Address correspondence to Alicia K. Crum, RDMS, Park Imaging, 220 Great Circle Rd, Suite 130, Nashville, TN 37228-1705, Ph: 615-254-8877; Fax: 615-242-2158; ¶ Vanderbilt University, Dept. of Pathology, § Dept. of Radiology

Synonyms: Arterial medial calcification of infancy, generalized arterial calcification of infancy (GACI), idiopathic arterial calcification of infancy, idiopathic obliterative arteriopathy, infantile arteriosclerosis, infantile calcifying arteriopathy, medial coronary sclerosis of infancy, occlusive infantile arteriopathy.

Definition: Idiopathic infantile arterial calcification is a diffuse disease of elastic and muscular arteries characterized by destruction and fragmentation of the arterial internal elastic membrane, deposition of calcium along the internal elastic membrane and intimal proliferation.

Prevalence: Idiopathic infantile arterial calcification is a rare disorder.  As of 1990 approximately 100 cases had been reported¹.  The incidence of occurrence is approximately equal for males and females^6,16.  The majority of cases reported have been caucasian¹⁶.

Etiology: The etiology of this disease is unknown, although a few hypotheses have been presented: 1) hereditary disorder of connective tissue8,10; 2) injury to or defect of the endothelium¹⁵; 3) altered iron metabolism¹⁷; 4) hemodynamic disturbance²¹.

Pathogenesis: Two theories exist as to the pathogenesis of the disease: 1) calcification of the internal elastic membrane is the primary lesion, and intimal proliferation is secondary^5,11; 2) intimal proliferation is the primary lesion, and calcifications are secondary and of less significance^6,18.  In either case, intimal proliferation usually leads to occlusion of the artery.  The coronary arteries are most commonly involved; in most cases, death is usually due to congestive heart failure and myocardial infarction^5,8,13,15,17

Associated anomalies: Rare:  aside from non-specified cardiac anomalies, one case each of hydro­neprosis²⁷, polycystic kidneys^25,27, trisomy 17 and 18²² have been reported.

Consequential anomalies: Prenatal: findings include non-immune hydrops¹, increased echogenicity of renal parenchyma due to ischemia^4,17, polyhydramnios^{10,15, 19,21}. Infancy: symptoms presenting after birth include complications due to pulmonary and cardiac failure^5,20, renal infarction^5,17, peripheral gangrene^5,6,19, bowel infarction^5,6.

Differential diagnosis: Endocardial fibroelastosis, myocardititis, storage disorders, infarction, anomalous insertion of the coronary arteries, cardiac anomalies, metastatic calcification due to renal disease, hypervitaminosis D, infections.

Prognosis: Poor. Most die before reaching one year of age^{1,2,4,5,8,11-13,17,20}.

Recurrence risk: No definite recurrence risk has been established, but there is evidence of familial clusters and thus a possible genetic factor^{3,5,6,8,10,11,17.}

Management: Treatments with thyroid extract, estrogens and steroids are currently being evaluated^4,6,8.

MESH Calcinosis; Arteries-pathology ICD9 747.8 CDC 747.880

Introduction

For many years idiopathic infantile arterial calcification was a disease that most likely was not diagnosed until after death^{1,4,5,7,10-12,20}.  Among the cases that were diagnosed before death, radiographs have provided the most pertinent information to obtain the diagnosis^5,7,10,13,15.  However, because the disease manifests in premature infants and siblings of affected babies, ultrasound could have an important role in screening for and diagnosis of this disease.

Case report

A 31-year-old G₆P₄₀₁₃ patient was referred to our institution because of an outside ultrasound examination revealing increased amniotic fluid and fetal scalp edema at approximately 33 weeks gestation.  The ultrasound examination done upon arrival showed a marked increase in amniotic fluid volume, anasarca, and a grossly normal heart with decreased contractility.  Note was made that the great vessels were brightly echogenic and that the descending aorta was difficult to see (fig. 1-2).

Sagittal scan. The hydrops and polyhydramnios are visible. The calcified aortic arch is highlighted by the arrows.

The calcified descending aorta (postnatal scan).

