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Generalized Arterial Calcification of Infancy

Synonyms: GACI, Idiopathic Infantile Arterial Calcification, IIAC

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

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Summary

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 extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), hearing loss, and development of rickets after infancy. While mortality in infancy is high, survival into the second and third decade has been reported.

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
  • Either identification of biallelic pathogenic variants in ENPP1 or ABCC6 or, if molecular genetic testing is not diagnostic, typical histologic findings on arterial biopsy.

Management.

Treatment of manifestations: Use of bisphosphonates (most commonly used is etidronate) appears to significantly increase survival. Standard anti-hypertensive therapy is warranted for hypertension. Aspirin therapy is warranted in those with severe coronary stenosis who are at increased risk for coronary thrombosis.

Prevention of secondary complications: Prior to elective endotracheal intubation perform a lateral cervical spine x-ray to evaluate for cervical spine fusion secondary to periarticular calcifications. If cervical spine fusion is present, fiberoptic intubation is recommended. Because patients undergoing treatment of rickets are at risk for nephrocalcinosis and calcifications in other tissues (e.g., liver, pancreas) it is appropriate to maintain urinary excretion of calcium below 4 mg/kg/d.

Surveillance: No specific guidelines address the issue of surveillance. The appropriate intervals for monitoring depend on the clinical findings.

Agents/circumstances to avoid: Although no clinical studies have been conducted, it seems prudent to avoid the use of warfarin if possible.

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.

Pregnancy management: Pregnancy needs to be managed by a high-risk maternal fetal obstetrician.

Genetic counseling.

GACI is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Diagnosis

Suggestive Findings

Generalized arterial calcification of infancy (GACI) should be suspected in individuals with a combination of the following:

  • 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 [Nitschke et al 2012]
  • Development of rickets after infancy [Rutsch et al 2008]

Imaging

Computed tomography (CT) is the preferred imaging modality to assess for calcifications. Multi-detector computed tomography (MDCT) has been reported to detect not just 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 echo brightness 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.

Standard x-rays can sometimes detect arterial calcifications, but with low sensitivity, and many times arterial calcifications are detected only on reexamination of x-rays after the diagnosis of GACI was made postmortem [Glatz et al 2006].

Magnetic resonance imaging (MRI) and angiography (MRA) 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].

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 identification of biallelic pathogenic variants in ENPP1 or ABCC6 (see Table 1) or, if molecular genetic testing is not diagnostic, typical histologic findings on arterial biopsy.

Molecular Genetic Testing

One genetic testing strategy is serial single gene molecular genetic testing based on the order in which pathogenic variants most commonly occur (i.e., ENPP1 followed by ABCC6). Typically sequence analysis would be performed first, followed by deletion/duplication analysis if one or no pathogenic variant is identified.

An alternative genetic testing strategy is use of a multigene panel that includes ENPP1, ABCC6, and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.

Table 1.

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

Gene 1Proportion of GACI Attributed to Mutation of This Gene 2Test Method
ENPP162/92 3Sequence analysis 4
Deletion/duplication analysis 5
ABCC68/92 6Sequence analysis 4
Deletion/duplication analysis 5
Unknown 722/92NA
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.
3.

Biallelic ENPP1 pathogenic variants were detected in 8 of 11 [Rutsch et al 2003], 18 of 23 [Ruf et al 2005], 41 of 55 [Rutsch et al 2008], and 62 of 92 individuals with GACI [Nitschke et al 2012], accounting for 67%-78% of all cases of GACI. In retrospect, in two of the individuals described by Rutsch et al [2003] and three described by Rutsch et al [2008] either one or both ENPP1 alleles harbored variants currently considered to be benign rather than pathogenic. Even disregarding the data of these three individuals, the frequency of biallelic ENPP1 pathogenic variants in GACI is still 38/55 (69%), close to the more recent estimate of 62/92 (67%) [Nitschke et al 2012].

