FAQ/Glossary of Terms
Frequently Asked Questions
Get answers to the most frequently asked questions about GACI and ARHR2! If you don’t see the answer to your question here, you could try navigating via the sitemap at the bottom of the page or using the search option. If you still have unanswered questions, please email us at info@brighterhopefoundation.org.
What is the survival rate?
Survival rates for Generalized Arterial Calcification of Infancy (GACI) vary widely and depend on factors such as the severity of arterial calcification, early diagnosis, and timely access to treatment. While outcomes have improved over the years thanks to advances in medical care, survival can still be difficult to predict because every child’s presentation is unique. You can read more detailed information on survival rates and factors that influence long-term outcomes.
Will my child live a normal life with GACI/ARHR2?
With proper medical care and treatment, your child can live a full and happy life. They will likely have to take medication daily and have regular follow-up appointments with their medical care team, but this should not stop them from attending school or participating in hobbies.
Are there any approved treatments for GACI / ARHR2?
There are currently no approved treatments for GACI or ARHR2.
At what age does ARHR2 tend to develop?
Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2) often becomes noticeable in early childhood as skeletal symptoms begin to develop. Many children may show signs such as delayed growth, bone pain, or limb bowing once they start walking. However, the age of onset can vary, and some individuals are not diagnosed until later in childhood or adolescence when symptoms progress. You can learn more about the condition, typical presentations, and diagnosis on our ARHR2 information page.
What signs and symptoms of ARHR2 should I be looking for/how is ARHR2 diagnosed?
Bone pain and bone deformities may be the first externally visible signs of ARHR2. However, ARHR2 can be diagnosed, before any bone changes occur, by plasma (blood) test. ARHR2 does not always show up on an X-ray in the way that normal rickets would. Therefore patients with GACI Type 1 should have routine blood tests to ensure any elevated plasma alkaline phosphatase levels are investigated.
How long are patients generally on treatment for ARHR2?
Treatment for ARHR2 is typically long-term and often continues throughout childhood and into adulthood, depending on the individual’s needs and symptom progression. Most treatment plans focus on correcting low phosphate levels and improving bone health through oral phosphate supplements, active forms of vitamin D, or newer therapies as recommended by specialists. Because treatment needs can vary over time, regular monitoring is essential. To learn more about available therapies and how they support bone development, visit our treatment options page.
How does ARHR2 differ from more common forms of rickets?
Rickets develops when growing bones fail to mineralize. There are many different forms of rickets. Some forms of rickets are caused by nutritional deficits while other forms of rickets are caused by genetic defects. Researchers have described several forms of genetic hypophosphatemic rickets, which are distinguished by their pattern of inheritance and the gene responsible. The most common form of the disorder is known as X-linked Hypophosphatemic Rickets (XLH). It has an x-linked dominant pattern of inheritance. Autosomal recessive forms of rickets, such as ARHR2, are much rarer, but the main point of difference is the genetic cause of the disease. They are similar in the fact that both conditions lead to elevated FGF23 levels. FGF23 is a protein that is responsible for phosphate and vitamin D metabolism.
How do I find doctors or hospitals that have experience who have experience in treating GACI/ARHR2 near where I live?
Because GACI and ARHR2 are extremely rare disorders, finding doctors or hospitals with specific experience can be challenging. Families often benefit from working with major medical centers, metabolic bone clinics, or genetic specialists who are familiar with rare metabolic and calcification disorders.
Brighter Hope Foundation may be able to help guide families by sharing information about centers that have treated other patients or by connecting families through our community network. Speaking with your primary care provider or local hospital about referral options is also an important step. Please contact us at info@brighterhopefoundation.org for more information.
What health professionals may be a part of my child’s medical team?
Depending on their symptoms and what type of complications they are diagnosed with, patients with GACI are usually followed by a team of specialists that may include cardiology, endocrinology, nephrology, orthopedics, audiology, ophthalmology, pulmonology, otolaryngology, physical therapy, dental, and gastroenterology.
