GARD :
20
The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 51608 Definition A rare genetic vascular disease characterized by early onset (between in utero to infancy) of extensive calcification and stenosis of the large and medium sized arteries. Presentation is typically with respiratory distress, congestive heart failure and systemic hypertension. Epidemiology Approximately 300 cases have been reported worldwide in the medical literature. The prevalence is unknown; however, based on carrier frequency of the recognized pathogenic variants, the frequency of 1/566,000 has been suggested. Clinical description Disease onset is either early (in utero to within the first week of life) or late (median age three months). Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. Additional findings can include extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum, hearing loss, and development of rickets after infancy. Pathologically, the condition is characterized by deposition of calcium along the internal elastic membrane of arteries, accompanied by fibrous thickening of the intima, which causes luminal narrowing. Etiology Causal mutations have been identified in the genes ENPP1 ( chromosome 6q23.2) and ABCC6 (chromosome 16p13.11) respectively encoding ectonucleotide pyrophosphatase/ phosphodiesterase 1 and multidrug resistance-associated protein 6, a transmembrane protein belonging to the family of ATP-binding cassette (ABC) transport proteins. Pathological variants lead to aberrant tissue mineralization, and the subsequent luminal narrowing invariably leads to coronary arterial occlusion and myocardial ischemia or stenoses of different arteries leading to end- organ damage. ENPP1 mutations also cause autosomal recessive hypophosphatemic rickets, which is associated with longer survival. Diagnostic methods Diagnosis of is made by the combination of clinical, imaging or histopathological findings, together with genetic results. The preferred imaging modality to assess calcifications extension is whole-body computed tomography combined with CT angiography. Differential diagnosis Differential diagnosis includes endocardial fibroelastosis, myocardititis, storage disorders, infarction, anomalous insertion of the coronary arteries, cardiac anomalies, metastatic calcification due to renal disease, hypervitaminosis D, infections, and non-immune fetal hydrops, Takayasu arteriitis. Antenatal diagnosis Antenatal diagnosis has been reported, with findings of arterial calcifications, hydrops, abnormal cardiac contractility, and hyperechoic kidneys. The diagnosis is essential for genetic counseling, and for screening of siblings at risk for developing the disease. Genetic counseling The pattern of inheritance is autosomal recessive. The sibling-recurrence risk is 25%. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known. Management and treatment Use of bisphosphonates appears to significantly increase survival. Standard anti-hypertensive therapy is warranted for hypertension. Aspirin therapy is warranted in those with severe coronary stenosis who are at increased risk for coronary thrombosis. Anti-hypertensive therapy is warranted for hypertension. Treatment of hypophosphatemic rickets involves calcitriol and oral phosphate supplements. It seems prudent to avoid the use of warfarin if possible. Where endotracheal intubation is required, lateral cervical spine x-ray is recommended to evaluate for cervical spine fusion, and thereby avoid secondary complications. Prognosis Prognosis is poor; most infants die from myocardial infarction within the first year of life, with the greatest number of deaths occurring within the first six months. Nevertheless, long-term survival into the second and third decade has been reported.
MalaCards based summary :
Arterial Calcification of Infancy, also known as
generalized arterial calcification of infancy, is related to
pseudoxanthoma elasticum and
calcification of joints and arteries. An important gene associated with Arterial Calcification of Infancy is
ENPP1 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 1), and among its related pathways/superpathways are
Purine metabolism and
Starch and sucrose metabolism. Affiliated tissues include
heart,
eye and
bone, and related phenotypes are
calcification of the aorta and
hepatic calcification
Disease Ontology :
12
A vascular disease that is characterized by generalized calcification of the arterial internal elastic lamina, leading to rupture of the lamina and occlusive changes in the tunica intima with stenosis and decreased elasticity of the vessel wall.
MedlinePlus Genetics :
43
Generalized arterial calcification of infancy (GACI) is a disorder affecting the circulatory system that becomes apparent before birth or within the first few months of life. It is characterized by abnormal accumulation of the mineral calcium (calcification) in the walls of the blood vessels that carry blood from the heart to the rest of the body (the arteries). This calcification often occurs along with thickening of the lining of the arterial walls (the intima). These changes lead to narrowing (stenosis) and stiffness of the arteries, which forces the heart to work harder to pump blood. As a result, heart failure may develop in affected individuals, with signs and symptoms including difficulty breathing, accumulation of fluid (edema) in the extremities, a bluish appearance of the skin or lips (cyanosis), severe high blood pressure (hypertension), and an enlarged heart (cardiomegaly).People with GACI may also have calcification in other organs and tissues, particularly around the joints. In addition, they may have hearing loss or softening and weakening of the bones (rickets).Some individuals with GACI also develop features similar to those of another disorder called pseudoxanthoma elasticum (PXE). PXE is characterized by the accumulation of calcium and other minerals (mineralization) in elastic fibers, which are a component of connective tissue. Connective tissue provides strength and flexibility to structures throughout the body. Features characteristic of PXE that also occur in GACI include yellowish bumps called papules on the underarms and other areas of skin that touch when a joint bends (flexor areas); and abnormalities called angioid streaks affecting tissue at the back of the eye, which can be detected during an eye examination.As a result of the cardiovascular problems associated with GACI, individuals with this condition often do not survive past infancy, with death typically caused by a heart attack or stroke. However, affected individuals who survive their first six months, known as the critical period, can live into adolescence or early adulthood.
KEGG :
36
Generalized arterial calcification of infancy (GACI) is a rare and often fatal genetic disorder, characterized by calcification of the internal elastic lamina, fibrotic myointimal proliferation of muscular arteries, and resultant arterial stenosis. GACI is associated with biallelic inactivating mutations in ENPP1 in about 75% of the cases. ENPP1 generates PPi that inhibits hydroxyapatite crystal growth.
Wikipedia :
73
Generalized arterial calcification of infancy (GACI) is an extremely rare genetic disorder. It is caused...
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Rare circulatory system diseases 
