Hereditary Hypophosphataemic Rickets

Hereditary hypophosphataemic rickets is a group of genetic disorders that prevent the kidneys from properly handling phosphate, a mineral essential for building strong bones and teeth. When phosphate levels drop too low, children develop bone abnormalities like bowed legs, while adults experience bone pain and weakness.

Table of contents

• What is hereditary hypophosphataemic rickets
• How common is the condition
• Signs and symptoms
• What causes the condition
• Genetics and inheritance patterns
• Diagnosis and testing
• Treatment approaches

What is hereditary hypophosphataemic rickets

Hereditary hypophosphataemic rickets is a disorder related to low levels of phosphate in the blood, a condition called hypophosphataemia. Phosphate is a mineral that plays a critical role in the normal formation of bones and teeth, in making bones grow and stay strong during childhood, and in maintaining bone strength in adults^[1].

Phosphate levels in the body are controlled mainly by the kidneys. Under normal circumstances, the kidneys excrete excess phosphate in urine and reabsorb this mineral into the bloodstream when more is needed. However, in people with hereditary hypophosphataemic rickets, the kidneys cannot reabsorb phosphate effectively. Too much of this mineral is excreted from the body in urine, resulting in not enough phosphate being available in the bloodstream to participate in normal bone development and maintenance^[1].

This condition is sometimes called by several other names, including X-linked hypophosphataemic rickets, familial hypophosphataemic rickets, vitamin D-resistant rickets, or hereditary hypophosphatemic rickets with hypercalciuria^[6].

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How common is the condition

X-linked hypophosphataemic rickets is the most common form of rickets that runs in families. It affects about 1 in 20,000 newborns^[1][5]. The overall prevalence ranges from 1.7 per 100,000 children to 4.8 per 100,000 persons when both children and adults are counted^[12].

Each of the other forms of hereditary hypophosphataemic rickets has been identified in only a few families, making them much rarer than the X-linked form^[1].

Signs and symptoms

In most cases, the signs and symptoms of hereditary hypophosphataemic rickets begin in early childhood. The features of the disorder vary widely, even among affected members of the same family^[1].

Children

Mildly affected individuals may have hypophosphataemia without other signs and symptoms. More severely affected children experience slow growth and are shorter than their peers^[1]. Affected children develop bone abnormalities that can interfere with movement and cause bone pain^[1].

The most noticeable of these abnormalities are bowed legs or knock knees. These abnormalities become apparent with weight-bearing activities such as walking. Signs typically manifest in the first two years of life when leg bowing becomes apparent with the onset of weight bearing^[5]. If untreated, they tend to worsen with time^[1].

Other signs and symptoms in children include^[5][10]:

• Impaired growth
• Bone tenderness
• Muscle weakness
• Dental abscesses
• Increased tendency for fractures
• Muscle spasms
• Wrist widening
• Hearing loss
• Kidney stones

The disorder may also cause premature fusion of the skull bones, a condition known as craniosynostosis, and dental abnormalities^[1]. Hereditary hypophosphataemic rickets can cause abnormal bone growth where ligaments and tendons attach to joints, a condition called enthesopathy^[1].

Adults

In adults, hypophosphataemia is characterised by a softening of the bones known as osteomalacia^[1]. Adults experience musculoskeletal pain, stiffness, osteoarthritis and enthesopathies, all resulting in impaired physical functioning and mobility^[16]. Musculoskeletal complications such as osteoarthritis, enthesopathy and spinal stenosis can begin as early as 20 years old and accumulate with age^[16].

Other complications in both children and adults include hyperparathyroidism, obesity and impaired hearing as early as age 11 years^[16].

What causes the condition

Hereditary hypophosphataemic rickets can result from mutations in several genes. Mutations in the PHEX gene, which are responsible for X-linked hypophosphataemic rickets, occur most frequently. Mutations in other genes cause the less common forms of the condition^[1].

The genes associated with hereditary hypophosphataemic rickets are involved in maintaining the proper balance of phosphate in the body. Many of these genes, including the PHEX gene, directly or indirectly regulate a protein called fibroblast growth factor 23 (FGF23)^[1].

This protein normally inhibits the kidneys’ ability to reabsorb phosphate into the bloodstream. Gene mutations increase the production or reduce the breakdown of fibroblast growth factor 23. The resulting overactivity of this protein reduces phosphate reabsorption by the kidneys, leading to hypophosphataemia and the related features of hereditary hypophosphataemic rickets^[1].

The observed abnormality is decreased proximal renal tubular resorption of phosphate, resulting in renal phosphate wasting and hypophosphataemia. This defect is due to circulating factors called phosphatonins. The principle phosphatonin in hereditary hypophosphataemic rickets is fibroblast growth factor-23^[3].

