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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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Generalized Arterial Calcification of Infancy

Synonyms: GACI, Idiopathic Infantile Arterial Calcification (IIAC)

, MD, PhD, , MD, PhD, and , MD.

Author Information and Affiliations

Initial Posting: ; Last Update: December 30, 2020.

Estimated reading time: 29 minutes


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.


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.


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.


No consensus clinical diagnostic criteria for generalized arterial calcification of infancy (GACI) have been published.

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


  • 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 1

A multigene panel that includes some or all of the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

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)

Gene 1, 2Proportion of GACI Attributed to Pathogenic Variants in Gene 3, 4Proportion of Pathogenic Variants 5 Detectable by Method
analysis 6
Gene-targeted deletion/duplication analysis 7
ABCC6 ~9%88% 812% 8
ENPP1 ~67%96% 84% 8
Unknown 9~24%NA

Genes are listed in alphabetic order.


While a majority of cases of GACI are caused by biallelic pathogenic variants in ENPP1, pathogenic variants in ABCC6 can cause a clinically indistinguishable phenotype.


See Molecular Genetics for information on variants detected in these genes.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017] and personal unpublished data


22 of 92 individuals with GACI reported by Nitschke et al [2012] did not have biallelic pathogenic variants in either ENPP1 or ABCC6; however, two were heterozygous for an ENPP1 pathogenic variant, and six individuals in five unrelated families were heterozygous for an ABCC6 pathogenic variant.

Clinical Characteristics

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

Feature% of Persons with FeatureComment
Arterial calcification88%-95%Most common sites: aorta, pulmonary, coronary, renal
50%-60%Most common site: hip; sternoclavicular joint commonly involved
~20%Onset of skin findings in childhood; onset of retinal findings more commonly in adulthood
rickets / osteomalacia
>90% (ENPP1-GACI only)Mediated by FGF23
Nephrocalcinosis50% (ENPP1-GACI mainly)More commonly a complication of rickets/osteomalacia treatment
Cervical spine fusion~25% (ENPP1-GACI only)Affects posterior elements
Hearing loss50%-75% (ENPP1-GACI only)Variable age of onset


A review of published information on 161 individuals with GACI [Chong & Hutchins 2008] identified the following:

  • A bimodal age of presentation. 48% had early onset (i.e., in utero or within the first week of life) and 52% had late onset (median age three months).
  • In early-onset GACI, the most common initial findings were fetal distress (46%), heart failure (44%), polyhydramnios (38%), hypertension (33%), respiratory distress (30%), hydrops fetalis (28%), edema (24%), "visceral" effusions (20%), cyanosis (22%), cardiomegaly (17%), and ascites (13%).
  • In late-onset GACI, the most common presenting findings were respiratory distress (66%), cyanosis (43%), refusal to feed (34%), heart failure (29%), vomiting (24%), irritability (21%), failure to thrive (17%), fever (16%), hypertension (12%), and edema (7%).
  • Males and females were affected with similar frequency: 43% of those with early-onset GACI and 48% of late-onset GACI were female.

For individuals with fetal involvement, arterial calcifications are commonly detected at the time of prenatal ultrasound (most commonly in the third trimester, but imaging diagnosis in the second trimester is also possible). For infants with postnatal late-onset GACI, the presenting findings (respiratory distress, cyanosis, refusal to feed, heart failure) lead to imaging studies such as echocardiography and/or CT, and the detection of arterial calcification suggests the diagnosis.

Arterial Calcification

Autopsy studies (reviewed by Chong & Hutchins [2008]) noted that the most commonly calcified arteries in early-onset GACI were hepatic (81%), aorta (80%), pulmonary (67%), coronary (53%), and renal (39%). The most commonly calcified arteries in late-onset GACI were coronary (88%), renal (55%), pulmonary (49%), aorta (36%), adrenal (34%), splenic (31%), pancreatic (28%), and mesenteric (26%).

In a cohort of long-term survivors of GACI, the most common sites of arterial calcification were the aorta (14/16), and renal (11/16), mesenteric (11/16), coronary (10/16), iliac (10/16), and pulmonary (10/16) arteries [Ferreira et al 2021a].

