Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2)

What is ARHR2?

ARHR2 stands for Autosomal Recessive Hypophosphatemic Rickets Type 2.  Many patients who survive GACI go onto develop ARHR2; however, it has occasionally been seen in patients without a prior history of GACI.  It is a very rare disease typically caused by mutations in the ENPP1 gene.  It is also referred to as ENPP1 Deficiency.  Patients with ARHR2 suffer from low phosphate levels in the blood (hypophosphatemia) as a result of renal phosphate wasting.  The correct balance of phosphate is essential for the normal formation of teeth and bones.  All bones in the body can be affected by rickets.  The frequency of the disease is unknown.

Symptoms of ARHR2

Symptoms of ARHR2 begin in early childhood.  Like GACI, the manifestations of the disorder can vary widely, even among members of the same family.

  • Bone deformities that may limit movement – The most noticeable bone changes are Genu Varum or Varus (bowed legs) or Genu Valgum or Valgus (knock knees).  However, bone changes in the skull, ribs, and other parts of the body can also be the result of ARHR2.  If your child is treated for ARHR2 with regular phosphate and active Vitamin D, any deformity in the bones may start to correct naturally if the child is still growing.
  • Craniosynostosis – This is the premature fusion of the skull bones.
  • Bone pain – Bone pain as a result of ARHR2 can be very severe, and pain relief may be required.  You should consult your doctor to find out what pain medication and dose would be best for your child. If your child is treated for ARHR2 with regular medication, the bone pain may be eliminated.  In cases where the pain isn’t eliminated or returns as the patient gets older, pain management may be necessary and even essential.  Pain in the bones, joints, hips, and neck may be experienced even with satisfactory blood test results.
  • Fatigue – Rest may be required to relieve aching, pain, and tiredness.  Gentle exercises (e.g. swimming, pilates, aqua aerobics, walking, etc.) can help to relieve aches and pains and avoid stiffness.
  • Dental issues – Over-retained primary teeth, infraocclusion, submerging of previously erupted teeth, increased cementum, and other dental abnormalities are possible effects of ARHR2.  Patients with ARHR2 should visit the dentist regularly to ensure their teeth remain healthy.
  • Short Stature
  • Hypophosphatemia – Low level of phosphate in the blood
  • Hyperphosphaturia – Too much phosphate in the urine
  • Elevated Plasma Alkaline Phosphatase
  • Cervical Fusion of the Spine – Patients with GACI/ARHR2 should be evaluated by their doctors for cervical spine fusion (by way of lateral cervical spine x-ray) in advance of elective surgeries that may require intubation.  Fiberoptic intubation may be considered as an effective technique for establishing airway access in patients with both anticipated and unanticipated difficult airways.  Cervical fusion of the spine can cause back and neck pain, and a reduced range of movement in the neck. 
  • Calcific Enthesopathy – Calcific Enthesopathies can develop over time. This is when calcium deposits develop in the sites where ligaments and tendons attach to the bones.  This may be inflammatory and can cause pain in the area it affects.

Early Diagnosis

If your child is having regular blood tests for GACI, the signs of ARHR2 may be identified long before any bone abnormalities or bone pain have appeared.  Doctors of patients with GACI need to be aware of this and monitor patients appropriately for the development of ARHR2.  If rickets are not treated promptly, bone deformities may develop and surgical interventions may be necessary.  A blood test that shows low levels of phosphate (Phosphate Inorg.) and high levels of alkaline phosphatase (Alk Phos) can be indicators of ARHR2.  The creatinine to calcium ratio in the urine and blood levels of parathyroid hormone (PTH) should also be monitored in patients under therapy, to avoid overtreatment.

Rickets can develop at any age and have been seen in newborn babies diagnosed with GACI.  If you notice that your baby is crying a lot or appears to be in pain when you’re changing their clothing or holding them, don’t hesitate to bring them to your doctor and ask for an evaluation for ARHR2.

