Generalized Arterial Calcification of Infancy

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).

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Generalized Arterial Calcification of Infancy (GACI)

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.

Table 2.

GACI: Frequency of Select Features

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.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with GACI

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with GACI

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.

Table 6.

Recommended Surveillance for Individuals with GACI

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

Literature Cited

• Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I, Braddock AA, Covo MS, Tehan M, Yang G, Cheng Z, Bouchard K, Yu ZX, Thorn S, Wang X, Folta-Stogniew EJ, Negrete A, Sinusas AJ, Shiloach J, Zubal G, Madri JA, De La Cruz EM, Braddock DT. ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nat Commun. 2015;6:10006. [PMC free article: PMC4686714] [PubMed: 26624227]

• Bassil Eter R, Dulac Y, Acar P. Pulmonary diffuse arterial calcifications: a very rare complication in the recipient of a twin-to-twin transfusion syndrome. Cardiol Young. 2009;19:410–2. [PubMed: 19450382]

• Boyce AM, Gafni RI, Ferreira CR. Generalized arterial calcification of infancy: new insights, controversies, and approach to management. Curr Osteoporos Rep. 2020;18:232–41. [PMC free article: PMC9506683] [PubMed: 32172442]

• Brachet C, Mansbach AL, Clerckx A, Deltenre P, Heinrichs C. Hearing loss is part of the clinical picture of ENPP1 loss of function mutation. Horm Res Paediatr. 2014;81:63–6. [PubMed: 24216977]

• Cheng K-S, Chen M-R, Ruf N, Lin S-P, Rutsch F. Generalized arterial calcification of infancy: different clinical courses in two affected siblings. Am J Med Genet A. 2005;136:210–3. [PubMed: 15940697]

• Chong CR, Hutchins GM. Idiopathic infantile arterial calcification: the spectrum of clinical presentations. Pediatr Dev Pathol. 2008;11:405–15. [PubMed: 17990935]

• Ciana G, Trappan A, Bembi B, Benettoni A, Maso G, Zennaro F, Ruf N, Schnabel D, Rutsch F. Generalized arterial calcification of infancy: two siblings with prolonged survival. Eur J Pediatr. 2006;165:258–63. [PubMed: 16315058]

• Dursun F, Atasoy Öztürk T, Güven S, Kırmızıbekmez H, Seymen Karabulut G, Kalın S, Sözeri B. Magnesium and anti-phosphate treatment with bisphosphonates for generalised arterial calcification of infancy: A case report. J Clin Res Pediatr Endocrinol. 2019;11:311–8. [PMC free article: PMC6745454] [PubMed: 30525344]

• Eytan O, Morice-Picard F, Sarig O, Ezzedine K, Isakov O, Li Q, Ishida-Yamamoto A, Shomron N, Goldsmith T, Fuchs-Telem D, Adir N, Uitto J, Orlow SJ, Taieb A, Sprecher E. Cole disease results from mutations in ENPP1. Am J Hum Genet. 2013;93:752–7. [PMC free article: PMC3791268] [PubMed: 24075184]

• Farquhar J, Makhseed N, Sargent M, Taylor G, Osiovich H. Idiopathic infantile arterial calcification and persistent pulmonary hypertension. Am J Perinatol. 2005;22:121–5. [PubMed: 15838744]

• Feigenbaum A, Müller C, Yale C, Kleinheinz J, Jezewski P, Kehl HG, MacDougall M, Rutsch F, Hennekam RC. Singleton-Merten syndrome: an autosomal dominant disorder with variable expression. Am J Med Genet A. 2013;161A:360–70. [PubMed: 23322711]

• 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. Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI). Genet Med. 2021a;23:396–407. [PMC free article: PMC7867608] [PubMed: 33005041]

• Ferreira CR, Kavanagh D, Oheim R, et al. Response of the ENPP1-deficient skeletal phenotype to oral phosphate supplementation and/or enzyme replacement therapy: Comparative studies in humans and mice. J Bone Miner Res. 2021b;36:942–55. [PMC free article: PMC8739051] [PubMed: 33465815]

