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Arterial calcification, generalized, of infancy, 2(GACI2)

MedGen UID:
477791
Concept ID:
C3276161
Disease or Syndrome
Synonyms: ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2; GACI2
 
Gene (location): ABCC6 (16p13.11)
 
Monarch Initiative: MONDO:0013768
OMIM®: 614473

Disease characteristics

Excerpted from the GeneReview: Generalized Arterial Calcification of Infancy
Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), periarticular calcifications, development of rickets after infancy, cervical spine fusion, and hearing loss. While mortality in infancy is high, survival into the third and fourth decades has occurred. [from GeneReviews]
Authors:
Shira G Ziegler  |  William A Gahl  |  Carlos R Ferreira   view full author information

Additional descriptions

From OMIM
Generalized arterial calcification of infancy (GACI) is a severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. GACI is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure (summary by Rutsch et al., 2003 and Cheng et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of GACI, see GACI1 (208000). Pseudoxanthoma elasticum (PXE; 264800) is an allelic disorder caused by mutation in the ABCC6 gene; it has been suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders (Nitschke et al., 2012).  http://www.omim.org/entry/614473
From MedlinePlus Genetics
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.  https://medlineplus.gov/genetics/condition/generalized-arterial-calcification-of-infancy

Clinical features

From HPO
Nephrocalcinosis
MedGen UID:
10222
Concept ID:
C0027709
Disease or Syndrome
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Mitral regurgitation
MedGen UID:
7670
Concept ID:
C0026266
Disease or Syndrome
An abnormality of the mitral valve characterized by insufficiency or incompetence of the mitral valve resulting in retrograde leaking of blood through the mitral valve upon ventricular contraction.
Myocardial infarction
MedGen UID:
10150
Concept ID:
C0027051
Disease or Syndrome
Necrosis of the myocardium caused by an obstruction of the blood supply to the heart and often associated with chest pain, shortness of breath, palpitations, and anxiety as well as characteristic EKG findings and elevation of serum markers including creatine kinase-MB fraction and troponin.
Cardiogenic shock
MedGen UID:
48650
Concept ID:
C0036980
Pathologic Function
Severely decreased cardiac output with evidence of inadequate end-organ perfusion (i.e., tissue hypoxia) in the presence of adequate intravascular volume.
Sinus tachycardia
MedGen UID:
11700
Concept ID:
C0039239
Disease or Syndrome
Heart rate of greater than 100 beats per minute.
Tricuspid regurgitation
MedGen UID:
11911
Concept ID:
C0040961
Disease or Syndrome
Failure of the tricuspid valve to close sufficiently upon contraction of the right ventricle, causing blood to regurgitate (flow backward) into the right atrium.
Right atrial enlargement
MedGen UID:
677114
Concept ID:
C0748427
Disease or Syndrome
Increase in size of the right atrium.
Arterial calcification
MedGen UID:
223922
Concept ID:
C1168153
Pathologic Function
Pathological deposition of calcium salts in one or more arteries.
Coronary artery calcification
MedGen UID:
345985
Concept ID:
C1611184
Pathologic Function
An accumulation of calcium and phosphate in arteries with mineral deposits in the intimal or medial layer of the vessel wall in a coronary artery.
Reduced left ventricular ejection fraction
MedGen UID:
868398
Concept ID:
C4022792
Finding
A diminution of the volumetric fraction of blood pumped out of the ventricle with each cardiac cycle.
Hypophosphatemic rickets
MedGen UID:
309957
Concept ID:
C1704375
Disease or Syndrome
Rickets due to low serum phosphate concentrations, the cause of which can be nutritional or genetic. This condition is characterized by normal parathyroid hormone concentrations, usually caused by renal phosphate wasting occurring in isolation or as part of a renal tubular disorder, and characterized by resistance to treatment with ultraviolet radiation or vitamin D.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Boyce AM, Gafni RI, Ferreira CR
Curr Osteoporos Rep 2020 Jun;18(3):232-241. doi: 10.1007/s11914-020-00577-4. PMID: 32172442Free PMC Article
Li Q, van de Wetering K, Uitto J
Am J Pathol 2019 Feb;189(2):216-225. Epub 2018 Nov 7 doi: 10.1016/j.ajpath.2018.09.014. PMID: 30414410Free PMC Article
Nitschke Y, Rutsch F
Curr Osteoporos Rep 2017 Aug;15(4):255-270. doi: 10.1007/s11914-017-0370-3. PMID: 28585220