Is surgery an option?
There is some clinical evidence that heart transplants can be successful in patients with GACI, without recurrence of calcification. Heart transplant for individuals with GACI has occurred in at least 4 known cases in the US, Italy, and Spain, with the youngest patient being 4 months old.
For patients with ARHR2, there are some surgical options available if treatment with medication was not started soon enough or did not produce the desired results. The two surgical options to correct the bone deformities caused by ARHR2 are eight-plate surgery or osteotomy. Read more here.
In at least one case, surgery was successfully performed to remove the periarticular calcification of a patient with GACI to improve the range of motion and function of the joint.
Where can I talk to others who have or are taking care of someone with GACI/ARHR2?
We have a private Facebook group specifically for families and patients. Please keep in mind that this group is strictly for families directly impacted by GACI/ARHR2. It is not a group for extended relatives, friends, etc. This group exists to provide a place for these families to connect, communicate, commiserate, and support each other.
What is Pyrophosphate?
Pyrophosphate (PPi) is important in controlling calcification and other mineralization in the body.
The ENPP1 gene provides instructions for making a protein that helps to break down a molecule called ATP (adenosine triphosphate) when it is found outside the cell (extracellular). Extracellular ATP is broken down into AMP (adenosine monophosphate) and pyrophosphate. Mutations in the ENPP1 gene result in low levels of pyrophosphate.
The ABCC6 gene provides instructions for making a protein called MRP6 (ABCC6 protein). Mutations in the ABCC6 gene lead to non-functional or absent MRP6 protein. It is thought that the lack of MRP6 protein impedes the release of ATP from cells and as a result, pyrophosphate production is limited.
Glossary of Terms
Below you will find a glossary of terms related to Generalized Arterial Calcification of Infancy and Autosomal Recessive Hypophosphatemic Rickets Type 2.
ABCC6 Deficiency – ABCC6 Deficiency is an inherited genetic disorder caused by mutations in the ABCC6 gene, which plays a role in regulating calcium and phosphate balance in the body. When this gene is not functioning properly, calcium can deposit abnormally in the arteries, skin, and other tissues. This condition can cause GACI Type 2 and PXE (Pseudoxanthoma Elasticum), both of which involve abnormal tissue calcification.
ABCC6 Gene – The ABCC6 gene (ATP-binding cassette sub-family C member 6) provides instructions for a protein that helps transport molecules across cell membranes, particularly in the liver and kidneys. Mutations in this gene reduce the availability of inorganic pyrophosphate (PPi), a natural inhibitor of calcification. When the ABCC6 gene is defective, calcium builds up in tissues and arteries, contributing to diseases like GACI and PXE.
Angioid Streak – Small breaks in Bruch’s membrane, an elastic tissue containing membrane of the retina that may become calcified and crack.
ARHR2 (Autosomal Recessive Hypophosphatemic Rickets Type 2) – ARHR2 is a bone disorder caused by mutations in the ENPP1 gene, leading to low phosphate levels in the blood and poor bone mineralization. Many children who survive GACI Type 1 may later develop ARHR2, as both conditions share the same genetic cause. It results in rickets-like symptoms, such as bone pain, short stature, and delayed growth, due to phosphate loss through the kidneys.
Atherosclerosis – Atherosclerosis is a progressive condition in which arteries become narrowed and stiff due to the buildup of plaque along the artery walls.
Audiology – the branch of science that studies hearing, balance, and related disorders.
Bisphosphonates – This is a class of drug that prevents the loss of bone density, usually used to treat osteoporosis and similar diseases. Etidronate, Risedronate, and Pamidronate are examples of bisphosphonates that have shown some success in treating patients with GACI.
Calcific Enthesopathy – Calcific enthesopathy refers to abnormal calcium buildup at the sites where tendons or ligaments attach to bones. This condition can cause stiffness, pain, and limited mobility. Calcific enthesopathy may develop as part of the broader spectrum of soft tissue and vascular calcifications seen in GACI and related disorders.
