What Is Generalized Arterial Calcification Of Infancy?

  • Maha AhmedMBBS, Intarnal Medicine and General Surgery, Cairo University, Egypt


Generalised arterial calcification of infancy (GACI) is a very rare genetic disease that affects the circulatory system in infants, typically presenting within the first few months of life.1 GACI causes the mineral calcium to build up in the large and medium-sized blood vessels of infants.1 This calcium build-up hardens blood vessels and blocks the blood supply to major organs in the body, causing symptoms like heart failure or hypertension (high blood pressure).2 However, the symptoms of GACI vary between individuals, with no two individuals with GACI having the same symptoms.2 Since its discovery in 1899, there have only been slightly over 200 cases of GACI worldwide.3

GACI is usually diagnosed in babies soon after they are born. The disorder can be diagnosed through imaging scans, symptoms the baby presents with after birth and genetic testing.3 Currently, there is no cure for GACI, and the infant mortality rate for the condition is high.2 However, the use of bisphosphonates, a medication that reduces the buildup of calcium, may increase the survival rates in some cases.4 Medications such as antihypertensives (anti-high blood pressure) are also used to manage the conditions associated with GACI.5 

Causes of GACIs

General arterial calcification of infancy is a genetic condition and is caused by a mutation (change in the DNA) in one of the two genes, the ENPP1 or the ABCC6 gene. GACI can be subdivided into two types.2 

GACI type 1 is caused by a mutation in the ENPP1 and occurs in 75% of patients.2 The gene ENPP1 is responsible for making an enzyme (a type of protein) that generates a molecule called pyrophosphate. Pyrophosphate regulates calcification (buildup of calcium) in the body. When there is a mutation in ENPP1, there are low levels of pyrophosphate, leading to increased build-up of calcium in the blood vessels. This hardens and narrows the blood vessels, restricting the blood flow which leads to various complications.1,3

GACI type 2 is caused by a mutation in the ABCC6 gene and occurs in 10% of patients.2 This gene is responsible for the production of a protein called MRP6 that is thought to transport molecules like pyrophosphate, but the exact mechanism is unknown. Mutations in the ABCC6 gene are also associated with low levels of pyrophosphate.3

Some cases of GACI do not have an underlying mutation in the ENPP1 or ABCC6 gene. The cause of GACI is unknown in these cases.3

Inheritance of GACIs

GACIs are inherited disorders, which means that they are passed down in the genes from parents to the children. GACIs are inherited in an autosomal recessive pattern, which means that a child with GACI has inherited two mutated copies of either the ENPP1 or ABCC6 gene, one from each parent. The parents themselves will not experience the condition as they only have one copy of the mutated gene and one normal gene. They will instead be carriers of the condition (as they ‘carry’ the condition to pass down to their children), as the normal gene will compensate for the abnormal one.1,3

For two parents who are carriers of GACIs, with each pregnancy, there is a: 

  • 25% chance that their child will inherit the abnormal gene from both parents and so have GACI.
  • 50% chance that their child will inherit an abnormal gene from only one parent and be a carrier of GACI.  
  • 25% chance that their child will inherit a normal gene from each parent and neither carry nor have GACI. 

Signs and symptoms 

Almost 50% of babies are diagnosed with GACI soon after they are born due to the presence of GACI symptoms. Other cases of GACI are diagnosed up to 6 months after birth.4 

Newborns with GACI may experience various cardiovascular (circulatory system) complications due to the build-up of calcium in the blood vessels.3 These symptoms include:  

  • Difficulty breathing 
  • An enlarged heart (cardiomegaly) 
  • Reduced or absent pulses 
  • Lips and skin looking blueish (cyanosis) 
  • Accumulation of fluid in the extremities (oedema) 
  • High blood pressure (hypertension) or heart failure 

Some cases of GACI are recognised 3-6 months after birth due to the development of additional symptoms such as: 

  • Feeding difficulties 
  • Failure to thrive 
  • Irritability 

Infants with GACI may develop other symptoms due to obstructed blood flow to other parts of the body.3 These include:

  • Complications with the digestive system: inflammation of the intestine, irritability, blood in stool). These symptoms usually go away as the infant grows. 
  • Calcium builds up in the joints such as in the hip, ankle, wrist, shoulder, elbow, knee, fingers, toes and spine.
  • Hearing loss.
  • Dental issues, including having primary teeth for too long or teeth that don’t fully erupt. 

In type 1 GACI, many patients go on to develop a rare form of rickets (a condition affecting bone growth in children) called Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2). This can cause bone and joint pain, bone deformities, dental issues, calcium build-up in ligaments and short stature (reduced height).6

In type 2 GACI, the ABCC6 gene mutation can also lead to the development of a condition called pseudoxanthoma elasticum (PXE), which causes calcium to be deposited in the elastic tissues of the body. This affects the skin, eyes, digestive and circulatory systems.6

GACI affects every individual differently, and the symptoms of the condition vary greatly, even within the same family.3


A diagnosis of GACI is made using a combination of evaluation of symptoms, imaging and genetic testing. Almost half of GACI cases are diagnosed early, generally soon after birth, due to the presentation of symptoms including heart failure, high blood pressure, an enlarged heart, difficulty breathing and excess fluid (symptoms listed above).1,6 

