Introduction
Idiopathic infantile arterial calcification is a rare disease characterised by widespread calcification in medium and large arteries. It is a genetically inherited autosomal recessive disease. Reference Mune, Gadgil, Shaikh and Fugare1 Approximately 69–80% of cases develop as a result of a mutation in the ectonucleotide pyrophosphatase/phosphodiesterase-1 gene on chromosome 6q23. Reference Yunfeng, Tongyan, Jing and Xiaomei2 Most cases of idiopathic infantile arterial calcification are diagnosed postnatally or at autopsy. Eighty-five percent of liveborn infants with idiopathic infantile arterial calcification die within the first 6 months of life. Reference Mulcahy, Mone and Mc Auliffe3 The most common cause of death is rapidly progressive heart failure. Reference Mune, Gadgil, Shaikh and Fugare1 It is important to correctly diagnose this rare disease, as genetic counselling and follow-up are mandatory. A case of idiopathic infantile arterial calcification causing hydrops fetalis is presented in this study.
Case
A 23-year-old woman who was 27 weeks pregnant was referred from a local hospital with a diagnosis of hydrops fetalis. Her first child was born at 29 weeks at a local hospital with hydrops and died at 28 days of age due to idiopathic infantile arterial calcification. Genetic testing at that time revealed that both parents were carriers of the ectonucleotide pyrophosphatase/phosphodiesterase-1 gene mutation. The patient’s fetal echocardiogram revealed a heart floating in pericardial fluid. A 19.1 mm pericardial effusion adjacent to the lateral wall of the left ventricle at end-diastole and ascites were observed in the abdomen (Figure 1( b )). The ascending aorta (2.3 mm), arcus aorta, abdominal aorta, main pulmonary artery (2.4 mm), and its branches were markedly hyperechoic and thickened (Figures 1( a ), 2( a ), 2( b )). The left ventricular lateral wall was observed to be thickened. At the end of diastole, the lateral wall thickness of the left ventricle was 3 mm (Z score + 2.68) (Figure 1( b )). In addition, the tricuspid valve was hyperechoic, and valve movement was mildly restricted (Figures 1( b ), 2( c ), 2( d )). The mitral valve opening diameter was measured at 5.2 mm, while the tricuspid valve opening diameter was measured at 3.08 mm. Turbulent flow and gradient increase were observed in the tricuspid valve. The valve peak velocity was measured as 59 cm/s (Z score + 2.9) (Figures 1( b ), 2( c )). Mitral valve, aortic valve, and pulmonary valve peak velocities were normal (41, 80, 77 cm/sn, respectively). A homozygous mutation in ectonucleotide pyrophosphatase/phosphodiesterase-1 was detected in the chorionic villus sampling performed for diagnostic purposes. The patient was diagnosed with early-onset idiopathic infantile arterial calcification and hydrops fetalis. The baby died eight days later, and the patient underwent a medical abortion.
( a ) Thickened aorta and main pulmonary artery in three-vessel view. ( b ) Heart floating in widespread pericardial fluid, thickening of the left ventricular wall and a thick, hyperechoic tricuspid valve in four chamber view. Ao = Aorta; DAo = Descending Aorta; MPA = Mean Pulmonar Artery; LV = Left Ventricle; RV = Right Ventricle; TV = Tricuspid Valve; & = Pericardial Effusion; * = Ascites.
( a ) Hyperechoic, thickened aorta. ( b ) Hyperechoic, thickened main pulmonary artery. ( c, d ) Hyperechoic, thickened tricuspid valve and turbulent flow in the valve. AsAo = Ascending Aorta; DAo = Descending Aorta; MPA = Mean Pulmonar Artery; RV = Right Ventricle; & = Pericardial Effusion; * = Tricuspid valve.
Discussion
Idiopathic infantile arterial calcification is an autosomal recessive genetic disorder with an estimated prevalence of 1 in 200,000 individuals. Reference Ramirez-Suarez, Cohen, Barrera, Levine, Goldberg and Otero4 Idiopathic infantile arterial calcification type 1 occurs in 75% of cases and is caused by mutations in the ectonucleotide pyrophosphatase/phosphodiesterase-1 gene. Idiopathic infantile arterial calcification type 2 occurs in 10% of cases and is caused by mutations in the ABCC6 gene. Reference Ramirez-Suarez, Cohen, Barrera, Levine, Goldberg and Otero4–Reference Nitschke and Rutsch6 New variations in these genes are increasingly being reported in the literature. Mutations in these genes cause a decrease in the levels of endogenous inhibitors of bone mineralisation, which leads to ectopic mineralisation of arteries and other tissues. In addition, there is vascular smooth muscle cell proliferation, which further reduces the lumen diameter and impedes blood flow. Reference Hailu, Derbew and Hailemeriam7 The ectonucleotide pyrophosphatase/phosphodiesterase-1 gene mutation, as in our patient, has also been detected in our patient’s parents and in their first baby, whom they lost previously. Genetic counselling had previously been recommended to the parents, but the family had not taken any action.
