Case Report
Prenatal Ultrasonographic Diagnosis of Generalized Arterial Calcification of Infancy Aytul Corbacioglu Esmer, MD,1 Ibrahim Kalelioglu,1 Rukiye Eker Omeroglu,2 Hulya Kayserili,3 Mine Gulluoglu,4 Recep Has,1 Atıl Yuksel1 1
Department of Obstetrics and Gynecology, Istanbul University Faculty of Medicine, Capa/Fatih, 34090, Istanbul, Turkey 2 Department of Pediatric Cardiology, Istanbul University Faculty of Medicine, Capa/Fatih, 34090, Istanbul, Turkey 3 Department of Medical Genetics, Istanbul University Faculty of Medicine, Capa/Fatih, 34090, Istanbul, Turkey 4 Department of Pathology, Istanbul University Faculty of Medicine, Capa/Fatih, 34090, Istanbul, Turkey Received 4 April 2013; accepted 1 November 2013
ABSTRACT: A healthy 19-year-old nulliparous pregnant woman was referred to our clinic because of fetal pericardial effusion and ascites. The sonographic examination performed at 28 weeks’ gestation revealed scalp edema, severe skin edema, bilateral hydrocele, ascites, and pleural and pericardial effusion. Fetal echocardiographic examination showed that both ventricles were dilated with severely depressed contractility. The aortic annulus, ascending aorta, aortic arch, descending aorta, common iliac arteries, main pulmonary artery, tricuspid valve, and mitral chordae tendinae were hyperechogenic. Right ventricular outflow tract was narrow with decreased blood flow. There was tricuspid and mitral valve regurgitation and tricuspid valve stenosis. On the basis of these findings, we made the diagnosis of generalized arterial calcification, which is characterized by extensive calcification of internal elastic lamina and intimal proliferation of medium-sized and large arteries. This diagnosis was confirmed histologC 2014 Wiley ically after the termination of pregnancy. V Periodicals, Inc. J Clin Ultrasound 43:50–54, 2015; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jcu.22121 Keywords: arterial calcification; generalized; idiopathic; ultrasound; prenatal diagnosis
G
eneralized arterial calcification of infancy (GACI), also known as idiopathic infantile arterial calcification, refers to a rare disease characterized by extensive calcification of internal elastic lamina and intimal proliferation of Correspondence to: A. Corbacioglu Esmer C 2014 Wiley Periodicals, Inc. V
50
medium-sized and large arteries.1 It is mostly diagnosed in the neonatal period or early infancy as the cause of rapidly progressive heart failure and refractory hypertension.1 A few cases have been detected prenatally by sonographic examination and represent a severe form with a worse prognosis.1–9 GACI may present, at sonographic examination, mostly at the beginning of the third trimester of gestation, as nonimmune hydrops fetalis, following greatvessel calcification, polyhydramnios, and hypertrophic cardiomyopathy with pericardial effusion.2 We report a case of GACI revealed as hydrops fetalis at 28 weeks’ gestation.
CASE REPORT
A healthy 19-year-old nulliparous pregnant woman at 28 weeks’ gestation was referred to our center because of fetal pericardial effusion and ascites. Her husband was her first cousin. The sonographic examination performed revealed scalp edema, severe skin edema, bilateral hydrocele, ascites, and pleural and pericardial effusion. Middle cerebral artery peak systolic velocity was 27 cm/s. Fetal echocardiographic examination showed that both ventricles were dilated with severely depressed contractility (Figure 1). The aortic annulus, ascending aorta, aortic arch, descending aorta, common iliac arteries, main pulmonary artery, tricuspid and mitral valves, and chordae tendinae were diffusely hyperechogenic (Figure 2). Right ventricular outflow tract was narrow with JOURNAL OF CLINICAL ULTRASOUND
GENERALIZED ARTERIAL CALCIFICATION OF INFANCY
decreased blood flow through the pulmonary artery measuring 4.8 mm (reference values 4.9– 6.9 mm).10 Left ventricular outflow tract was 5.3 mm and the peak systolic velocity was high (125 cm/s).11 There was tricuspid and mitral valve regurgitation and mitral valve stenosis (Figure 3). Maternal antibody screening and serologic tests for toxoplasmosis, rubella, cyto-
FIGURE 1. Four-chamber view of the heart demonstrating severely enlarged heart with pericardial effusion (arrow).