Although generally spared, the cerebral arteries have been involved in several reported individuals [Glatz et al 2006, van der Sluis et al 2006]; presenting manifestations can thus include seizures [Galletti et al 2011], strokes [Van Dyck et al 1989], or recurrent transient ischemic attacks due to cerebrovascular insufficiency [Thomas et al 1990]. Cystic encephalomalacia is rarely reported [Galletti et al 2011, Nitschke et al 2012].

Peripheral arterial calcifications can present with decreased peripheral pulses; in exceptional cases, gangrene has occurred in the distal extremities [Witzleben 1970, Lussier-Lazaroff & Fletcher 1973], likely caused by a combination of vessel luminal narrowing and left ventricular systolic dysfunction.

Pulmonary hypertension refractory to medical therapy is possible [Farquhar et al 2005, Shaireen et al 2013].

Spontaneous resolution of calcification has been reported in several individuals [Sholler et al 1984, Ciana et al 2006]. In those without continued evidence of calcification, arterial stenoses associated with intimal thickening have been observed [Marrott et al 1984, Thiaville et al 1994, Nitschke et al 2012]. Generalized arterial stenoses without prior evidence of arterial calcification are also possible [Nitschke et al 2012, Ferreira et al 2021a].

Arterial calcifications or intimal proliferation may also explain the high frequency of recurrent pregnancy loss (≥4 miscarriages per family in 25% vs in 1%-2% in the general population) and hematochezia (15% vs 2% in the general population) [Ferreira et al 2021a].

Extravascular Calcifications

Periarticular calcifications have been noted in eight of 16 surviving individuals with GACI [Ferreira et al 2021a]. The most common site of involvement is the hip; other commonly affected joints include the wrist, shoulder, elbow, knee, and sternoclavicular joint [Chong & Hutchins 2008, Ferreira et al 2021a].

Other sites of extravascular calcification include the ear lobes [Vera et al 1990, Nitschke et al 2012, Brachet et al 2014], myocardium, and brain parenchyma [Ferreira et al 2021a].

Pseudoxanthoma Elasticum (PXE) Findings

Individuals with GACI can manifest PXE-like changes; these were seen in four of 20 survivors, with onset between ages two and 43 years [Ferreira et al 2021a]. Skin findings typically manifest during childhood, while retinal findings (peau d'orange, angioid streaks, choroidal neovascularization with subsequent retinal hemorrhage) commonly do not appear until adulthood. However, typical retinal findings of PXE were reported in a girl age four years with ENPP1 deficiency [Freychet et al 2014], indicating that earlier onset of ocular complications is possible.

It has been speculated that children with GACI and findings of PXE were not reported until recently because most died before they developed typical signs of PXE, and many features of PXE (e.g., angioid streaks and skin lesions) are frequently overlooked in the clinical examination of individuals with GACI [Nitschke & Rutsch 2012]. See Pseudoxanthoma Elasticum.

Hypophosphatemic Rickets / Osteomalacia

Individuals with GACI caused by pathogenic variants in ENPP1 who survive the first six months of life (i.e., the critical period) can develop bone deformities, hypophosphatemia, hyperphosphaturia, and elevated alkaline phosphatase, with all the clinical manifestations of autosomal recessive hypophosphatemic rickets type 2 (ARHR2; see Genetically Related Disorders). Conversely, several individuals with ARHR2 have had asymptomatic undiagnosed vascular involvement. Thus, ARHR2 and GACI represent a phenotypic spectrum.

The average age for the development of hypophosphatemia was 1.6 years [Ferreira et al 2021a]. In a cohort of surviving individuals with ENPP1 deficiency (mean age 11.7 years), 11 of 16 (69%) had already developed rickets, with a Kaplan-Meier estimate that almost all individuals would develop rickets/osteomalacia by age 14 years [Ferreira et al 2021a]. This form of rickets/osteomalacia is mediated by FGF23, and can lead to painful calcification of the entheses (insertion sites of ligaments and tendons) in adulthood [Kotwal et al 2020, Ferreira et al 2021a].

