Hypophosphatemic Rickets (Hereditary Hypophosphatemic Rickets, Hypophosphatemic Osteomalacia)

Hypophosphatemic Rickets
Body Parts: Whole Body
Medical Subjects: Children's Health Bone Genetic disease

What Is Hypophosphatemic Rickets?

What is hypophosphatemic rickets?

Hypophosphatemic rickets are metabolic bone diseases that occur in children.

Hypophosphatemic rickets is a metabolic bone disease that causes renal tubular reabsorption of phosphorus for various reasons, resulting in excessive loss of phosphorus in the kidney and bone dysplasia. Children with HYPOPHOSPHATEMIC RICKETS often present with hypophosphatemia, short stature, bone deformities of both lower limbs, etc.

The cause of hypophosphatemic rickets is primarily congenital or hereditary, or secondary to neoplasia and other renal tubular diseases. The treatment focuses on preventing the occurrence or aggravation of bone deformities, and surgical treatment is required if necessary.

Is hypophosphatemic rickets common?

Hypophosphatemic rickets is a metabolic bone disease that occurs in children, and it is uncommon in terms of prevalence, occurring in one case per 25,000 people.

Are hypophosphatemic rickets and hypophosphatemic osteomalacia the same disease?

These two diseases actually belong to a class of diseases from the pathogenesis, both of which are due to the obstacle of phosphorus absorption by the proximal convoluted tubules of renal tubules, resulting in excessive phosphorus loss from the kidney, increased urine phosphorus and decreased blood phosphorus, leading to bone problems.

The disease in childhood can cause rickets, so it is called hypophosphatemic rickets, and the disease in adulthood can cause osteomalacia, so it is called Hypophosphatemic Osteomalacia. Therefore, the two diseases are different manifestations of the same disease in different age groups.

What are the types of hypophosphatemic rickets?

Hypophosphatemic rickets can be divided into two types according to the cause of disease, i.e., congenital inheritance and acquired inheritance. Congenital inheritance is the most common one, including:

  • X- linked hypophosphatemic rickets, abbreviated as XLH, caused by PHEX gene mutation is the most common type of hypophosphatemic rickets, with more female patients.
  • Autosomal dominant hypophosphatemic rickets, abbreviated as ADHR, is caused by mutations in the fibroblast growth factor (FGF)-23 gene, and the incidence of this form is low.
  • Autosomal recessive hypophosphatemic rickets, abbreviated as ARHR, caused by mutations in the MPl gene and the ENPPl gene, which are relatively rare.
  • Autosomal recessive hypophosphatemic rickets with hypercalciuria caused by SLC34A3 gene mutation, abbreviated as HHRH, is different from other types. This type of hypophosphatemia can stimulate the production of active vitamin D in the body, increase the absorption of calcium and phosphate in the intestinal tract, generate hypercalciuria, and inhibit the synthesis of parathyroid hormone.

And as for acquired have the following circumstances:

  • Fanconi syndrome characterized by proximal tubular acidosis, increased urine glucose with normal blood glucose, hypophosphatemia, hypouricemia, hypokalemia, aminoaciduria, and proteinuria.
  • Tumor-associated hypophosphatemic osteomalacia, abbreviated as TIO, is a rare paraneoplastic syndrome caused by long bone stromal tumors and tumors of the distal extremities, sinus, nasopharynx and groin. The tumors are mostly benign and grow slowly, usually manifesting as skeletal muscle pain, muscle weakness and bone fracture.
  • Single or multiple fibrous dysplasia of bone (such as McCune-Albright syndrome).


What Is The Cause Of Hypophosphatemic Rickets?

What is the cause of the hypophosphatemic rickets?

Phosphorus is an important element that constitutes the body cell tissue, 85% of phosphorus is stored in bone tissue, so phosphorus is quite important for the health of bone tissue.

Food is the main source of phosphorus for the body. Phosphorus in food is absorbed through the small intestine. Phosphorus is mainly excreted through the kidneys. About 80% of phosphorus is re-absorbed into the body when passing through the proximal tubules of the kidneys. Only about 20% of phosphorus is excreted from urine.

The intestinal absorption of phosphorus and the kidney excretion of phosphorus are in balance under the regulation of the body, ensuring the stability of phosphorus in bone tissues. Among them, fibroblast growth factor -23 (abbreviated as FGF-23, also known as dephosphorizing hormone) can increase urinary phosphorus excretion.

In addition, parathyroid hormone (abbreviated PTH), growth hormone (since abbreviated GH), insulin (abbreviated INS), insulin-like growth factor -1 (abbreviated IGF-1), epidermal growth factor, thyroid hormone, glucocorticoids, and active vitamin D(1,25- dihydroxyvitamin D3) also regulate kidney absorption and excretion of phosphorus.

When something goes wrong with a certain part of the body, such as gene mutation or some other reason that affects the above regulatory factors and leads to excessive kidney phosphorus removal, urine phosphorus will be increased and blood phosphorus will be decreased. If the disease occurs in infancy, it will eventually lead to hypophosphatemic rickets.

