Bisphosphonate therapy in an infant with generalized arterial calcification with an ABCC6 mutation

Ali, S Akhtar; Ng, Calvin S.H.; Votava‐Smith, Jodie K.; Randolph, Linda M.; Pitukcheewanont, Pisit

doi:10.1007/s00198-018-4639-x

Cited by 13 publications

(11 citation statements)

References 24 publications

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“…summarized 23 cases of prenatal diagnosis, of which 17 were diagnosed at 28 weeks or later, with rare cases diagnosed in the second trimester. The earliest reported prenatal diagnosis of GACI occurred at 19 weeks of gestation 14 . The three cases described in the present report had hyperechogenic valves or annuli as the first presentation during routine sonographic fetal heart screening in the second trimester.…”

Section: Discussionmentioning

confidence: 55%

Prenatal diagnosis of generalized arterial calcification of infancy in the second trimester

Dai

Liu

et al. 2022

Prenatal Diagnosis

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Objectives: Generalized arterial calcification of infancy (GACI) is a rare autosomal recessive disorder characterized by subintimal fibrous proliferation and deposition of calcium salts in the internal elastic lamina, leading to extensive arterial calcification and stenosis of large and medium-sized arteries. Prenatal diagnosis is usually made in the third trimester by detection of aortic and pulmonary calcification with associated nonimmune hydrops; earlier prenatal diagnosis is rare. This study was performed to examine the prenatal ultrasound and genetic features of fetuses with GACI. Methods:We retrospectively reviewed the ultrasound findings, their progression in utero, and the clinical features in three fetuses with GACI ascertained using ultrasound in the second trimester. GACI was subsequently confirmed through pathological examination and/or molecular genetic testing.Results: All three fetuses had hyperechogenic valves or annuli as the first detectable manifestation in the second trimester, followed by relatively rapid progression to arterial wall calcification. Three novel mutations of the ENPP1 gene associated with GACI were found in two of the cases (c.26dupG, c.1454A > G, and c.263C > G).Conclusions: GACI should be suspected when hyperechogenic cardiac valves, annuli, or arterial walls are noted after ruling out other causes of arterial calcification. Genetic testing is important for prenatal and future preimplantation genetic diagnosis. Key pointsWhat's already known about this topic? � Historically, generalized arterial calcification of infancy (GACI) has often been diagnosed retrospectively. Prenatal diagnosis is usually made in the third trimester by the detection of calcifications in the aortic, pulmonary, and other large arterial walls, with associated nonimmune hydrops in some cases. What does this study add?� We present three cases of GACI diagnosed prenatally using ultrasound in the second trimester, in which hyperechogenic valves and/or annuli were the early manifestation. We also report three novel mutations of the ENPP1 gene associated with GACI.Lihong Pu and Xiaohui Dai are co-authors.

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Section: Discussionmentioning

confidence: 55%

Prenatal diagnosis of generalized arterial calcification of infancy in the second trimester

Dai

Liu

et al. 2022

Prenatal Diagnosis

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“…Historically, calcifications were believed to be mediated by endothelin-1 [2][3][4] ; however, more recent studies have identified pathogenic variants in ABCC6 or ENPP1, which, when found in a compound heterozygous or homozygous state, are known to cause GACI. 5,6 This report is the first to note this phenotype with this variant in the ABCC6 gene and is unique in the finding of a single variant. This case raises multiple possibilities, whether (1) an undetected second pathogenic variant was present; (2) this was an incidental finding; or, (3) the presence of a single variant in ABCC6 is sufficient to cause a phenotype in the appropriate environmental context (increased cardiac myocyte strain and turbulent flow in the great vessels of the recipient twin in TTTS).…”

Section: Discussionmentioning

confidence: 67%

“…The most commonly calcified vessel is the main pulmonary artery, implying a significant right heart strain, which is the dominant side of the heart in utero. Historically, calcifications were believed to be mediated by endothelin‐1 2–4 ; however, more recent studies have identified pathogenic variants in ABCC6 or ENPP1 , which, when found in a compound heterozygous or homozygous state, are known to cause GACI 5,6 …”

Section: Discussionmentioning

confidence: 99%

Twin‐twin transfusion syndrome recipient with arterial calcification and heterozygous variant in ABCC6: Evidence of a gene‐environment interaction?