Recent clinical studies

Etiology

Ramirez-Suarez KI, Cohen SA, Barrera CA, Levine MA, Goldberg DJ, Otero HJ
Pediatr Radiol 2022 Nov;52(12):2329-2341. Epub 2022 Apr 19 doi: 10.1007/s00247-022-05364-0. PMID: 35438330Free PMC Article
Ferreira CR, Kintzinger K, Hackbarth ME, Botschen U, Nitschke Y, Mughal MZ, Baujat G, Schnabel D, Yuen E, Gahl WA, Gafni RI, Liu Q, Huertas P, Khursigara G, Rutsch F
J Bone Miner Res 2021 Nov;36(11):2193-2202. Epub 2021 Aug 16 doi: 10.1002/jbmr.4418. PMID: 34355424Free PMC Article
Ferreira CR, Hackbarth ME, Ziegler SG, Pan KS, Roberts MS, Rosing DR, Whelpley MS, Bryant JC, Macnamara EF, Wang S, Müller K, Hartley IR, Chew EY, Corden TE, Jacobsen CM, Holm IA, Rutsch F, Dikoglu E, Chen MY, Mughal MZ, Levine MA, Gafni RI, Gahl WA
Genet Med 2021 Feb;23(2):396-407. Epub 2020 Oct 2 doi: 10.1038/s41436-020-00983-0. PMID: 33005041Free PMC Article
Boyce AM, Gafni RI, Ferreira CR
Curr Osteoporos Rep 2020 Jun;18(3):232-241. doi: 10.1007/s11914-020-00577-4. PMID: 32172442Free PMC Article
Nitschke Y, Rutsch F
Curr Osteoporos Rep 2017 Aug;15(4):255-270. doi: 10.1007/s11914-017-0370-3. PMID: 28585220

Diagnosis

Seefried L
Arch Pediatr 2024 Sep;31(4S1):4S33-4S36. doi: 10.1016/S0929-693X(24)00155-6. PMID: 39343472
Mercurio SA, Chunn LM, Khursigara G, Nester C, Wray K, Botschen U, Kiel MJ, Rutsch F, Ferreira CR
Hum Mutat 2022 Dec;43(12):1673-1705. Epub 2022 Oct 8 doi: 10.1002/humu.24477. PMID: 36150100
Ramirez-Suarez KI, Cohen SA, Barrera CA, Levine MA, Goldberg DJ, Otero HJ
Pediatr Radiol 2022 Nov;52(12):2329-2341. Epub 2022 Apr 19 doi: 10.1007/s00247-022-05364-0. PMID: 35438330Free PMC Article
Kozák E, Fülöp K, Tőkési N, Rao N, Li Q, Terry SF, Uitto J, Zhang X, Becker C, Váradi A, Pomozi V
Exp Dermatol 2022 Apr;31(4):548-555. Epub 2021 Nov 17 doi: 10.1111/exd.14498. PMID: 34758173Free PMC Article
Ferreira CR, Kintzinger K, Hackbarth ME, Botschen U, Nitschke Y, Mughal MZ, Baujat G, Schnabel D, Yuen E, Gahl WA, Gafni RI, Liu Q, Huertas P, Khursigara G, Rutsch F
J Bone Miner Res 2021 Nov;36(11):2193-2202. Epub 2021 Aug 16 doi: 10.1002/jbmr.4418. PMID: 34355424Free PMC Article

Therapy

Khursigara G, Huertas P, Wenkert D, O'Brien K, Sabbagh Y
Bone 2023 Jun;171:116750. Epub 2023 Mar 30 doi: 10.1016/j.bone.2023.116750. PMID: 37003563
Ramirez-Suarez KI, Cohen SA, Barrera CA, Levine MA, Goldberg DJ, Otero HJ
Pediatr Radiol 2022 Nov;52(12):2329-2341. Epub 2022 Apr 19 doi: 10.1007/s00247-022-05364-0. PMID: 35438330Free PMC Article
Kozák E, Fülöp K, Tőkési N, Rao N, Li Q, Terry SF, Uitto J, Zhang X, Becker C, Váradi A, Pomozi V
Exp Dermatol 2022 Apr;31(4):548-555. Epub 2021 Nov 17 doi: 10.1111/exd.14498. PMID: 34758173Free PMC Article
Boyce AM, Gafni RI, Ferreira CR
Curr Osteoporos Rep 2020 Jun;18(3):232-241. doi: 10.1007/s11914-020-00577-4. PMID: 32172442Free PMC Article
Li Q, van de Wetering K, Uitto J
Am J Pathol 2019 Feb;189(2):216-225. Epub 2018 Nov 7 doi: 10.1016/j.ajpath.2018.09.014. PMID: 30414410Free PMC Article

