Arterial Calcification, Generalized, Of Infancy, 1

A number sign (#) is used with this entry because of evidence that generalized arterial calcification of infancy-1 (GACI1) is caused by homozygous or compound heterozygous mutation in the ENPP1 gene (173335) on chromosome 6q23.

Mutation in ENPP1 also causes an autosomal recessive form of hypophosphatemic rickets (see ARHR2, 613312).

Description

Generalized arterial calcification of infancy (GACI) is a severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. GACI is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure (summary by Rutsch et al., 2003 and Cheng et al., 2005).

Genetic Heterogeneity of Arterial Calcification

Generalized arterial calcification of infancy-2 (GACI2; 614473) is caused by mutation in the ABCC6 gene (603234) on chromosome 16p13.

Homozygous or compound heterozygous mutation in the NT5E gene (129190) can cause adult-onset of calcification of arteries and joints (211800).

Clinical Features

Generalized arterial calcification has been noted in multiple sibs (Hunt and Leys, 1957). It may be fundamentally a defect of elastic fiber. Calcification occurs particularly in the internal elastic lamina. Material with the staining properties of mucopolysaccharide accumulates around the elastic fibers. Fine calcium incrustation of the lamina is the minimal lesion. Later the lamina is ruptured and occlusive changes in the intima take place. Death from myocardial infarction usually occurs in the first 6 months. Calcification in a peripheral artery with EKG changes of occlusive coronary artery disease suggests the diagnosis.

Menten and Fetterman (1948) described 3 male infants, 2 of them brothers, who all died between 7 and 8 weeks of life with cyanosis and respiratory difficulty. Autopsy revealed generalized arteriosclerosis, with medial sclerosis of multiple arteries, including the coronary, pulmonary, gastric, mesenteric, renal, and hepatic arteries; in addition, there was cardiac hypertrophy and coronary artery stenosis with myocardial infarction. The 2 brothers, who had an older sib who died under similar conditions at about the same age, were also noted to have parenchymatous degeneration of the kidneys, and the other patient had glomerulosclerosis. Menten and Fetterman (1948) stated that the disease process, where well advanced, actually involved all 3 arterial coats, and might be termed a 'diffuse' arterial sclerosis.

Raphael et al. (1970) reported 2 brothers who died in respiratory distress after lengthy hospitalizations at 3 months and 5 months of age, respectively. Autopsy showed left ventricular hypertrophy and calcific changes involving arteries in many organs, consisting of replacement of the elastica by dense, sharply delineated calcific material. Endocardial fibroelastosis was seen on microscopic examination in 1 patient but not the other. No evidence of renal or bone disease was seen in either case. One of the brothers had a twin sib who died at 8 days of age, reportedly of pneumonia, but no autopsy was performed.

Witzleben (1970) suggested that calcification has been overemphasized and is really only a secondary phenomenon. 'Infantile coronary sclerosis' is too restrictive in its topographic implications. He suggested 'occlusive infantile arteriopathy' as the preferred term.

Sholler et al. (1984) reported 3 unrelated patients. One was 7 years old at the time of report and showed spontaneous regression of calcification.

One of 2 affected sibs reported by Anderson et al. (1985) had an extensive acute panarteritis suggesting to the authors that IIAC may be the result of an inflammatory or infectious process. Ultrastructural examination confirmed that the deposits are hydroxyapatite and showed further a content of iron. No matrix vesicles or mitochondrial calcifications that might serve as nucleation sites for crystalline calcium phosphate were found. They raised the possibility that altered iron metabolism may be involved in the pathogenesis.

Van Dyck et al. (1989) described an infant in whom the diagnosis was made at age 2 weeks and therapy with diphosphonate resulted in complete resolution of vascular calcification. At the age of 2 years the child was 'doing well' but required medical treatment for arterial hypertension.

Stuart et al. (1990) described the disorder in 2 sibs. In the second-born sib, serial fetal echocardiography showed the development of pericardial effusion and calcification of the great vessels by 33 weeks of gestation. One sib died at 11 weeks and the other at 6 weeks of age. Diphosphonate was of no apparent benefit. Although survival to adulthood has been reported (Sholler et al., 1984; Marrott et al., 1984), most patients die in the first 6 months of life.

Rutsch et al. (2008) performed retrospective observational analysis of 55 GACI patients, 19 (34%) of whom survived infancy. In the 8 surviving patients who were tested, all developed hypophosphatemia due to reduced renal tubular phosphate resorption during childhood. Eleven (65%) of 17 patients treated with bisphosphonates survived, whereas only 8 (31%) of 26 patients who survived the first day of life and were not treated with bisphosphonates survived beyond infancy.

Intrafamilial Phenotypic Variability

Cheng et al. (2005) studied 2 Taiwanese sibs with generalized arterial calcification of infancy who had markedly different clinical courses despite their identical genotype (see MOLECULAR GENETICS) and similar sonographic and radiographic findings: the male infant died with severe heart failure and hypertension at the age of 6 weeks, whereas the female infant was clinically well upon examination at 18 months of age, with normal growth and psychomotor development and normal blood pressure.

