Phosphate diabetes is a genetically determined violation of mineral metabolism, in which the absorption and assimilation of phosphorus compounds in the body suffers, which leads to pathology of the bone system. According to the latest data, it is a whole group of hereditary diseases. It is manifested by hypotension of muscles, rickety changes in the skeleton (varus deformities of the bones of the lower extremities, rickety rosaries and others), lag in growth. The diagnosis of phosphate diabetes is based on the results of laboratory tests of blood and urine (the level of alkaline phosphatase, calcium ions, the active form of vitamin D) and molecular genetic analyses. Treatment of this disease is carried out by the appointment of high doses of vitamin D, phosphorus and calcium compounds, orthopedic or surgical correction of skeletal deformities.
Phosphate diabetes (vitamin D-resistant rickets) is the collective name of a number of genetically determined tubulopathies (pathological disorders of the transport of substances in the renal tubules), in which the reabsorption of phosphate ions is disrupted with the development of their deficiency in the body. One of the most common familial forms of this disease, transmitted by a dominant, X-linked mechanism, was described back in 1937.
In subsequent years, geneticists have identified several more types of phosphate diabetes with different etiology, method of hereditary transmission and clinical picture. However, they all have common features – they are caused by impaired absorption of phosphorus in the kidneys, are characterized by ricketlike symptoms and are resistant to the use of conventional dosages of vitamin D to varying degrees. To date, familial forms of phosphate diabetes have been identified, the transmission of which is linked to the X chromosome (both dominant and recessive), autosomal dominant and autosomal recessive. The occurrence of the most common varieties of this condition is 1:20,000 (X-linked dominant form), other types are much less common.
Causes and classification
Despite the pronounced genetic heterogeneity of phosphate diabetes, the immediate causes of hypophosphatemia in different forms of the disease are the same – a violation of the reverse absorption (reabsorption) of phosphates in the convoluted tubules of the kidneys. This makes it possible to attribute this condition to tubulopathies or pathologies of the urinary system, however, when it occurs, the entire body and especially the musculoskeletal system suffer. In addition, some forms of phosphate diabetes are accompanied by impaired absorption of calcium in the intestines and kidneys, the development of urolithiasis, abnormal activity of the parathyroid glands. There is a clear correlation between the genetic and clinical varieties of the disease, which allows us to build its clear generally accepted classification, including 5 forms of pathology.
X-linked dominant phosphate-diabetes – is the most common variant of this pathology, caused by a mutation of the PHEX gene. It encodes an enzyme – endopeptidase, which controls the activity of ion channels of the kidneys and small intestine. As a result of a genetic defect, the resulting enzyme is unable to perform its functions, therefore, the active transport of phosphate ions through the cell membrane in the above organs slows down sharply. This leads to an increase in the loss of phosphate ions in the urine and difficulty in their assimilation in the gastrointestinal tract, which causes hypophosphatemia to develop in the blood, and rickets-like changes occur in the bone tissue due to a deficiency of mineral components.
X-linked recessive phosphate-diabetes – unlike the previous variant affects exclusively men, whereas women can only act as carriers of the pathological gene. The cause of this form of the disease is mutations of the CLCN5 gene, which encodes the sequence of the chlorine ion channel protein. As a result of a genetic defect, the transport of all ions (including phosphates) through the membranes of nephron epithelial cells is disrupted, which is why phosphate diabetes develops.
Autosomal dominant phosphate diabetes is a form of the disease caused by a mutation of the FGF23 gene located on the 12th chromosome. The product of its expression is a protein that is mistakenly called fibroblast growth factor-23, although it is mainly secreted by osteoblasts and accelerates the release of phosphate ions in the urine. Phosphate diabetes develops with FGF23 mutations, as a result of which the protein produced by it becomes resistant to the effects of blood proteases, which causes its accumulation and, accordingly, an increase in the effect with the development of hypophosphatemia. This type of disease is considered a relatively mild form of phosphate diabetes.
Autosomal recessive phosphate diabetes is a rather rare type of pathology caused by mutations of the DMP1 gene located on the 4th chromosome. The gene encodes an acidic matrix dentin phosphoprotein, mainly formed in dentin and bone tissue, where it regulates their development. The pathogenesis of phosphate diabetes in this genetic variant has not been thoroughly studied.
Autosomal recessive phosphate diabetes with hypercalciuria is also a rare type of this disease caused by a mutation of the SLC34A3 gene located on the 9th chromosome. It encodes the sequence of the sodium-dependent phosphate ion channel in the kidneys and, with a defect in the structure, leads to an increase in the excretion of calcium and phosphorus in the urine with their simultaneous decrease in blood plasma.
There are also forms of phosphate diabetes, accompanied by hyperparathyroidism, urolithiasis and other disorders. Some varieties of this disease are associated with genes such as ENPP1, SLC34A1 and some others. The study of all possible causes of phosphate diabetes is still being carried out.