Calcinosis – Calcinosis is the deposition of calcium salts in soft tissues such as the skin, muscles, and internal organs. It can cause hard lumps under the skin and lead to discomfort or inflammation. In GACI and ENPP1/ABCC6 Deficiencies, calcinosis reflects the body’s impaired regulation of calcium and phosphate, resulting in excessive calcification beyond bones and teeth.
Cardiology – The branch of medicine that deals with diseases and abnormalities of the heart.
Cardiomegaly – A medical condition in which the heart is enlarged.
Cardiomyopathy – A disease of the heart muscle that makes it harder for the heart to pump blood to the rest of the body.
Cardiovascular – Relating to the circulatory system, which comprises the heart and blood vessels.
Craniosynostosis – The premature fusion of the skull bones.
CT Scan – Computed Tomography scan – A CT scan combines a series of X-ray images taken from different angles around your body and uses computer processing to create cross-sectional images (slices) of the bones, blood vessels, and soft tissues inside your body.
Cyanosis – Bluish cast to the skin and mucous membranes. Peripheral cyanosis is when there is a bluish discoloration to your hands or feet. It’s usually caused by low oxygen levels in the red blood cells or problems getting oxygenated blood to your body.
DEXA Scan – Dual-energy x-ray absorptiometry – a scan to measure bone density. The scan is fast and the dose of radiation used is low.
Echocardiograms – Often referred to as an echo, an echocardiogram is a sonogram of the heart.
Echogenicity – Echogenicity refers to how bright or reflective tissues appear on an ultrasound image. In GACI, increased echogenicity of the arteries is often one of the first signs seen on prenatal or early-life ultrasounds, indicating calcium buildup in the vessel walls. This finding helps doctors identify vascular calcifications and may prompt further testing to confirm a diagnosis of GACI.
Edema – A medical term for swelling.
Eight-Plate Surgery – A surgical procedure where a plate is attached to one side of the growth plate above or below the knee or sometimes both above and below the knee. Over time, as the patient grows, this helps to realign the legs.
EKG/ECG’s – Electrocardiogram – a recording/graph of voltage versus time – of the electrical activity of the heart using electrodes placed on the skin.
Endocrinology – The branch of physiology and medicine concerned with endocrine glands and hormones.
ENPP1 Deficiency – ENPP1 Deficiency is a rare inherited disorder caused by mutations in the ENPP1 gene, which is responsible for producing an enzyme that generates inorganic pyrophosphate (PPi). Low PPi levels result in abnormal calcium deposits within arteries and joints. This condition causes GACI Type 1 in infancy and may progress to ARHR2 in survivors, linking vascular calcification and skeletal abnormalities. It can also cause hearing loss, dental issues, and many other complications.
ENPP1 Gene – The ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase 1) provides instructions for an enzyme that controls the production of inorganic pyrophosphate (PPi), a molecule that prevents soft tissue calcification. When this gene is mutated, PPi levels drop, allowing calcium to deposit in blood vessels and tissues. Defects in the ENPP1 gene cause GACI Type 1 and are also associated with ARHR2.
ERT (Enzyme Replacement Therapy) – Enzyme Replacement Therapy (ERT) is a medical treatment designed to replace a missing or deficient enzyme in the body. For conditions like GACI caused by ENPP1 Deficiency and ABCC6 Deficiency, ERT aims to restore normal enzyme function, increase PPi levels, and reduce calcification.
FGF23 – Fibroblast growth factor 23 is a protein that in humans is encoded by the FGF23 gene. It is a member of the fibroblast growth factor (FGF) family which is responsible for phosphate and vitamin D metabolism.
GACI (Generalized Arterial Calcification of Infancy) – GACI is a rare genetic disorder that causes calcium deposits to form in the walls of arteries, restricting blood flow and leading to serious cardiovascular complications. It is most often caused by mutations in the ENPP1 or ABCC6 genes. GACI can be detected before or after birth, and while once fatal, advances in early diagnosis and potential therapies are improving outcomes. GACI Type 1 is associated with ENPP1 Deficiency and GACI Type 2 is associated with ABCC6 Deficiency. When you just see GACI on our website, it relates to both type 1 and type 2. Calcification may also occur in internal organs – most frequently in the heart – as well as in the joints and soft tissues.
