Antenatal diagnosis of idiopathic infantile arterial calcification (IIAC): a single centre experience and review of the literature
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Idiopathic infantile arterial calcification (IIAC) is a rare autosomal recessive disorder characterised by extensive calcification and proliferation of the intimal layer of the large and medium size arteries.
We report 4 antenatal cases of IIAC in our institution over a 10 year period from 2006 to 2016. Clinical outcomes, prenatal ultrasound findings, radiological and postmortem investigations are summarized. A literature review of this rare autosomal recessive disease is presented. The possible aetiology of this condition and the role of biphosphonates in the management of this condition are discussed.
This case series highlights the frequent poor outcome of IIAC, consistent with the literature, the phenotypical variability of the disease even within the same family and the role of biphosphonates in one prenatally diagnosed case. Hyperechogenicity of the fetal vasculature detected on prenatal ultrasound particularly if there is a history of IIAC in an index pregnancy may aid earlier prenatal diagnosis. A multidisciplinary approach to parental counselling can then occur in order to optimise a plan of care in the neonatal period.
KeywordsIdiopathic infantile arterial calcification Generalized arterial calcification of infancy Arterial calcification Prenatal diagnosis Fetal echocardiography
- ARHR type 2
Autosomal recessive hypophosphatemic rickets type 2
Chorionic villus sampling
- ENPP 1
Ectonucleotide pyrophosphatase /phosphodiesterase 1
Generalized infantile arterial calcification
Idiopathic arterial calcification of infancy (IACI)
Idiopathic infantile arterial calcification
Idiopathic infantile arterial calcification (IIAC) is an autosomal recessive condition associated with premature onset of arterial calcification and intimal proliferation secondary to unregulated hydroxyapatite deposition leading to vascular stenoses . Other terms to describe the same condition include arterial calcification of infancy, generalized infantile arterial calcification (GACI), idiopathic arterial calcification of infancy (IACI), occlusive infantile arterial calcification and occlusive infantile arteriopathy. Mutations in the ENPP1 gene are associated with IIAC in approx 75% of patients  which lead to decreased levels of inorganic pyrophosphate which is an inhibitor of hydroxyapatite crystal deposition in the vessel wall . Circa just over 200 cases of IIAC have been reported to date since the condition was first described in 1901 by Bryant and White ; most of which have been diagnosed in the postnatal period or at autopsy. 85% of liveborn infants with IIAC die within the first 6 months of life. The majority of prenatally diagnosed cases described to date die in utero or within 5 months of birth [5, 6]. Calcification of the coronary arteries is a poor prognostic feature and is estimated to occur in 85% of cases  leading to cardiac ischaemia, myocardial infarction and ultimately death in the majority of cases due to heart failure. We present 4 prenatally diagnosed cases in our institution over a ten year period from 2006 to 2016. The role of prenatal biphosphonate treatment in one prenatally diagnosed case with successful outcome is discussed.
The last systematic review by Mastrolia et al. in 2015  summarized 23 prenatally diagnosed cases [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24] of IIAC including two from their own institution. Our review has revealed an additional seven since then [25, 26, 27, 28, 29, 30, 31]. To the best of our knowledge there are two reports of similarly early prenatal detection of IIAC in the second trimester without hydrops before 24 weeks as in both our first two cases. The earliest reported case following an extensive review of the literature was in the recipient fetus of a set of monochorionic diamniotic twins affected by twin to twin transfusion syndrome at 18 + 4 weeks gestation . Fetal ultrasound revealed hepatic hyperechogenicity consistent with hepatic vascular calcification which became more progressive eventually resulting in hydrops and preterm delivery at 28 weeks. The donor fetus had a pericardial effusion at 25 weeks. The recipient twin was found to have calcification of the deep cerebral arteries, thoracoabdominal aorta, main pulmonary artery and coronary arteries and hepatic vasculature. The donor twin was found to have aortic and pulmonary arterial calcification. In the second reported case a fetal anatomy scan at 20 weeks revealed an echogenic intracardiac focus and echogenicity of the mitral valve leaflet . This progressed to calcification of the aorta, common iliac arterial and inferior vena caval walls and polyhydramnios developed. The fetus was delivered at 32 weeks because of hydrops and died on day 3 of life. In a subsequent pregnancy a scan at 23 weeks revealed hyperechogenicity of the wall of the fetal aorta and common iliac arteries. This progressed to hydrops and intrauterine demise at 31 weeks gestation. There are only two previously reported cases of early prenatal detection of calcification of the mitral and tricuspid valve [9, 10] as in our first case.
Few articles have reported cerebral artery involvement as in our fourth case and in the recipient twin described above . Calcification of the cerebral arteries has been described in four cases [32, 33, 34, 35], the earliest reported case in 1948 . Glatz et al. 2006  described a case of rare focal parenchymal microcalcifications in the area of the corpus striatum, internal capsule and choroid plexus on postmortem. Jones et al. 1972  reported calcific change in the cerebral and coronary arteries on postmortem of a grossly hydropic infant and diffuse opacification of the Circle of Willis on postmortem x- rays. Juul et al. 1990  reported calcification of the basal ganglia on postmortem in two of three siblings diagnosed with IIAC with pituitary involvement in one of the three, which has never been described before.