• Freychet C, Gay C, Lavocat MP, Teyssier G, Patural H, Bacchetta J, Cottalorda J, Meunier BB, Linglart A, Baujat G, Stephan JL. GACI syndrome: a case report with a neonatal beginning. Arch Pediatr. 2014;21:632–6. [PubMed: 24768072]

• Galletti S, Nitschke Y, Malavolti AM, Aquilano G, Faldella G, Corvaglia L, Rutsch F. Generalized arterial calcification of infancy: fatal clinical course associated with a novel mutation in ENPP1. JIMD Rep. 2011;1:23–7. [PMC free article: PMC3509810] [PubMed: 23430823]

• Giovannoni I, Callea F, Travaglini L, Amodeo A, Cogo P, Secinaro A, Bizzarri C, Cutrera R, El Hachem M, Francalanci P. Heart transplant and 2-year follow up in a child with generalized arterial calcification of infancy. Eur J Pediatr. 2014;173:1735–40. [PubMed: 25367056]

• Glatz AC, Pawel BR, Hsu DT, Weinberg P, Chrisant MRK. Idiopathic infantile arterial calcification: two case reports, a review of the literature and a role for cardiac transplantation. Pediatr Transplant. 2006;10:225–33. [PubMed: 16573612]

• Grange DK, Balfour IC, Chen SC, Wood EG. Familial syndrome of progressive arterial occlusive disease consistent with fibromuscular dysplasia, hypertension, congenital cardiac defects, bone fragility, brachysyndactyly, and learning disabilities. Am J Med Genet. 1998;75:469–80. [PubMed: 9489789]

• Green R, Gu X, Kline-Rogers E, Froehlich J, Mace P, Gray B, Katzen B, Olin J, Gornik HL, Cahill AM, Meyers KE. Differences between the pediatric and adult presentation of fibromuscular dysplasia: results from the US Registry. Pediatr Nephrol. 2016;31:641–50. [PubMed: 26525198]

• Greenberg SB, Gibson J. New findings in idiopathic arterial calcification of infancy detected by MDCT. AJR Am J Roentgenol. 2005;185:530–2. [PubMed: 16037532]

• 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. Cardiol Young. 2008;18:624–7. [PubMed: 18842162]

• Hollwey A, Forster C, Mushtaq T. P031 Use of disodium etidronate and sodium thiosulfate in a premature neonate with generalised arterial calcification of infancy. Arch Dis Child. 2019;104:e2.

• Khan T, Sinkevicius KW, Vong S, Avakian A, Leavitt MC, Malanson H, Marozsan A, Askew KL. ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy. Dis Model Mech. 2018;11:dmm035691. [PMC free article: PMC6215426] [PubMed: 30158213]

• Kingman J, Uitto J, Li Q. Elevated dietary magnesium during pregnancy and postnatal life prevents ectopic mineralization in Enpp1asj mice, a model for generalized arterial calcification of infancy. Oncotarget. 2017;8:38152–60. [PMC free article: PMC5503522] [PubMed: 28402956]

• Kotwal A, Ferrer A, Kumar R, Singh RJ, Murthy V, Schultz-Rogers L, Zimmermann M, Lanpher B, Zimmerman K, Stabach PR, Klee E, Braddock DT, Wermers RA. Clinical and biochemical phenotypes in a family with ENPP1 mutations. J Bone Miner Res. 2020;35:662–70. [PMC free article: PMC7771569] [PubMed: 31826312]

• Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, Manor E, Buriakovsky S, Hadad Y, Goding J, Parvari R. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010;86:273–8. [PMC free article: PMC2820183] [PubMed: 20137772]

• Li Q, Guo H, Chou DW, Harrington DJ, Schurgers LJ, Terry SF, Uitto J. Warfarin accelerates ectopic mineralization in Abcc6(-/-) mice: clinical relevance to pseudoxanthoma elasticum. Am J Pathol. 2013;182:1139–50. [PMC free article: PMC3620423] [PubMed: 23415960]

• Lorenz-Depiereux B, Schnabel D, Tiosano D, Häusler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010;86:267–72. [PMC free article: PMC2820166] [PubMed: 20137773]