Hypercalciuria – Hypercalciuria is a condition in which the kidneys excrete excessive calcium into the urine. This imbalance can lead to kidney stones or affect bone health. In patients with ENPP1 Deficiency or ABCC6 Deficiency, hypercalciuria may appear as part of the broader metabolic disturbance involving calcium and phosphate regulation, which contributes to abnormal calcification in the arteries and tissues.
Hyperphosphaturia – The presence of excess phosphate in the urine.
Hypertension – High blood pressure.
Hypophosphatemia – Low level of phosphate in the blood.
Infraocclusion – This is a condition frequently associated with primary molars, where primary teeth remain in a fixed position, while teeth adjacent to them continue to erupt.
Inorganic Pyrophosphate (PPi) – Inorganic pyrophosphate (PPi) is a natural molecule that prevents unwanted calcification in soft tissues and regulates normal bone mineralization. In disorders like GACI, ENPP1 Deficiency, and ABCC6 Deficiency, low PPi levels allow calcium to accumulate in arteries, skin, and joints. Maintaining sufficient PPi is essential for balancing mineral deposition between bones and soft tissues.
Intima – The intima is the innermost layer of a blood vessel, made up of endothelial cells that line the arteries and veins. In GACI, calcium deposits often form within or beneath the intima, leading to narrowing of the arteries and reduced blood flow. Damage or thickening of the intima is a key feature in the vascular changes seen in GACI and related conditions
Intimal Hyperplasia – Intimal hyperplasia is the thickening of the innermost layer of a blood vessel due to excessive cell growth. In GACI, this process occurs alongside arterial calcification, further restricting blood flow and putting stress on the heart. The combination of calcification and hyperplasia contributes to many of the cardiovascular symptoms associated with ENPP1Deficiency or ABCC6 Deficiency.
Lamina (Internal Elastic Lamina) – The internal elastic lamina is a thin, flexible layer of elastic tissue that separates the inner and middle layers of a blood vessel. It helps arteries expand and contract with blood flow. In GACI, calcium can deposit along this lamina, reducing elasticity and contributing to vessel stiffness and narrowing, which are hallmark features of the disease.
MRI – Magnetic Resonance Imaging is a scan that uses powerful magnets, radio waves, and a computer to make detailed pictures inside your body. MRI scans typically take longer, are louder, and do not use x-rays or other radiation.
Mutation – A permanent alteration in the DNA sequence that makes up a gene, such that the sequence differs from what is found in most people.
Nephrocalcinosis – Nephrocalcinosis refers to the buildup of calcium deposits in the kidneys. This condition can interfere with normal kidney function. In ENPP1 Deficiency, it may result from low levels of pyrophosphate and can be worsened by phosphate supplementation used to treat rickets (ARHR2), increasing the risk of ectopic calcification.
Nephrology – Nephrology is the branch of medicine focused on diagnosing and treating diseases of the kidneys. For patients living with GACI, ENPP1 Deficiency, or ABCC6 Deficiency, nephrologists play an important role in monitoring kidney health and managing complications such as nephrocalcinosis or hypercalciuria.
Ophthalmology – The branch of medicine and surgery, which deals with the diagnosis and treatment of eye disorders.
Orthopedics – Orthopedics is the medical specialty concerned with the bones, joints, and muscles. Many individuals with ARHR2 or ENPP1 Deficiency experience skeletal complications, including rickets-like symptoms, bone pain, and deformities that require orthopedic care. Orthopedic specialists may assist with managing fractures, limb alignment, and joint mobility to help improve quality of life and physical function in those living with these rare conditions.