Manifestations of phosphate diabetes due to the genetic heterogeneity of this disease are characterized by a fairly wide range of severity – from an almost asymptomatic course to obvious severe disorders. Some cases of pathology (for example, caused by mutations of the FGF23 gene) may manifest only hypophosphatemia and an increase in the level of phosphorus in the urine, while there are no clinical symptoms. However, most often phosphate diabetes leads to a picture of typical rickets and mainly develops in childhood – 1-2 years, shortly after the child begins to walk.
One of the first manifestations of phosphate diabetes may be muscle hypotension in infancy, but it is not observed in all cases. Most often, the development of the disease begins with an O-shaped deformity of the legs, which can lead to a violation of gait. With the further course of phosphate diabetes, other clinical signs of rickets may occur – growth retardation and physical development, impaired tooth formation (especially in the autosomal recessive form of the disease), alopecia. Pathological fractures, the appearance of rickety “rosaries”, thickening of the metaphysical bones of the extremities are characteristic. Also, with phosphate diabetes, there may be pain in the back (usually of a neurological nature) and bones, in rare cases, due to pain in the legs, the child is unable to walk. Intellectual development disorders in this disease, as a rule, are not noted.
One of the earliest methods of diagnosing phosphate diabetes is a general examination of a sick child and the study of the reaction of the disease to the use of conventional doses of vitamin D. As a rule, in this pathology, there is a clinical picture of rickets with resistance to the use of traditional preparations of this vitamin (fish oil, oil solution). For a more accurate determination of phosphate diabetes, methods of biochemical blood and urine testing, X-ray studies, molecular genetic analyses are used. A permanent manifestation of this disease is hypophosphatemia or a decrease in the level of phosphate ions in blood plasma, which is determined by biochemical analysis. At the same time, the calcium level may be normal or even elevated, but some forms of phosphate diabetes (caused by a mutation of the SLC34A3 gene) are also characterized by hypocalcemia. Also, with phosphate diabetes, there may be an increase in the level of alkaline phosphatase and sometimes an increase in the level of parathyroid hormones. Biochemical examination of urine reveals high phosphorus excretion (hyperphosphaturia) and in some cases hypercalciuria.
Radiologically, with phosphate diabetes, the classic signs of rickets are determined – deformities of the bones of the lower legs, knee and hip joints, the presence of osteoporosis (in some cases, local osteosclerosis may occur) and osteomalacia. The bone structure has been changed – the cortical layer thickens, the trabecular pattern becomes coarser, the diaphyses are expanded. Often, the bone radiological age in phosphate diabetes is significantly behind the actual age, which indicates a delay in the development of the skeleton. Modern genetics makes it possible to diagnose almost all types of this disease, as a rule, the method of direct sequencing of genes associated with pathology is used. In some cases, the study of the patient’s hereditary history can indicate the genetic nature of phosphate diabetes.
Phosphate diabetes is treated with a combination of vitamin therapy, orthopedic and sometimes surgical techniques. Despite the other name of this pathology (vitamin D-resistant rickets), this vitamin is actively used in the treatment of this condition, but the dosages should be significantly increased. In addition, patients with phosphate diabetes are prescribed calcium and phosphorus preparations, vitamins A, E and group B. It is also important that therapy with fat-soluble vitamins (especially D and A) should be carried out exclusively under the supervision of a doctor and with careful observance of dosages to prevent undesirable side reactions and complications. To monitor the effectiveness of therapy and the correctness of the prescribed dose of medication, regular measurement of the level of phosphate and calcium in the urine is performed. In especially severe forms of phosphate diabetes, the use of vitamin D can be indicated for life.
With early diagnosis of this disease, its treatment necessarily includes the prevention of skeletal disorders by conventional orthopedic techniques – wearing a bandage for the spine. At a later detection of phosphate diabetes with pronounced skeletal deformities, surgical correction may be indicated. Asymptomatic forms of this disease, manifested only by hypophosphatemia and hyperphosphaturia, according to most experts, do not need intensive treatment. However, careful monitoring of the state of the skeleton, muscular system, kidneys (prevention of urolithiasis) is required, which is carried out through regular medical examinations by an endocrinologist.
Prognosis and prevention
The prognosis of phosphate diabetes can be different and depends on many factors – the type of disease, the severity of symptoms, the age at which the pathology is determined and the start of proper treatment. More often, the prognosis is favorable, but there may be a lifelong need to use vitamin D, calcium and phosphorus preparations. Pronounced skeletal deformities developed as a result of late diagnosis or improper treatment of phosphate diabetes can worsen the patient’s quality of life. Prevention of this hereditary disease is possible only in the form of medical and genetic counseling of parents before conception of a child, methods of prenatal diagnosis have been developed for some forms.