There are no reports of hypophosphatemia in individuals with GACI caused by pathogenic variants of ABCC6, although one individual in the series of Nitschke et al [2012] had GACI with hypophosphatemic rickets and was heterozygous for an ABCC6 pathogenic variant.


Bilateral medullary nephrocalcinosis was seen in five of ten individuals with ENPP1 deficiency who received standard treatment for hypophosphatemic rickets/osteomalacia, while it was not detected in any of seven individuals who were naïve to treatment. Cortical nephrocalcinosis can be seen in the absence of treatment. While medullary nephrocalcinosis is likely a complication from treatment of rickets/osteomalacia (and thus seen only in ENPP1 deficiency), cortical nephrocalcinosis likely represents a consequence of ischemia (and can be seen either with ENPP1 or ABCC6 deficiency) [Ferreira et al 2021b].

Cervical Spine Fusion

Fusion of the posterior elements of the cervical spine (posterior vertebral bodies, articular processes, laminae) was seen in four of 16 individuals with ENPP1 deficiency [Ferreira et al 2021a].

Hearing Loss

In GACI, hearing loss can be conductive, sensorineural, or mixed, and can present as early as in the neonatal period [Brachet et al 2014]. It developed in ten of 16 survivors (63%) with ENPP1-GACI at a median age of 3.7 years, with a Kaplan-Meier estimate of developing hearing loss of 20% by age two years, 50% by four years, and 75% over a lifetime [Ferreira et al 2021a].

Sensorineural hearing loss is presumably due to calcifications of the arteries supplying the inner ear [Lorenz-Depiereux et al 2010], while conductive hearing loss is due to stapedovestibular ankylosis [Nitschke et al 2012, Freychet et al 2014].


Although cognitive development has not been formally assessed in a cohort of individuals with GACI, the majority appear to have normal development. However, the authors are aware of a few individuals with severe global developmental delay in the setting of prior strokes or encephalomalacia. In individuals with periarticular calcifications, motor milestones can be delayed due to pain around the affected joints [Authors, personal observation].


In one family in which the father and son were homozygous for the same ENPP1 pathogenic variant, the father presented with hypophosphatemia and rickets and later developed an aortic root dissection at age 28 years, while the son had GACI and hypophosphatemia [Lorenz-Depiereux et al 2010]. Sibs harboring the same pathogenic variants have been reported to have markedly different clinical courses [Ferreira et al 2021a].


In a series of 55 children, the mortality rate at age six months was 30 of 55 (55%) despite intensive therapy [Rutsch et al 2008]. Only one individual died after age six months; thus, the mortality rate was markedly decreased in those who survived the first few months of life. Causes of death were myocardial infarction, congestive heart failure, persistent arterial hypertension, or multiorgan failure.

Long-term survivors, with several in their 20s, include twins age 21 years [Rutsch et al 2008], a woman age 22 years [Marrott et al 1984], individuals age 25 and 26 years at last follow up [Ferreira et al 2021a], and a woman age 37 years [Authors, personal observation]. The oldest individual with ENPP1 deficiency reported to date is a woman age 62 years [Saito et al 2011].

Bisphosphonate treatment was associated with survival beyond infancy in 11 of 17 individuals, while 18 of 26 individuals not treated with bisphosphonates died in infancy [Rutsch et al 2008] (see Treatment of Manifestations). It remains unclear whether bisphosphonate use improves survival [Authors, personal observation].

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.


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.


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].

Differential Diagnosis

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].


No clinical practice guidelines for GACI have been published.

