Hypophosphatemic vitamin-D-resistant rickets - Causes, symptoms and treatment. MF.

Family hypophosphatemic rickets, or phosphate-diabetes, or vitamin-D-resistant rickets( HYPOPHOSPHATEMIC VITAMIN D-RESISTANT RICKETS; HPDR; 307800), was first described by Albrigt et al.in 1937X-linked hypophosphatemic rickets is the most common form of hypophosphataemia, with a frequency of about 1 in 20,000-25,000.

Causes of hypophosphatemic rickets

The disease has an X-linked dominant type of inheritance. It is characterized by full penetrance for hypophosphatemia and incomplete for bone changes. Women transmit a pathological symptom to daughters and sons with a probability of 50%, men - only to daughters with a probability of 100%.In boys, the disease is more severe than that of girls.

The molecular genetic cause of the disease is a mutation in the PHEX gene( Phosphat regulating hormone with homologies to endopeptidases on the X-chromosome).The gene consists of 18 exons and codes for phosphate-regulating endopeptidase( homologous to neutral endopeptidases that regulate the activity of other proteins) controlling the membrane transport of phosphate in the renal tubules, small intestine and possibly other organs. How mutations in the PHEX gene through hypothetical phosphaturic hormone lead to renal phosphate loss and vitamin D metabolism disturbances are still unclear and opinions on this issue are highly controversial. Hypothetical model: it is assumed that the endopeptidase PHEX causes the activation of phosphaturitic hormone. If the mutation in the PHEX gene leads to a loss of endopeptidase activity, then the activity of phosphatonin decreases and, as a result, phosphate loss through the kidneys occurs and no inhibition of the inactivation of 1,25-( OH) 3-vitamin-D occurs.

Diagnosis of

A genetic defect leads to disturbances in the reabsorption of phosphate in the tubules of the kidneys and its absorption in the small intestine. It is manifested by hyperphosphaturia, hypophosphatemia, increased activity of alkaline phosphatase and the development of rachitis-like changes that can not be treated with vitamin D in normal doses. Hypocalcemia( lack of calcium) is not present or it is insignificant. The concentration of nitrogenous slag and electrolytes in the blood is normal. Other partial kidney functions are normal. The level of citrates in the blood is normal, in contrast to hypocitratemia with normal vitamin-D-deficiency rickets.

The radiograph of bones reveals significant changes in the epi- and metaphyseal zones. The structure of diaphyses differs from that of conventional rickets: along with growth zones, there are zones of osteosclerosis. There is a thickening of the tubular bones due to the one-sided, often medial layer of the periosteum.

Symptoms of hypophosphatemic rickets

The disease begins at the end of the first or the beginning of the second year of life. In patients with children, muscle hypotension, varus deformities of bones, especially the lower extremities, rachitic "bracelets", "rosary", gait disturbance - "duck" gait, lag in growth. Sometimes spontaneous fractures are observed. Teeth erupt normally, but are quickly damaged by caries. Mental development does not suffer.

After the closure of the epiphyseal growth zones, the manifestations of the disease are weakened, but in untreated patients there are severe bone lesions in adulthood.

In adults, hereditary hypophosphatemia can be combined with osteomalacia. Clinically, it is manifested by pain in the bones, muscle weakness, a decrease in growth due to compression of the vertebrae. The level of calcium in the blood is not disturbed, but there is a negative calcium-phosphorus balance.

Treatment of hypophosphatemic rickets

There is no satisfactory therapy for hypophosphatemic rickets.

Drug treatment does not affect the underlying genetic defect, but it achieves a clinical cure for rickets and an improvement in bone histology. Treatment should begin as early as possible so that bone deformation can be avoided. The necessary dosages depend on the severity of rickets and the age of the patient. They are higher in young children( or at the beginning of therapy and in older children), then decrease so that during a growth jump during puberty again increase.

In hereditary hypophosphatemic vitamin D-resistant rickets, there is a pronounced tolerance to ergocalciferol preparations. Assigning them in doses appropriate to the physiological needs or used to treat rickets due to vitamin D deficiency does not lead to an increase in the phosphate content in the blood, nor to a decrease in the symptoms of rickets or osteomalacia.

Therefore, for the treatment of phosphatidiabet use drugs in large doses( an average of 30 000-100 000 ME and more per day).Differences in the efficacy of cholecalciferol and ergocalciferol were not detected in this disease. Instead of these funds, dihydrotachysterine can be administered at 0.5-1.5 mg per day. By chemical structure, the latter is close to ergocalciferol.

Under the influence of large doses of ergocalciferol or dihydrotachysterin, calcium absorption in the intestine is enhanced, the balance of calcium and phosphorus is improved, the activity of alkaline phosphatase decreases, presumably due to the inhibitory effect of large doses of these drugs. In this regard, the phenomenon of rickets and osteomalacia subsides. Nevertheless, the excretion( excretion) of phosphate in the urine does not decrease. Therefore, their level in the blood remains reduced, but the growth of patients at the same time is normalized.

Prognosis and complications of

After puberty, the disease can go even without treatment. In adults who survived vitamin D-resistant rickets in childhood, hypophosphatemia, short stature, post-traumatic deformities of the pelvic limbs, often causing caesarean section in women, persists. Relapses are possible during the period of exertion of the mineral metabolism( pregnancy, lactation).