Case 1 involved a healthy 28-year-old woman (gravida 6 para 4, abortion 1), with a previous history of neonatal death at 2 months of age owing to cardiovascular disease (unconfirmed diagnosis). Her husband was her first cousin. The fetal anatomy scan at 20 weeks' gestation was normal apart from an echogenic intracardiac focus in the left ventricle and echogenicity in the mitral valve leaflets. The woman's routine antenatal blood tests were all within normal limits and her blood group was AB rhesus positive. She had a normal glucose challenge test at 25 weeks. Owing to a disproportionately large fundal height, an obstetric ultrasound examination was performed at 29 weeks' gestation. It revealed generalized fetal hydrops and polyhydramnios. There was hyper- echogenicity in the entire aortic wall, common iliac arterial and inferior vena cava walls (Figure 1). The fetal heart was markedly enlarged with thickened ventricular walls and calcified valve leaflets.
Based on these findings, a diagnosis of idiopathic infantile arterial calcification (IIAC) was made. The work-up for the mother revealed normal hemoglobin; a negative Kleihauer–Betke test; negative tests for toxoplasmosis, rubella, herpes simplex and parvovirus; negative Venereal Disease Research Laboratory test; negative antibody screen; normal middle cerebral artery peak systolic velocity; and normal glucose 6-phosphate dehydrogenase level. The maternal serum calcium, phosphorus and alkaline phosphatase levels were all within normal limits.
Based on some previous case reports documenting survival beyond infancy, an emergency Cesarean section was performed at 32 weeks because of the abnormal biophysical profile (2/10). The male infant was delivered alive with an Apgar score of 2, 0 and 0 at 1, 5 and 10 min, respectively. The neonate had no dysmorphic features, but had generalized anasarca and he required immediate intubation. He did not respond to resuscitation and died within 3 min of delivery. Neonatal karyotyping revealed 46,XY. No autopsy or postmortem imaging studies were performed owing to the parents' refusal.
One year later, the woman in Case 1 presented again at 10 weeks' gestation. Fetal nuchal translucency thickness was normal at 12 weeks. At 20 weeks' gestation, fetal ultrasonography showed normal anatomy but with increased nuchal fold thickness (6.3 mm) and a bilateral echogenic intracardiac focus for which a genetic amniocentesis was performed; this indicated 46,XY. A follow-up ultrasound examination at 23 weeks' gestation showed hyperechogenicity in the wall of the fetal aorta and the common iliac arteries (Figure 2a). Based on these findings and the history of the previous affected pregnancy, the diagnosis of IIAC was made. All investigations performed in the previous pregnancy were repeated, with normal findings. At 26 weeks' gestation, ultrasonography showed progression of the disease in the form of hyper- echogenicity of the mitral and tricuspid valves, the papillary muscles and the walls of major arteries. At 28 weeks' gestation, the fetus developed generalized hydrops and polyhydramnios, in addition to increased cardiac ventricular wall thickness and markedly echogenic walls of the major arteries (Figure 2b). A follow-up examination was performed at 31 weeks and the fetus was discovered to be dead. Two days later there was spontaneous vaginal delivery of a macerated stillborn male with hydropic changes, weighing 2550 g. A computed tomography (CT) scan of the stillborn infant was performed to confirm the diagnosis. It showed generalized calcification of all major arteries as well as the inferior vena cava (Figure 2c).
This case involved a 33-year-old woman (gravida 7 para 4, abortion 2) with no known significant medical or surgical history. She had a history of one Cesarean section followed by three full-term, normal vaginal deliveries. Her husband was her first cousin. She presented at 9 weeks' gestation, and her routine antenatal investigations, including a 50-g glucose challenge test, were all within normal limits. Her blood group was O rhesus positive. At 20 weeks' gestation, fetal ultrasonography showed normal anatomy, although it also detected an echogenic intracardiac focus. Ultrasound examination was repeated at 25 weeks and revealed ventricular hypertrophy and increased echogenicity of all major arteries, including of the ascending and descending aorta, abdominal aorta and common iliac arteries (Figure 3a). The diagnosis of IIAC was made, and investigations relating to the disease and fetal hydrops (as performed in the previous cases) were conducted. All results were within normal limits. Genetic amniocentesis for fetal karyotyping revealed 46,XY.
At 28 weeks, a follow-up ultrasound examination showed generalized fetal hydrops and polyhydramnios with increased arterial calcifications including of the inferior vena cava (Figure 3b). One week later, an ultrasound scan showed intrauterine fetal death. A few days later, the patient presented to the labor and delivery room in labor and progressed smoothly to a spontaneous vaginal delivery of a macerated stillborn boy weighing 1950 g. A CT scan of the stillborn infant showed generalized calcification of all major arteries, including the thoracic and abdominal aorta, renal, common iliac and femoral arteries (Figure 3c).
The patient's 12-year-old daughter suffers from refractory hypertension uncontrolled by multiple combination therapy, which raised suspicions that she had the same disease. This suspicion was confirmed after magnetic resonance imaging and renal angiography were performed.
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.