megalovirus, and parvovirus were negative. On the basis of these findings, we made the diagnosis of GACI. The family was counseled on the unfavorable prognosis of GACI by a committee involving fetal-maternal medicine specialist, pediatric geneticist, and pediatric cardiologist, and the pregnancy was terminated as requested by the family. Postmortem CT examination of the fetus revealed vascular calcific densities in the aorta and common iliac arteries (Figure 4). Autopsy confirmed the diagnosis of GACI. The aorta and pulmonary arteries were thick-walled and diffusely narrowed with yellowish white surface irregularities (Figure 5A and 5B). Cutting into the vessel was difficult. Histological examination showed diffuse calcification in the mitral, tricuspid, pulmonary and aortic valves, coronary arteries, chordae tendineae, aorta, iliac arteries, carotid arteries, renal arteries, and bronchial arteries (Figure 5C). A skin biopsy was taken for the molecular analysis of ENPP1 and ABCC6 genes, but we have not been able get the results at the time of submission of this article.
FIGURE 2. (A) Sonography of the long axis of the aorta and common iliac arteries shows extensive calcification. (B) Sagittal plane depicting widespread calcification in the ascending aorta, aortic arch, and thoracic aorta. (C) Right ventricular outflow tract view from the fetal echocardiogram shows calcified main pulmonary artery (arrow). VOL. 43, NO. 1, JANUARY 2015
51
CORBACIOGLU ESMER ET AL
FIGURE 4. Postmortem axial CT shows calcification of the abdominal aorta (arrow). FIGURE 3. Four-chamber view of the heart shows tricuspid regurgitation (arrow). The tricuspid valve was thick and located just next to the septum.
DISCUSSION
GACI is a rare widespread vaso-occlusive disease characterized by calcium hydroxyapatite deposition in the internal elastic lamina, disrupting elastic fibers, with extensive intimal fibrous proliferation, of large and medium-sized arteries.12 The extent of vascular calcification does not correlate with the severity of disease, and intimal proliferation is thought to be more deleterious, as patients without intimal proliferation might have spontaneous resolution or lack severe vascular occlusion, thus benefiting from longer disease-free life and longer survival.12,13 Affected neonates usually present with cardiorespiratory distress, and 85% of cases die within 6 months. Multiorgan ischemia, refractory hypertension, and left-sided cardiac failure are the usual findings. The constellation of affected tissues varies, but the coronary arteries are almost always involved, and myocardial ischemia and infarction are the main causes of death.12 Periarticular calcification, joint swelling, gangrene of extremities, visceral infarction, motor and mental retardation, and seizures are the other possible findings after birth. Progressive hepatic failure due to reduced flow in calcified and narrowed hepatic arteries and cerebral atrophy secondary to reduced flow through the carotid arteries have been reported.14 Furthermore, as with the present case, more severe forms may present as hydrops fetalis or fetal demise in the latter half of pregnancy.1,3,8,9 Dystrophic calcification during fetal life results in decreased vessel compliance and hypertension with resultant cardiac failure and hypertrophy of the chambers leading to the development of hydrops.8 In the present case, 52
calcification was observed mainly on large arteries. In addition, unlike the previously reported cases, calcification involved the tricuspid, mitral, aortic, and pulmonary valves, as well as the chordae tendineae. To the best of our knowledge, there is only one case report in which the involvement of mitral and tricuspid valves was demonstrated on prenatal echocardiography.1 In two cases, increased valvular echogenicity was detected postnatally.4,15 The gold standard for GACI diagnosis is arterial biopsy.16 However, a combination of imaging techniques such as CT and sonography may replace this invasive technique. Prenatal diagnosis is possible by sonographic examination, revealing dilated cardiac ventricles, hyperechogenic large vessels, and hydrops fetalis.16 However, diagnosis is not easy in the early pregnancy, because vascular calcification may not be visible until late gestation or