In other cases, GACI is diagnosed 3-6 months after birth as symptoms such as difficulties with feeding, irritability or hearing loss may develop (symptoms listed above).1,6  

If a baby is born with heart failure or high blood pressure, imaging techniques such as X-rays, CT (computed tomography) scans or MRI scans may be used to see if calcium is being deposited in the blood vessels.1 

Genetic testing of the baby (and parents) for the ENPP1 and ABCC6 genes can help diagnose GACI. Genetic testing can also be done before the baby is born by analysing a small amount of tissue from the placenta (chorionic villus sampling) or fluid from the sac protecting the foetus (amniocentesis).3

An earlier diagnosis of GACI means that treatment can be started earlier, which can improve outcomes. In some cases, GACI can be diagnosed even before the birth of the baby via ultrasound scans during pregnancy, which can show abnormalities related to the heart and blood vessels. This can allow doctors to start treating the condition even before birth.1,6 

Management and treatment 

Unfortunately, there is currently no cure for GACI. The most widely used treatment for GACI is bisphosphonates, which are medications usually used to treat osteoporosis (weakened bones). Bisphosphonates work by reducing the calcium build-up. The most common bisphosphonate is called etidronate. However, it is still unclear whether bisphosphonates increase survival rates.1

Managing the symptoms of GACI is also a part of the treatment, such as using antihypertensives for hypertension or hearing aids for hearing loss.1 

Other treatments have been used or are currently being researched for their use in GACI. The medication sodium thiosulfate helps remove calcium from the blood vessels. In enzyme replacement therapy, a form of the enzyme ENPP1 is given to patients to prevent calcium build-up and improve hypertension and heart function. Heart transplants may be successful in treating GACI without calcium buildup recurring.1,5

Individuals with GACI may also be monitored to track the progression of the disease. Imaging such as CT scans can be used to monitor the calcium buildup in blood vessels, and scans and blood tests can be used to monitor circulatory system issues.1

It is also important that families of individuals with GACI receive genetic counselling, which involves them receiving information about the genetic condition and how it is inherited so that they can make well-informed medical and personal decisions.1  


The overall mortality rate in individuals with GACI before the age of 6 months is, unfortunately quite high at 55%.1 However, for those who survive past the first few months of life, the mortality rate significantly decreases, with some patients surviving into adulthood. In fact, in some rare cases, the calcium build-up resolves on its own without any medical involvement. In other cases, patients who survive often experience complications like osteoarthritis (wear and tear of the joints).1,2 


Generalised arterial calcification of infancy (GACI) is a rare genetic condition that usually presents in the first few months of life. GACI leads to the buildup of calcium in blood vessels, restricting blood flow and resulting in symptoms such as heart failure, hypertension or an enlarged heart. Following diagnosis via imaging, symptom assessment and genetic testing, GACI is usually treated using bisphosphonates, which may reduce calcium build-up in some cases. The mortality rate for GACI is high initially but decreases after the first few months. Unfortunately, there is no cure, but research into new treatments and early diagnosis and treatment may lead to improved management and patient outcomes. 


  1. Ziegler SG, Gahl WA, Ferreira CR. Generalized arterial calcification of infancy. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2023 Aug 23]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK253403/
  2. Kawai K, Sato Y, Kawakami R, Sakamoto A, Cornelissen A, Mori M, et al. Generalized arterial calcification of infancy (Gaci): optimizing care with a multidisciplinary approach. JMDH [Internet]. 2022 Jun 1 [cited 2023 Aug 23];15:1261–76. Available from: https://www.dovepress.com/generalized-arterial-calcification-of-infancy-gaci-optimizing-care-wit-peer-reviewed-fulltext-article-JMDH
  3. Generalized arterial calcification of infancy - symptoms, causes, treatment | nord [Internet]. [cited 2023 Aug 23]. Available from: https://rarediseases.org/rare-diseases/generalized-arterial-calcification-of-infancy/
  4. Donuru A, Kandula V, Oliver E, Saul D. Generalized arterial calcification of infancy. Radiology: Cardiothoracic Imaging [Internet]. 2020 Aug 1 [cited 2023 Aug 23];2(4):e190226. Available from: http://pubs.rsna.org/doi/10.1148/ryct.2020190226
  5. Ziegler SG, Gahl WA, Ferreira CR. Generalized Arterial Calcification of Infancy. In: GeneReviews®. University of Washington, Seattle, Seattle (WA); 1993. PMID: 25392903. 2020 December  [cited 2023 Aug 23]. Available from: https://europepmc.org/article/NBK/nbk253403
  6. Philadelphia TCH of. Generalized arterial calcification of infancy(Gaci) [Internet]. 2015 [cited 2023 Aug 23]. Available from: https://www.chop.edu/conditions-diseases/generalized-arterial-calcification-infancy-gaci
This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Ria Kejariwal

MBBS, Medicine, Imperial College London

Ria is a third-year medical student at Imperial College London, with a strong passion for research and health writing. Her experience of crafting articles and publishing a book allows her to combine her passion with her writing skills to inspire and educate the public on ways to live richer and healthier lives.

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