NORD gratefully acknowledges GACI Global and it's medical advisors for the preparation of this report.
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a skeletal condition that is characterized by rickets, bone pain, bone deformities, increased risk of bone fractures, fatigue, short stature, and calcium deposits in the sites where ligaments and tendons attach to the bones (calcific enthesopathy).
ARHR2 is an extremely rare condition, characterized by low phosphate levels in the blood (hypophosphatemia) resulting from renal phosphate wasting. ARHR2 affects males and females equally and occurs in populations all around the world. ARHR2 can develop at any time in childhood and has been seen in newborn babies. The manifestations of ARHR2 can vary widely, even among members of the same family. The prevalence of ARHR2 is unknown.
ARHR2 is caused by changes (mutations) in the ENPP1 gene, and is thus part of ENPP1 deficiency. Depending on age, ENPP1 deficiency can manifest in two different presentations (phenotypes): ARHR2 and generalized arterial calcification of infancy (GACI) type 1. GACI type 1 causes pathological soft tissue calcification, including mineralization of the arteries, heart, kidneys, and joints. Most infants with ENPP1 deficiency who survive GACI type 1 will develop ARHR2, although ARHR2 can also be seen in patients without a prior history of GACI.
ARHR2 is treated with daily phosphorus and active vitamin D supplementation. The phosphorus is typically taken every four to six hours to maintain proper levels in the body. Regular blood and urine tests are required to ensure the correct balance is achieved. Early diagnosis and prompt treatment can help prevent/correct bone deformities and relieve bone pain.
Bone deformity, bone pain, increased risk of bone fractures, and short stature are symptoms of ARHR2. The most noticeable bone changes are bowed legs (genu varum) or knock knees (genu valgum), but bone changes in the skull (craniosynostosis), ribs, and other parts of the body can also be the result of ARHR2. All bones in the body can be affected by ARHR2.
ARHR2 doesn’t always present with the typical X-ray features of rickets, and diagnosis can be confirmed by a blood test that shows low levels of phosphate (hypophosphatemia) and elevated alkaline phosphatase and FGF23, in the setting of ENPP1 mutations. Patients also have too much phosphate in their urine (hyperphosphaturia) due to renal phosphate wasting.
Over-retained primary teeth, teeth that don’t fully erupt (infraocclusion), increased cementum, ankylosis, and slow orthodontic movement are also possible symptoms of ENPP1 deficiency.
Calcium deposits that develop in the sites where ligaments and tendons attach to the bones (calcific enthesopathies) can also be a symptom of ARHR2 in later life. This may be inflammatory and can cause pain in the area it affects.
ARHR2 is caused by mutations in the ENPP1 gene and is also known as ENPP1 deficiency. ENPP1 encodes a protein called ectonucleotide pyrophosphatase / phosphodiesterase 1 (NPP1), which is a major generator of extracellular pyrophosphate (PPi). Because PPi inhibits calcification, two inactivating mutations in the ENPP1 gene are also responsible GACI type 1.
In patients with ARHR2, high circulating levels of FGF23 have been described. FGF23 is a secreted protein, which reduces the activity of sodium-phosphate co-transporters NPT2a and NPT2c resulting in renal phosphate wasting, diminishes the renal 1α-hydroxylase, and increases the 24-hydroxylase activity. Moreover, FGF23 acts at the parathyroid gland to decrease parathyroid hormone synthesis and secretion. Currently, it is unclear how mutations in the ENPP1 gene results in high FGF23 levels.
Some researchers hypothesize that patients with ENPP1 deficiency develop a state of low phosphate in their serum, known as hypophosphatemia, as a compensatory mechanism for the state of low PPi in order to inhibit or decrease ectopic calcification. This hypophosphatemia leads to rickets in affected patients.
ARHR2 is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
ARHR2 affects males and females equally and occurs in populations all across the world. The manifestations of ARHR2 can vary widely, even among members of the same family. ARHR2 can affect patients of any age but symptoms are most likely to appear in childhood. The prevalence of ARHR2 is unknown.
If a patient with GACI type 1 is having regular blood tests, the signs of ARHR2 may be identified long before any bone abnormalities or bone pain have appeared. A blood test that shows low levels of phosphate and high levels of alkaline phosphatase can be indicators of ARHR2.
If there is no history of GACI type 1, ARHR2 should be considered in patients presenting with bone deformities, frequent bone fractures, and bone pain. ARHR2 doesn’t always present with the typical X-ray features of rickets, and diagnosis can be confirmed by a blood test that shows low levels of phosphate (hypophosphatemia) and elevated alkaline phosphatase and FGF23 in the setting of ENPP1 deficiency. Patients also have too much phosphate in their urine (hyperphosphaturia) due to renal phosphate wasting.
To confirm an ARHR2 diagnosis the patient (and sometimes parents) may be genetically tested for mutations in the ENPP1 gene.
Ongoing monitoring of ARHR2 includes ultrasounds, X-rays, frequent lab and urine work, orthopaedic evaluation/ intervention, and physical therapy.
Significant improvement in symptoms can be achieved if corrective action is taken while the bones are still actively growing. Early diagnosis and prompt treatment can help prevent/correct bone deformities and relieve bone pain.
Potential side effects of phosphorus supplementation can include gastrointestinal upset, diarrhea, and nausea. Patients should also be monitored via kidney ultrasound as a build-up of calcium in the kidneys (nephrocalcinosis) is another possible side effect of phosphate supplementation.
ARHR2 is treated with daily phosphorus and active Vitamin D supplementation which maintains proper levels in the body as determined by regular blood and urine tests. Phosphorus is typically taken every four to six hours to maintain proper levels in the body. Even with treatment, patients will continue to waste phosphate through their urine, but the frequent medication administration replaces the lost phosphate.
Early diagnosis and prompt treatment can help prevent/correct bone deformities and relieve bone pain. If bone deformities are not corrected at a young age through medication, surgical intervention may be required. There are two possible options for surgery to correct deformities of the legs – eight-plate surgery (also known as guided growth) and bone realignment surgery (osteotomy).
Patients with ARHR2 are usually followed by a team of specialists which may include endocrinology, nephrology, orthopaedics, physical therapy, dental, and audiology.
In 2015, Demetrios Braddock, MD, PhD, a pathologist and professor from Yale University along with his team published an article in Nature Communications demonstrating reduction of calcification and prevention of mortality in a mouse model of GACI given a replacement version of the enzyme ENPP1. This discovery has led to the establishment of a biotechnology company developing new medicines to treat rare disorders of calcification including GACI. These medicines may also be used to treat ARHR2.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 613312. 07/23/2014. Available at: https://www.omim.org/entry/613312 Accessed Nov 5, 2019.
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