• Louis R, Levy-Erez D, Cahill AM, Meyers KE. Imaging studies in pediatric fibromuscular dysplasia (FMD): a single-center experience. Pediatr Nephrol. 2018;33:1593–9. [PMC free article: PMC6082421] [PubMed: 29869115]

• Lussier-Lazaroff J, Fletcher BD. Idiopathic infantile arterial calcification: roentgen diagnosis of a rare cause of coronary artery occlusion. Pediatr Radiol. 1973;1:224–8. [PubMed: 4779072]

• Marrott PK, Newcombe KD, Becroft DM, Friedlander DH. Idiopathic infantile arterial calcification with survival to adult life. Pediatr Cardiol. 1984;5:119–22. [PubMed: 6473121]

• Meradji M, de Villeneuve VH, Huber J, de Bruijn WC, Pearse RG. Idiopathic infantile arterial calcification in siblings: radiologic diagnosis and successful treatment. J Pediatr. 1978;92:401–5. [PubMed: 416189]

• Morton R. Idiopathic arterial calcification in infancy. Histopathology. 1978;2:423–32. [PubMed: 730123]

• Nasrallah FK, Baho H, Sallout A, Qurashi M. Prenatal diagnosis of idiopathic infantile arterial calcification with hydrops fetalis. Ultrasound Obstet Gynecol. 2009;34:601–4. [PubMed: 19813208]

• Nitschke Y, Baujat G, Botschen U, Wittkampf T, du Moulin M, Stella J, Le Merrer M, Guest G, Lambot K, Tazarourte-Pinturier MF, Chassaing N, Roche O, Feenstra I, Loechner K, Deshpande C, Garber SJ, Chikarmane R, Steinmann B, Shahinyan T, Martorell L, Davies J, Smith WE, Kahler SG, McCulloch M, Wraige E, Loidi L, Höhne W, Martin L, Hadj-Rabia S, Terkeltaub R, Rutsch F. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet. 2012;90:25–39. [PMC free article: PMC3257960] [PubMed: 22209248]

• Nitschke Y, Rutsch F. Generalized arterial calcification of infancy and pseudoxanthoma elasticum: two sides of the same coin. Front Genet. 2012;3:302. [PMC free article: PMC3529400] [PubMed: 23269929]

• Nitschke Y, Yan Y, Buers I, Kintziger K, Askew K, Rutsch F. ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP. Exp Mol Med. 2018;50:1–12. [PMC free article: PMC6204430] [PubMed: 30369595]

• Oheim R, Zimmerman K, Maulding ND, Stürznickel J, von Kroge S, Kavanagh D, Stabach PR, Kornak U, Tommasini SM, Horowitz MC, Amling M, Thompson D, Schinke T, Busse B, Carpenter TO, Braddock DT. Human heterozygous ENPP1 deficiency is associated with early onset osteoporosis, a phenotype recapitulated in a mouse model of Enpp1 deficiency. J Bone Miner Res. 2020;35:528–39. [PMC free article: PMC7184798] [PubMed: 31805212]

• Omarjee L, Nitschke Y, Verschuere S, Bourrat E, Vignon MD, Navasiolava N, Leftheriotis G, Kauffenstein G, Rutsch F, Vanakker OM, Martin L. Severe early-onset manifestations of pseudoxanthoma elasticum resulting from the cumulative effects of several deleterious mutations in ENPP1, ABCC6 and HBB: transient improvement in ectopic calcification with sodium thiosulfate. Br J Dermatol. 2020;183:367–72. [PubMed: 31646622]

• Otero JE, Gottesman GS, McAlister WH, Mumm S, Madson KL, Kiffer-Moreira T, Sheen C, Millán JL, Ericson KL, Whyte MP. Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy. J Bone Miner Res. 2013;28:419–30. [PubMed: 22972716]

• Pao DG, DeAngelis GA, Lovell MA, McIlhenny J, Hagspiel KD. Idiopathic arterial calcification of infancy: sonographic and magnetic resonance findings with pathologic correlation. Pediatr Radiol. 1998;28:256–9. [PubMed: 9545482]

• Popek EJ, Strain JD, Neumann A, Wilson H. In utero development of pulmonary artery calcification in monochorionic twins: a report of three cases and discussion of the possible etiology. Pediatr Pathol. 1993;13:597–611. [PubMed: 8247958]

