Rare Classroom: X-Linked Hypophosphatemia

Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

X-Linked Hypophosphatemia

Also known as familial hypophosphatemia.

What is X-Linked Hypophosphatemia?

  • XLH is an inherited metabolic bone disease​
  • People with XLH have low serum phosphate levels​
  • Phosphate levels are low due to excessive phosphate loss in the urine​
  • Urine phosphate loss is caused by excess fibroblast growth factor 23(FGF23) production in bone cells​
  • Low phosphate levels lead to poor bone mineralization which causes a variety of clinical manifestations​
  • The term Vitamin D-Resistant Rickets was initially used for this disorder because XLH was first recognized by the ineffectiveness of normal diets to prevent rickets​
  • Today the syndrome is defined by the root cause of the disorder, rather than on the role played by Vitamin D​
  • The chief aspects of poor health in XLH are the metabolic processes linked to phosphate, such as the effect on bone formation and growth
  • XLH occurs in about every 1:20,000 people​
  • In families with XLH, several extended family members are usually affected​
  • Some reports indicate that the disease may be more severe in males​
  • XLH affects males and females in equal number​
  • Studies suggest there are approximately 12,000 XLH patients in the United States ​​

How Do You Get It?

  • A genetic disorder​
  • Caused by mutations in the PHEX gene​
  • Approximately 175 different mutations have been identified for XLH​
  • Can have the condition without any family history, known as a spontaneous case​
  • Can inherit the disorder from parents​
    • Is X-Linked and dominant​
    • Gene is on X chromosome​
    • If a person has the mutated gene they have XLH​
    • There are no carriers – meaning you either display symptoms or you don’t have the disorder​

What Are The Symptoms?

  • Symptoms of XLH tend to appear when a child begins to bear weight on his or her legs
  • Can go undiagnosed in those with mild to moderate symptoms
  • Osteomalacia (softening of the bones)​
  • Bow legs​
  • Waddling gait​
  • Spontaneous tooth abscesses​
  • Muscle pain and weakness​
  • Growth plate abnormalities in children​
  • Short stature​
  • Bone pain​
  • Fracture​
  • Arthritis​
  • Pain caused by abnormal mineralization​
  • Abnormal bone and tooth development ranging from mild to severe​
  • Hip deformities (coxa vara)​
  • Spinal stenosis – in older adults​
  • Scoliosis – in older adults​
  • Dolichocephaly (abnormally tall, narrow head) – in infants​
  • Vertigo​
  • Tinnitus​
  • Hearing Loss​​​​

How Is It Treated?

  • Treated by endocrinologists and nephrologists with expertise in metabolic bone disorders
  • No cure
  • Medication
    • Active form of Vitamin D (Rocaltrol (Calcitriol) or ONE-ALPHA)​
    • Phosphorus (such as K-PHOS®, Neutra-Phos®, or PHOSPHATE-SANDOZ)​
    • Medications need to be taken in association with regular blood and urine chemistries
  • Surgery/Orthopedic treatment
    • Osteotomy to realign extremely distorted leg curvatures may be necessary for children whose diagnosis was delayed or whose initial treatment was inadequate​
    • Skull deformity may require treatment for synostosis (abnormal fusion of bones)​
    • Spontaneous abscesses often require periodic dental procedures​
  • In Children
    • Medical Therapy
      • Activated vitamin D (calcitriol or alfacalcidol)​
      • Phosphate​
      • Treatment during growth partially corrects leg deformities, decreases the number of surgeries and improves adult height​
    • Monitoring
      • Lab monitoring at 3 month intervals​
      • Normalization of the serum phosphate concentration is not the goal and may harm the patient​
      • X-rays every 2 years after diagnosis​
    • Growth Hormone
      • Sometimes used but there have been a lack of studies proving that benefit outweighs potential side effects​
    • Surgical and Dental Care
      • Surgery used for leg bowing that is unlikely to improve with medical management alone​
      • Epiphysiodesis (fusing of the growth plate of a bone) to correct differential growth of the growth plate​
      • Rigorous dental hygiene​
      • Sealants for teeth often recommended​
    • Expected Outcomes of Treatment
      • Improved growth (treatment at an early age improves height outcomes)​
      • Improved skeletal deformities​
  • In Adults
    • Medical Therapy
      • Activated vitamin D (calcitriol or alfacalcidol)​
      • Phosphate​
      • Burosumab (Crysvita)
        • FDA approved in 2018, used in patients age one or older
      • Medical treatment recommended only if it results in improved clinical condition.  Medical treatment is recommended in patients with the following concerns:​
        • Spontaneous fractures​
        • 3-6 months before planned joint replacement surgery to shorten healing time​
        • Elevated serum alkaline phosphatase activity​
        • Disabling skeletal pain​
    • Monitoring
      • Careful monitoring is used when adults are given medical therapy​
      • Recommended every 3-4 months the first year and every 6-9 months thereafter​
    • Surgery and Dental Care
      • Joint replacement surgery is frequently needed​
      • Good dental hygiene recommended​
      • No dental therapy has been shown to reduce the dental complications that adults with XLH experience​
    • Expected Outcomes
      • Reduce pain​
      • Reduce the softening of bones (Osteomalacia)​
      • Improve fracture healing and surgical recovery​

Where Can I Learn More???

  • Check out our cornerstone on this disease here.
  • Learn more about this disease from the XLH Network.


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