Clinical characteristics.

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.

Diagnosis/testing.

The diagnosis of GACI is established in a proband with cardiovascular symptoms during infancy associated with widespread arterial calcification on imaging (once secondary causes have been ruled out) and biallelic pathogenic variants in ENPP1 or ABCC6 identified on molecular genetic testing.

Management.

Treatment of manifestations: It remains unclear whether bisphosphonates (most commonly used is etidronate) increase survival. Standard anti-hypertensive therapy is warranted for hypertension. Aspirin therapy is warranted in those with severe coronary stenosis. Intravitreal VEGF inhibitors for choroidal neovascularization, calcitriol and oral phosphate supplement for hypophosphatemic rickets, and hearing aids (as indicated) are all used in the management of this disorder.

Surveillance: No specific guidelines address the issue of surveillance. The appropriate intervals for monitoring depend on the clinical findings. Low-dose CT scan every 3-4 months is used for the first year of life to monitor arterial calcification; echocardiography and troponin are used at regular intervals to monitor cardiovascular issues. Annual (or more frequent) retinal exam for PXE retinal findings and regular lab testing to assure mineral homeostasis associated with the development of rickets. Due to risk for nephrocalcinosis with treatment for rickets, urine calcium is monitored to maintain calciuria below 4 mg/kg/d and yearly renal ultrasound is performed. Evaluate for cervical spine fusion prior to elective endotracheal intubation by a lateral cervical spine x-ray.

Agents/circumstances to avoid: Although no clinical studies have been conducted, it seems prudent to avoid the use of warfarin if possible. Similarly, the use of burosumab, an anti-FGF23 monoclonal antibody, remains controversial due to theoretic concerns.

Evaluation of relatives at risk: It is appropriate to evaluate the younger sibs of a proband with GACI in order to identify as early as possible those who would benefit from treatment.

Genetic counseling.

GACI is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GACI-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither pathogenic variant. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.

Suggestive Findings

GACI should be suspected in individuals with a combination of the following.

Clinical findings

• Typical cardiovascular findings including heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly
• Characteristic imaging findings of widespread arterial calcification and/or narrowing of large and medium-sized vessels
• Appearance of typical clinical and histologic skin findings of pseudoxanthoma elasticum (PXE) and/or angioid streaks on fundoscopy
• Development of hypophosphatemic rickets after infancy

Imaging

• Computed tomography (CT) is the preferred imaging modality to assess for calcifications. Multi-detector computed tomography has been reported to detect not only arterial wall calcification but also intimal thickening causing luminal narrowing [Greenberg & Gibson 2005], which appears as a target or bull's eye with a center of high attenuation (the lumen) surrounded by low attenuation (the thickened intima), which is again surrounded by high attenuation (the calcification of the arterial wall).
• Echocardiogram can:
  • Detect echobrightness of the arteries near the heart, including the coronary and pulmonary arteries, ascending aorta and aortic arch, and large arteries originating from the aortic arch;
  • Detect the presence of left ventricular hypertrophy and/or pericardial effusion.
• Ultrasound examination of the abdomen and head can be used to detect echo-bright vessels.
• Plain radiographs can sometimes detect arterial calcifications, but with low sensitivity, and many times arterial calcifications are detected only on reexamination of radiographs after the diagnosis of GACI has been made post mortem [Glatz et al 2006].
• Magnetic resonance imaging and angiography are insensitive to detecting arterial wall calcification, but can detect luminal stenosis [Pao et al 1998], especially when performed with breath-hold and cardiac gating techniques [Tran & Boechat 2006].
• Coronary angiography can be normal despite the presence of extensive arterial wall calcifications, likely because widespread involvement of all coronary arteries results in diffuse narrowing without the focal areas of stenosis detectable by angiography [Hault et al 2008].