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.

5.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6.

Biallelic pathogenic variants in ABCC6 were found in 8 of 92 individuals with GACI, accounting for ~9% of all GACI cases and ~27% of individuals with GACI and no detectable ENPP1 pathogenic variants [Nitschke et al 2012].

7.

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.

Histologic Findings

In the past, the diagnosis of GACI was usually made at autopsy. When diagnosed pre-mortem, the diagnostic gold standard was a biopsy of a medium-sized artery, typically the temporal artery [Rutsch et al 2000], and less frequently the radial artery [Marrott et al 1984, Vera et al 1990] that showed typical histologic changes consistent with GACI. Recently, however, such an invasive procedure has been considered unnecessary for the diagnosis.

Histologic changes typically include fragmentation of and calcium deposition in the internal elastic lamina, and fibrointimal hyperplasia causing luminal narrowing [Moran 1975]. Of note, the fibrointimal proliferation can occur in areas devoid of calcification [Witzleben 1970] and, conversely, calcification can occur in areas lacking fibrointimal thickening [Morton 1978]. The material laid down in the internal elastic lamina stains positively with Prussian blue [Rani et al 2010] and Hale’s colloidal iron (indicating iron deposition), periodic acid-Schiff (indicating deposition of acid mucopolysaccharides), and alizarin red and Von Kossa stains (indicating calcium deposition) [Morton 1978].

A giant cell reaction surrounds the areas of calcification, probably as a reaction to foreign material [Prior & Bergstrom 1948, Morton 1978, Maayan et al 1984, Eronen et al 2001, Glatz et al 2006].

Electron microscopy shows that the intimal hyperplasia comprises proliferation of fibroblasts and smooth muscle cells [Morton 1978].

Histologic findings in other tissues:

Clinical Characteristics

Clinical Description

In a review of the English language medical literature, Chong & Hutchins [2008] found 161 individuals with GACI in 110 articles. They identified 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%).
  • There was no gender predilection: 43% of those with early-onset GACI and 48% of late-onset GACI were female.
  • At autopsy, 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%) and pulmonary (49%), aorta (36%), adrenal (34%), splenic (31%), pancreatic (28%), and mesenteric (26%). However, the authors acknowledged that individual factors (e.g., the thoroughness of an autopsy) may have influenced the determination of calcification.

Spontaneous resolution of calcification was reported in several cases [Sholler et al 1984, Ciana et al 2006]. In one case, calcification involved the radial arteries at age three months; however, radial artery biopsy at age 16 years no longer showed calcification but did reveal intimal thickening resembling fibromuscular dysplasia [Marrott et al 1984]. In another case report treatment with bisphosphonates resolved calcification, but not renal artery stenosis, which was presumably due to persistence of intimal proliferation [Thiaville et al 1994]. One individual with biallelic ABCC6 pathogenic variants was reported to have generalized arterial stenoses without evidence of arterial calcification [Nitschke et al 2012].

Although generally spared, the cerebral arteries are involved in several reported cases [Glatz et al 2006, van der Sluis et al 2006]; presenting manifestations can include seizures [Prior & Bergstrom 1948, 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 was reported in one individual with mutation of ENPP1 [Galletti et al 2011] and one with mutation of ABCC6 [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 with left ventricular systolic dysfunction. The first individual reported with GACI in the English language medical literature had gangrene of his right foot [Bryant & White 1901].

Other vascular complications include pulmonary hypertension [Morton 1978] refractory to medical therapy [Farquhar et al 2005, Shaireen et al 2013], and thoracic aorta coarctation with aneurysm of the abdominal aorta in one individual [Vera et al 1990].

Gastrointestinal complications include case reports of obstruction due to stenosis and ulcerating inflammation of the wall of the small intestine [Nielsen 1961], ileus [Witzleben 1970], volvulus with intestinal malrotation [Milner et al 1984], jejunal atresia requiring jejunostomy [Wax et al 2001], and meconium peritonitis [Sawyer et al 2009]. These complications are thought to arise from intestinal ischemia as a consequence of early vascular compromise [Sawyer et al 2009].

