Last updated:
05/17/2023
Years published: 2019, 2023
NORD gratefully acknowledges GACI Global and its medical advisors for the preparation of this report.
Summary
Generalized arterial calcification of infancy (GACI) is a rare genetic disorder that affects the circulatory system in addition to other body systems. It occurs in approximately 1:200,000 pregnancies. GACI affects males and females equally and occurs in populations all around the world. It has an autosomal recessive inheritance pattern and usually affects infants during the first 6 months of life. There have been slightly over 200 cases documented since GACI was first described in medical literature in 1899.
Symptoms of GACI include respiratory distress, arterial calcification, gastrointestinal issues, joint calcification, hearing loss, high blood pressure, stroke, reduced or absent pulses, and heart failure. GACI manifests itself differently even within families with the same genetic cause of the disease. No two people with GACI will have identical medical characteristics.
GACI type 1 occurs in 75% of patients, is caused by variants in the ENPP1 gene, and is also called ENPP1 deficiency. Patients with ENPP1 deficiency are at risk of developing autosomal recessive hypophosphatemic rickets type 2 (ARHR2). ARHR2 can cause bone pain, bone deformities (knocked knees, bowed legs), dental problems, calcification of ligaments and short stature. With proper treatment the bones can be strengthened, and side effects minimized.
GACI type 2 occurs in 10% of patients, is caused by variants in the ABCC6 gene, and is also called ABCC6 deficiency. As they get older, patients with ABCC6 deficiency are at risk of developing characteristics similar to pseudoxanthoma elasticum (PXE), involving the elastic tissue of the skin, the eye, cardiovascular and gastrointestinal systems.
Sometimes individuals affected with GACI do not have variants in the ENPP1 or ABCC6 genes, and in those cases the cause of the disorder is unknown.
Currently, there is no curative treatment for GACI and survival rates vary greatly. Treatment with bisphosphonates might lead to increased survival rates. Spontaneous regression of arterial calcifications can occur, and antihypertensive treatment can be tapered off gradually.
Newborns with GACI may exhibit symptoms such as difficulty breathing, reduced or absent pulses, cardiomyopathy, cardiomegaly or accumulation of fluid in the extremities (edema). They may struggle with heart failure or high blood pressure (hypertension). Newborns with GACI may also present with feeding difficulties, irritability or failure to thrive. On ultrasound or echocardiograph, the condition is characterized by calcification of the arteries or the valves of the heart accompanied by thickening of the lining of the arteries (intima).
Calcification in blood vessels may cause arterial stiffness/hardening, therefore making pulses faint or absent altogether.
Infants with GACI may suffer from gastrointestinal complications such as inflammation of the wall of the small intestine or obstruction due to stenosis. Infants with gastrointestinal complications may present with irritability and/or bloody stool. The gastrointestinal complications tend to go away as the child grows.
In nearly 50% of cases, babies are diagnosed soon after birth due to these symptoms. In other babies, GACI is recognized later, usually around 1-6 months of age after gradual or persisting symptoms.
Joint calcifications are seen in roughly 30% of babies with GACI. These calcifications are frequently seen in the hip, ankle, wrist, shoulder, elbow, knee, foot and sternoclavicular (SC) joint.
Many patients with GACI type 1 go on to develop a rare form of rickets known as autosomal recessive hypophosphatemic rickets type 2 (ARHR2). This can result in bone and joint pain, bone deformities, calcification of ligaments and short stature.
Individuals with GACI are at risk for developing hearing loss. The hearing loss can be conductive, sensorineural, or mixed and can present as early as infancy. The hearing loss might be caused by calcification of the arteries supplying the inner ear, immobility of the ear bone (stapedovestibular ankylosis) and/or abnormal remodeling of small bones (ossicles) in the middle ear.