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of GACI is established in a proband with cardiovascular symptoms during infancy associated with widespread arterial calcification on imaging once secondary causes have been ruled out (see Differential Diagnosis), and either biallelic pathogenic variants in ENPP1 or ABCC6 on molecular genetic testing (see Table 1) or, if testing is not diagnostic, histologic findings on arterial biopsy [Morton 1978].

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing), depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of GACI has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Generalized arterial calcification of infancy (GACI) can result either from ENPP1 deficiency (ENPP1-GACI), or from ABCC6 deficiency (ABCC6-GACI) associated with biallelic pathogenic variants in ENPP1 or ABCC6 respectively. To date, around 250 individuals have been identified with GACI [Authors, personal observation]. The following description of the phenotypic features associated with this condition is based on these individuals.

Genotype-Phenotype Correlations

Marked phenotypic heterogeneity, even among surviving sibs with identical genotypes, argues against a genotype-phenotype correlation in GACI [Ferreira et al 2021a].

Otero et al [2013] (full text; see Supporting Information, Appendix) reported an affected individual with biallelic ENPP1 pathogenic variants and a heterozygous pathogenic variant in ABCC6, which theoretically could have contributed to the severity of GACI. The individual's healthy mother and brother both were doubly heterozygous for an ENPP1 pathogenic variant and the ABCC6 pathogenic variant; thus, it appears that the presence of one heterozygous ENPP1 pathogenic variant and one ABCC6 pathogenic variant does not cause GACI.

Nomenclature

In the past, generalized arterial calcification of infancy (GACI) has been variously referred to as idiopathic obliterative arteriopathy, infantile calcifying arteriopathy, occlusive infantile arteriopathy, medial coronary sclerosis of infancy, diffuse arterial calcifying elastopathy of infancy, and arteriopathia calcificans infantum.

Prevalence

GACI shows no ethnic or racial predilection, and has been described throughout the world.

The disease frequency is estimated at one in 200,000 pregnancies, and the carrier frequency at one in 223 individuals [Ferreira et al 2021a].

Disorders with Vascular Calcification

Singleton-Merten syndrome (OMIM 182250 and 616298) is an autosomal dominant disorder caused by pathogenic variants in IFIH1 or DDX58.

• Severe aortic calcification, dental anomalies (delayed eruption and early loss of permanent teeth, alveolar bone erosion), osteopenia, and acroosteolysis are salient features of the disease [Feigenbaum et al 2013].
• Unlike generalized arterial calcification of infancy (GACI), aortic calcification in Singleton-Merten syndrome starts later in life (age range at diagnosis: 6-39 years).

Metastatic calcification due to hypervitaminosis D, hyperparathyroidism, or end-stage renal disease

• Diffuse arterial calcification tends to affect the media of the vessels, and extensive extravascular calcification involves the renal tubules, bronchial walls, and basal mucosa and muscularis mucosae of the stomach.
• Compared with GACI, metastatic calcification exhibits a different distribution of extravascular calcification, and the microscopic vascular changes occur in the media with little intimal proliferation.

Twin-twin transfusion syndrome (TTTS) and twin reversed arterial perfusion (TRAP) sequence

• Increased echogenicity due to calcification has been described in the wall of the pulmonary trunk, proximal branch pulmonary arteries [Saxena & Soni 2003, Bassil Eter et al 2009], and ascending aorta in the recipient twin of TTTS [Saxena & Soni 2003]. Pulmonary artery calcification has also been described in pump twins in TRAP sequence [Royston & Geoghegan 1983, Popek et al 1993]. Since this always occurs in the volume-overloaded fetus (recipient twin in TTTS and pump twin in TRAP sequence), it presumably results from increased cardiac output in utero [Popek et al 1993].
• Histologically, calcium is deposited primarily in the media [Popek et al 1993], whereas in GACI it is deposited along the internal elastic lamina. Additionally, in TTTS and TRAP sequence calcification does not occur elsewhere in the body [Saxena & Soni 2003].