Extravascular calcifications. Periarticular calcifications have been noted prenatally or during infancy in 16 of 55 cases (29%) [Rutsch et al 2008]. In decreasing order of frequency, these calcifications are seen surrounding the hip > ankle, wrist and shoulder >> elbow > knee and foot > phalanges, tarsal bones, spine, and sternoclavicular joint [Chong & Hutchins 2008].

Other sites of extravascular calcification include the ear lobes [Vera et al 1990, Nitschke et al 2012, Brachet et al 2014], myocardium [Moran 1975, Thomas et al 1990, Hault et al 2008], and pancreas, liver, and kidneys [Nitschke et al 2012, Freychet et al 2014].

Pseudoxanthoma elasticum (PXE) findings. There is a close relationship between GACI and PXE.

Sakata et al [2006] reported a family in which the first child presented with sudden death at age three years and showed marked coronary and renal artery intimal thickening with fragmentation of the internal elastic lamina, reminiscent of GACI. The second child presented at age 11 years with typical clinical and histologic skin findings of PXE.

Le Boulanger et al [2010] reported a family in which the younger brother presented with myocardial infarction complicated by heart failure at age six months; a skin biopsy performed at age one year revealed elastorrhexis. The child subsequently died of a second myocardial infarction at age 15 months. Pathologic findings were strikingly reminiscent of GACI. His older brother, who presented 25 years later with typical clinical and histologic skin findings of PXE and angioid streaks on fundoscopy, was found to have biallelic pathogenic variants in ABCC6.

Nitschke et al [2012] described three individuals with GACI resulting from biallelic ENPP1 pathogenic variants who subsequently developed typical PXE skin lesions and/or angioid streaks between ages five and eight years. Two of the three also had hypophosphatemic rickets, and two had large angiomatous lesions of the chest and back.

Freychet et al [2014] reported a girl age 4.5 years with biallelic ENPP1 pathogenic variants who had retinal findings typical of PXE and diffuse capillary angiomas. As a neonate she had presented with periarticular calcifications; an echocardiogram at that time was reportedly unremarkable.

Li et al [2012] reported a girl age two years with biallelic pathogenic variants in ENPP1 who had a relatively mild form of GACI with cardiomyopathy, renovascular hypertension, coronary artery calcification, and hearing loss as well as typical clinical and histologic skin findings of PXE. At age two years she is the youngest child with GACI reported to have PXE findings.

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].

Hearing loss. In GACI hearing loss can be conductive, sensorineural, or mixed, and can present as early as in the neonatal period.

Lorenz-Depiereux et al [2010] reported a child who developed sensorineural deafness at age four years, presumably due to calcifications of the arteries supplying the inner ear.

Nitschke et al [2012] reported three individuals with GACI resulting from mutation of ENPP1 who went on to develop typical PXE-like findings later in life; all three had hearing loss, two due to stapedovestibular ankylosis. Freychet et al [2014] also reported a child with conductive hearing loss due to stapedovestibular ankylosis presenting at age three years.

Brachet et al [2014] reported a girl with mixed hearing loss diagnosed at postnatal day nine: the conductive component of her hearing loss resolved; however, the sensorineural component persisted into adulthood.

Hypophosphatemia and hyperphosphaturia. 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 (ARHR) type 2 (see Genetically Related Disorders). In contrast, it remains unknown whether individuals with ARHR caused by mutation of ENPP1 could have had asymptomatic undiagnosed vascular calcifications during infancy that resolved with the onset of hyperphosphaturia and hypophosphatemia. Thus, ARHR type 2 and GACI could represent a phenotypic spectrum.