Dlamini et al. (2009) reported 3 Caucasian sibs with GACI and striking phenotypic variability. The proband was a 5-year-old boy who had left ventricular hypertrophy noted in infancy and developed hypertension at 14 months of age; arch aortogram showed severe stenosis of the celiac axis, superior mesenteric artery, renal arteries, and both internal and external carotid arteries, and coronary angiography showed normal caliber coronary arteries with no calcification. The proband had 2 deceased younger sibs: a female sib was stillborn, in whom ultrasound at 30 weeks' gestation had shown echogenicity of the myocardium and aortic root suggestive of calcification, and a male sib died 12 hours after birth from myocardial infarction, in whom intracardiac calcification was detected prenatally. Review of the proband's radiographs and echocardiography showed no evidence of typical GACI calcification; however, reevaluation by CT scan revealed high-density foci compatible with calcification in the left internal carotid artery siphon, cervical portions of the common carotid and right brachiocephalic arteries, aortic root, and descending aorta. The proband and his male sib were found to be compound heterozygous for the same ENPP1 mutations (see MOLECULAR GENETICS). At 5 years of age, the proband was healthy and developmentally age-appropriate, on antihypertensive and antiplatelet agents. Dlamini et al. (2009) concluded that GACI may be underrecognized and suggested that the diagnosis should be considered in patients with multiple arterial stenoses even in the absence of radiographic calcification.

Features of Pseudoxanthoma Elasticum in GACI Patients

Nitschke et al. (2012) described 3 unrelated GACI patients with homozygous or compound heterozygous ENNP1 mutations (see MOLECULAR GENETICS) who developed clinical features of pseudoxanthoma elasticum in later childhood. One boy with GACI, who was previously studied by Dlamini et al. (2009), developed at 8 years of age pseudoxanthomatous skin lesions around his umbilicus and on his neck, which were histologically proven to be typical PXE lesions. A 12-year-old French boy, born of consanguineous parents, was diagnosed with GACI in the neonatal period and treated with oral bisphosphonates, resulting in disappearance of the ectopic calcifications. At 9 years of age, he presented with yellowish papules on the neck and periumbilical region and large angiomatous atrophic macules on the anterior chest. He also had abnormal calcifications of the ear cartilage, cervical fusion between C3 and C5, and microcalcifications of the left kidney, but no cardiovascular or ophthalmologic calcifications were detected. He had short stature with progressive genu valgum, and radiologic signs of rickets were present; he was found to have hypophosphatemia with decreased renal phosphate reabsorption, normal vitamin D levels, and normal glomerular filtration rate. Reexamination at 12 years of age showed development of otosclerosis with stapedovestibular ankylosis, resulting in hearing loss. An eye exam showed no angioid streaks. Histopathologic studies of the yellowish neck papules confirmed the diagnosis of PXE, with calcium deposits in elastic fibers that were stained by carboxylated, but not noncarboxylated, anti-MGP (154870) antibodies. The patient's mother also presented with yellow papules characteristic for PXE, and his 9-year-old sister had angiomatous linear lesions of the left flank. The other GACI patient with features of PXE was a 5-year-old French girl with short stature, hypophosphatemic rickets, and cardiovascular, pancreatic, hepatic, and renal calcifications, who developed diffuse angiomatous lesions on her back and had angioid streaks in the Bruch membrane of the retina that were typical for PXE. She did not have any pseudoxanthomatous skin lesions. At 4 years of age, she had also developed conductive deafness and required hearing aids.

Dental Features in GACI Survivors

Thumbigere-Math et al. (2018) studied the teeth of 5 unrelated patients with GACI, including patients previously reported by Li et al. (2012), Rutsch et al. (2008), and Ferreira et al. (2016) (patients 2, 4, and 5). All presented significant hypercementosis of cervical cementum, with radiographic evidence of unusually protruding cervical root morphology, in primary and/or secondary dentition. Dental histories of 4 of the patients included evidence for infraocclusion, overretained primary teeth, possible ankylosis, and/or ineffective orthodontic tooth movement, suggesting altered mineral metabolism contributing to disrupted tooth movement and exfoliation. High-resolution micro-CT analyses of extracted primary teeth from 3 of the patients revealed a 4-fold increased cervical cementum thickness and a 23% increase in cementum mineral density compared to age-matched healthy control teeth. There were no differences in enamel or dentin densities between GACI patients and controls. Histologic examination showed markedly expanded cervical cementum in GACI teeth, including cementocyte-like cells and unusual patterns of cementum resorption and repair.