postnatally. Nasrallah et al1 reported three fetuses with GACI, one of which was diagnosed as early as 23 weeks. An echogenic intracardiac focus was observed at 20 weeks’ gestation in all three cases. The authors suggested that this might be an early sign in patients with a family history. GACI may also present as in utero meconium peritonitis due to mesenteric ischemia.17 Furthermore, Wax et al reported a prenatally diagnosed GACI case that presented with hepatic vascular calcification at the 18th week of gestation.2 Postnatally, MRI, plain X-ray, sonographic examination, and CT scan can be used to demonstrate vessel calcifications.1,8,9,15 In neonates, ultrasonography and CT scan appear to be more sensitive than X-rays due to better contrast resolution.12 As MRI is not particularly effective in the demonstration of calcifications, contrast enhancement is suggested, but is not possible postmortem.15 Hence, in the present case, we JOURNAL OF CLINICAL ULTRASOUND
GENERALIZED ARTERIAL CALCIFICATION OF INFANCY
FIGURE 5. (A) Endocardial surface of the aortic valve and endothelial surface of the ascending aorta displays calcified areas appearing as yellowish white surface irregularities. (B) The abdominal aorta and the common iliac arteries with extensive calcification. (C) Microscopic examination of the tricuspid valve shows calcification in the intima (H&E stain, 3100, original magnification).
preferred to use postmortem CT, which demonstrated calcification in the aorta and the common iliac arteries. GACI was reported to be caused by mutations in ENPP1 gene localized on chromosome 6q22, inactivating the ecto-nucleotide pyrophosphatase/phosphodiesterase 1, which generates the inorganic pyrophosphate, a physiologic inhibitor of calcium deposition.18 Rutsch et al19 identified 40 different homozygous or compound heterozygous mutations in 75% of the patients and concluded that these mutations have no effect on survival except for the p.P305T mutation, which was universally lethal when present on both alleles. Numakura et al also stated that GACI is a genetically heterogenous disorder, and that the atypical, late-onset phenotype may not be associated with ENNP1 abnormalities.20 Recently, Nitschke et al21 analyzed the ABCC6 gene in 28 GACI patients and identified 13 different ABCC6 mutations in 14 patients. Therefore, genetic counseling is very important, and the molecular analysis of ENPP1 and ABCC6 genes should be offered to the family, because early prenatal diagnosis by mutation analysis is possible, if disease-causing mutations have been VOL. 43, NO. 1, JANUARY 2015
identified previously in an index case in the same family.22 Many cases of previous sibling death due to GACI diagnosed at infancy or undiagnosed causes of renal or heart failure have been reported, and an autosomal-recessive inheritance pattern has been described.1,5 In the present case, the parental consanguinity supported this pattern, and the parents were instructed of the 25% recurrence risk of this disease in future pregnancies. Although GACI is generally lethal, a few cases that responded to treatment with biphosphonates have been reported.23 Biphosphonates are pyrophosphate derivatives and are used with the aim of preventing or reversing abnormal calcium deposition. Bellah et al6 attempted to reduce calcification by giving etidronate to a 30-week fetus by means of percutaneous puncture, but the fetus died at the age of 7 months because of the progression of intimal vascular occlusive disease.6 The effect of intrauterine administration of biphosphonate may vary according to the severity of disease. Spontaneous resolution of calcification has been reported in the literature, which makes the value of drug therapy questionable.24 Therefore, 53
CORBACIOGLU ESMER ET AL
more cases are needed to draw a conclusion regarding the therapy. In our case, the family requested termination of pregnancy because of the adverse prognosis. Therefore, we were not able to apply in utero treatment. In conclusion, GACI is a rare cause of fetal hydrops and can be diagnosed in the latter half of pregnancy. When there is a family history, the first signs of calcification should alert the sonographer. Serial sonographic examination of these fetuses may allow earlier diagnosis and better management.
11.
12.
13.
