Necessary for diagnosis and treatment: "hypophosphatemic rickets", a rare endocrine disease

The main points of diagnosis and treatment of hypophosphatemic rickets are organized in one article.

Hypophosphatemic rickets are a group of bone mineralization disorders characterized by hypophosphatemia due to a variety of genetic or acquired causes that lead to increased excretion of phosphorus from the kidneys.
It has a high degree of disability, Teratogenicity.

It is called rickets in childhood, and it mainly manifests as square skull, chicken breast, rib beaded, bent limbs (O-shaped or X-shaped legs), and growth retardation.

Adult onset is called osteomalacia, which manifests as fatigue, changes in body shape, short stature, multiple fractures, bone pain, and even disability.

 Etiology and epidemiology Normal calcium and phosphorus levels are a prerequisite for bone mineralization.

In patients with hypophosphatemic rickets, due to genetic mutations such as PHEX, FGF23, DMP1, or other acquired causes, excessive production or degradation of phosphate-regulating factor fibroblast growth factor 23 (FGF23) in the body or degradation of FGF23 is caused, resulting in an increase in the level of FGF23 in the circulation.
The Na-Pi cotransporter in the epithelium of the proximal renal tubule reduces the reabsorption of urinary phosphorus and reduces the renal phosphorus threshold.

At the same time, FGF23 can inhibit the activity of 1α-hydroxylase in the kidney, reduce the production of 1,25(OH)2D, reduce the absorption of calcium and phosphorus in the intestine, and further aggravate hypophosphatemia, leading to bone mineralization disorders and causing rickets Or the performance of osteomalacia.

Hereditary hypophosphatemic rickets are divided into: X-linked dominant inherited hypophosphatemic rickets (XLH), autosomal dominant inherited hypophosphatemic rickets (ADHR), autosomal recessive inherited hypophosphatemic rickets (ARHR), hypophosphatemic rickets Hemophosphate rickets with hyperparathyroidism (HRHPT), McCune-Albright syndrome (MAS), craniofacial dysplasia (OGD), etc.

The most common type of acquired hypophosphatemia osteomalacia is neoplastic osteomalacia (TIO), and others include Fanconi syndrome.

Among them, the pathogenic genes of hereditary hypophosphatemia rickets are shown in Table 1.

 Table 1 Summary of the pathogenic genes of hereditary hypophosphatemic rickets.
Foreign reports have reported that the incidence of hypophosphatemic rickets is about 3.
9/100,000, and the prevalence is about 1/21 000.
The epidemiology of this type of disease in my country The information has yet to be improved.

 Children with clinical manifestations of hypophosphatemic rickets mainly present with square skull, chicken breast, beaded ribs, bracelet sign, foot bracelet sign, and Henry's groove.
Lower limb deformities usually appear when they begin to bear weight at the age of nearly one year, which can be manifested as knee varus ( O-leg) or knee valgus (X-leg), accompanied by growth retardation, short stature, wagging gait, progressive bone deformity, multiple fractures, bone pain, and abnormal tooth development (poor dentin, toothache) , It is not easy to regenerate after falling off) and so on.

The imaging manifestations are skeletal deformities, widening and blurring of the metaphyses of long bones, which are like a cup mouth, and many thin strips of calcification like brush-like shadows can be seen in the cup mouth.

In adulthood, the main manifestations are weakness of limbs, restricted mobility, bone pain, frequently-occurring fractures (long bones, ribs, pelvis and vertebrae can occur), and height reduction.

The imaging manifestations are generally reduced bone density, blurred trabeculae, ground glass-like, pelvic deformities, false fracture lines, and biconcave deformation of the vertebral body.

 Auxiliary examination 1.
Laboratory examination of blood phosphorus level decreased, blood calcium normal or low, urine phosphorus increased, renal phosphorus threshold decreased, blood alkaline phosphatase level increased, PTH may be normal or slightly increased, 1, 25 ( OH) 2D3 is often low (see in patients with FGF23-related hypophosphate rickets), and 25(OH)D can be normal or high.

TIO patients may also be associated with Fanconi syndrome, accompanied by urinary amino acid, urine glucose, or renal tubular acidosis.

As the degree of activity of ADHR patients may be related to abnormal iron metabolism, it is recommended to improve blood routine, peripheral blood smear, serum iron, ferritin and other indicators.

 2.
X-rays of imaging examinations showed that the long bones of the extremities were X-legs or O-legs, metaphyseal cup-like or brush-like changes, and X-rays of the skull, vertebrae, and pelvis showed a general decrease in bone density and trabecular bone.
Fuzziness is ground glass, pelvic deformities, false fracture lines, and vertebral bodies are biconcave and deformed. For patients with neoplastic osteomalacia, after a definitive diagnosis, somatostatin receptor imaging and 68Ga-DOTATATE-PET/CT should be further improved to find tumor lesions.
For local lesions with positive findings, CT and MRI should be further performed Wait for the imaging examination to confirm the location diagnosis.

 3.
Molecular biology testing For patients with a positive family history, an earlier age of onset, or no clear tumor detection, genetic testing such as PHEX, FGF23, DMP1, ENPP1, and SLC34A3 should be perfected to determine whether it is caused by a known disease-causing gene mutation.
Caused by hereditary hypophosphatemic rickets.

 The diagnosis and diagnosis of hypophosphatemic rickets mainly include the following points: 1.
The history collection should pay attention to whether there are symptoms such as bone pain, fatigue, skeletal deformity, restricted activity, pathological fractures, and short height.
Ask about the time of sun exposure, For dairy products intake, calcium supplementation, etc.
, ask whether to take anti-hepatitis B virus drugs (adefovir dipivoxil, tenofovir), aminoglycoside drugs, etc.