• Rosenberg HG. Systemic arterial disease and chronic arsenicism in infants. Arch Pathol. 1974;97:360–5. [PubMed: 4825098]

• Royston D, Geoghegan F. Disseminated arterial calcification associated with acardius acephalus. Arch Dis Child. 1983;58:641–3. [PMC free article: PMC1628306] [PubMed: 6684415]

• 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, et al. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 2008;1:133–40. [PMC free article: PMC2794045] [PubMed: 20016754]

• Saito T, Shimizu Y, Hori M, Taguchi M, Igarashi T, Fukumoto S, Fujitab T. A patient with hypophosphatemic rickets and ossification of posterior longitudinal ligament caused by a novel homozygous mutation in ENPP1 gene. Bone. 2011;49:913–6. [PubMed: 21745613]

• Saxena A, Soni NR. Pulmonary artery calcification in recipient twins of twin to twin transfusion syndrome: a report of three cases. Pediatr Cardiol. 2003;24:80–3. [PubMed: 12574984]

• Shaireen H, Howlett A, Amin H, Yusuf K, Kamaluddeen M, Lodha A. The mystery of persistent pulmonary hypertension: an idiopathic infantile arterial calcification. BMC Pediatr. 2013;13:107. [PMC free article: PMC3724600] [PubMed: 23855924]

• Sholler GF, Yu JS, Bale PM, Hawker RE, Celermajer JM, Kozlowski K. Generalized arterial calcification of infancy: three case reports, including spontaneous regression with long-term survival. J Pediatr. 1984;105:257–60. [PubMed: 6747757]

• Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]

• Thiaville A, Smets A, Clercx A, Perlmutter N. Idiopathic infantile arterial calcification: a surviving patient with renal artery stenosis. Pediatr Radiol. 1994;24:506–8. [PubMed: 7885787]

• Thomas P, Chandra M, Kahn E, McVicar M, Naidich J, LaCorte M. Idiopathic arterial calcification of infancy: a case with prolonged survival. Pediatr Nephrol. 1990;4:233–5. [PubMed: 2400650]

• Tran KH, Boechat MI. Idiopathic infantile arterial calcification: imaging evaluation and the usefulness of MR angiography. Pediatr Radiol. 2006;36:247–53. [PubMed: 16429273]

• van der Sluis IM, Boot AM, Vernooij M, Meradji M, Kroon AA. Idiopathic infantile arterial calcification: clinical presentation, therapy and long-term follow-up. Eur J Pediatr. 2006;165:590–3. [PubMed: 16649023]

• Van Dyck M, Proesmans W, Van Hollebeke E, Marchal G, Moerman P. Idiopathic infantile arterial calcification with cardiac, renal and central nervous system involvement. Eur J Pediatr. 1989;148:374–7. [PubMed: 2707283]

• Vera J, Lucaya J, Garcia Conesa JA, Aso C, Balaguer A. Idiopathic infantile arterial calcification: unusual features. Pediatr Radiol. 1990;20:585–7. [PubMed: 2251001]

• Volonghi I, Frigerio M, Mardighian D, Gasparotti R, Del Zotto E, Giossi A, Costa P, Poli L, Jeannin G, Gregorini GA, Padovani A, Pezzini A. Grange syndrome: an identifiable cause of stroke in young adults. Am J Med Genet A. 2012;158A:2894–8. [PubMed: 22987684]

• Wax JR, Blackstone J, Pinette MG, Cartin A. Hepatic vascular calcification: an early second trimester sonographic feature of idiopathic infantile arterial calcinosis. Am J Obstet Gynecol. 2001;185:1267–8. [PubMed: 11717671]

• Weymann S, Yonekawa Y, Khan N, Martin E, Heppner FL, Schinzel A, Kotzot D. Severe arterial occlusive disorder and brachysyndactyly in a boy: a further case of Grange syndrome? Am J Med Genet. 2001;99:190–5. [PubMed: 11241488]

• Witzleben CL. Idiopathic infantile arterial calcification--a misnomer? Am J Cardiol. 1970;26:305–9. [PubMed: 4196111]