Older patients with GACI may go on to develop symptoms of pseudoxanthoma elasticum (PXE). PXE is a disorder that causes select elastic tissue in the body to become mineralized due to calcium and other minerals being deposited in the tissue. This can result in changes in the skin and eyes. The changes to the skin frequently present on the neck, underarms, inside of the elbows, the groin and behind the knees. It may resemble a rash or have a cobblestone appearance. Another complication is the possible development of angioid streaks in the eye. Angioid streaks are small breaks in Bruch’s membrane, an elastic tissue between the retina and underlying blood vessels, that may become calcified and crack.
Patients with GACI frequently present with dental issues such as teeth that don’t fully erupt (infraocclusion), over-retained primary teeth, ankylosis, slow orthodontic movement and excessive build-up of normal cementum on the roots of the teeth.
In 2003 it was discovered that variants in the ENPP1 gene were the cause of approximately 75% of cases of GACI. The ENPP1 gene provides the instructions for making a protein that helps to break down a molecule called adenosine triphosphate (ATP), when it is found outside the cell (extracellular). Extracellular ATP is broken down into adenosine monophosphate (AMP) and pyrophosphate (PPi). Variants in the ENPP1 gene result in low levels of pyrophosphate. Pyrophosphate is important in controlling calcification and other mineralization in the body. Low pyrophosphate levels allow calcification to develop in the arteries. Low AMP levels lead to narrowing of the blood vessels, with restriction of blood flow.
In 2008, variants in the ABCC6 gene were identified as a cause of GACI in approximately 10% of patients. The ABCC6 gene provides instructions for making a protein called MRP6 (ABCC6 protein). Variants in the ABCC6 gene lead to non-functional or absent MRP6 protein. Although not proven, some researchers think that the lack of MRP6 protein impedes the release of ATP from cells and as a result pyrophosphate production is limited.
There are rare cases where patients with GACI do not have variants in either the ENPP1 or ABCC6 gene. Therefore, it is thought that there may still be at least one other unknown gene that could be responsible for causing GACI in patients, or that variants in one of the two known genes were missed by the sequencing technology.
GACI 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 of having 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.
GACI affects males and females equally and occurs in populations all across the world. There have been slightly over 200 cases documented since GACI was first described in the medical literature in 1899. It is estimated to occur in approximately 1 out of every 200,000 pregnancies with the carrier rate being 1:223. Survival statistics vary greatly but are currently estimated at around 50%.
GACI usually affects infants during the first 6 months of life, but mild cases may go undiagnosed until later in life, when other complications of the condition lead to a diagnosis.
GACI should always be considered in infants and children presenting with hypertension, cardiac failure or sudden death. Ultrasonography can aid in the diagnosis. The preferred imaging modality to assess calcifications extension is whole-body computed tomography (CT) scan combined with CT angiography.
Prenatal diagnosis has been reported and an ultrasound may reveal polyhydramnios (excess amniotic fluid), pericardial effusion (fluid around the heart) or echogenicity (brightness) of the major arteries, abnormal cardiac contractility, hydrops or hyperechoic kidneys.
To confirm a GACI diagnosis the baby (and parents) may be genetically tested for variants in the ENPP1 or ABCC6 genes. Prenatal genetic testing for GACI can be confirmed through an amniocentesis or chorionic villus sampling (CVS) if the specific gene variants in the parents have been determined.
Medical Monitoring
Newborn babies with GACI are closely observed and are usually hospitalized in the neonatal intensive care unit (NICU).
Ongoing monitoring of GACI includes ultrasounds, echocardiograms, electrocardiogram (EKG/ECG’s), CT scans, X-rays, regular blood pressure measurements, checking pulses in all extremities, frequent lab and urine tests and hearing tests.
Treatment
Currently, there is no curative treatment for GACI. Use of certain bisphosphonates appears to increase survival rates. Prenatal and postnatal treatment with bisphosphonates resulted in complete resolution of vascular calcifications in some patients; of note, complete resolution has also been noted in patients who never received treatment with bisphosphonates.