Decreased intestinal calcium and phosphate absorption also occurs. Deficient bone mineralisation is due to low phosphate levels and osteoblast dysfunction^[3].

Genetics and inheritance patterns

Researchers have described several forms of hereditary hypophosphataemic rickets, which are distinguished by their pattern of inheritance and genetic cause^[1].

X-linked hypophosphataemic rickets

The most common form of the disorder is known as X-linked hypophosphataemic rickets (XLH). It has an X-linked dominant pattern of inheritance^[1]. The condition is X-linked, meaning that the mutated gene is carried on the X chromosome^[5].

If a father has XLH, all of his daughters will have XLH because daughters always inherit an X chromosome from their father. No sons will have XLH because sons get the X chromosome from their mother^[6].

If a mother has XLH, her children (both sons and daughters) each have a 50% chance of also having XLH. This is because all children inherit an X chromosome from their mother^[6].

An affected male passes the gene variant to all of his daughters and none of his sons, while an affected female passes the variant to 50 percent of her offspring. Given that males possess an X and Y chromosome they are more likely to be affected, while females (with 2 X chromosomes) are less likely to be affected^[5].

Although XLH is a hereditary condition, it can also occur spontaneously in those without any family history. About 20% to 30% of people develop XLH as a result of spontaneous mutations, which can then be passed on to their future children^[6].

Other forms

X-linked recessive, autosomal dominant, and autosomal recessive forms of the disorder are much rarer^[1]. There are several different types of hereditary hypophosphataemic rickets, all of which have variable clinical features and different modes of inheritance and are caused by mutations in a range of genes^[4].

Another rare type of the disorder is known as hereditary hypophosphataemic rickets with hypercalciuria (HHRH). In addition to hypophosphataemia, this condition is characterised by the excretion of high levels of calcium in the urine, a condition called hypercalciuria^[1].

Diagnosis and testing

The diagnosis of hereditary hypophosphataemic rickets is based on signs of rickets or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency^[12]. The diagnosis is based on clinical findings, imaging, blood work and family history^[5].

Clinical findings

Clinical findings that prompt consideration of hereditary hypophosphataemic rickets include the signs and symptoms described earlier, particularly leg bowing, short stature, bone pain, and dental problems^[5].

Imaging tests

X-rays may show bony abnormalities of the upper extremities, lower extremities and sometimes ribs. Occasionally, X-rays may reveal bone fractures^[5]. Kidney ultrasound may reveal kidney stones, a complication of this condition^[5].

Blood tests

Blood work typically reveals low levels of phosphorus and high levels of alkaline phosphatase^[5]. Blood calcium levels and vitamin D 25 (OH) levels are typically normal^[5].

Laboratory tests show that calcium levels in the blood are normal, but that phosphate levels are low. Urine is also tested to detect the levels of phosphate that have been excreted. The phosphate levels in the urine are high^[18].

Genetic testing

Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 before treatment^[12]. Genetic testing can help confirm the diagnosis^[18].

Siblings of children who are affected should have a medical evaluation, including laboratory testing, imaging tests, and sometimes genetic testing. Genetic testing also may be offered to other family members^[18].

Treatment approaches

Treatment of hereditary hypophosphataemic rickets is aimed at raising phosphate levels in the blood, which promotes normal bone formation^[18]. The treatment depends on the underlying cause^[9].

Conventional treatment

Phosphate can be taken by mouth and should be combined with calcitriol, the activated form of vitamin D. Taking vitamin D alone is not enough^[18]. Treatment is oral phosphate plus calcitriol^[3].

The amounts of phosphate and calcitriol must be adjusted carefully because this treatment often leads to high levels of calcium in the blood and urine, a build up of calcium in the kidneys, or kidney stones. These side effects can harm the kidneys and other tissues^[18].

Treatment with vitamin D and phosphate is effective^[8]. Adding vitamin D or calcium to the diet generally corrects the bone problems associated with rickets^[19].

Burosumab treatment

People who have the most common form of hypophosphataemic rickets (X-linked hypophosphataemia) are given the medication burosumab and are not given the phosphate and calcitriol therapy^[18].

Burosumab is a monoclonal antibody and is given as an injection under the skin. It helps increase the levels of phosphorus in the blood, helps decrease the severity of rickets, and in children may increase height. Burosumab can be given to children and adults^[18].

This medication represents an anti-FGF23 antibody treatment for X-linked hypophosphataemia^[9].

Multidisciplinary care

Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organised by a metabolic bone disease expert^[12].

When rickets is due to another underlying medical problem, the child may need additional medicines or other treatment. Some skeletal deformities caused by rickets may require corrective surgery^[19].