X-linked Hypophosphatemic Rickets

Introduction

X-linked hypophosphatemic (XLH) rickets is a rare genetic disorder. Children with XLH have low levels of phosphate in the blood (hypophosphatemia).

Causes

XLH is caused by a defect in the PHEX gene, which plays a crucial role in phosphate balance in our body.

With mutations in the PHEX gene, it results in enhanced secretion of a hormone called fibroblast growth factor 23 (FGF23). With high FGF23 level, it leads to impaired kidney ability to reabsorb phosphate into the bloodstream. As a result, too much phosphate gets excreted through the kidneys and the body becomes depleted of its phosphate stores. Since phosphate is an essential mineral for bone and teeth formation, as well as helping with muscle contraction, the condition leads to a constellation of signs and symptoms described in the subsequent sessions.

Mode of Inheritance

XLH is a X-linked condition. This means that the gene defect is carried on the X chromosome. Given that males possess one X and one Y chromosome, while females possess two X chromosomes, an affected father passes the gene defect to all of his daughters but none of his sons, while an affected mother passes the gene defect to 50% of her children (irrespective of gender).

Sometimes, the gene defect could occur spontaneously (de novo condition). In fact, approximately one-third of affected individuals do not have any family history of XLH.

Prevalence

XLH is a rare condition with a prevalence ranging from 1.7 per 100,000 children to 4.8 per 100,000 persons (adults and children).

Signs and Symptoms

• Legs bowing (outward curving of the lower extremities): children of XLH typically present in the first two years of life when they start to stand, walk and bear weight, and the leg bowing becomes apparent
• Impaired growth/short stature
• Bone pain
• Wrists swelling/widening
• Muscle weakness, delayed walking or unsteady walking
• Dental abscesses
• Muscle spasms
• Hearing loss

The severity of the disease varies, even within the same family with the same genetic defect.

Diagnosis

The diagnosis could be made based on the child’s medical history and family history, x-ray, blood works and urine studies. Your doctor will also examine your child to look for signs and symptoms of XLH.

Generic tests

Initial investigations include:

• X-ray: to look for abnormal bony changes at upper and lower extremities, sometimes ribs.
• Blood work: typically reveals low levels of phosphorous, and high levels of alkaline phosphatase and FGF23. Blood calcium levels and vitamin D levels are typically normal.
• Urine studies: to determine if the kidneys are appropriately reabsorbing phosphate.

Further investigations would be arranged to confirm the diagnosis. These include lab tests (blood or saliva may be checked and the tests would include genetic testing).

Special tests / investigations available in HKCH

In HKCH, your child will be assessed by a multidisciplinary team (MDT) with paediatric endocrinologists, orthopaedic surgeons, clinical geneticists, dental surgeons, paediatric radiologists, physiotherapists and occupational therapists for joint assessment. This MDT service model is the worldwide trend as the standard care for children with rare bone disorders. This one-stop service allows joint discussions between teams and save your travelling time for repeated hospital visits.

Management

General

The main goal of treatment in children with XLH focuses on the correction of low phosphate levels in the blood and oral vitamin D therapy to allow optimal bone growth and development. With early diagnosis, pain and leg bowing usually improve with medical treatment.

Conventional medical treatment:

• Oral administration of phosphate and calcitriol/alphacalcidol (active form of vitamin D) therapy: oral phosphate should be given as frequent as possible, typically 4-6 times daily, to maintain steady phosphate level in blood.
• Calcium supplements: nutritional calcium intake should be kept within the normal range for age. Calcium supplements are not recommended.
• Good oral hygiene with flossing and regular dental follow-up is encouraged to prevent dental abscesses.

Alternative medical treatment:

• Burosumab, a monoclonal antibody that inhibits the activity of FGF23, could be used as an alternative treatment in patients with XLH.
• It is given subcutaneously (injection under the skin) every two-weekly.
• Locally, it is reserved for children with more severe symptoms.

Special treatment options available in HKCH

• In HKCH, children with XLH would be followed by a multidisciplinary team (MDT) consisting of paediatric endocrinologists, orthopaedic surgeons, clinical geneticists, dental surgeons, paediatric radiologists, physiotherapists and occupational therapists.
• Children would be seen in the MDT clinic to facilitate one-stop service and communications between various expert teams.
• Children with XLH would also be assigned to a case manager (a paediatric endocrine nurse):
  • To enhance communication with the MDT
  • To support on daily care and integration into the community
• For children with severe limbs deformity, orthopaedic surgery would be needed.

The following surveillance are required in children with XLH:

• Blood work: regular monitoring of phosphate, calcium, kidney function, alkaline phosphatase, parathyroid hormone and vitamin D level
• Urine studies: calcium, phosphate and creatinine
• Assessment of growth and limbs deformity:
  • Clinical: physical exam by MDT and measurement of the distance between the knees/or feet (intercondylar and/or intermalleolar distance)
  • X-ray: lower extremity X-rays to assess the bony response to therapy
• Kidney ultrasound: to assess for kidney stones, which could be a complication to conventional treatment
• Dental examinations
• Hearing assessment

References and Useful Resources

• Little People of Hong Kong
• Rare Disease Hong Kong
• Asia XLH Link
• Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019 Jul;15(7):435-455.

Acknowledgement

Principal author: Dr Joanna Tung Yuet-ling on behalf of Endocrine Team, HKCH
Initial posting: Mar 2024

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