Clinical Management

Ferreira et al. (2016) reported a 22-year-old man who was diagnosed with GACI at age 6 weeks, at which time he was tachycardic with left ventricular hypertrophy and poor systolic function, and had hepatomegaly and splenomegaly. Cardiac catheterization revealed severe attenuation of the left coronary artery with subtotal occlusion of the first obtuse marginal branch and occlusion proximal to the circumflex, and proximal occlusion of the right coronary artery. CT scan showed calcification of the descending aorta as well as the coronary, brachial, renal, splenic, and superior mesenteric arteries. Bisphosphonate treatment ameliorated his cardiac function, and CT scan at 7 months of age showed reduced calcifications. At 13 months, the calcifications had regressed completely except for mild calcification of the aortic annulus, and bisphosphonate treatment was discontinued at 24 months of age. At age 13 years, the patient developed progressive pain in the ankles and knees, and x-rays showed significant anterior bowing and thinning of the lower ends of both femora. He was diagnosed with hypophosphatemic rickets at 14.5 years of age and treated with phosphorus and calcium supplementation. At 22 years of age, multidetector helical CT from neck to legs revealed minimal calcification of the aortic root, inferior portion of the heart, and left popliteal artery, with no calcifications elsewhere, including no nephrocalcinosis. Anterior femoral bowing was noted. Cardiac CT showed no coronary artery calcification. The authors concluded that long-term treatment of rickets in the setting of GACI can be accomplished without worsening of vascular calcifications.

Molecular Genetics

Spontaneous periarticular and aortic calcifications in early life and systemic lowering of nucleotide pyrophosphatase/phosphodiesterase (NPP) activity and inorganic pyrophosphate levels are shared features of the phenotype of idiopathic infantile arterial calcification (IIAC) and of homozygous 'tiptoe walking' (ttw/ttw) mice, which carry a spontaneous nonsense mutation in Enpp1 (Okawa et al., 1998; Rutsch et al., 2001). Rutsch et al. (2001) found reduced levels of expression of ENNP1 in an individual with IIAC born to consanguineous parents and demonstrated heterozygosity for a mutation at the ENNP1 locus (173335.0002). Using a high-density microsatellite marker panel for 6q, the site of the ENPP1 gene, Rutsch et al. (2003) identified a recombination event in this proband that had obscured homozygosity with respect to the critical region. Screening for mutations in ENPP1 in 11 unrelated families with IIAC found mutations in 8 of them, either in homozygous or compound heterozygous state, compatible with a functional inactivation of both alleles. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase-1, a cell surface enzyme that generates inorganic pyrophosphate, a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification.

Lorenz-Depiereux et al. (2010) restudied 1 of the families previously described by Rutsch et al. (2003) ('family 4') and identified homozygosity for a missense mutation in the ENPP1 gene (173335.0011) in a father and son with different phenotypes: the son had generalized arterial calcification of infancy (GACI) and hypophosphatemia, whereas his father had hypophosphatemic rickets (ARHR2; 613312). Ultrasound examination of large blood vessels in the father showed normal carotid and renal arteries and a normal thoracic and abdominal aorta.

In a Taiwanese brother and sister with GACI who had markedly different clinical courses, Cheng et al. (2005) identified compound heterozygosity for missense mutations in the ENPP1 gene (see 173335.0008 and 173335.0009).

Rutsch et al. (2008) identified homozygosity or compound heterozygosity for 40 different mutations in the ENPP1 gene in 41 (75%) of 55 GACI patients. The most frequently detected mutation was P305T (173335.0016); Rutsch et al. (2008) noted that P305T was universally lethal when present on both alleles, but stated that no other clear genotype/phenotype correlation was seen.

In 2 Caucasian brothers with GACI, 1 deceased of myocardial infarction 12 hours after birth and 1 healthy at 5 years of age, Dlamini et al. (2009) identified compound heterozygosity for a missense and a 2-bp deletion in the ENPP1 gene (173335.0014 and 173335.0015). Nitschke et al. (2012) provided follow-up on the living brother, who at 8 years of age developed pseudoxanthomatous skin lesions that were histologically proven to be typical of pseudoxanthoma elasticum.

In 2 patients with GACI, a 12-year-old French boy and an unrelated 5-year-old French girl, who developed features of PXE in later childhood, Nitschke et al. (2012) identified homozygous and compound heterozygous mutations in the ENNP1 gene (see, e.g., 173335.0017-173335.0019, respectively).

In a 22-year-old man with GACI who underwent bisphosphonate treatment with near-total resolution of arterial calcifications by age 2 years (see CLINICAL MANAGEMENT), Ferreira et al. (2016) reported compound heterozygosity for missense mutations in the ENPP1 gene, R481Q and Y471C. In adolescence, the patient developed hypophosphatemic rickets, which was treated with phosphorus and calcium supplementation without any worsening of vascular calcifications.

Animal Model

Using high-resolution micro-CT, Thumbigere-Math et al. (2018) analyzed the mandibular molars of Enpp1-null mice and observed a 4-fold increased cervical cementum thickness and 5-fold increase in volume compared to wildtype mice, as well as a nonsignificant 5% increase in mineral density. Apically located cellular cementum showed significantly increased volume and height on the mesial root surface, but no change in thickness or density in the null mice compared to wildtype. The authors noted that histologically the molars of Enpp1-null mice resembled those of GACI patients, including dramatically expanded cervical cementum with abnormal inclusion of embedded nucleated cementocyte-like cells and lacunae.