 2.
Physical examination Pay attention to whether there are typical signs of rickets (square skull, chicken breast, beaded ribs, bracelet sign, foot bracelet sign, knee varus, knee valgus, etc.
).

 3.
Biochemical examination It is recommended to check blood phosphorus, blood calcium, PTH, 25OHD, serum alkaline phosphatase levels, renal phosphorus threshold, serum protein electrophoresis or immunofixation electrophoresis.

 4.
Imaging examination pay attention to whether there are signs of rickets.

For patients with suspected TIO, functional imaging examinations such as octreotide imaging and 68Ga-DOTATATE-PET/CT are recommended to screen for TIO lesions.

 5.
Detection of pathogenic gene mutations Screen for genetic hypophosphatemic rickets related pathogenic genes mutations.

 Differentiated diseases required for differential diagnosis include vitamin D deficiency or vitamin D-dependent rickets (hereditary type I, type II), osteoporosis, osteogenesis imperfecta, multiple myeloma, and primary hyperparathyroidism Disease, ankylosing spondylitis, tumor bone metastasis and other metabolic bone diseases.

Vitamin D-dependent rickets type I can start at an early age, with typical clinical manifestations of rickets, but laboratory tests usually have significantly lower blood calcium levels, normal or low blood phosphorus, and low urine calcium and phosphorus levels.
1, The level of 25(OH)2D3 is low.

Primary osteoporosis is more common in postmenopausal women or elderly patients.
It can be manifested as short height, kyphosis, and vertebral compression fractures, but the imaging manifestations are sparse trabecular bones, thinning of bone cortex, and no false fracture lines , No pelvic deformation, the patient's blood phosphorus level is normal, and the bone turnover index ALP and β-CTX are usually not high.

Children with osteogenesis imperfecta can manifest as repeated fractures, skeletal deformities, short stature, blue sclera, hearing loss, dentin hypoplasia, etc.
On imaging, they can manifest as repeated fractures, skeletal deformities, slender long bones, and interstitial bones of the skull.
The metaphysis showed popcorn-like changes, collapsed thorax, scoliosis, etc.
, but its blood phosphorus levels were normal, and the bone turnover indicators ALP and β-CTX were usually not high.

Patients with multiple myeloma may have pathological fractures, but in addition to bone destruction, patients are often accompanied by elevated blood calcium, anemia, renal insufficiency, positive M protein, etc.
, and abnormal plasma cells can be seen in bone biopsy.

Patients with primary hyperparathyroidism may have hypophosphatemia, but it is often accompanied by elevated blood calcium and PTH.
Patients may have pathological fractures, fibrocystic osteitis, kidney stones and other manifestations.

Patients with ankylosing spondylitis may present with low back pain, restricted spine movement, straightening of lumbar spine curvature, and ligament calcification on imaging.

In addition to spine involvement, patients may also be accompanied by other system involvement, such as scleritis, etc.
, which may be associated with HLA-B27 positive.
Patients usually have normal blood phosphorus, low alkaline phosphatase, and no pathological fractures.

Patients with tumor bone metastases often have manifestations of the tumor’s primary disease, which are often accompanied by hypercalcemia, elevated ALP, and β-CTX, and pathological fractures may also occur.
The patient's blood phosphorus level is usually normal, and local bone lysis is performed on imaging.
Sexual or osteogenic bone destruction is the main cause, with no typical osteomalacia manifestations.

Treatment of hypophosphatemic rickets 1.
For acquired hypophosphatemic rickets, it is necessary to actively remove the cause.

Patients with suspected TIO should actively look for tumor lesions.
If the location is clear, surgery is the first choice. Patients with Fanconi syndrome caused by adefovir dipivoxil and other drugs or poisons should stop contact with related drugs or poisons.

2.
For the inability to resolve the cause or hereditary low phosphorus rickets, it is usually recommended to give treatment with neutral phosphorus and active vitamin D, generally calcitriol 30-60ng/(kg·d) (0.
5-1.
0µg, divided into 2 doses) Take), phosphorus element 1～4g/d, take 5～6 times.
Generally, calcium supplement is not recommended.

Neutral phosphorus solution formula: disodium hydrogen phosphate (Na2HPO4·12H2O) 73.
1g + potassium dihydrogen phosphate (KH2PO4) 6.
4g, add water to 1000ml (each 100ml contains 779mg of phosphorus).

It should be taken several times in small amounts.

During treatment, blood calcium, phosphorus, alkaline phosphatase, and parathyroid hormone concentrations should be monitored to adjust the dosage, observe changes in patients with bone pain and fatigue symptoms, observe changes in height, and regularly review bone X-rays and renal ultrasound.

If combined with renal tubular acidosis at the same time, attention should be paid to acid correction treatment while supplementing phosphorus.

3.
Combined with severe skeletal deformities, such as scoliosis, thoracic deformation, etc.
, which affect normal organ function, or severe knee varus/knee valgus deformities of the lower extremities, affect appearance and height, or occur pathological fractures that affect daily life , Can choose surgical treatment to improve the quality of life.

Patients with severe vertebral compression fractures should avoid weight-bearing, and external fixation with spinal braces can be used to avoid further aggravation of vertebral compression fractures.

4.
For patients with hereditary low-phosphorus rickets, when conditions permit, it is recommended that family members be screened for corresponding biochemical indicators, bone imaging or gene mutations according to different genetic methods to diagnose as soon as possible.

If combined with pregnancy, prenatal genetic counseling should be recommended.

Diagnosis and treatment process (see figure below) The above content is extracted from: National Health Commission of the People's Republic of China.
Guidelines for the diagnosis and treatment of rare diseases (2019 edition) [J].
Official website of the National Health Commission of the People's Republic of China.