It is postulated that biphosphonates promote resolution of calcifications but fail to alleviate the myointimal proliferation that the leads to vascular stenosis and organ ischaemia and ultimately organ death . The cases discussed here highlight the phenotypic variation of this condition even within the same family leading some authors  to speculate that there are different types of IIAC depending on the degree of myointimal thickening; those with mainly myointimal proliferation being more likely to experience infarction of the heart, kidneys and spleen whereas those with calcification and little intimal thickening experiencing longer survival and even spontaneous regression.
In a retrospective cohort study by Rutsch et al. 2008  biphosphonate therapy was associated with survival in 11 (65%) of 17 treated patients whereas 69% of the patients not treated with biphosphonates died. Only 8 (31%) of 26 patients who survived the first day of life and were not treated with biphosphonates survived beyond infancy. However they do acknowledge that the clinical phenotype of the untreated group was probably more severe than the treated group and that hyperphosphatemia and hyperphosphaturia are more likely to be associated with survival beyond infancy. Subjects who died were also more likely to have pulmonary, renal and coronary artery involvement.
ENPP 1 regulates inorganic pyrophosphate (PPi). PPi inhibits extracellular matrix calcification. A subset of those that survive develop hypophosphatemic rickets as in our second case. Hypophosphataemia and hypophosphaturia have been associated with increased survival in such patients. However, later investigators found that the ENPP1 gene mutation was also associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR 2) . To the best of our knowledge there are reports in the literature of 11 long term survivors (greater than or equal to 2 yrs. of age) [7, 38, 39, 40, 41, 42]; 4 of these 11 were treated with biphosphonates; of this subgroup the longest surviving adult was reported in 2006 to be 25 years of age . In this case a sibling had died of IIAC. Despite a normal physical examination after delivery in view of the siblings history this infant underwent investigations. X-rays revealed calcification of the carotid, radial, femoral and dorsalis pedis arteries and abdominal aorta and ligamentous calcification of the shoulder. It is thought that resolution of calcification occurs between four months and two years of therapy. However in this case after only 2.5 weeks of etidronate therapy all calcifications had disappeared. As in our second case it is difficult to ascertain if this resolution of calcification represents a milder phenotype of the disease with spontaneous improvement or whether to resolution is due to the biphosphonate therapy. Stuart et al.  report two siblings who died despite Etidronate treatment. However one of these two cases presented as a fetal case and both had extensive calcification at the commencement of treatment. Votava-Smith et al.  reported a case of arterial calcification in a recipient fetus of monochorionic twins after successful laser treatment for twin to twin transfusion syndrome. Both twins were diagnosed with a heterozygous ABCC6 gene mutation associated with GACI. The recipient fetus was started on Etidronate and underwent surgery at four months of age to augment the stenosed main and branch pulmonary arteries and ascending aorta. The infant remained well on Etidronate therapy at 18 months of age. The donor twin remained well at 18 months of age with no evidence of arterial calcification.
Spontaneous regression of calcification at eighteen months of age treatment was described in a case presented by Sholler et al. in 1984 . The calcification disappeared completely by five years of age. Nine further cases of spontaneous resolution without diphosphonate treatment have been described since [7, 19, 32, 43, 44, 45]. The longest survivor was reported to be 22 years after spontaneous resolution .
This case series highlights the high mortality of IIAC, consistent with the literature, the clinical and genetic heterogeneity of the condition even within the same family and the vital role of prenatal diagnosis in case management. If there is a history of IIAC in an index pregnancy serial early fetal echocardiograms in a subsequent pregnancy may aid earlier prenatal diagnosis of this condition in order to plan appropriate care. Hyperechogenicity of mitral or tricuspid valves or vessel walls on prenatal ultrasound should prompt referral to fetal cardiology so that appropriate prenatal genetic counseling and molecular genetic testing for IIAC can occur. Early prenatal diagnosis of this condition will facilitate earlier commencement of biphosphonate therapy in the immediate neonatal period. More prenatal cases of biphosphonate therapy are needed to elucidate whether resolution or improvement in arterial calcification is due to the biphosphonate therapy or the milder phenotype of the disease. Our in-utero case of prenatal biphosphonate therapy highlights the potential important future role of this prenatal treatment in helping to reduce in-utero arterial calcification.
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All authors helped to draft the manuscript and approved the final manuscript.
Ethics approval and consent to participate
Within our centre, prospective general consent is obtained from patients booking for antenatal care for inclusion of data for research purposes, hence additional consent was not obtained. No research was performed on human or animal subjects. No identifying information is presented in this case series.
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The authors declare that they have no competing interests.
This case series was presented as an oral poster presentation at ISUOG Rome Sept 2016.
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