14. REFERENCES 1. Nasrallah FK, Baho H, Sallout A, et al. Prenatal diagnosis of idiopathic infantile arterial calcification with hydrops fetalis. Ultrasound Obstet Gynecol 2009;34:601. 2. Wax JR, Balckstone J, Pinette MG, et al. Hepatic vascular calcification: an early second trimester sonographic feature of idiopathic infantile arterial calcinosis. Am J Obstet Gynecol 2001;185:1267. 3. Crade M, Lewis DF, Nageutte MP. In utero appearance of idiopathic infantile calcification: ultrasound study of a 28-week fetus. Ultrasound Obtet Gynecol 1001;1:2844. 4. Kutty S, Cava JR, Frommelt MA. Idiopathic infantile arterial calcification: a case report of prenatal and postnatal echocardiographic diagnosis. Echocardiography 2009;26:862. 5. Eronen M, Puhjavuori M, Heikkila. Fatal outcome of two siblings with idiopathic arterial calcification of infancy diagnosed in utero. Pediatr Cardiol 2001;22:167. 6. Bellah RD, Zawodniak L, Librizzi RJ, et al. Idiopathic arterial calcification of infancy: prenatal and postnatal effects of therapy in an infant. J Pediatr 1992;121:930. 7. Samson LM, Ash KM, Murdison KA. Aorto-pulmonary calcification: an unusual manifestation of idiopathic calcification of infancy evident antenatally. Obstet Gynecol 1995;85:863. 8. Nagar AM, Hanchate V, Tandon A, et al. Antenatal detection of idiopathic arterial calcification with hydrops fetalis. J Ultrasound Med 2003;22:653. 9. Heuser CC, Puchalski M, Kennedy A, et al. Radiographic and pathologic evaluation of idiopathic infantile arterial calcification. Obstet Gynecol 2010;115:465. 10. Shapiro I, Degani S, Leibovitz Z, et al. Fetal cardiac measurements derived by transvaginal and transabdominal cross-sectional echocardiography
54
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
from 14 weeks of gestation to term. Utrasound Obstet Gynecol 1998;12:404. Abuhamad A, Chaoui R. Pulsed Doppler echocardiography. In: A Practical Guide to Fetal Echocardiography. Philadelphia: Lippincott Williams & Wilkins; 2010, p 99. Farquhar J, Makhseed N, Sargent M, et al. Idiopathic infantile arterial calcification and persistent pulmonary hypertension. Am J Perinat 2005;22:121. Guimaraes S, Lopes JM, Oliviera JB, et al. Idiopathic infantile arterial calcification: a rare cause of sudden unexpected death in childhood. Patholog Res Int 2010;2010:185314. Whitehall J, Smith M, Altamirano L. Idiopathic infantile arterial calcification: sonographic findings. J Clin Ultrasound 2003;31:497. Tran KH, Boechat MI. Idiopathic infantile arterial calcification: imaging evaluation and the usefulness of MR angiography. Pediatr Radiol 2006;36: 247. Van der Sluis IM, Boot AM, Vernooij M, et al. Idiopathic infantile arterial calcification: clinical presentation, therapy and long-term follow up. Eur J Pediatr 2006;165:590. Sawyer T, Stacey M, Mulreany M, et al. Generalized arterial calcification of infancy associated with meconium peritonitis: a case report and review of the literature. Am J Perinat 2009;26: 711. Rutch F, Ruf N, Vaingankar S, et al. Mutations in ENNP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 2003;34:379. Rutsch F, B€oyer P, Nitschke Y, et al. Hypophosphatemia, hyperphosphaturia and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet 2008;1:133. Numakura C, Yamada M, Ariyasu D, et al. Genetic and enzymatic analysis for two Japanese patients with idiopathic infantile arterial calcification. J Bone Miner Metab 2006;24:48. Nitschke Y, Baujat G, Botschen U, et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet 2012;90:25. Kalal IG, Seetha D, Panda A, et al. Molecular diagnosis of generalized arterial calcification of infancy (GACI). J Cardiovasc Dis Res 2012;3:150. Chong CR, Hutchins GM. Idiopathic infantile arterial calcification: the spectrum of clinical presentations. Pediatr Dev Pathol 2008;11:405. Scholler GF, Yu JS, Bale PM, et al. Generalized arterial calcification of infancy: three reports, including spontaneous regression with long-term survival. J Pediatr 1984;105:257.
