What Is Familial Hypophosphatemia?

Introduction

Familial hypophosphatemia is an inherited disorder characterised by a low level of phosphate in the body, due to impaired kidney conservation of phosphate, low dietary intake, or poor phosphate absorption by the intestine.¹

Phosphate is an important mineral that makes up 85% of bones, 15-20% of soft tissues, and is an important part of DNA. It also affects the amount of calcium and regulates neural function. The understanding of the disease is important for everyone because it can also affect people with no prior heritable history of hypophosphatemia.²

The disease can be inherited as an X-linked dominant disorder or an autosomal dominant disorder affecting different genes.¹ This article will cover all the aspects of hypophosphatemia, from inherited patterns and symptoms to the significance and metabolism of phosphate, diagnosis, and treatments.

Causes

Inheritable factors 

The disorder is most often inherited as an X-linked dominant disorder, but some variants are due to autosomal dominant conditions. As an X-linked condition, the gene PHEX on the X chromosome is mutated, resulting in a variant PHEX protein.

As an autosomal dominant condition, a mutation in the specific gene FGF23 located on the autosomal chromosome 12 causes a higher-than-normal level of phosphate excretion in urine. The level of FGF23 increases in blood, resulting in the conservation of phosphate and vitamin D.¹ Both the mutant genes result in hypophosphatemia.

Role of phosphate metabolism

The human body takes in phosphate in both organic and inorganic forms. The absorption of phosphate starts from the intestine through different pathways based on the level of phosphate available. After that, the kidney balances the phosphate levels by regulating renal excretion and reabsorption of phosphate. Phosphate provides strength to bones and also regulates bone metabolism.²

Hypophosphatemia occurs when the kidney excretes an increased level of phosphate from the body, or when phosphate absorption decreases in the GI tract.

Impact of mutations on phosphate 

Inherited hypophosphatemia is developed due to variant genes, which cause mutations in chromosomes. The disease will be inherited by the child if one of the parents carries the mutant gene, known as dominant hypophosphatemia, or if both parents carry the gene, called recessive hypophosphatemia.

A defect in the gene PHEX causes X-linked hypophosphatemia, the most common type.

Another type is autosomal dominant hypophosphatemic rickets (ADHR), in which the mutant gene is FGF23. Increased levels of FGF23 impact the kidney's function of phosphate regulation, resulting in redundant phosphate excretion. As mentioned, phosphate builds up most of the skeletal system, and a reduced level of phosphate causes bone weakness and dental problems. Another autosomal condition is autosomal recessive hypophosphatemic rickets (ARHR); the variant gene is DMP1, an important gene that helps develop bones and cartilage. In all three conditions, phosphate levels are decreased, eventually affecting bone health.³

Symptoms

The first sign of familial hypophosphatemia is usually seen after years of birth.

Rickets in children is characterised by soft bones and lower limb deformities. Other symptoms in children include bow or knock knees, short stature, and pain during active work.

Infants may have conditions like dolichocephaly, scaphocephaly or craniosynostosis, and hip deformities. 

Adults may have osteomalacia, fractures, arthritis, and pain during muscle movements. They can also have scoliosis or spinal stenosis.¹

Other symptoms 

Dental problems similar to decay and falling of teeth, cavities at a young age, and enamel problems can be caused by low phosphate levels.

Muscle cramps, limited shoulder movements, muscle weakness, and physical pain or stiffness are also hypophosphatemia-related symptoms.

Diagnosis

• Medical history and physical examination 
• Laboratory tests: Serum phosphate levels and low phosphate levels in blood or urine are indicators of positive hypophosphatemia. In children, the normal phosphate ranges from 4.5-6.5mg/dl, and for adults the normal range is 2.5- 4.5 mg/dl phosphate. A phosphate level lower than this is considered hypophosphatemia 
• Kidney function tests to assess the kidney function in retaining phosphate, calcium or vitamin D are additional tests to diagnose hypophosphatemia⁴
• In children, the signs and symptoms can be investigated by X-ray for further investigation, and biochemical tests can be used to confirm the disease
• Genetic testing: family history is very helpful in diagnosing inherited hypophosphatemia. It can be done by checking the specific chromosome responsible for the altered level of phosphate, or analysing family history

Treatment

• Phosphate and calcitriol supplementation
• Oral phosphate salts and vitamin D are given in multiple daily dosage regimens and used in treating moderate-level disease. Unfortunately, they are not permanent cures but help in bone healing and balancing phosphate levels. Safe dosing prevents excess vitamin D levels

An FDA-approved antibody, burosumab, can inhibit FGF23 activity and can be used in children from age 1, as well as adults.¹

Surgical intervention

After careful radiographic findings, some surgical methods can be used to treat lower limb deformities in children and adults if the patient does not show any improvement from medications. 

Osteotomies are performed in children with XLH to improve lower limb functions and appearance. Unfortunately, there is a chance of the condition recurring.

For children with growth issues resulting in short stature, growth hormone therapies may be effective.

In adults, the guided growth method is used in treating lower limb deformities; the method is less harmful, and the patient usually quickly adjusts to the changes. Several other deformities are corrected by internal implants and external fixators; surgical procedures can usually reduce the burden on patients and improve patients' lives.⁵

Conclusion

Hypophosphatemia is a bone disease associated with low phosphate blood levels due to variant genes that regulate bone formation. The disorder can be sex-linked or autosomal, affecting people assigned male or female at birth equally, while the most common form is X-linked hypophosphatemia. Phosphate is an important bone mineral; therefore, low levels may lead to bone weakness, bone deformities and muscle pain. Symptoms range from short stature, deformed lower limbs, rickets in children, osteomalacia in adults, dental problems, and spinal stenosis. Diagnosis is done by physical examination of patients, lab tests that show the levels of phosphate, X-rays, radiographic findings, and genetic testing.

Treatment generally includes phosphate and vitamin D medications that can treat the mild levels of disease, but when the medications fail, orthopaedics would suggest surgical methods that may help in the better functioning of affected bones.

Genetic testing is important in finding out the severity of the disease and knowing which gene is affected, as well as the targeted methods to treat it. 

Patients suffering from familial hypophosphatemia should undergo genetic counselling. The counsellor can provide the right education to patients and their families, and they also provide better diagnosis and treatment options and help in reducing the stress of family members.