Although ARHR type 2 is usually manifest within the first decade of life, at least one individual with GACI did not manifest rickets (bone pain and deformities) until age 14 years [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, while the son had GACI and hypophosphatemia [Rutsch et al 2003, Rutsch et al 2008, Lorenz-Depiereux et al 2010]. Of note, the father developed an aortic root dissection at age 28 years [Lorenz-Depiereux et al 2010].

There are no reports of hypophosphatemia in individuals with GACI caused by mutation 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.

Eight of the 19 children with GACI reported by Rutsch et al [2008] who survived infancy had serial measurements of serum phosphate levels and maximal renal tubular phosphate reabsorption (TmP/GFR) after infancy. All eight developed hypophosphatemia and hyperphosphaturia (first noted between the second and third year of life), and five developed signs of rickets, including bone pain, bowed femora, and short stature between ages eight months and 11 years. Since the mean of the serum phosphate level and the TmP/GFR level in all survivors was significantly lower than the lowest reference values for age, hypophosphatemia and hyperphosphaturia were considered to be characteristic of GACI in those who survived infancy.

Development. Although cognitive development has not been formally assessed in a cohort of patients with GACI, the majority seem 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].

Prognosis. Older reports mention a mortality rate of 53 of 62 (85%) at age six months [Moran 1975].

In a more recent series of 55 children with GACI, six were stillborn and 30 were delivered prematurely [Rutsch et al 2008]. The mortality rate at age six months was 30 of 55 (55%) despite intensive therapy. Only one patient 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 multi-organ failure.

There are case reports of patients dying at a later age (e.g., at age 11 years) [Thomas et al 1990].

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], and a male age 22 years at last follow up [Authors, personal observation]. The oldest individual with GACI reported to date is a male age 25 years [Ciana et al 2006].

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).

Other. Plasma and urinary pyrophosphate levels and nucleoside triphosphate pyrophosphohydrolase enzyme activity have been measured.

  • A very low plasma concentration of pyrophosphate (0.6 μmol/L; normal, 1-6 μmol/L) was detected in one affected infant [Stuart 1993].
  • Low urinary pyrophosphate levels have also been reported in spot urines, ranging from 0.5 to 6.3 μmol/mmol creatinine (normal, 7.7-56.7 μmol/mmol creatinine) [Rutsch et al 2000].
  • Low activity in plasma and cultured fibroblasts of the enzyme nucleoside triphosphate pyrophosphohydrolase, which generates inorganic pyrophosphate, has been reported [Rutsch et al 2001].

Markedly elevated C-reactive protein (CRP) levels have been reported in the absence of infection [Freychet et al 2014]. In at least one instance, elevated CRP in conjunction with the typical finding of congestive heart failure led to the incorrect diagnosis of septic shock [Authors, personal communication].

Genotype-Phenotype Correlations

Except for homozygosity for the ENPP1 pathogenic variant p.Pro305Thr, associated with death in infancy in all reported cases [Rutsch et al 2008], no genotype-phenotype correlations are known. In fact, sibs harboring the same pathogenic variants have been reported to have markedly different clinical courses [Cheng et al 2005, Ruf et al 2005, Dlamini et al 2009].

Otero et al [2013] (full text; see Supporting Information, Appendix) reported an individual with biallelic ENPP1 pathogenic variants and a heterozygous pathogenic variant in ABCC6, which theoretically could have contributed to the severity of GACI. The patient’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

No formal study has evaluated the prevalence of the disease. Approximately 200 individuals with GACI have been reported in the medical literature [Chong & Hutchins 2008].

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

The disease frequency can be estimated at one in 391,000 individuals, and the carrier frequency would approximate one in 312 (0.32%) [Authors, personal observation]. This estimate is based on the report of Rutsch et al [2008] of 40 ENPP1 pathogenic variants accounting for 41 of 55 cases of GACI. However, in retrospect three of those variants were found to be common benign variants (p.Leu611Val, p.Glu668Lys and p.Arg774Cys). Thus, 37 pathogenic variants accounted for 38 of 55 (69%) cases of GACI. By estimating the carrier frequency of those 37 ENPP1 pathogenic variants in NHLBI ESP6500 (16 carriers in 6021 individuals), one can estimate a carrier frequency of one in 376 (0.27%), and a disease frequency of one in 566,000 individuals.