The range of clinical findings that indicate the possibility of idiopathic infantile arterial calcification can be divided into two categories: early onset and late-onset. Reference Mune, Gadgil, Shaikh and Fugare1 Early-onset (approximately 48%) refers to cases that occur during the fetal period or within one month after birth. Reference Yunfeng, Tongyan, Jing and Xiaomei2 In early-onset idiopathic infantile arterial calcification, the most commonly calcified artery is the hepatic artery (81%), followed by the aorta (80%), pulmonary artery (67%), coronary artery (53%), and renal artery (39%). Reference Fãgãrãşan, Gozar and Ghiragosian5,Reference Yunfeng, Tongyan, Jing and Xiaomei2 The main clinical findings are respiratory distress, severe heart failure, pulmonary hypertension, fetal oedema, and hypertension. Reference Yunfeng, Tongyan, Jing and Xiaomei2 Our case also had an early onset. Our patient had widespread calcification in the aorta and pulmonary artery and their branches, but there was no hepatic or renal artery involvement.
Late-onset (approximately 52%) refers to cases where symptoms begin within the first month after birth. The predominant clinical findings include cyanosis, respiratory failure, heart failure, hypertension, ischaemic, and hypoxic damage to other organs. Cerebrovascular calcification and neurological ischaemic-hypoxic brain parenchymal damage have been reported in several studies. Reference Yunfeng, Tongyan, Jing and Xiaomei2
Careful analysis of the case history, autopsy findings, and auxiliary tests such as ultrasound, DNA analysis for the ectonucleotide pyrophosphatase/phosphodiesterase-1 gene, and artery biopsy is essential in diagnosing idiopathic infantile arterial calcification. Reference Mune, Gadgil, Shaikh and Fugare1 Fetal echocardiography is the preferred method for prenatal diagnosis of idiopathic infantile arterial calcification. Fetal hydrops should be suspected when there are findings of hyperechogenicity and cardiomegaly in the walls of large arteries and hypertrophy of the heart chambers. Reference Mune, Gadgil, Shaikh and Fugare1 Vascular calcification seen in infancy is not specific to idiopathic infantile arterial calcification; it can also be seen in various conditions such as hypervitaminosis D, intrauterine infections, parathyroid abnormalities, progeria, pseudoxanthoma elastium, Singleton-Merten syndrome, and William syndrome. However, the clinical presentations of these cases are different. Reference Mune, Gadgil, Shaikh and Fugare1
After diagnosis, detailed information should be provided to the family, and genetic counselling should be recommended for subsequent pregnancies.
Most cases die in utero within the first six months after birth. Only a few cases have survived for more than six months. Reference Attia, Abd Alhamed, Selim, Haggag and Fathalla8 Despite intensive treatment, most patients die within the first six months of their lives due to the rapid progression of arterial stenosis and heart failure. Reference Hailu, Derbew and Hailemeriam7,Reference Yunfeng, Tongyan, Jing and Xiaomei2 In addition to rare cases of spontaneous resolution of calcifications, successful treatment with bisphosphonates and other experimental drugs has been reported. Reference Ramirez-Suarez, Cohen, Barrera, Levine, Goldberg and Otero4,Reference Fãgãrãşan, Gozar and Ghiragosian5 The preferred treatment for resolving arterial calcification is Editronat (Sodium Bisphosphonate). Reference Ramjan, Roscioli, Rutsch, Sillence and Munns9 It alters calcium balance by inhibiting hydroxyapatite crystal formation and prevents calcium accumulation in existing calcified lesions. However, despite treatment, the prognosis for idiopathic infantile arterial calcification patients is poor. Coronary artery calcification is a poor prognostic indicator. Children may die suddenly due to myocardial infarction. Reference Mune, Gadgil, Shaikh and Fugare1
Conclusion
This case report reminds paediatric cardiologists, radiologists, and perinatologists that they should be familiar with widespread arterial calcification. It emphasises that idiopathic infantile arterial calcification, a very rare condition, should be considered among the etiologic factors when hydrops fetalis is detected on ultrasound.
Financial support
None.
Competing interests
The authors declare no conflict of interest.
Ethical standard
The authors assert that this work complies with the ethical standards of the relevant national guidelines and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the Ethical Review Committee at the University of Yuzuncu Yil, Turkey.