Treatment

ARHR2 is treated with daily phosphorus and active Vitamin D supplementation.  The phosphorus is typically taken every 6 hours to maintain proper levels in the body. Regular blood and urine tests are done to ensure the correct balance is achieved. Vitamin D3 (cholecalciferol) is often taken in conjunction with active Vitamin D (e.g. calcitriol or alfacalcidol).

Doctors differ in their opinion on whether medication should be taken during waking hours only or spread evenly throughout the day and night (i.e. waking the child at night to take a dose).  Your own doctor will advise you on what way they recommend you should administer medication.

Even when a patient is treated with medication for ARHR2, it is not expected that the phosphate (Phosphate Inorg.) level in blood tests will return to normal.  This is not the objective of treatment.  The patient continues to waste phosphate through their urine, and the medication, taken multiple times a day, replaces the phosphate. If the treatment is successful, the Alkaline Phosphatase (Alk Phos) level in the blood should return to the normal range.

Side Effects of Treatment

Nephrocalcinosis can develop in patients being treated for ARHR2 (Rickets) with phosphate supplementation. Nephrocalcinosis is a build-up of calcium in the kidneys which can be seen in a renal ultrasound. This is different from the type of calcification that GACI causes. There is no known cure for nephrocalcinosis.  Rickets medication levels may need to be reduced to prevent further damage to the kidneys while still allowing the bones some chance to heal.  Patients on medication for ARHR2 should have regular kidney ultrasounds to monitor for nephrocalcinosis.  The nephrology and endocrinology teams will need to work closely together to set medication doses, to ensure both the kidneys and bones are protected.

Another side effect of the medication for ARHR2 is gastrointestinal upset including diarrhea and nausea.  You can discuss with your doctor reducing the amount of phosphate taken in each dose and adding in an extra dose to compensate if stomach upset occurs.  Your doctor will need to work this out with you to ensure the correct balance of phosphate and vitamin D is maintained.  You may need to advise your child’s school or caregiver that your child may need to make frequent and urgent trips to the bathroom as a side effect of their medication.

Surgical Intervention

It wasn’t always known that ARHR2 was associated with GACI.  Patients went untreated because they didn’t present with the typical x-ray features of rickets.  As a result bone deformity had already occurred by the time patients were diagnosed and treated with medication.

For bone deformities to be corrected by medication, the patient must be young and still have some growth in height left to do.  If correct biochemical balances are achieved during this growth period, bones can begin to heal and realign.  In some cases, improvement will be significant enough to avoid surgery.

If a surgical route cannot be avoided, there are two possible options for surgery to correct deformities of the legs – eight plate surgery (also known as guided growth) or osteotomy.  Your orthopedic surgeon will advise which surgical option would suit best if required.

Eight Plate Surgery
A plate is attached to one side of the growth plate above or below the knee or sometimes both above and below the knee.  This plate temporarily inhibits growth on the side of the growth plate that it is attached to, while the opposite side continues to grow naturally.  Over time, as the patient grows, this helps to realign the legs.

The plates can remain in place anywhere from several months to one year or more and are removed when the legs are aligned.  Both the insertion and removal of eight plates are performed under general anesthetic.  The area of insertion/removal will be stiff and quite sore in the days after surgery, but mobility should quickly return.

Osteotomy
An osteotomy is a surgical procedure that is performed where a bone is cut to change its alignment.  A wedge-shaped piece of bone is removed and then the bone is pinned together in the correct alignment to heal.   The procedure is done under a general anesthetic and the recovery may be extensive and take up to 6 months or more.  Normally only one leg is operated on at a time and the surgery on the second leg would not be performed until after the patient has recovered from the first surgery.

Bone Deformities in Other Areas

ARHR2 can also affect the bones of the skull, ribs, and other parts of the body.  Parents should discuss with their doctors and orthotic specialists the benefits of using an orthotic brace, helmet therapy, etc. to treat the individual areas of the body that are affected by ARHR2. Significant improvement can be achieved if correct action is taken while the bones are still actively growing.