Differential Diagnosis

Disorders with Vascular Calcification

Singleton-Merten syndrome (OMIM 182250), an autosomal dominant disorder with severe aortic calcification, dental anomalies (delayed eruption and early loss of permanent teeth, alveolar bone erosion), osteopenia, and acroosteolysis, has been reported in 11 individuals to date [Feigenbaum et al 2013]. The aortic calcification in Singleton-Merten syndrome starts later in life (age range at diagnosis is 6-39 years). The gene in which mutation is causative is unknown.

Metastatic calcification due to hypervitaminosis D, hyperparathyroidism, or end-stage renal disease. In infants receiving 20,000 to 40,000 IU of vitamin D daily, 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 [Ross 1952]. 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 [Sholler et al 1984].

Congenital syphilis. Syphilitic aortitis, which is associated with calcification of the ascending aorta, can be distinguished from GACI in the following ways:

  • Calcification is confined to the proximal aorta;
  • Diagnosis is usually later in life (rarely before age 19 years) [Bonugli 1961];
  • It is accompanied by other signs of congenital syphilis such as:
    • Hutchinson teeth, interstitial keratitis, sabre tibiae, or saddle-shaped nose
    • Histologic findings characterized by endarteritis obliterans of vasa vasorum with perivascular plasma cell and lymphocytic cuffing and adventitial fibrosis [Heggtveit 1964].

Of note, although the occasional giant cells in the vessels of persons with GACI occur in relation to the calcium deposits, they do not represent a granulomatous reaction [Morton 1978].

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]. In fact, one recipient twin of a TTTS with isolated calcification of the proximal aorta and central pulmonary arteries was reported as having GACI [Samon et al 1995], while in all likelihood it was not GACI [Saxena & Soni 2003]. In another report of pulmonary arterial and intracranial calcification in the recipient twin of a TTTS [Kei et al 2002], the authors surmised that GACI was the likely cause.

Iliac artery calcification in healthy infants. Calcification of the internal elastic lamina in the common and internal iliac arteries, detected by a modified von Kossa stain, has been described in 13 of 24 term newborns [Meyer and Lind 1972]; after age one year, it was noticed in 48 of 63 infants, so resorption of calcification is unlikely to occur with growth. The distribution of calcification in the iliac arteries is likely the result of increased hemodynamic flow, as in utero the umbilical arteries directly connect the flow from the placenta into the internal iliac arteries. The latter mechanism appears to be substantiated by the finding that in children with a single umbilical artery the calcification is more conspicuous in the iliac artery that receives flow from the single umbilical artery [Meyer & Lind 1974].

Disorders with Occlusive Arteriopathy

Grange syndrome (OMIM 602531). 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]. Seven individuals have been reported to date [Volonghi et al 2012]. The inheritance pattern remains unknown [Grange et al 1998].

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].

Twin-twin transfusion syndrome (TTTS). Intimal thickening (in the aortic arch, thoracic aorta, abdominal aorta, and iliac arteries) was described in the recipient twin of a TTTS [Nicosia et al 1981].Initimal thickening was most striking in the abdominal aorta and iliac arteries.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with generalized arterial calcification of infancy (GACI), the following evaluations are recommended:

  • Consultation with a clinical geneticist and/or genetic counselor
  • Physical examination with particular attention to blood pressure and peripheral pulses, as well as presence of bowing of the long bones (i.e., evidence of autosomal recessive hypophosphatemic rickets)
  • Metabolic workup including serum creatinine, serum phosphorus, urine phosphorus, urine creatinine, and alkaline phosphatase to evaluate for evidence of hypophosphatemic rickets by measuring the tubular reabsorption of phosphate (TRP) and the ratio of the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP/GFR)
  • Serum levels of cardiac-specific troponin T or troponin I to evaluate for evidence of ischemia
  • Pediatric cardiology consultation including:
    • ECG to assess for signs of left ventricular hypertrophy or ischemia
    • Echocardiogram to monitor left ventricular systolic function and to assess for the presence of calcifications, left ventricular hypertrophy, or pericardial effusion
  • CT of the chest, abdomen and pelvis (if possible with runoff to lower extremities) to evaluate the extent and distribution of vascular calcification
  • Skeletal survey to assess for either periarticular calcification or findings typical of rickets such as widening of the growth plate, bowing of the long bones, or metaphyseal widening, cupping, or fraying. Include cervical films to evaluate for cervical spine fusion.
  • Audiologic assessment for conductive or sensorineural hearing loss
  • Pediatric nephrology consultation in the setting of refractory hypertension

Treatment of Manifestations

Treatment of arterial calcification

  • Bisphosphonate therapy. In a non-randomized, retrospective study, Rutsch et al [2008] compared 43 infants who survived their first day of life (including 17 treated with bisphosphonates) to 26 who did not receive bisphosphonates. Infants treated with bisphosphonates showed significantly increased survival (p=0.026, log-rank test).
  • Etidronate, a non-nitrogen-containing bisphosphonate, is the most commonly used based on its potent antimineralization effect. Etidronate doses vary from 5 mg/kg/d [Corbatón Blasco et al 1991] to as high as 35 mg/kg/d [Van Dyck et al 1989], with a usual dose of 20 mg/kg/d [Edouard et al 2011].
  • Nitrogen-containing bisphosphonates such as pamidronate and risedronate were originally formulated to be more potent antiresorptive drugs and, thus, to have a less potent antimineralization effect at therapeutic levels [Otero et al 2013]. The dose of pamidronate has varied from 0.1 mg/kg/week to as high as 5 mg/kg/d IV [Rutsch et al 2008]; the dose of risedronate is 1 mg/kg/week PO [Ramjan et al 2009].
    Of note, death can occur even if treatment is started early with etidronate [Stuart et al 1990, Stuart 1993, Galletti et al 2011] or pamidronate [Kalal et al 2012].
    After initiation of therapy, vascular calcifications have been reported to disappear as early as 2.5 weeks (as assessed by x-rays, a relatively insensitive method) [van der Sluis et al 2006] and as late as two years [Meradji et al 1978]. Vascular calcifications do not reappear after discontinuation of treatment [Meradji et al 1978], even after ten years [van der Sluis et al 2006]. However, arterial stenosis has been known to persist despite resolution of calcification [Thiaville et al 1994].
    Periarticular calcifications have disappeared in some individuals [Meradji et al 1978], whereas in others they have persisted despite treatment, disappearing only after treatment was discontinued [Otero et al 2013].
    Prolonged etidronate use in patients with GACI has been associated with severe skeletal toxicity, including radiographic findings resembling hypophosphatasia (pan craniosynostosis, bowing of long bones, metaphyseal cupping and fraying, radiolucent tongues) or osteopetrosis (osteosclerosis and femoral Erlenmeyer flask deformity) [Otero et al 2013]. The optimal duration of treatment remains unclear, with reports of children being treated for almost 18 months [Van Dyck et al 1989], two years [Edouard et al 2011], three years [Ramjan et al 2009], and almost seven years (in 1 child) [Otero et al 2013].
    Given the risk of severe adverse skeletal effects with prolonged bisphosphonate treatment and the failure of calcifications to reappear after discontinuation of treatment, 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].
    From current available data (which are limited by small sample size and lack of randomized control data) it is difficult to determine if bisphosphonate treatment is truly protective or if resolution of findings reflects the natural history of the disease.