Sodium thiosulfate (STS) is a calcium-chelating agent typically used by patients who have excess calcium in their arteries due to kidney disease. In recent years, STS has also been used anecdotally to treat patients with GACI. STS is typically administered intravenously through a central line in the chest.
PGE1 infusion was successfully used in one baby with GACI complicated by severe hypertension refractory to conventional treatment.
Infants must reach a certain weight to allow for a transplant. There is some clinical evidence that heart transplants can be successful, without recurrence of calcifications. Heart transplant for individuals with GACI has occurred in at least three known cases.
Patients with GACI are usually followed by a team of specialists which may include cardiology, endocrinology, nephrology, orthopedics, physical therapy, dental, audiology, and ophthalmology.
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.
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.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Ferreira CR, van Karnebeek CDM, Vockley J, Blau N. A proposed nosology of inborn errors of metabolism. Genet Med. 2019;21(1):102-106. doi:10.1038/s41436-018-0022-8
Albright RA, Stabach P, Cao W, et al. ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nat Commun. 2015;6:10006. Published 2015 Dec 1. doi:10.1038/ncomms10006
Giovannoni I, Callea F, Travaglini L, et al. Heart transplant and 2-year follow up in a child with generalized arterial calcification of infancy. European Journal of Pediatrics. 2014; 173(12): 1735–1740. doi:10.1007/s00431-014-2447-7. ISSN 0340-6199. PMID 25367056.
Sharmila N, Prashant S, Joshi, Ravikumar V. Idiopathic Infantile arterial calcification–A Very rare case. Online Journal of Health and Allied Sciences. 2010; 9 (1). ISSN 0972-5997.
Dlamini N, Splitt M, Durkan A, et al. Generalized arterial calcification of infancy: Phenotypic spectrum among three siblings including one case without obvious arterial calcifications. American Journal of Medical Genetics Part A 2009; 149A (3): 456–60. doi:10.1002/ajmg.a.32646. PMID 19206175.
Nasrallah FK, Baho H, Sallout, Qurashi M. Prenatal diagnosis of idiopathic infantile arterial calcification with hydrops fetalis. Ultrasound in Obstetrics and Gynecology 2009: 34 (5): 601–4. doi:10.1002/uog.7438. PMID 19813208.
Ramjan KA, Roscioli T,Rutsch F, Sillence D, Munns CFJ. Generalized arterial calcification of infancy: Treatment with bisphosphonates. Nature Clinical Practice Endocrinology & Metabolism 2009; 5 (3): 167–72. doi:10.1038/ncpendmet1067. PMID 19229237.
Chong CR.; HutchinsGM. Idiopathic Infantile Arterial Calcification: The Spectrum of Clinical Presentations”. Pediatric and Developmental Pathology. 2008; 11 (5): 405–15. doi:10.2350/07-06-0297.1. PMID 17990935.
Hault K, Sebire NJ, Ho SY, Sheppard MN. The difficulty in diagnosing idiopathic arterial calcification of infancy, its variation in presentation, and the importance of autopsy. Cardiology in the Young. 2008;18 (6): 624–7. doi:10.1017/S1047951108003168. PMID 18842162.
Rutsch F, Böyer P, Nitschke Y, et al. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 2008;1(2):133-140. doi:10.1161/CIRCGENETICS.108.797704
Eller P, Hochegger K, Feuchtner GM, et al. Impact of ENPP1 genotype on arterial calcification in patients with end-stage renal failure. Nephrology Dialysis Transplantation 2007; 23 (1): 321–7. doi:10.1093/ndt/gfm566. PMID 17848394.
Abu-Asbeh J, Khan J, Shallal A. Idiopathic infantile arterial calcification associated with leukomalacia. Journal of the Arab Neonatology Forum. 2006; 3 (1): 15–9.