Is hypophosphatemic rickets contagious?

Hypophosphatemic rickets are not contagious.

Is hypophosphatemic rickets hereditary?

Most hypophosphatemic rickets are inherited as a hereditary disease. The most common form of hypophosphatemic rickets is the X- linked inheritance, which accounts for 80% of familial hypophosphatemic rickets. Rare have autosomal dominant inheritance. Rare with autosome recessive inheritance, etc.


What Are The Symptoms Of Hypophosphatemia Rickets?

What are the common manifestations of hypophosphatemic rickets?

The main manifestations of hypophosphatemic rickets are as follows:

  • Slow growth, usually normal height at birth but later reduced growth rate which can eventually lead to short stature, lower extremity bone involvement being more pronounced than upper extremity bone (lower extremity being particularly short).
  • Skeletal malformations such as the square skull, beaded ribs (i.e., dilated as pearls at the junction of ribs and costal cartilage) and Harrion's sulcus (an oblique depression in the lateral chest wall in infancy) can be seen in infancy.
  • Upper and lower limb malformations such as genu valgus (X-leg) and genu varus (O-leg) may occur when crawling or walking is initiate in infancy.
  • Repeated fractures can also aggravate bone deformity and bone or joint pain, most of which are aggravated after the activity.
  • Retarded dentition, calcified dentin, teeth injury, easy to fall off and periodontal abscess.
  • Other manifestations include the children's susceptibility to burnout, crying and underweight.

What are the serious consequences of hypophosphatemic rickets?

The main serious consequences of hypophosphatemic rickets are as follows:

  • Slow growth, short stature.
  • Skeletal deformity.
  • Bone pain, fracture, etc.


How To Check For Hypophosphatemic Rickets?

How to diagnose hypophosphatemic rickets?

In making the diagnosis of hypophosphatemic rickets, the doctor mainly referred to the presentation, tests and examinations of the child.

Hypophosphatemic rickets is almost certain if the child presents with severe rickets at around the age of L. For example:

  • Lower limb bending deformity and other more serious manifestations.
  • Laboratory blood phosphorus significantly decreased.
  • Calcium in blood is normally low.
  • L, 25-(OH)2-D3 normal or decreased.
  • Elevated or normal serum parathyroid hormone.
  • Urinary phosphorus is increased and the renal tubular phosphorus reabsorption rate is often less than 85%.

If conditions permit, further detection of gene mutation is required and the diagnosis can be further confirmed if the mutated gene can be detected.

What tests are needed to diagnose hypophosphatemic rickets?

Physical examinations, blood and urine tests, imaging examinations, and gene mutation tests are generally required.

Physical examination: It is mainly used to understand the height of the child and whether there is deformity, record the height of the child, knee spacing and other values, and observe the manifestations of bone deformity.

Blood and urine tests: Used chiefly to aid in diagnosis. Include values for blood phosphorus, blood calcium, alkaline phosphatase (ALP), L, 25-(OH)2-D3, 24-hour urine phosphorus, and urine calcium. Hypophosphatemic rickets are characterized by low blood phosphorus, high urinary phosphorus, increased blood alkaline phosphatase, normal blood calcium, normal or low urine calcium, normal or decreased L, 25-(OH)2-D3, and normal parathyroid hormone. According to the urine phosphorus, blood phosphorus, creatinine can calculate renal tubular phosphorus heavy absorption rate (abbreviated as PTR), if the index is less than 85%, it suggests that high urine phosphorus, support the performance of low phosphorus rickets. The detection of blood fibroblast growth factor -23 (abbreviated as FGF-23) is important for diagnosis.

Imaging examination: mainly B-scan of kidney, to understand whether there are abnormal conditions such as kidney stones. X-ray film of bone to look for the imaging manifestations of hypophosphatemic rickets, such as vague brush-like or cup-like changes in the metaphysis, thinning of the bone cortex, bone rarefaction, and vague or absent calcification bands at the distal ends of ulna and radius. If tumor-induced hypophosphatemic rickets is suspected, imaging examinations such as CT, magnetic resonance imaging, and PET-CT can be performed to help find the tumor.

Gene mutation detection: Blood was drawn out for related pathogenic genes, such as PHEX DMPl, ENPPl, FAM20c, SLC34A3 and CLCN5.

What diseases are easy to confuse with hypophosphatemic rickets? How to distinguish?

Children with hypophosphatemic rickets and vitamin D deficiency rickets presented with rickets and were therefore confused and misdiagnosed.

Hypophosphatemic rickets is characterized by increased urinary phosphorus, decreased blood phosphorus and ineffective treatment with conventional calcium and vitamin D. However, after treatment with conventional vitamin D and calcium for 2–4 weeks, the symptoms of vitamin D-deficient rickets significantly improved, and the blood calcium, phosphorus and alkaline phosphatase contents also tended to be normal.