Disorders with Occlusive Arteriopathy

Pediatric fibromuscular dysplasia (FMD). This noninflammatory arteriopathy can be unifocal or multifocal, is associated with hypertension, and commonly affects the renal and mesenteric arteries and the abdominal aorta [Green et al 2016, Louis et al 2018], all common sites of stenosis in GACI. In fact, a child with a clinical diagnosis of pediatric FMD was eventually found to have ENPP1 deficiency [Ferreira et al 2021a]; thus, other individuals with pediatric FMD could benefit from molecular genetic testing of ENPP1.

Grange syndrome (OMIM 602531) is an autosomal recessive disorder caused by pathogenic variants in YY1AP1. This extremely rare syndrome is characterized by diffuse vascular stenoses with intimal thickening [Weymann et al 2001] in a distribution pattern resembling fibromuscular dysplasia, brachysyndactyly, and osteopenia with increased bone fragility [Grange et al 1998, Volonghi et al 2012].

Chronic arsenic poisoning. Diffuse thickening of the intima of medium- and small-sized arteries (without calcification) has been described in chronic arsenic poisoning, leading to death by myocardial infarction in children as young as age two years [Rosenberg 1974].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with generalized arterial calcification of infancy (GACI), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

No specific guidelines address the issue of surveillance. The appropriate intervals for monitoring depend on clinical findings and need to be more frequent in those with a more severe presentation.

Agents/Circumstances to Avoid

Although no clinical studies have been conducted, it seems prudent to avoid the use of warfarin if possible. The matrix Gla protein (MGP), a potent anti-mineralization factor, needs to be activated by a vitamin K-dependent enzyme, and warfarin interferes with the vitamin K cycle. Warfarin has also been shown to accelerate ectopic mineralization in Abcc6 knockout mice [Li et al 2013].

One question is whether burosumab, an anti-FGF23 monoclonal antibody approved by the FDA for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, could also treat the hypophosphatemic rickets of ENPP1 deficiency. This approach, however, remains controversial due to theoretic concerns that it could worsen ectopic calcification by lowering pyrophosphate concentrations. However, one individual with ENPP1-related rickets, who was initially thought to have X-linked hypophosphatemia, received burosumab for months without developing any vascular calcification [Boyce et al 2020].

Evaluation of Relatives at Risk

It is appropriate to evaluate the younger sibs of a proband with GACI in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. Evaluations can include:

• Molecular genetic testing if the GACI-causing pathogenic variants in the family are known;
• Imaging studies if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Enzyme replacement therapy. The administration of a recombinant form of ENPP1 prevents calcification and mortality [Albright et al 2015], improves hypertension and cardiac function [Khan et al 2018], and prevents intimal proliferation [Nitschke et al 2018] in mouse models of ENPP1 deficiency. It also prevented the osteomalacia, increased bone density, and markedly improved bone strength in mutant mice, while preventing the development of nephrocalcinosis [Ferreira et al 2021b].

Magnesium. In a mouse model of ENPP1 deficiency, increased dietary magnesium during pregnancy and continued postnatally was shown to prevent ectopic mineralization, likely by competing with calcium for phosphate binding [Kingman et al 2017].

One infant who did not initially respond to etidronate administration eventually showed improvement with a combination of etidronate, magnesium, and calcium carbonate [Dursun et al 2019]; however, it is impossible to know whether this child would have shown spontaneous regression of calcification even in the absence of magnesium administration.

Sodium thiosulfate. A combination of etidronate and sodium thiosulfate was administered in a child with GACI, with no improvement of calcification and demise after one month [Hollwey et al 2019]. The administration of intravenous sodium thiosulfate led to improvement of calcific stenosis of celiac and mesenteric arteries in a child with a complex genotype [Omarjee et al 2020]. Thus, the use of sodium thiosulfate has not been associated with consistent improvement, and its benefits remain unclear.

