Also known as: ARHR2; ENPP1 deficiency Background Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2) is an extremely rare skeletal condition, characterized by low phosphate levels in the blood (hypophosphatemia) as a result of high phosphate excretion in the urine (renal phosphate wasting). 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 calcification 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. Credits Medical text written April 2020 by GACI Global and their medical advisors on behalf of GACI Global. Although great care has been taken in the compilation and preparation of all entries to ensure accuracy, we cannot accept responsibility for any errors or omissions. Any medical information is provided is for education/information purposes and is not designed to replace medical advice by a qualified medical professional. What are the symptoms? Bone deformity.Bone pain.Increased risk of bone fractures.Short stature.Bone changes in the skull (craniosynostosis).Dental issues e.g. over retained primary teeth, teeth that don’t fully erupt.Calcium deposits where ligaments and tendons attach to the bone (calcific enthesopathies). The most noticeable bone changes are bowed legs (genu varum) or knock knees (genu valgum), but bone changes in other parts of the body can also be the result of ARHR2. What are the causes? ARHR2 is caused by mutations in the ENPP1 gene and is also known as ENPP1 deficiency. 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 pyrophosphate (PPi) in order to inhibit or decrease calcification in the soft tissues/joints. This hypophosphatemia leads to rickets in affected patients. How is it diagnosed? 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. How is it treated? 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. Inheritance patterns and prenatal diagnosis Inheritance patterns ARHR2 is inherited in an autosomal recessive pattern. 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. Is there support? GACI Global Tel: +353-87-244-4488Email: info@gaciglobal.orgWebsite: gaciglobal.org GACI Global is a nonprofit organization whose mission is to connect families affected by Generalized Arterial Calcification of Infancy or Hypophosphatemic Rickets caused by ENPP1or ABCC6 Deficiencies to each other and to the medical community. The organization strives to provide current educational resources and supports ongoing research. Their goal is to provide information about what complications can occur due to ENPP1 and ABCC6 Deficiencies (e.g. GACI, ARHR2) and to provide hope for families impacted by the condition. They hope that their website, newsletter, and social media outlets act as a resource not only for medical information, but for personal support during your own GACI/ARHR2 journey. Their community is small, but growing and they hope to offer support and information to families affected by this disorder around the world. Group details added April 2020.
What are the symptoms? Bone deformity.Bone pain.Increased risk of bone fractures.Short stature.Bone changes in the skull (craniosynostosis).Dental issues e.g. over retained primary teeth, teeth that don’t fully erupt.Calcium deposits where ligaments and tendons attach to the bone (calcific enthesopathies). The most noticeable bone changes are bowed legs (genu varum) or knock knees (genu valgum), but bone changes in other parts of the body can also be the result of ARHR2. What are the causes? ARHR2 is caused by mutations in the ENPP1 gene and is also known as ENPP1 deficiency. 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 pyrophosphate (PPi) in order to inhibit or decrease calcification in the soft tissues/joints. This hypophosphatemia leads to rickets in affected patients. How is it diagnosed? 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. How is it treated? 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. Inheritance patterns and prenatal diagnosis Inheritance patterns ARHR2 is inherited in an autosomal recessive pattern. 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. Is there support? GACI Global Tel: +353-87-244-4488Email: info@gaciglobal.orgWebsite: gaciglobal.org GACI Global is a nonprofit organization whose mission is to connect families affected by Generalized Arterial Calcification of Infancy or Hypophosphatemic Rickets caused by ENPP1or ABCC6 Deficiencies to each other and to the medical community. The organization strives to provide current educational resources and supports ongoing research. Their goal is to provide information about what complications can occur due to ENPP1 and ABCC6 Deficiencies (e.g. GACI, ARHR2) and to provide hope for families impacted by the condition. They hope that their website, newsletter, and social media outlets act as a resource not only for medical information, but for personal support during your own GACI/ARHR2 journey. Their community is small, but growing and they hope to offer support and information to families affected by this disorder around the world. Group details added April 2020.
What are the symptoms? Bone deformity.Bone pain.Increased risk of bone fractures.Short stature.Bone changes in the skull (craniosynostosis).Dental issues e.g. over retained primary teeth, teeth that don’t fully erupt.Calcium deposits where ligaments and tendons attach to the bone (calcific enthesopathies). The most noticeable bone changes are bowed legs (genu varum) or knock knees (genu valgum), but bone changes in other parts of the body can also be the result of ARHR2.
What are the causes? ARHR2 is caused by mutations in the ENPP1 gene and is also known as ENPP1 deficiency. 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 pyrophosphate (PPi) in order to inhibit or decrease calcification in the soft tissues/joints. This hypophosphatemia leads to rickets in affected patients.
How is it diagnosed? 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.
How is it treated? 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.
Inheritance patterns and prenatal diagnosis Inheritance patterns ARHR2 is inherited in an autosomal recessive pattern. 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.
Is there support? GACI Global Tel: +353-87-244-4488Email: info@gaciglobal.orgWebsite: gaciglobal.org GACI Global is a nonprofit organization whose mission is to connect families affected by Generalized Arterial Calcification of Infancy or Hypophosphatemic Rickets caused by ENPP1or ABCC6 Deficiencies to each other and to the medical community. The organization strives to provide current educational resources and supports ongoing research. Their goal is to provide information about what complications can occur due to ENPP1 and ABCC6 Deficiencies (e.g. GACI, ARHR2) and to provide hope for families impacted by the condition. They hope that their website, newsletter, and social media outlets act as a resource not only for medical information, but for personal support during your own GACI/ARHR2 journey. Their community is small, but growing and they hope to offer support and information to families affected by this disorder around the world. Group details added April 2020.