Glatz AC, Pawel BR, Hsu DT Daphne T, Weinberg P, Chrisant MRK. Idiopathic infantile arterial calcification: Two case reports, a review of the literature and a role for cardiac transplantation. Pediatric Transplantation. 2006; 10 (2): 225–33. doi:10.1111/j.1399-3046.2005.00414.x. PMID 16573612.
Inwald DP, Yen Ho S, Shepherd MN, Daubeney PEF. Idiopathic infantile arterial calcification presenting as fatal hypertensive cardiomyopathy. Archives of Disease in Childhood. 2006; 91 (11): 928. doi:10.1136/adc.2006.103093. PMC 2082956. PMID 17056867.
Sluis IM, Boot AM, Vernooij M Meradji M, Kroon AA. Idiopathic infantile arterial calcification: Clinical presentation, therapy and long-term follow-up. European Journal of Pediatrics 2006; 165 (9): 590–3. doi:10.1007/s00431-006-0146-8. PMID 16649023.
Tran KH, Boechat M. Idiopathic infantile arterial calcification: Imaging evaluation and the usefulness of MR angiography. Pediatric Radiology. 2006; 36(3): 247–53. doi:10.1007/s00247-005-0044-7. PMID 16429273.
Ciana G, Trappan A, Bembi B, et al. Generalized arterial calcification of infancy: Two siblings with prolonged survival. European Journal of Pediatrics. 2005; 165 (4): 258–63. doi:10.1007/s00431-005-0035-6. PMID 16315058.
Cheng K-S, Chen M-R, Ruf N, et al. Generalized arterial calcification of infancy: Different clinical courses in two affected siblings. American Journal of Medical Genetics Part A. 2005; 136A (2): 210–3. doi:10.1002/ajmg.a.30800. PMID 15940697.
Greenberg SB, Gibson J. New findings in idiopathic arterial calcification of infancy detected by MDCT. AJR Am J Roentgenol. 2005;185(2):530-532. doi:10.2214/ajr.185.2.01850530
Sundaram S, Kuruvilla S, Thirupuram S. Idiopathic arterial calcification of infancy – a case report. Images in Paediatric Cardiology 2004; 6 (1): 6–12. PMC 3232550. PMID 22368635.
Rutsch F, Ruf N; Vaingankar S, et al. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nature Genetics. 2003; 34 (4): 379–81. doi:10.1038/ng1221. PMID 12881724.
Nagar AM, Hanchate V, Tandon A,et al. Antenatal Detection of Idiopathic Arterial Calcification With Hydrops Fetalis. Journal of Ultrasound in Medicine. 2003; 22 (6): 653–9. doi:10.7863/jum.2003.22.6.653. PMID 12795564.
Whitehall J, Smith M, Altamirano L. Idiopathic infantile arterial calcification: Sonographic findings. Journal of Clinical Ultrasound.2003; 31 (9): 497–501. doi:10.1002/jcu.10208. PMID 14595743.
Rutsch F, Vaingankar S, Johnson K, et al. PC-1 Nucleoside Triphosphate Pyrophosphohydrolase Deficiency in Idiopathic Infantile Arterial Calcification. The American Journal of Pathology. 2001; 158 (2): 543–54. doi:10.1016/S0002-9440(10)63996-X. PMC 1850320. PMID 11159191.
Levine JC, Campbell J Nadel A. Prenatal Diagnosis of Idiopathic Infantile Arterial Calcification. Circulation. 2001; 103 (2): 325–6. doi:10.1161/01.CIR.103.2.325. PMID 11208697.
INTERNET
Generalized arterial calcification of infancy. Genetic Home Reference-US National Library of Medicine. Jan 2015. https://ghr.nlm.nih.gov/condition/generalized-arterial-calcification-of-infancy. Accessed April 17, 2023.
Ziegler SG, Gahl WA, Ferreira CR. Generalized Arterial Calcification of Infancy. 2014 Nov 13 [Updated 2020 Dec 30]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK253403/ Accessed April 17, 2023.
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View report