JOURNAL OF CLINICAL ULTRASOUND
Prenatal Ultrasonographic Diagnosis of Generalized Arterial Calcification of Infancy Aytul Corbacioglu Esmer, MD,1 Ibrahim Kalelioglu,1 Rukiye Eker Omeroglu,2 Hulya Kayserili,3 Mine Gulluoglu,4 Recep Has,1 Atıl Yuksel1 1
Department of Obstetrics and Gynecology, Istanbul University Faculty of Medicine, Capa/Fatih, 34090, Istanbul, Turkey 2 Department of Pediatric Cardiology, Istanbul University Faculty of Medicine, Capa/Fatih, 34090, Istanbul, Turkey 3 Department of Medical Genetics, Istanbul University Faculty of Medicine, Capa/Fatih, 34090, Istanbul, Turkey 4 Department of Pathology, Istanbul University Faculty of Medicine, Capa/Fatih, 34090, Istanbul, Turkey Received 4 April 2013; accepted 1 November 2013
ABSTRACT: A healthy 19-year-old nulliparous pregnant woman was referred to our clinic because of fetal pericardial effusion and ascites. The sonographic examination performed at 28 weeks’ gestation revealed scalp edema, severe skin edema, bilateral hydrocele, ascites, and pleural and pericardial effusion. Fetal echocardiographic examination showed that both ventricles were dilated with severely depressed contractility. The aortic annulus, ascending aorta, aortic arch, descending aorta, common iliac arteries, main pulmonary artery, tricuspid valve, and mitral chordae tendinae were hyperechogenic. Right ventricular outflow tract was narrow with decreased blood flow. There was tricuspid and mitral valve regurgitation and tricuspid valve stenosis. On the basis of these findings, we made the diagnosis of generalized arterial calcification, which is characterized by extensive calcification of internal elastic lamina and intimal proliferation of medium-sized and large arteries. This diagnosis was confirmed histologC 2014 Wiley ically after the termination of pregnancy. V Periodicals, Inc. J Clin Ultrasound 43:50–54, 2015; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jcu.22121 Keywords: arterial calcification; generalized; idiopathic; ultrasound; prenatal diagnosis
G
eneralized arterial calcification of infancy (GACI), also known as idiopathic infantile arterial calcification, refers to a rare disease characterized by extensive calcification of internal elastic lamina and intimal proliferation of Correspondence to: A. Corbacioglu Esmer C 2014 Wiley Periodicals, Inc. V
50
medium-sized and large arteries.1 It is mostly diagnosed in the neonatal period or early infancy as the cause of rapidly progressive heart failure and refractory hypertension.1 A few cases have been detected prenatally by sonographic examination and represent a severe form with a worse prognosis.1–9 GACI may present, at sonographic examination, mostly at the beginning of the third trimester of gestation, as nonimmune hydrops fetalis, following greatvessel calcification, polyhydramnios, and hypertrophic cardiomyopathy with pericardial effusion.2 We report a case of GACI revealed as hydrops fetalis at 28 weeks’ gestation.
CASE REPORT
A healthy 19-year-old nulliparous pregnant woman at 28 weeks’ gestation was referred to our center because of fetal pericardial effusion and ascites. Her husband was her first cousin. The sonographic examination performed revealed scalp edema, severe skin edema, bilateral hydrocele, ascites, and pleural and pericardial effusion. Middle cerebral artery peak systolic velocity was 27 cm/s. Fetal echocardiographic examination showed that both ventricles were dilated with severely depressed contractility (Figure 1). The aortic annulus, ascending aorta, aortic arch, descending aorta, common iliac arteries, main pulmonary artery, tricuspid and mitral valves, and chordae tendinae were diffusely hyperechogenic (Figure 2). Right ventricular outflow tract was narrow with JOURNAL OF CLINICAL ULTRASOUND
GENERALIZED ARTERIAL CALCIFICATION OF INFANCY
decreased blood flow through the pulmonary artery measuring 4.8 mm (reference values 4.9– 6.9 mm).10 Left ventricular outflow tract was 5.3 mm and the peak systolic velocity was high (125 cm/s).11 There was tricuspid and mitral valve regurgitation and mitral valve stenosis (Figure 3). Maternal antibody screening and serologic tests for toxoplasmosis, rubella, cyto-
FIGURE 1. Four-chamber view of the heart demonstrating severely enlarged heart with pericardial effusion (arrow).