Approximately eight hours later, the patient had spontaneous rupture of membranes resulting in vaginal delivery of a 2770g, 33 week girl.  The infant had Apgars of 0 at one minute and 2 at five minutes.  Sonographic and radiographic exams performed in the Neonatal Intensive Care Unit demonstrated bilateral pleural effusions, abdominal ascites and calcification of the abdominal aorta (fig. 3-4), iliac vessels and arteries in the shoulder girdle area. 

Radiograph demonstrating the calcified descending aorta and bifurcation (arrows).

This was felt to be consistent with idiopathic infantile arterial calcification.  An echocardiogram also demonstrated calcification of the major arteries and coronaries.  After a deteriorating course, the infant died 13 days later.

Autopsy

Chromosome analysis revealed a normal female karyotype.  The heart was found to have evidence of myocardial hemorrhage in the posterior left ventricular free wall with involvement of the papillary muscles (fig. 5).  The right coronary artery had intimal proliferation with calcium deposition (fig. 6), while the left anterior descending and left circumflex coronary arteries showed intimal proliferation without calcium deposition.  There was also intimal proliferation in arteries of the larynx, lungs (fig. 6-8), liver and diaphragm. Calcifications were noted in parenchyma of the thymus, small bowel and kidneys.  There was ischemic damage to the liver.  Also of note were several areas of infarction in the brain with calcification of adjacent arteries (fig. 9-10).  The autopsy attributed death to complications of idiopathic infantile arterial calcification.  Research into the patient"s family history revealed a sibling who had died of idiopathic infantile arterial calcification ten years previously at one month of age.

Cross-section of the heart showing bi-ventricular hypertrophy and multiple myocardial infarctions at the interventricular septum and papillary muscle.

Section of the aorta with intimal proliferation (blue arrow) and calcification at the internal elastic lamina (yellow arrow). 72X Elastic stain.

Radiogram of the heart and lung block. The calcified vessels is clearly identified.

Lung parenchyma with two large vessels showing calcification and intimal proliferation (yellow arrows). H&E 72X.

Base of the brain with multiple infarctions.

Cerebral vessels with intimal proliferation and luminal narrowing (arrow) 420X. :

Calcification of the same vessels (Alizarin red stain) 720X.

Discussion

The first case of idiopathic infantile arterial calcification was described by Bryant and White in 1891²⁴.

Pathogenesis

Vascular calcifications in infants can be seen in association with several underlying disease processes such as renal disease, hypervitaminosis D, vascular or cardiac malformations and hyperparathyroidism^{6,7,10,14,21,22}.  When the cause of vascular calcification cannot be attributed to one of these or any other factor, such as infection, the diagnosis of idiopathic infantile arterial calcification has to be considered.  This disease process is rare and, because of the vague symptoms and rapidly deteriorating course of affected infants, not much is known about the pathogenesis.

Pathology

Idiopathic infantile arterial calcification is a diffuse vascular disorder that can affect any artery^4,11.  Characteristic of the disease process is a patchy destruction or fragmentation of the internal elastic membrane with calcific deposits and intimal proliferation (fig. 6).  There is disagreement as to whether the calcium deposition or intimal proliferation is the primary pathologic process^5,6,11,18.  The coronary arteries are the most commonly affected, and death is usually attributed to heart failure secondary to ischemia or infarct due to occlusion of the arteries by intimal thickening^{5,8,13,15,17,18}.  There has been a case reported where death was attributed to bowel infarction secondary to idiopathic infantile arterial calcification6.  The cerebral arteries are the least commonly affected11; however, in our case there were multiple areas of infarction with calcification of the adjacent arteries. There have been other documented cases of cerebrovascular involvement⁹.

Etiology

The etiology is unknown, but there are several theories that have been presented in the literature:

A hereditary disorder of connective tissue, supported by findings of calcium deposits in other elastic tissues such as ligaments⁸

An injury to or defect of the endothelium may initiate the intimal proliferation¹⁵

An alteration in iron metabolism that triggers calcium deposition¹⁷

Hemodymamic disturbances secondary to an insult or stress sustained in utero may prime the arteries for later development of idiopathic infantile arterial calcification²¹.

The incidence of the disease in siblings, as was seen in our case, lends credence to the theory of a genetic transmission^6,8,10,11,17.  The equal distribution of the disease between male and female contradicts a sex-linked chromosome disorder (19 males and 18 females in the cases we reviewed). Whether this is a dominant or recessive trait is still under debate6,8,  but an autosomal recessive transmission is thought to be most likely^3,7.