Osteotomy – An osteotomy is a surgical procedure in which a bone is cut and repositioned to correct deformities or improve alignment. For patients with ARHR2 or ENPP1 Deficiency, where phosphate imbalance can weaken bones and affect growth, osteotomy may be used to address bowing of the legs or other skeletal abnormalities. This surgery helps improve mobility and relieve pain associated with bone deformities.
Otolaryngology – The branch of medicine that deals with conditions of the ear, nose, and throat and related structures of the head and neck.
Periarticular – Periarticular refers to the tissues surrounding a joint, including ligaments, tendons, and muscles. In conditions like ENPP1 Deficiency or ABCC6 Deficiency, calcium deposits can form in periarticular tissues, leading to stiffness, reduced range of motion, and discomfort. This type of soft-tissue calcification often occurs alongside calcific enthesopathy, highlighting how systemic mineral imbalances affect both vascular and musculoskeletal systems.
Pericardial Effusion – Pericardial effusion occurs when excess fluid builds up between the heart and its surrounding membrane (the pericardium). In infants with GACI, this may result from severe arterial calcification that places stress on the cardiovascular system. The presence of pericardial effusion can interfere with heart function, making early detection and management critical in improving outcomes for children with calcification-related disorders.
PGD (Preimplantation Genetic Diagnosis) – Preimplantation Genetic Diagnosis (PGD) is a reproductive technology used during in vitro fertilization (IVF) to test embryos for specific genetic mutations before implantation. Families affected by GACI, ENPP1 Deficiency, or ABCC6 Deficiency may use PGD to help prevent passing these rare conditions to their children. This approach allows carriers to make informed reproductive choices with the guidance of genetic counselors.
Polyhydramnios – Polyhydramnios describes an excessive buildup of amniotic fluid during pregnancy. In some cases of GACI, this can be detected on prenatal ultrasounds and may signal underlying vascular or skeletal abnormalities caused by genetic mutations such as ENPP1 or ABCC6. Monitoring polyhydramnios is important, as it can indicate early signs of complications requiring specialized maternal-fetal care.
Pyrophosphate (PPi) – Pyrophosphate (PPi) is a naturally occurring molecule that prevents unwanted calcium buildup in soft tissues while supporting normal bone mineralization. In GACI, ENPP1 Deficiency, and ABCC6 Deficiency, PPi levels are abnormally low, leading to calcification of arteries, joints, and other tissues. Restoring or mimicking PPi levels is a key focus in emerging research and potential treatments for these conditions.
Sodium Thiosulfate (STS) – STS is a calcium-chelating agent that is used by patients who have excess calcium in their arteries due to kidney disease. It has also shown some success in patients with GACI.
Soft-Tissue Calcification – Soft-tissue calcification occurs when calcium deposits form in tissues that are normally flexible, such as skin, muscles, and blood vessels. In GACI, ENPP1 Deficiency, and ABCC6 Deficiency, reduced levels of pyrophosphate (PPi) allow calcium to accumulate abnormally, causing stiffness and inflammation. This widespread calcification can impact movement, circulation, and organ function throughout the body.
Stapedovestibular Ankyloses – Stapedovestibular ankylosis is the abnormal fusion of the stapes bone (in the middle ear) to the vestibule, which can cause hearing loss. In patients with GACI caused by ENPP1 Deficiency this may occur due to calcium buildup in the ear’s delicate structures. Recognizing this condition early allows for potential hearing interventions and improved quality of life.
Stenosis – Stenosis refers to the abnormal narrowing of a blood vessel or body passage. In GACI, calcification and thickening of arterial walls lead to stenosis of major arteries, restricting blood flow and placing strain on the heart. This vascular narrowing is one of the hallmark complications of ENPP1 Deficiency and ABCC6 Deficiency often detected through imaging such as ultrasound or echocardiography.
Tendinopathy – Also known as tendinitis or tendinosis, is a type of tendon disorder that results in pain, swelling, and impaired function. Can be related to calcium deposits.
Vascular – Relating to, affecting, or consisting of a vessel or vessels, especially those which carry blood.