Springman,

Forde,

Tolusso

et al. 2023

Prenatal Diagnosis

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We report a case of a twin-twin transfusion syndrome (TTTS) recipient who, after successful fetoscopic surgery, developed a large pericardial effusion and calcifications of the aorta and main pulmonary artery. The donor fetus never had cardiac strain and never developed cardiac calcifications. A heterozygous likely pathogenic variant in ABCC6 (c.2018T > C, p.Leu673Pro) was identified in the recipient twin.While TTTS recipient twins are at risk of arterial calcifications and right heart failure secondary to the disease, calcifications of the great vessels are also observed in generalized arterial calcification of infancy, a Mendelian genetic disorder with associated biallelic pathogenic variations in ABCC6 or ENPP1, which can result in significant pediatric morbidity or mortality. The recipient twin in this case had some degree of cardiac strain prior to TTTS surgery; however, the progressive calcification of the aorta and pulmonary trunk occurred weeks after TTTS resolution. This case raises the possibility of a gene-environment interaction and emphasizes the need for genetic evaluation in the setting of TTTS and calcifications. Key points What's already known about this topic?� Recipient cardiomyopathy is a feature of twin-twin transfusion syndrome (TTTS). Pathogenic compound heterozygosity and homozygosity in ABCC6 can lead to general arterial calcifications of infancy, a rare and potentially lethal disease. What does this study add?� TTTS in combination with heterozygosity in ABCC6 led to numerous arterial calcifications in utero without significant pediatric disease.Andrea Springman and Braxton Forde contributed equally and share primary authorship of this report.

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“…Case reports demonstrate that bisphosphonates and thiosulfates have been successfully used to treat rapid calcification associated with CKD in calciphylaxis patients 239 , 240 and general calcification of infancy. 241 These extreme cases demonstrate the potential of altering mineral formation for therapeutic benefit; however, more studies are needed to determine how to best interact with mineral to reduce cardiovascular risk in the general CKD population. Most studies showing reduced valvular and vascular calcification fail to demonstrate improved cardiovascular risk.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease

Hutcheson

Goettsch

2023

Circulation Research

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Patients with chronic kidney disease (CKD) exhibit tremendously elevated risk for cardiovascular disease, particularly ischemic heart disease, due to premature vascular and cardiac aging and accelerated ectopic calcification. The presence of cardiovascular calcification associates with increased risk in patients with CKD. Disturbed mineral homeostasis and diverse comorbidities in these patients drive increased systemic cardiovascular calcification in different manifestations with diverse clinical consequences, like plaque instability, vessel stiffening, and aortic stenosis. This review outlines the heterogeneity in calcification patterning, including mineral type and location and potential implications on clinical outcomes. The advent of therapeutics currently in clinical trials may reduce CKD-associated morbidity. Development of therapeutics for cardiovascular calcification begins with the premise that less mineral is better. While restoring diseased tissues to a noncalcified homeostasis remains the ultimate goal, in some cases, calcific mineral may play a protective role, such as in atherosclerotic plaques. Therefore, developing treatments for ectopic calcification may require a nuanced approach that considers individual patient risk factors. Here, we discuss the most common cardiac and vascular calcification pathologies observed in CKD, how mineral in these tissues affects function, and the potential outcomes and considerations for therapeutic strategies that seek to disrupt the nucleation and growth of mineral. Finally, we discuss future patient-specific considerations for treating cardiac and vascular calcification in patients with CKD—a population in need of anticalcification therapies.

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Bisphosphonate therapy in an infant with generalized arterial calcification with an ABCC6 mutation

Cited by 13 publications

References 24 publications

Prenatal diagnosis of generalized arterial calcification of infancy in the second trimester

Prenatal diagnosis of generalized arterial calcification of infancy in the second trimester

Twin‐twin transfusion syndrome recipient with arterial calcification and heterozygous variant in ABCC6: Evidence of a gene‐environment interaction?

Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease

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