megalovirus, and parvovirus were negative. On the basis of these findings, we made the diagnosis of GACI. The family was counseled on the unfavorable prognosis of GACI by a committee involving fetal-maternal medicine specialist, pediatric geneticist, and pediatric cardiologist, and the pregnancy was terminated as requested by the family. Postmortem CT examination of the fetus revealed vascular calcific densities in the aorta and common iliac arteries (Figure 4). Autopsy confirmed the diagnosis of GACI. The aorta and pulmonary arteries were thick-walled and diffusely narrowed with yellowish white surface irregularities (Figure 5A and 5B). Cutting into the vessel was difficult. Histological examination showed diffuse calcification in the mitral, tricuspid, pulmonary and aortic valves, coronary arteries, chordae tendineae, aorta, iliac arteries, carotid arteries, renal arteries, and bronchial arteries (Figure 5C). A skin biopsy was taken for the molecular analysis of ENPP1 and ABCC6 genes, but we have not been able get the results at the time of submission of this article.
FIGURE 2. (A) Sonography of the long axis of the aorta and common iliac arteries shows extensive calcification. (B) Sagittal plane depicting widespread calcification in the ascending aorta, aortic arch, and thoracic aorta. (C) Right ventricular outflow tract view from the fetal echocardiogram shows calcified main pulmonary artery (arrow). VOL. 43, NO. 1, JANUARY 2015
51
CORBACIOGLU ESMER ET AL
FIGURE 4. Postmortem axial CT shows calcification of the abdominal aorta (arrow). FIGURE 3. Four-chamber view of the heart shows tricuspid regurgitation (arrow). The tricuspid valve was thick and located just next to the septum.
DISCUSSION
GACI is a rare widespread vaso-occlusive disease characterized by calcium hydroxyapatite deposition in the internal elastic lamina, disrupting elastic fibers, with extensive intimal fibrous proliferation, of large and medium-sized arteries.12 The extent of vascular calcification does not correlate with the severity of disease, and intimal proliferation is thought to be more deleterious, as patients without intimal proliferation might have spontaneous resolution or lack severe vascular occlusion, thus benefiting from longer disease-free life and longer survival.12,13 Affected neonates usually present with cardiorespiratory distress, and 85% of cases die within 6 months. Multiorgan ischemia, refractory hypertension, and left-sided cardiac failure are the usual findings. The constellation of affected tissues varies, but the coronary arteries are almost always involved, and myocardial ischemia and infarction are the main causes of death.12 Periarticular calcification, joint swelling, gangrene of extremities, visceral infarction, motor and mental retardation, and seizures are the other possible findings after birth. Progressive hepatic failure due to reduced flow in calcified and narrowed hepatic arteries and cerebral atrophy secondary to reduced flow through the carotid arteries have been reported.14 Furthermore, as with the present case, more severe forms may present as hydrops fetalis or fetal demise in the latter half of pregnancy.1,3,8,9 Dystrophic calcification during fetal life results in decreased vessel compliance and hypertension with resultant cardiac failure and hypertrophy of the chambers leading to the development of hydrops.8 In the present case, 52
calcification was observed mainly on large arteries. In addition, unlike the previously reported cases, calcification involved the tricuspid, mitral, aortic, and pulmonary valves, as well as the chordae tendineae. To the best of our knowledge, there is only one case report in which the involvement of mitral and tricuspid valves was demonstrated on prenatal echocardiography.1 In two cases, increased valvular echogenicity was detected postnatally.4,15 The gold standard for GACI diagnosis is arterial biopsy.16 However, a combination of imaging techniques such as CT and sonography may replace this invasive technique. Prenatal diagnosis is possible by sonographic examination, revealing dilated cardiac ventricles, hyperechogenic large vessels, and hydrops fetalis.16 However, diagnosis is not easy in the early pregnancy, because vascular calcification may not be visible until late gestation or