Arterial Calcification, Generalized, Of Infancy, 2

A number sign (#) is used with this entry because of evidence that generalized arterial calcification of infancy-2 (GACI2) can be caused by homozygous or compound heterozygous mutation in the ABCC6 gene (603234) on chromosome 16p13.11.

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).

For a general phenotypic description and a discussion of genetic heterogeneity of GACI, see GACI1 (208000).

Pseudoxanthoma elasticum (PXE; 264800) is an allelic disorder caused by mutation in the ABCC6 gene; it has been suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders (Nitschke et al., 2012).

Clinical Features

Glatz et al. (2006) described 2 patients with idiopathic infantile arterial calcification (IIAC). The first was an infant girl who presented at 33 days of life with tachypnea, tachycardia, cool extremities, and poor peripheral pulses. Echocardiography demonstrated cardiac dysfunction and an electrocardiogram and cardiac enzyme levels were suggestive of myocardial infarction (MI). Despite intensive care, her condition deteriorated over the next 2 weeks and the patient died after withdrawal of support at 6.5 weeks of age. Autopsy revealed a markedly enlarged heart, with multiple areas of focal hemorrhage, necrosis, and calcification consistent with MI. Microscopic examination of the vasculature revealed calcification of all major coronary arteries, as well as involvement of the aorta, main and branch pulmonary arteries, celiac, hepatic, suprarenal, pancreaticoduodenal, splenic, mesenteric, renal, and lumbar arteries. Involved arteries showed calcification primarily of the internal elastic lamina, with varying degrees of calcification of the external elastic lamina in areas of heavy calcification, which was circumferential in many sections. Inflammation was not a prominent feature. Intraparenchymal arterial calcifications were found in the spleen, pancreas, diaphragm, thymus, thyroid, trachea, larynx, and salivary glands. Extensive intratubular calcifications were found in the kidneys. Gross examination of the brain showed mild convolutional abnormalities, and microscopy showed rare focal parenchymal calcifications and a single vessel in the corpus striatum with early calcific changes. The second patient with IIAC was an infant girl who presented at age 2 months in cardiogenic shock, and after initial recovery was readmitted in the third month of life with severe heart failure, at which time cardiac MRI showed a large anterolateral and apical aneurysm of the left ventricle, with thinning of the myocardium and moderate to severe mitral regurgitation. The patient had progressively intractable heart failure and died at 4.5 months of age. Autopsy revealed a severely enlarged heart, with severe ischemic changes in the myocardium of the left ventricle and calcification within the subendocardial area. Upon microscopic examination of the arterial system, elastic arteries showed calcification primarily of the outer elastic layers, whereas muscular arteries had preferential calcification of the media with intimal proliferation, accompanied by a foreign body giant cell reaction. These findings were present in the coronary, pulmonary, and renal arteries, as well as the aorta and its branches in the neck. The coronary arteries showed luminal obstruction with near-occlusive changes in segments. Examined veins were normal.

Intrafamilial Phenotypic Variability

Le Boulanger et al. (2010) studied a nonconsanguineous French family in which a younger brother died of a condition 'strikingly reminiscent' of generalized arterial calcification of infancy (GACI) at 15 months of age, whereas his older brother developed uncomplicated pseudoxanthoma elasticum (PXE; 264800) in adolescence. The younger brother had a myocardial infarction complicated by heart failure at 6 months of age; skin biopsy at 1 year of age for evaluation of a possible connective tissue disorder showed elastic fiber dystrophy, with clumped and fragmented fibers in the mid dermis, as well as calcifications on the elastic fibers and sporadically in vessel walls of the subcutis. There were no periarticular calcifications on x-ray, and serum phosphate and calcium levels were normal. At 15 months of age, he had a second, fatal MI. Autopsy showed fibrosis of the coronary arteries with calcifications involving the intima, internal elastic lamina, and media, and medium-sized arteries in the adrenal glands, pancreas, thyroid, and testes also showed extensive arterial calcification. At 28 years of age, the older brother presented for evaluation of yellowish papules on his neck; he had no cardiovascular symptoms and cardiac examination and echocardiography were normal. Skin samples from the brother with PXE showed heavy staining of mineralized mid-dermal elastic fibers, with active MGP (154870) and fetuin-A (AHSG; 138680) antibodies, and fetuin-A also showed striking staining of the subepidermal area. All arteries in autopsy samples from the brother with GACI showed the same immunohistochemical profile, as well as calcifications.

Molecular Genetics

In an infant girl with generalized arterial calcification who died at 6.5 weeks of age, Glatz et al. (2006) analyzed the gene associated with GACI1 (208000), ENPP1 (173335), but no pathogenic mutations were found. Nitschke et al. (2012) restudied this patient and identified compound heterozygosity for splice site mutations in the ABCC6 gene (603234.0015 and 603234.0029).

In a 28-year-old French man with pseudoxanthoma elasticum (PXE; 264800), who had a younger brother who died of GACI at age 15 months, Le Boulanger et al. (2010) identified compound heterozygosity for missense mutations in the known causative gene for PXE, ABCC6 (603234.0025 and 603234.0026), which were also found in heterozygosity in each of his unaffected parents, respectively. No disease-causing mutations were found in ENPP1. Although no DNA material was available from the deceased younger brother, his disease was presumed to be related to the familial ABCC6 mutations. Le Boulanger et al. (2010) concluded that GACI may represent an atypical and severe end of the vascular phenotypic spectrum of PXE.

Nitschke et al. (2012) analyzed the ABCC6 gene in 28 GACI patients from 25 unrelated families who were negative for mutation in the ENNP1 gene, as well as 2 unrelated GACI patients in whom only 1 ENNP1 mutation had been detected. They identified homozygosity or compound heterozygosity for mutations in ABCC6 in 8 unrelated GACI patients (see, e.g., 603234.0001 and 603234.0006, and 603234.0027-603234.0029), including 1 of the infant girls originally described by Glatz et al. (2006) (see 603234.0029). In 6 patients from 5 unrelated families, only 1 mutation was detected in ABCC6; the authors noted that there was no phenotypic difference between these patients and those with biallelic mutations in ABCC6, and stated that mutations in regulatory untranslated regions of ABCC6 might not have been detected by their approach. No mutation in the ABCC6 gene was found in 16 patients from 14 unrelated families, including the 2 patients who were known to carry monoallelic mutations in ENNP1. Overall, 13 different ABCC6 mutations were identified in GACI patients, all but 2 of which had previously been identified in typical PXE patients who had a much milder phenotype than the GACI patients. Based on the considerable overlap of phenotype and genotype of GACI and pseudoxanthoma elasticum, Nitschke et al. (2012) suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than 2 distinct disorders.