at a rate of 1.29-2.26 mol / l). Serum calcium is normal.
The reabsorption of phosphates in the kidneys decreases to 20-30% or less, the excretion of phosphorus in the urine increases to 5 g / day; the activity of alkaline phosphatase is increased (2-4 times compared with the norm). Hyperaminoaciduria and glucosuria are uncommon. Calcium excretion is not changed.
There are 4 clinical and biochemical variants of phosphate-diabetes according to the reaction to the administration of vitamin D. In the first variant, an increase in the content of inorganic phosphates in the blood during therapy is associated with an increase in their reabsorption in the renal tubules, in the second, the reabsorption of phosphates in the kidneys and intestines, in the third – an increase in reabsorption takes place only in the intestine, with the fourth – the sensitivity to vitamin D increases significantly, so that even relatively small doses of vitamin D cause the appearance of signs of intoxication.
Type II – a form of hypophosphatemic rickets – is an autosomal dominant disease that is not linked to the X chromosome. The disease is characterized by:
- the onset of the disease at the age of 1-2 years;
- curvature of the legs with the beginning of walking, but without changing growth, strong physique, skeletal deformities;
- hypophosphatemia and hyperphosphaturia with normal calcium levels and a moderate increase in alkaline phosphatase activity;
- radiographically: mild 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 serum. Changes in urine are uncommon.
Type III – autosomal recessive dependence on vitamin D (hypocalcemic rickets, osteomalacia, hypophosphatemic vitamin D-dependent rickets with aminoaciduria). The cause of the disease is in the impaired formation of 1.25 (OH) 2D3 in the kidneys, which leads to impaired absorption of calcium in the intestine and impaired direct effect of vitamin D on specific bone receptors, hypocalcemia, hyperaminoaciduria, secondary hyperparathyroidism, impaired 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 blood alkaline phosphatase activity. It is increased by the concentration of parathyroid hormone in the 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 reveals severe rickety changes in the growth zones 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 the blood is sharply reduced.
Type IV – vitamin D3 deficiency – is inherited in an autosomal recessive manner or occurs sporadically, mostly girls are ill. 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 an anomaly of the teeth;
- radiographically revealed rickety changes of varying degrees.
Diagnosis of phosphate diabetes
One of the markers that allows one to suspect phosphate-diabetes is the ineffectiveness of standard dosages 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 denote phosphate-diabetes, is not entirely correct.
Laboratory diagnostics of phosphate-diabetes
In patients with hypophosphatemic rickets, hyperphosphaturia and hypophosphatemia are found. The content of parathyroid hormone in the blood is not changed 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 dosages of phosphorus preparations.
Instrumental diagnosis of phosphate-diabetes
X-ray examination of bones reveals a wide metaphysis, a thickening of the cortical layer of tubular bones. The calcium content in bones is usually increased.
Differential diagnosis of phosphate-diabetes
It is necessary to differentiate hereditary phosphate-diabetes with vitamin D-deficient rickets, which responds well to complex treatment, de Toni-Debre-Fanconi syndrome, osteopathy in chronic renal failure.
When symptoms of phosphate-diabetes occur for the first time in an adult, oncogenic hypophosphatemic osteomalacia should be assumed. This variant of the paraneoplastic syndrome is observed in many tumors, including the skin (multiple dysplastic nevi).
What should be examined?
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Phosphate diabetes treatment
Treatment includes oral phosphate 10 mg / kg 4 times a day in the form of a neutral phosphate solution or tablets. Since phosphate can cause hyperparathyroidism, vitamin D is prescribed in the form of 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 the level of phosphate and a decrease in the level of alkaline phosphatase, the disappearance of the symptoms of rickets and an increase in the growth rate. Hypercalcemia, hypercalciuria, and nephrocalcinosis with decreased renal function may complicate treatment. In adult patients with oncogenic rickets, a sharp improvement occurs after removal of a small-cell mesenchymal tumor, which produces a humoral factor that reduces phosphate reabsorption in the proximal renal tubules.
It is recommended to start treatment of phosphate-diabetes with the introduction of phosphorus preparations (1-2 g / day), and then start using vitamin D. This technique allows you to achieve an 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. It is mandatory to control the excretion of calcium in the urine (test according to Sulkovich). The absence of symptoms of intoxication, a small 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. Shown are combinations of vitamin D with diphosphonate (xidiphon) or with Albright’s mixture (80 ml of solution-mixture in 1 day in 5 doses). The presence of gross deformities of the skeletal system is 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, throughout life, treatment with vitamin D, the prognosis for life and the normalization of mineral metabolism in forms III and IV is favorable.
It’s important to know!
In clinical medicine, there is no disease anechoic formation in the kidney, because this is one of the diagnostic signs of some nephrological pathologies, which is detected during the ultrasound examination of the kidneys. Read more…! Found an error? Select it and press Ctrl + Enter. Did you like this article?
Diabetes is often linked to high blood sugar, but the condition can vary. Pathologies are not always caused by a malfunction of the pancreas, although they have similar names. Phosphate diabetes belongs to hereditary diseases, so the first signs appear even in childhood.