Br Heart J 1990;64:156-9

Idiopathic infantile arterial calcification in twosiblings: failure of treatment with diphosphonate

Graham Stuart, Christopher Wren, Hugh Bain

AbstractTwo siblings with idiopathic infantilearterial calcification are reported. Thefetal and postnatal echocardiographicfeatures were a large pericardialeffusion, thickened pulmonary andaortic valves, poor pulsation of thedescending aorta, and calcification of thegreat vessels. In one patient calcificationwas first detected at 33 weeks' gestation.Despite treatment with disodiumetidronate both children died.

Idiopathic infantile arterial calcification is arare congenital disorder that is usually fatal inthe first six months of life. It is characterisedby widespread fibrous proliferation in elasticand muscular arteries and is associated withareas of patchy calcification of elastic tissue.Myocardial ischaemia resulting in refractorycardiac failure is the usual cause of death. Wereport two siblings with this disorder; in onethe diagnosis was made by fetal echo-cardiography. Both children died despitetreatment with diphosphonate.

Department ofPaediatric Cardiology,Freeman Hospital,Newcastle upon TyneG StuartC WrenH BainCorrespondence toDr Graham Stuart,Department ofPaediatric Cardiology,Freeman Hospital,Newcastle upon TyneNE7 7DN.Accepted for publication13 March 1990

Case reportsPATIENT 1

This was the first child of unrelated teenageparents. The pregnancy was complicated byhydramnios and hypertension at 34 weeks.Spontaneous labour developed at 35 weeksand despite intravenous salbutamol a 2580 ggirl was delivered vaginally one week later.Within a few hours she became tachypnoeicand required oxygen for cyanosis. On exam-

ination she had biventricular hypertrophy,heart sounds were single, and there was a

grade 2/6 pulmonary ejection murmur. Onlythe femoral and axillary pulses were palpableand examination of the abdomen showed firm4 cm hepatomegaly and 3 cm splenomegaly.The chest x ray showed cardiomegaly withnormal pulmonary vascularity and the elec-trocardiogram was normal. A cross sectionalechocardiogram showed normal cardiac con-nections with a large pericardial effusion anddense echoes reflected from the pulmonaryand aortic valves. In addition, echocardio-graphic examination of the descending aortashowed very poor vessel pulsation. At cardiaccatheterisation there was pulmonary hyper-tension but no stenosis of the pulmonary oraortic valves. When pulmonary artery calcifi-cation was seen on fluoroscopy the chest x ray

was reviewed and linear calcification wasdetected in both axillary arteries and thedescending aorta. A biopsy specimen of theposterior tibial artery showed calcium deposi-tion within the internal elastic lamina andconfirmed the diagnosis of idiopathic infantilearterial calcification. Further investigationshowed a low plasma concentration of pyro-phosphate (0-6 umol/l (normal range in adults1-6 yumol/l)) but other investigationsincluding blood film; thyroid function tests;serum immunoglobulins; autoantibodies;TORCH (toxoplasma, rubella, cytomegalo-virus, and herpes virus) screen; serum para-thormone; plasma calcium, phosphate andmagnesium; serum alkaline phosphatase;plasma cholesterol and triglycerides; liverfunction tests; urine aminoacids, muco-polysaccharides, and excretion of calcium andhydroxyprolene were all normal. Over thenext 48 hours the infant required an exchangetransfusion for haemolytic jaundice thoughthere was no evidence of blood group in-compatability or sepsis. After this, treatmentwith chlorothiazide and spironolactone wasstarted and her cardiac failure and hepato-splenomegaly gradually regressed. Thentreatment with disodium etidronate (20 mgthree times a day) was started, and by fourweeks of age her hepatosplenomegaly hadresolved and she was gaining weight. At sixweeks the dose of disodium etidronate wasreduced to 11 mg three times a day andtreatment with diuretics was stopped.At 11 weeks she presented with screaming

episodes (probably angina pectoris) and acuteheart failure with electrocardiographic evi-dence of inferolateral myocardial ischaemia.Shortly after admission she suffered a cardiacarrest and resuscitation was unsuccessful. Atnecropsy the coronary arteries were grosslynarrowed by widespread endarteritis andthere was extensive calcium deposition be-tween the muscular and subintimal layers.

PATIENT 2Five years later the mother again becamepregnant. Serial fetal echocardiographyshowed the development of a pericardialeffusion and calcification of the great vesselsby 33 weeks' gestation (fig 1). In view of thedeveloping calcification and hydramnios,labour was induced at 35 weeks. When fetaldistress developed an emergency caesareansection was carried out and a male infant(2680 g) was delivered. On examination bothradial pulses were absent and the child wastachypnoeic. Chest and abdominal x rays

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Idiopathic infantile arterial calcification in two siblings: failure of treatment with diphosphonate

I._...... . "I O-Figure 1 Fetal echocardiograms in patient 2 showing (A) calcification (Ca) of the ascending aorta and apericardial effusion (PE). LV, leftventricle. (B) There was calcification of the aortic arch, descending aorta (Desc aorta), and right pulmonary artery (RPA).

Figure 2 Echocardiogram at one day of age in patient 2 showing (A) calcification (Ca) of the aorta and right pulmonary artery (RPA) with apericardial effusion (PE). LV, left ventricle. (B) There was prominent calcification of the aortic arch, right pulmonary artery (RPA), innominateartery (IA), left carotid artery (LCA), and left subclavian artery (LSA).