Prognosis

Ferreira CR, Kintzinger K, Hackbarth ME, Botschen U, Nitschke Y, Mughal MZ, Baujat G, Schnabel D, Yuen E, Gahl WA, Gafni RI, Liu Q, Huertas P, Khursigara G, Rutsch F
J Bone Miner Res 2021 Nov;36(11):2193-2202. Epub 2021 Aug 16 doi: 10.1002/jbmr.4418. PMID: 34355424Free PMC Article
Ferreira CR, Hackbarth ME, Ziegler SG, Pan KS, Roberts MS, Rosing DR, Whelpley MS, Bryant JC, Macnamara EF, Wang S, Müller K, Hartley IR, Chew EY, Corden TE, Jacobsen CM, Holm IA, Rutsch F, Dikoglu E, Chen MY, Mughal MZ, Levine MA, Gafni RI, Gahl WA
Genet Med 2021 Feb;23(2):396-407. Epub 2020 Oct 2 doi: 10.1038/s41436-020-00983-0. PMID: 33005041Free PMC Article
Amine M, Faten H, Rim H, Nidhal HS, Njim L, Moussa A, Zakhama A
Pathologica 2015 Mar;107(1):29-31. PMID: 26591630
Giovannoni I, Callea F, Travaglini L, Amodeo A, Cogo P, Secinaro A, Bizzarri C, Cutrera R, El Hachem M, Francalanci P
Eur J Pediatr 2014 Dec;173(12):1735-40. Epub 2014 Nov 1 doi: 10.1007/s00431-014-2447-7. PMID: 25367056
Cheng KS, Chen MR, Ruf N, Lin SP, Rutsch F
Am J Med Genet A 2005 Jul 15;136(2):210-3. doi: 10.1002/ajmg.a.30800. PMID: 15940697

Clinical prediction guides

Kato H, Ansh AJ, Lester ER, Kinoshita Y, Hidaka N, Hoshino Y, Koga M, Taniguchi Y, Uchida T, Yamaguchi H, Niida Y, Nakazato M, Nangaku M, Makita N, Takamura T, Saito T, Braddock DT, Ito N
J Bone Miner Res 2022 Jun;37(6):1125-1135. Epub 2022 Apr 11 doi: 10.1002/jbmr.4550. PMID: 35340077Free PMC Article
Cheng Z, O'Brien K, Howe J, Sullivan C, Schrier D, Lynch A, Jungles S, Sabbagh Y, Thompson D
J Bone Miner Res 2021 Aug;36(8):1594-1604. Epub 2021 May 5 doi: 10.1002/jbmr.4315. PMID: 33900645
Ferreira CR, Hackbarth ME, Ziegler SG, Pan KS, Roberts MS, Rosing DR, Whelpley MS, Bryant JC, Macnamara EF, Wang S, Müller K, Hartley IR, Chew EY, Corden TE, Jacobsen CM, Holm IA, Rutsch F, Dikoglu E, Chen MY, Mughal MZ, Levine MA, Gafni RI, Gahl WA
Genet Med 2021 Feb;23(2):396-407. Epub 2020 Oct 2 doi: 10.1038/s41436-020-00983-0. PMID: 33005041Free PMC Article
Li Q, van de Wetering K, Uitto J
Am J Pathol 2019 Feb;189(2):216-225. Epub 2018 Nov 7 doi: 10.1016/j.ajpath.2018.09.014. PMID: 30414410Free PMC Article
Rutsch F, Böyer P, Nitschke Y, Ruf N, Lorenz-Depierieux B, Wittkampf T, Weissen-Plenz G, Fischer RJ, Mughal Z, Gregory JW, Davies JH, Loirat C, Strom TM, Schnabel D, Nürnberg P, Terkeltaub R; GACI Study Group
Circ Cardiovasc Genet 2008 Dec;1(2):133-40. doi: 10.1161/CIRCGENETICS.108.797704. PMID: 20016754Free PMC Article

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