Cardiovascular treatment

  • Anti-hypertensive therapy. Since standard anti-hypertensive therapy is warranted for hypertension and since hypertension in GACI is likely caused by renal artery stenosis, in theory it may be beneficial to use medications that act on the renin-angiotensin system, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs).
  • In one case, severe hypertension refractory to conventional treatment responded to prostaglandin infusion (PGE1) at a dose of 0.017-0.068 μg/kg/min [Ciana et al 1997].

Prevention of coronary thrombosis. Aspirin therapy is warranted in patients with severe coronary stenosis, who are at increased risk for coronary thrombosis.

Treatment of hearing loss. Patients with sensorineural hearing loss may benefit from hearing aids.

Treatment of hypophosphatemic rickets involves calcitriol and oral phosphate supplements in standard doses of 15 ng/kg/d (calcitriol) and 40-60 mg/kg/d (phosphate) [Lorenz-Depiereux et al 2010], with doses adjusted according to serum phosphorus and alkaline phosphatase levels.

Hypercalciuria should be avoided in patients with hypophosphatemic rickets treated with calcitriol or other vitamin D analogs. Freychet et al [2014] reported one patient with biallelic ENPP1 pathogenic variants with calciuria of 5 mg/kg/d after institution of alfacalcidol who developed new-onset nephrocalcinosis; cardiac, hepatic, and pancreatic calcifications as evaluated by ultrasound; and recurrence of previously regressed periarticular calcifications as assessed by x-ray. While most of these calcifications regressed when the calciuria was maintained at less than 4 mg/kg/d, the nephrocalcinosis remained unchanged. Thus, it seems prudent to monitor calciuria in order to maintain it at levels below 4 mg/kg/d.

Orthopedics consultation should be obtained if bone deformities develop as a consequence of hypophosphatemic rickets, as surgical interventions may be necessary.

Prevention of Secondary Complications

Patients with GACI are predisposed to periarticular calcifications, and at least two individuals with cervical spine fusion have been reported [Gopalakrishnan et al 2008, Nitschke et al 2012]. Thus, it seems prudent to perform a lateral cervical spine x-ray when elective endotracheal intubation is necessary, for example, prior to surgery. In persons with cervical spine fusion, fiberoptic intubation is recommended and, if hypertension is also present, a nasal route may be preferred over an oral route since it produces a less prominent pressor response [Gopalakrishnan et al 2008].

Surveillance

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

  • One individual reported in the literature was followed with clinical evaluation and assessment of mineral homeostasis every three months; echocardiography, dual-energy x-ray absorptiometry (DXA), and low-dose radiation CT every six months; and x-rays of the wrists and knees every year [Edouard et al 2011].
  • Another individual was followed with weekly assessment of mineral homeostasis and troponin, monthly echocardiograms, and CT every three to four months [Michael A Levine, personal communication].

When individuals with GACI develop hypophosphatemic rickets that requires treatment with calcitriol and phosphorus supplementation, urine calcium should be followed regularly so as to avoid hypercalciuria.

Agents/Circumstances to Avoid

Although there have been no clinical studies, it seems prudent to avoid the use of warfarin if possible because 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].

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.

  • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the pathogenic variants in the family are not known, imaging studies can be used to clarify the genetic status of at-risk sibs.

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

Pregnancy Management

Pregnancy needs to be managed by a high-risk maternal fetal obstetrician.

Bisphosphonates have been tried antenatally, with both unsuccessful [Stuart 1993] and successful results [Michael A Levine, personal communication].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu 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.

Other

Intravenous sodium thiosulfate 25% diluted in D5W has been tried in at least two individuals at a dose of 12.5 mg/m2/day [Michael A Levine, personal communication]. Therapy was discontinued at age one year in one and at age three years in the other. Although both children are still alive at the ages of one and three years, it is not known if this is due to the natural course of the disease or a beneficial effect of the sodium thiosulfate. Of note, the daily administration of sodium thiosulfate requires the insertion of a central venous catheter.