postnatally. Nasrallah et al1 reported three fetuses with GACI, one of which was diagnosed as early as 23 weeks. An echogenic intracardiac focus was observed at 20 weeks’ gestation in all three cases. The authors suggested that this might be an early sign in patients with a family history. GACI may also present as in utero meconium peritonitis due to mesenteric ischemia.17 Furthermore, Wax et al reported a prenatally diagnosed GACI case that presented with hepatic vascular calcification at the 18th week of gestation.2 Postnatally, MRI, plain X-ray, sonographic examination, and CT scan can be used to demonstrate vessel calcifications.1,8,9,15 In neonates, ultrasonography and CT scan appear to be more sensitive than X-rays due to better contrast resolution.12 As MRI is not particularly effective in the demonstration of calcifications, contrast enhancement is suggested, but is not possible postmortem.15 Hence, in the present case, we JOURNAL OF CLINICAL ULTRASOUND
GENERALIZED ARTERIAL CALCIFICATION OF INFANCY
FIGURE 5. (A) Endocardial surface of the aortic valve and endothelial surface of the ascending aorta displays calcified areas appearing as yellowish white surface irregularities. (B) The abdominal aorta and the common iliac arteries with extensive calcification. (C) Microscopic examination of the tricuspid valve shows calcification in the intima (H&E stain, 3100, original magnification).
preferred to use postmortem CT, which demonstrated calcification in the aorta and the common iliac arteries. GACI was reported to be caused by mutations in ENPP1 gene localized on chromosome 6q22, inactivating the ecto-nucleotide pyrophosphatase/phosphodiesterase 1, which generates the inorganic pyrophosphate, a physiologic inhibitor of calcium deposition.18 Rutsch et al19 identified 40 different homozygous or compound heterozygous mutations in 75% of the patients and concluded that these mutations have no effect on survival except for the p.P305T mutation, which was universally lethal when present on both alleles. Numakura et al also stated that GACI is a genetically heterogenous disorder, and that the atypical, late-onset phenotype may not be associated with ENNP1 abnormalities.20 Recently, Nitschke et al21 analyzed the ABCC6 gene in 28 GACI patients and identified 13 different ABCC6 mutations in 14 patients. Therefore, genetic counseling is very important, and the molecular analysis of ENPP1 and ABCC6 genes should be offered to the family, because early prenatal diagnosis by mutation analysis is possible, if disease-causing mutations have been VOL. 43, NO. 1, JANUARY 2015
identified previously in an index case in the same family.22 Many cases of previous sibling death due to GACI diagnosed at infancy or undiagnosed causes of renal or heart failure have been reported, and an autosomal-recessive inheritance pattern has been described.1,5 In the present case, the parental consanguinity supported this pattern, and the parents were instructed of the 25% recurrence risk of this disease in future pregnancies. Although GACI is generally lethal, a few cases that responded to treatment with biphosphonates have been reported.23 Biphosphonates are pyrophosphate derivatives and are used with the aim of preventing or reversing abnormal calcium deposition. Bellah et al6 attempted to reduce calcification by giving etidronate to a 30-week fetus by means of percutaneous puncture, but the fetus died at the age of 7 months because of the progression of intimal vascular occlusive disease.6 The effect of intrauterine administration of biphosphonate may vary according to the severity of disease. Spontaneous resolution of calcification has been reported in the literature, which makes the value of drug therapy questionable.24 Therefore, 53
CORBACIOGLU ESMER ET AL
more cases are needed to draw a conclusion regarding the therapy. In our case, the family requested termination of pregnancy because of the adverse prognosis. Therefore, we were not able to apply in utero treatment. In conclusion, GACI is a rare cause of fetal hydrops and can be diagnosed in the latter half of pregnancy. When there is a family history, the first signs of calcification should alert the sonographer. Serial sonographic examination of these fetuses may allow earlier diagnosis and better management.
11.
12.
13.