Cardiac transplantation. One individual who received a heart transplant did well, with no recurrence of disease over two years of follow-up post transplant [Giovannoni et al 2014]. Another individual continues to do well several years post transplant [Authors, personal observation].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Generalized arterial calcification of infancy (GACI) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are typically heterozygous for an ENPP1 or ABCC6 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a GACI-causing pathogenic variant and to allow reliable recurrence risk assessment.
  • In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either: (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred de novo in the proband (de novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders such as GACI [Authors, personal observation]); (2) uniparental isodisomy and consequent homozygosity for the pathogenic variant transmitted by a heterozygous parent.
  • Note: In a consanguineous family, both the father and the proband were homozygous for the same ENPP1 pathogenic variants. (The father of the proband had autosomal recessive hypophosphatemic rickets type 2 while the proband was affected with GACI [Lorenz-Depiereux et al 2010]; see Genetically Related Disorders).
• Most heterozygotes are asymptomatic and are not at risk of developing the disorder. However, adult individuals with heterozygous ENPP1 pathogenic variants from two unrelated families were reported with fractures, low bone mineral density, hypophosphatemia, hyperphosphaturia, and elevated FGF23 [Oheim et al 2020]; thus, it appears that certain heterozygous variants in ENPP1 could lead to osteomalacia.

Sibs of a proband

• If both parents are known to be heterozygous for a GACI-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither pathogenic variant.
• A sib who inherits biallelic pathogenic variants may have a clinical course markedly different from that of the proband (see Clinical Description, Variability).
• Most heterozygotes are asymptomatic and are not at risk of developing the disorder, although it is possible that certain heterozygous pathogenic variants in ENPP1 could lead to osteomalacia in adulthood [Oheim et al 2020].

Offspring of a proband

• Because mortality in infancy is high, no individuals with GACI have been reported to have children to date.
• It is entirely possible that affected individuals who survive into adulthood will be able to conceive. For these individuals, offspring will be obligate heterozygotes for a pathogenic variant in ENPP1 or ABCC6 provided their reproductive partner is not affected or heterozygous (see Prevalence).

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a GACI-causing pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the ENPP1 or ABCC6 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the GACI-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Fetal ultrasound examination. The earliest detected prenatal manifestation of the disease was at 14 weeks' gestation, in the form of echogenic foci in the mitral valve [Ciana et al 2006]. Hepatic vascular calcification has been detected as early as 18 weeks' gestation [Wax et al 2001]. However, such early ultrasound findings are not typical, and other cases present with a normal anatomy ultrasound even later in pregnancy; thus, serial scans are important [Nasrallah et al 2009].

The detection of an echogenic intracardiac focus as early as 20 weeks' gestation has been proposed as an early marker of the disease in individuals with a family history of GACI [Nasrallah et al 2009]. Of note, the absence of identification of vessel echo brightness on fetal ultrasound in a fetus at term does not rule out GACI, since faint calcifications can be missed in utero but detected postnatally [Cheng et al 2005].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ENPP1 breaks the phosphodiester bonds of extracellular nucleotides. Its most important substrate is ATP, cleaved into AMP and inorganic pyrophosphate. A deficiency of ENPP1 activity thus leads to a deficiency of both AMP and inorganic pyrophosphate. Pyrophosphate is the main inhibitor of hydroxyapatite deposition, so its deficiency leads to ectopic calcification, while the deficiency of AMP (or downstream adenosine) leads to intimal proliferation and consequently arterial narrowing. ABCC6 encodes a plasma membrane transporter, the substrate of which is unknown, although ATP remains a candidate.

Mechanism of disease causation. The disease is caused by pathogenic variants in ENPP1 or ABCC6 leading to deficient enzymatic or transport activity, respectively.

Gene-specific laboratory technical considerations: ABCC6. Presence of two pseudogenes

Acknowledgments

This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute.

Revision History

• 30 December 2020 (ha) Comprehensive update posted live
• 13 November 2014 (me) Review posted live
• 25 June 2014 (cf) Original submission

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