No individuals with GACI have been reported to have received a heart transplant. One patient listed for transplant had a left ventricular assist device placed, but expired before she could receive the transplant [Glatz et al 2006].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face 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 obligate heterozygotes (i.e., carriers of one mutated allele).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • To date, no individuals with GACI have been reported to have children.
  • However, given that a few individuals have survived into their 20s, it is entirely possible that individuals who survive into adulthood will be able to conceive.
    • In such cases, unless an individual with GACI has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ENPP1 or ABCC6.
    • Because the carrier frequency in the population is low, the chance of having a child with GACI is less than 1 in 600 (carrier frequency x ½).

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the 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, clarification of carrier status, and discussion of the availability of prenatal 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. 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 of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis 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 patients 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].

Resources

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)

173335ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE 1; ENPP1
208000ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1; GACI1
603234ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 6; ABCC6
614473ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2; GACI2

Molecular Genetic Pathogenesis

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.

ENPP1

Gene structure. ENPP1 comprises 25 coding exons with one primary protein-coding transcript (NM_006208.2). For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Three variants previously identified as pathogenic are now considered benign based on population frequencies (Table 2 and Prevalence).

Pathogenic variants. More than 40 ENPP1 pathogenic variants have identified including missense, nonsense, splice site, and frameshift variants.

The pathogenic variant c.913C>A in exon 8 has been identified most frequently: in 19/41 of affected individuals [Rutsch et al 2008].

Table 2.

ENPP1 Variants Discussed in This GeneReview

Variant
Classification
DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Benignc.1831C>Gp​.Leu611ValNM_006208​.2
NP_006199​.2
c.2002G>Ap​.Glu668Lys
c.2320C>Tp​.Arg774Cys
Pathogenicc.913C>Ap.Pro305Thr

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. ENPP1 has 925 amino acids and comprises four domains: a nuclease-like domain, a phosphodiesterase-like catalytic domain, a somatomedin-B-like domain, and a transmembrane domain. Although pathogenic variants can occur throughout the entire protein, they localize primarily to the phosphodiesterase-like catalytic and nuclease-like domains [Rutsch et al 2008].

To date, pathogenic variants that cause GACI with PXE-like features have only been found in the phosphodiesterase-like catalytic domain.

Abnormal gene product. ENPP1 usually converts extracellular ATP into AMP and pyrophosphate (PPi). PPi is considered the principal negative regulator of calcification and mineralization. When ENPP1 is defective, there is less extracellular PPi and, subsequently, more calcification and mineralization.

ABCC6

Gene structure. ABCC6 comprises 31 exons with one primary protein-coding transcript (NM_001171.5). Note: There is a shorter transcript that is not an exporter but whose protein may play a role in hepatitis B infection. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date, 13 GACI-causing pathogenic variants have been identified in ABCC6, including missense, nonsense, and splice site variants and small deletions and insertions [Nitschke et al 2012]. Of these 13 pathogenic variants, 11 have been previously described as pathogenic in classic PXE.

Normal gene product. ABCC6 (NP_001162.4) has 1503 amino acids and comprises three transmembrane domains with intervening cytosolic loops containing two ATP-binding domains.

Abnormal gene product. ABCC6 is an ATP-dependent exporter whose ligand remains unknown. Recently, however, it has been hypothesized that ABCC6 either directly or indirectly transports a ligand involved in the extracellular ATP metabolism pathway [Markello et al 2011, Jansen et al 2013]. When ABCC6 is defective, this ligand cannot exert its anti-calcification/anti-mineralization effects on target cells and organs. It is likely that both GACI and PXE are caused by defects within the same pathway in extracellular ATP metabolism.

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Chapter Notes

Revision History

  • 13 November 2014 (me) Review posted live
  • 25 June 2014 (cf) Original submission
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