If sunshine increases after one year old and rickets symptoms aggravate, blood phosphorus and urine phosphorus should be checked timely, for example, blood phosphorus is reduced and urine phosphorus is increased, and when calcium and vitamin D treatment is ineffective, the diagnosis of hypophosphatemic rickets should be considered to avoid missed diagnosis and misdiagnosis.


How To Prevent Hypophosphatemic Rickets?

Can hypophosphatemic rickets be prevented?

Most of the hypophosphatemic rickets are congenital genetic diseases, and antenatal consultation should be conducted well for families with history of similar diseases, which is helpful to reduce the incidence of diseased children at birth.

How can patients with hypophosphatemic rickets prevent other illnesses?

Regular medication, regular re-examination, and adjustment of medication according to the re-examination indicators to balance the dose of calcitriol with the dose of phosphorus preparation can well prevent the occurrence of related complications.


How To Treat Hypophosphatemic Rickets?

What department does hypophosphatemic rickets need to see a doctor?

Endocrinology or pediatrics.

Can hypophosphatemic rickets heal themselves?

Most hypophosphatemic rickets are not self-sufficient due to congenital genetic factors and require long-term treatment. A small number of hypophosphatemic rickets are secondary to acquired certain diseases, such as tumor-associated hypophosphatemic rickets, which can be mostly recovered if the etiology of the tumor is removed.

How to treat hypophosphatemic rickets?

The therapeutic purpose of hypophosphatemic rickets is to prevent the occurrence and aggravation of bone deformity, increase blood phosphorus as much as possible, maintain it at a normal low value, normalize blood alkaline phosphatase, and prevent secondary hyperparathyroidism, hypercalcemia, and hypercalciuria.

Currently, combined therapy with phosphate cement and vitamin D derivative (i.e., calcitriol) is mainly administered, and the treatment lasts until the end of the growth and development period.

An important principle of treatment is that the dose of calcitriol is balanced with the dose of phosphorus preparation. Excessive dose of calcitriol can lead to hypercalcemia and hypercalciuria. Excessive phosphorus preparation can cause secondary hyperparathyroidism. The specific conditions are as follows:

  • When radiographs show an active lesion in the metaphysis, the amount of calcitriol and phosphate should be increased.
  • When parathyroid hormone is elevated and there is no hypercalcemia or hypercalciuria, the calcitriol dose should be increased alone.
  • Vitamin D poisoning should be considered when hypercalcemia or hypercalciuria occurs due to normal parathyroid hormone, and calcitriol needs to be reduced.

In conclusion, the specific drug dosage needs to be adjusted according to the specific situation and the test results.

It has been reported that recombinant human growth hormone (abbreviated as rhGH) can also be used in the above routine treatment, to promote the growth rate of children, increase the half-life of phosphate in the body, increase bone density and improve height. However, the therapeutic effect of this drug is not sure yet.

For patients with severe skeletal deformities, their condition is stable after medical treatment, and surgical correction should be considered after puberty.

What are the common side effects of using drugs to treat hypophosphatemic rickets?

  • Improper administration of phosphorus may result in diarrhea, bloody stool, and abdominal pain.
  • Secondary hyperparathyroidism occurs with excessive phosphorus doses.
  • Excessive doses of calcitriol can lead to vitamin D poisoning, hypercalcemia and hypercalciuria.

Can hypophosphatemic rickets be cured?

Hypophosphatemic rickets cannot be cured if they are caused by congenital genetic factors. If it is caused by acquired certain diseases, the hypophosphatemic rickets can be radically treated if the etiology of the disease can be removed, such as tumor-related hypophosphatemic rickets.


What Should Be Paid Attention To In Life For Patients With Hypophosphatemic Rickets?

What should patients with hypophosphatemia rickets pay attention to in their diet?

Food is the main source of phosphorus for the body. Most foods such as meat and fish are rich in phosphorus. Appropriately increase the intake of these foods. A balanced diet, no picky eaters, and no partial eclipse will help the treatment of this disease.

Does hypophosphatemia rickets need to be reviewed? How to review?

Hypophosphatemic rickets require periodic review:

  • Start treatment. Review monthly if medication is in adjustment phase.
  • Follow-up stabilization. Serum calcium and phosphorus, serum creatinine, alkaline phosphatase, 24-hour urine calcium and phosphorus, and urine creatinine were reviewed every three months.
  • Parathyroid hormone is reviewed every 6 months.
  • Renal ultrasound was monitored every 6 to 12 months.
  • Bone radiographs were reviewed every 2 years.

Treatment was adjusted according to the monitoring results by increasing the phosphorus dose if the alkaline phosphatase was elevated, increasing the calcitriol and/or reducing the phosphorus dose if the parathyroid hormone was above the normal range, and decreasing the calcitriol dose if high urinary calcium appeared.

Due to the large fluctuation of blood phosphorus level, changes in phosphorus absorption and metabolic kinetics, and the presence of low blood phosphorus when the patient was fasted, blood phosphorus level was not used as an indicator to measure phosphorus requirement. Complications such as hyperparathyroidism, kidney calculi and renal calcinosis were avoided during the treatment.

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