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Idiopathic infantile arterial calcification (IIAC) is a rare and nearly always fatal disorder. To date, prenatal diagnosis has been reported in fewer than 10 cases. We describe a series of three cases in which the diagnosis of IIAC was made at 23, 25 and 29 weeks' gestation. All three cases presented with a normal anatomy scan at 20 weeks' gestation with an echogenic intracardiac focus. Follow-up scans showed generalized hyperechogenicity and calcification of the walls of the large arteries, particularly the aorta and the iliac arteries. All cases developed hydrops fetalis with cardiomegaly and polyhydramnios later in gestation, resulting in intrauterine fetal death in two cases and neonatal death immediately following delivery in the third. This is the largest case series and the earliest gestational age of prenatal diagnosis of IIAC reported to date. When surveying for the disease, serial scans are important, perhaps from 20 weeks' gestation, with close examination of the iliac and aortic arteries. Detection of echogenic intracardiac focus could be an early marker in patients with a family history of the disease. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.
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First described in 1901 by Bryant and White1, IIAC is a very rare condition of unknown etiology and is nearly always fatal. It is characterized by widespread and extensive calcification and stenosis of large and medium-sized arteries2. This results from the deposition of calcium hydroxyapatite in the arterial internal elastic lamina layer, which leads to rapidly progressive ischemic heart failure and refractory hypertension either prenatally or, most commonly, in the neonatal and early infancy periods. The postulated mechanisms of calcification include altered iron metabolism, degeneration of elastin fibers, abnormal response to vascular injury, altered prostaglandin metabolism, and disorders of calcium and phosphorus metabolism3. There is a spectrum of disease that varies from fetal demise in the second half of pregnancy to later onset of symptoms in the first months of postnatal life. Most cases of IIAC are diagnosed at autopsy2 or during the first months of postnatal life. To date, 161 cases of IIAC have been reported in the literature4. The vast majority were diagnosed in the neonatal and infantile periods, whereas prenatal diagnosis is extremely rare with fewer than 10 reported cases3, 5.
It has been reported that IIAC is an autosomal recessive disorder6, 7. This is consistent with the cases described here. The first two cases described were siblings, and their parents were first-degree cousins with a history that included an infantile death at 2 months, which was probably due to cardiovascular disease based on the clinical presentation of heart failure, poor feeding and respiratory distress. The third case involved a mother with a living child affected by IIAC and a husband who was a first-degree cousin. Therefore, our cases support the autosomal recessive inheritance pattern as described in previous studies.
This series is noteworthy in that it is the largest case series of prenatal diagnoses of IIAC that has been presented. It also describes the earliest prenatal diagnosis of IIAC to date (Case 2 at 23 weeks' gestation). The earliest case previously described in the literature was diagnosed at 27 weeks3 and the second earliest was diagnosed at 28 weeks6. Furthermore, this case series is the first to report two prenatally diagnosed cases of IIAC in the same mother, and is also the first to describe the diagnosis in an elder sibling following the prenatal detection of the disease in a subsequent pregnancy.
Ultrasonography is the modality of choice for the prenatal diagnosis of IIAC. As observed in all of our cases, the prenatal sonographic findings are hyperechogenicity of the walls of major arteries and signs of fetal hydrops with heart chamber hypertrophy and cardiomegaly secondary to cardiac failure6. This may lead to premature delivery (as in Case 1) and/or stillbirth (as in Cases 2 and 3). As shown in our cases, a normal scan at around 20 weeks does not rule out the disease. However, the presence of an echogenic intracardiac focus was observed in all of our cases at that gestational age, and so could be an early marker for IIAC in patients with a family history. Therefore, if there is a personal or family history of IIAC, serial prenatal ultrasonography is essential to determine whether the disease is present and to allow planning of management.
For neonatal diagnosis, ultrasound and CT scans appear to be more sensitive than X-ray scans owing to their superior contrast resolution8, 9. The diagnosis of IIAC was confirmed in two of our cases by CT scan, which clearly showed calcified major arterial walls.
IIAC is associated with, and perhaps caused by, mutations on chromosome 6q22 that inactivate ectonucleotide pyrophosphate/phosphodiesterase 1. This cell surface enzyme generates inorganic pyrophosphate, a solute that regulates cell differentiation and serves as an essential inhibitor of calcification in the form of hydroxyapatite10. Since the identification of these mutations is used only for research purposes, prenatal genetic testing as a diagnostic tool is currently unavailable. In the future, however, prenatal DNA analysis may be possible.
Although less severe phenotypes of IIAC with spontaneous resolution of the calcifications and even long-term survival (with follow-up of up to 25 years) have been reported8, 11, 12, approximately 85% of affected patients die within the first 6 months of postnatal life3, 13. Death is most commonly due to cardiac ischemia secondary to coronary artery involvement3, 9. As the prognosis is extremely poor, with a fatal outcome likely, medical treatment using bisphosphonates is usually unsuccessful9, 12, 14. In conclusion, increased echogenicity of the fetal vasculature should alert the sonologist to this fatal condition, which can facilitate early diagnosis and further planning of management.