14. REFERENCES 1. Nasrallah FK, Baho H, Sallout A, et al. Prenatal diagnosis of idiopathic infantile arterial calcification with hydrops fetalis. Ultrasound Obstet Gynecol 2009;34:601. 2. Wax JR, Balckstone J, Pinette MG, et al. Hepatic vascular calcification: an early second trimester sonographic feature of idiopathic infantile arterial calcinosis. Am J Obstet Gynecol 2001;185:1267. 3. Crade M, Lewis DF, Nageutte MP. In utero appearance of idiopathic infantile calcification: ultrasound study of a 28-week fetus. Ultrasound Obtet Gynecol 1001;1:2844. 4. Kutty S, Cava JR, Frommelt MA. Idiopathic infantile arterial calcification: a case report of prenatal and postnatal echocardiographic diagnosis. Echocardiography 2009;26:862. 5. Eronen M, Puhjavuori M, Heikkila. Fatal outcome of two siblings with idiopathic arterial calcification of infancy diagnosed in utero. Pediatr Cardiol 2001;22:167. 6. Bellah RD, Zawodniak L, Librizzi RJ, et al. Idiopathic arterial calcification of infancy: prenatal and postnatal effects of therapy in an infant. J Pediatr 1992;121:930. 7. Samson LM, Ash KM, Murdison KA. Aorto-pulmonary calcification: an unusual manifestation of idiopathic calcification of infancy evident antenatally. Obstet Gynecol 1995;85:863. 8. Nagar AM, Hanchate V, Tandon A, et al. Antenatal detection of idiopathic arterial calcification with hydrops fetalis. J Ultrasound Med 2003;22:653. 9. Heuser CC, Puchalski M, Kennedy A, et al. Radiographic and pathologic evaluation of idiopathic infantile arterial calcification. Obstet Gynecol 2010;115:465. 10. Shapiro I, Degani S, Leibovitz Z, et al. Fetal cardiac measurements derived by transvaginal and transabdominal cross-sectional echocardiography
54
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
from 14 weeks of gestation to term. Utrasound Obstet Gynecol 1998;12:404. Abuhamad A, Chaoui R. Pulsed Doppler echocardiography. In: A Practical Guide to Fetal Echocardiography. Philadelphia: Lippincott Williams & Wilkins; 2010, p 99. Farquhar J, Makhseed N, Sargent M, et al. Idiopathic infantile arterial calcification and persistent pulmonary hypertension. Am J Perinat 2005;22:121. Guimaraes S, Lopes JM, Oliviera JB, et al. Idiopathic infantile arterial calcification: a rare cause of sudden unexpected death in childhood. Patholog Res Int 2010;2010:185314. Whitehall J, Smith M, Altamirano L. Idiopathic infantile arterial calcification: sonographic findings. J Clin Ultrasound 2003;31:497. Tran KH, Boechat MI. Idiopathic infantile arterial calcification: imaging evaluation and the usefulness of MR angiography. Pediatr Radiol 2006;36: 247. Van der Sluis IM, Boot AM, Vernooij M, et al. Idiopathic infantile arterial calcification: clinical presentation, therapy and long-term follow up. Eur J Pediatr 2006;165:590. Sawyer T, Stacey M, Mulreany M, et al. Generalized arterial calcification of infancy associated with meconium peritonitis: a case report and review of the literature. Am J Perinat 2009;26: 711. Rutch F, Ruf N, Vaingankar S, et al. Mutations in ENNP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 2003;34:379. Rutsch F, B€oyer P, Nitschke Y, et al. Hypophosphatemia, hyperphosphaturia and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet 2008;1:133. Numakura C, Yamada M, Ariyasu D, et al. Genetic and enzymatic analysis for two Japanese patients with idiopathic infantile arterial calcification. J Bone Miner Metab 2006;24:48. Nitschke Y, Baujat G, Botschen U, et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet 2012;90:25. Kalal IG, Seetha D, Panda A, et al. Molecular diagnosis of generalized arterial calcification of infancy (GACI). J Cardiovasc Dis Res 2012;3:150. Chong CR, Hutchins GM. Idiopathic infantile arterial calcification: the spectrum of clinical presentations. Pediatr Dev Pathol 2008;11:405. Scholler GF, Yu JS, Bale PM, et al. Generalized arterial calcification of infancy: three reports, including spontaneous regression with long-term survival. J Pediatr 1984;105:257.
JOURNAL OF CLINICAL ULTRASOUND