Classifications

At least two authors have proposed a 4-stage classification of the disorder^31,33. In stage I there is disruption of the internal elastic layer. Stage II demonstrates worsening with localized thickening of a section of the vessel and endothelial proliferation. The elastic layer is almost completely destroyed. In stage III, the lumen of the vessel is considerably narrowed, and calcium deposits are present in the media. Finally in stage IV, the media is replaced by a calcified shell that encloses the intimal fibrosis and is surrounded by a fibrous reaction. The classification is, however, of little help because of the rapid progression of the disease.

Associated anomalies

Associated anomalies are uncommon. A few case of unspecified cardiac anomalies²⁶, multiple malformations^28,29 as well as one case each of hydroneprosis²⁷, polycystic kidneys^25,27, trisomy 13-15 and 17-18²⁹ have been reported.

Ultrasound appearance

The prenatal findings include (Table 1):

• arterial calcifications
• hydrops
• abnormal heart contractility
• hyperechoic kidneys (from ischemia or calcium deposition ?)

Spear et al reported two cases where idiopathic infantile arterial calcification was suspected by ultrasound and confirmed by in utero CT1.  Because of a history of idiopathic infantile arterial calcification in a previous child, their patient had serial ultrasound examinations.  They reported that sonographically detectable changes were not seen until after 30 weeks of gestation. Other documented cases support this (fig. 11). Our findings of fetal hydrops and abnormal heart contractility were similar to theirs. Ischemic changes in renal parenchyma due to involvement of the renal arteries can also be detected sonographically4.  These changes present as a diffuse increase in echogenicity of the kidney.  There is evidence that this may occur in utero^17,36.

Prognosis

Idiopathic infantile arterial calcification should be added to the list of differential diagnoses for non-immune fetal hydrops.  Obtaining a detailed history from the patient, specifically whether they had a child die in infancy, could add valuable information. There is no evidence that early detection has a definite impact on the poor outcome of this disease process.  Most infants die within the first year of life^1,2,3,5, with the greatest number of deaths occurring withing the first six months^{8,11-13,17,20}.

Management

Treatments with thyroid extract, estrogens and steroids, have had some success4,6,8, but the long-term effectiveness is still unclear⁴.

References

1. Spear R, Mack LA, Benedetti TJ, et al: Idiopathic infantile arterial calcification: In utero diagnosis. J Ultrasound Med 9:473-6, 1990.

2. Bird T: Idiopathic arterial calcification in infancy.  Arch Dis Child 49:82-9, 1974.

3. Hamazaki M. Idiopathic arterial calcification in a 3-month-old child, associated with myocardial infarction.  Acta Pathol Jpn 30:301-8, 1980.

4. Rosenbaum DM, Blumhagen JD: Sonographic recognition of idiopathic arterial calcification of infancy.  AJR 146:249-50, 1986.

5. Stanley RJ, Edwards WD, Rommel DA, et al: Idiopathic arterial calcification of infancy with unusual clinical presentations in sisters.  Am J Cardiovasc Pathol 2:241-5, 1988.

6. Vade A, Eckner FAO, Rosenthal IM: Computerized tomography in occlusive infantile arteriopathy.  Pediatr Cardiol 10:221-4,1989.

7. Barson AJ, Campbell RHA, Langley FA, et al: Idiopathic arterial calcification of infancy without intimal proliferation.  Virchows Arch [A] 372:167-173, 1976.

8. Meradji M, de Villeneuve VH, Huber J, et al: Idiopathic infantile arterial calcification in siblings: radiologic diagnosis and successful treatment.  J Pediatr 92:401-5,1978.

9.Proesmans W, Dan Dyek M: Correspondence. Pediatr Nephol 5:96,1991.

10. Parker RJ, Smith EH, Stoneman MER: Generalized arterial calcification of infancy.  Clin Radiol 22:69-73,1971.

11. Morton R: Idiopathic arterial calcification in infancy.  Histopathology 2:423-32,1978.

12. Van Oort AM, Sengers RCA, Stadhoudrs AM, et al: Idiopathic arterial calcification of infancy.  Helv Paediat Acta 34:369-74,1979.