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

Cardiovascular Referral to a pediatric cardiologistIncl:
  • EKG & echocardiogram
  • Assessment of blood pressure 1 & peripheral pulses
CT of chest, abdomen, & pelvisTo evaluate extent & distribution of vascular calcification
Serum levels of cardiac-specific troponin T or troponin IAssess for evidence of myocardial ischemia.
Skeletal Skeletal radiographsAs needed to assess for periarticular calcification or cervical spine fusion
Metabolic workup incl:
  • Serum creatinine
  • Serum phosphorus
  • Urine phosphorus
  • Urine creatinine
  • Alkaline phosphatase
  • Serum calcium
  • Serum PTH
To evaluate for evidence of hypophosphatemic rickets by measuring:
  • Tubular reabsorption of phosphate
  • Ratio of renal tubular maximum reabsorption rate of phosphate to GFR
Hearing loss Audiology assessmentEvaluate for conductive or sensorineural hearing loss.
By genetics professionals 2To inform patients & families re nature, MOI, & implications of GACI in order to facilitate medical & personal decision making
Family support/

GFR = glomerular filtration rate; MOI = mode of inheritance; PTH = parathyroid hormone


Referral to a pediatric nephrologist is indicated in the setting of refractory hypertension


Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with GACI

Bisphosphonate therapy 1 using one of the following:
  • Etidronate (20 mg/kg/d PO)
  • Pamidronate (0.25 mg/kg on day 1, then 0.5 mg/kg/d on days 2 & 3 for 1st cycle, then 0.5 mg/kg/d x3 days IV per cycle; cycles rptd every 2 mos)
  • Risedronate (1mg/kg/wk PO)
  • After initiation of therapy, vascular calcifications have been reported to disappear as early as 2.5 wks (as assessed by radiographs) and as late as 2 yrs [van der Sluis et al 2006, Meradji et al 1978]
  • Vascular calcifications do not reappear after discontinuation of treatment even after 10 yrs [van der Sluis et al 2006]
  • Prolonged etidronate use in persons w/GACI has been assoc w/severe skeletal toxicity, incl radiographic findings resembling hypophosphatasia 2 or osteopetrosis 3 [Otero et al 2013]. Thus, some authors recommend close monitoring for resolution of arterial calcifications during treatment so that use of bisphosphonates can be discontinued as soon as possible [Otero et al 2013].
Hypertension Standard therapySince hypertension in GACI is likely caused by renal artery stenosis, it may be beneficial to use ACE inhibitors or angiotensin II type 1 receptor blockers.
Severe coronary
Aspirin therapy if coronary stenosis is present
PXE retinal
Intravitreal VEGF inhibitors for choroidal neovascularization
Calcitriol (15-25 ng/kg/d) & oral phosphate supplement (25-50 mg/kg/d in 3-5 daily doses)Doses adjusted based on alkaline phosphatase, PTH, & calciuria levels
Orthopedics eval if bone deformities developSurgical interventions may be necessary.
Hearing loss Hearing aids as indicated

ACE = angiotensin-converting enzyme; PTH = parathyroid hormone; VEGF = vascular endothelial growth factor


It remains unclear whether bisphosphonates (etidronate in particular) are associated with improved survival.


Radiographic findings resembling hypophosphatasia include pan craniosynostosis, bowing of long bones, metaphyseal cupping and fraying, and radiolucent tongues.


Radiographic findings resembling osteopetrosis include osteosclerosis and femoral Erlenmeyer flask deformity.


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

Arterial calcification Low-dose CT scanEvery 3-4 mos in 1st yr of life
  • Echocardiography
  • Troponin
At regular intervals depending on degree of severity (as per cardiologist)
PXE retinal findings Exam by retinal specialistAnnually, or more frequently as per specialist
Mineral homeostasis Serum phosphate, creatinine, alkaline phosphatase, calcium, PTH; urine phosphate & creatinineAnnually before development of rickets; quarterly while on rickets treatment; after 2 wks of dosage modification
Hypercalciuria assoc
w/treatment of
Urine calciumMaintain calciuria <4 mg/kg/d.
assoc w/treatment of
Renal ultrasoundAnnually
Cervical spine fusion Lateral cervical spine radiographPrior to elective endotracheal intubation / surgery

PTH = parathyroid hormone

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

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.
  • 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.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Generalized Arterial Calcification of Infancy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Generalized Arterial Calcification of Infancy (View All in OMIM)


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

Chapter Notes


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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