13. Kirchner SG, Heller RM, Kasselberg AG: Idiopathic arterial calcification of infancy.  South Med J 72:1328-30,1979.

14. Liu CT, Singer DB, Frates R: Idiopathic arterial calcification in infancy: report of a case in a premature fetus.  Arch Pathol Lab Med 104:589-91,1980.

15. Chen H, Fowler M, Yu CW: Generalized arterial calcification of infancy in twins. Birth Defects:Original Article Series 18(3B):67-80,1982.

16. Lie JT: Correspondence.  Hum Pathol 16:1178-9,1985.

17. Anderson KA, Burbach JA, Fenton LJ, et al: Idiopathic arterial calcification of infancy in newborn siblings with unusual light and electon microscope manifestations.  Arch Pathol Lab Med 109:838-42,1985

18. Witzleben CL: Idiopathic infantile arterial calcification—a misnomer ?  Am J Cardiol 26:305-9,1970.

19. Lussier-Lazaroff J, Fletcher BD: Idiopathic infantile arterial calcification: Roentgen diagnosis of a rare cause of coronary artery occlusion.  Pediatr Radiol 1:224-8,1973.

20. Holm V: Arteriopathia calcificans infantum.  Acta Paed Scand 56:537-40,1967.

21. Royston D, Goeghegan F: Disseminated arterial calcification associated with acardius acephalus.

22. Gerbeaux J, Couvreur J, Steinschneider R, et al: Artériopathie calcifiante infantile (à propos d"une observation). Ann Méd Interne 120:221-227, 1969.

23. Gabilan JC, Habib R, Lajouanine P, et al: L"artériopathie calcifiante infantile. Arch Franc Ped 23:179-97, 1966.

24. Bryant JH, White WH: A case of calcification of the arteries and obliterative endoarteritis with hydronephrosis in a child aged 6 months. Guy"s Hosp Rep 55:17, 1891.

25. Stryker WA: Arterial calcification in infancy with special reference to the coronary arteries. Am J Pathol 22:1007, 1946.

26. Whalgren F: Arteriosclerosis-like arterial disease with myocardial infarcts in an infant. Cardiologica 21:373, 1952

27. Andersen DH, Schlesinger ER: Renal hyperparathyroidism with calcification of the arteries in infancy. Am J Dis Child 63:102, 1942.

28. Greenstein NM, Kamer L: Metastatic calcification in the newborn. Am J Dis Child 82:37, 1951.

29. Rosenfield R, Briebart S, Isaacs H, et al: Trisomy of chromosomes 13-15 and 17-18. Association with infantile arteriosclerosis. Am J Med Sci 244:763, 1962.

30. Rain B, Martin E, Gabilan JC, et al: Artériopathie calcifiante infantile—Revue de la littérature à propos d"un cas. Arch Anat Cytol Path 24:419-22, 1976.

31. Perreault G, Bonnin A, Davignon A: Calcification artérielle idiopathique du nourrisson. Union Med Can 95:808-12, 1966.

32. Tegllund L: Infantil arteriel kalcifikation. Ugeskr Laeger151:448-9, 1989.

33. Althen B, Wiedersberg H: Beitrag zur Klinik, Morphologie und Heredität der Arteriopathia calcificans infantum. Kinderarztl Prax 53:127-32, 1985.

34. Vera J, Lucaya J, Garcia Conesa JA, et al.: Idiopathic infantile arterial calcification: unusual features. Pediatr Radiol 20:585-7,1990.

35. Stuart G, Wren C, Bain H: Idiopathic infantile arterial calcification in two siblings: failure of treatment with diphosponate. Br Heart J 64:156-9,1990.

36. Van Reempts PJ, Boren KJ, Spitaels SE, et al.: Idiopathic arterial calcification of infancy. Calcif Tissue Int 48:1-6,1991.

37. Juul S, Ledbetter D, Wight TN, et al.: New insights into idiopathic infantile arterial calcinosis. Am J Dis Child 144:229-33,1990.

38. Carles D, Serville F, Dubecq  JP, et al.: Idiopathic arterial calcification in a stillborn complicated by pleural hemorrhage and hydrops fetalis. Arch Pathol Lab Med 116:293-5, 1992