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158 Stuart, Wren, Bain

confirmed the presence of widespread arterialcalcification. Cross sectional echocardio-graphy showed that the heart was structurallynormal but prominent calcification of theaorta and proximal pulmonary arteries wasevident (fig 2). Further investigations includ-ing cranial ultrasound, plasma calcium andphosphate, serum alkaline phosphatase, serumcreatinine, plasma electrolytes, serumalbumin, and urine calcium and phosphatewere normal. Treatment with disodiumetidronate (20 mg three times a day), spiro-nolactone, chlorothiazide, and digoxin wasstarted. A thoracic computerised tomographicscan at three weeks showed calcification inboth the thoracic and descending aorta. Fiveweeks later the child was readmitted in cardiacfailure with clinical angina. There was elec-trocardiographic evidence of left ventricularhypertrophy with anterolateral ischaemia anddespite treatment with glyceryl trinitrate andmorphine his condition deteriorated. He diedfive days later. Permission for necropsy wasrefused.

DiscussionIdiopathic infantile arterial calcification is veryrare. Its incidence is unknown but over 100cases have been reported. Symptoms usuallydevelop in the first few months of life althougha few cases present in childhood or adoles-cence.' 2 The sexes are equally represented andthough it is not uncommon for siblings to beaffected34 the karyotype is usually normal. Anautosomal recessive inheritance has beenpostulated.45 Presentation in preterm infants isassociated with a higher incidence of aorticcalcification and a more severe form of thedisease.56Our patients presented with the typical non-

specific features of poor feeding, cyanosis,heart failure, lethargy, and respiratory distress.Clinical examination is often not helpful andthe diagnosis is usually made by the recognitionof arterial calcification on chest and abdominalx rays.7 Soft tissue calcification (especiallyperiarticular) is often an associated feature.78Peripheral pulses may be normal, absent, orweak and hypertension may be present.8-lo Theelectrocardiogram is often normal but mayshow signs of left ventricular hypertrophy ormyocardial ischaemia.9" At cardiac catheteri-sation evidence of stiffness in the pulmonaryand systemic artery walls, a low diastolicpressure, and a wide pulse pressure have beenreported.'2 Aortography may show coronaryartery occlusion or stenosis. 3 In many cases,however, the diagnosis is not made until afterdeath." "' The histopathological featuresinclude intimal fibrous proliferation in elasticand muscular arteries with elastic tissuedegeneration and secondary calcification."This intimal proliferation is thought to bethe fundamental pathological change andWitzleben has suggested that "occlusiveinfantile arteriopathy" is a more appropriateterm for the condition.''

Biochemical investigations are usuallynormal and there is no identifiable abnormality

of calcium metabolism. In patient 1 the plasmaconcentration ofpyrophosphate was lower thanthe normal adult range. Pyrophosphate is apotent inhibitor of calcification and it ispossible that idiopathic infantile calcification isdue to a deficiency of pyrophosphate. Analternative explanation is that the low pyro-phosphate concentration is a secondary eventrelated to calcium deposition. Others suggestedthat the underlying defect may be dystrophiccalcification occurring in a previously injuredarterial wall,'6 a disorder of iron metabolism,3or an inherited disorder of elastin structure.9

Antenatal diagnosis by fetal echocardio-graphy has not been reported thoughRosenbaum and Blumhagen noted strikingacoustic shadowing of the aorta on abdominalultrasound in a preterm infant.'7 In our secondpatient calcification was first detected at 33weeks' gestation. If this is typical thendiagnosis by fetal echocardiography may allowelective preterm delivery before the onset ofcardiac failure but it will be too late fortermination of pregnancy.Although spontaneous regression and

survival to adult life have been reported,'2 1685% of patients with idiopathic infantilearterial calcification die in the first six monthsof life.'5 Corticosteroids'8 and a combination ofcorticosteroids, thyroid hormone, and oestro-gen7 have been used to treat this condition withno convincing evidence of efficacy. Meradji etal used disodium etidronate and reportedregression of calcification within a few weeksand complete and permanent disappearance bytwo years.9 This compound is a diphosphonateused to treat metastatic calcification.'9 We usedthis compound in both our patients in a dosethat is known rapidly to suppress boneturnover in adults. Despite this there wasno objective improvement in the radiologicaland echocardiographic appearances and bothchildren died. The patient described byMeradji had only mild coronary involvementand no signs of cardiac failure and may havehad a milder variant ofthe condition. There hasbeen no subsequent report of the successful useof diphosphonate in this condition.

We thank Dr John Kanis, Department of Human Metabolismand Clinical Biochemistry, University of Sheffield for perform-ing the plasma pyrophosphate analysis. GS is supported by theSir Jules Thorn Charitable Trust.

1 Rangaswami N, Chaudhar S, Flinn G, Sanyal S. Idiopathiclinear calcification of the ascending aorta in an adolescent.Am J Dis Child 1979;133:860-1.

2 Moran JJ, Steiner GC. Idiopathic arterial calcification in afive year old child. A case report. Am J Clin Pathol 1962;37:521-6.

3 Moran JJ, Becker SM. Idiopathic arterial calcification ofinfancy. Report of two cases occurring in siblings andreview ofthe literature. Am J Clin Pathol 1959;31:517-29.

4 Chen H, Fowler M, Cheng WY. Generalised arterialcalcification of infancy in twins. Birth Defects 1982;18(3B):67-80.

5 Anderson KA, Burbach JA, Fenton LJ, Jaqua RA, BarlowJF. Idiopathic arterial calcification of infancy in newbornsiblings with unusual light and electron microscopicmanifestations. Arch Pathol Lab Med 1985;109:838-42.

6 Bacon JF. Arterial calcification in infancy. JAMA 1964;188:933-5.

7 Lussier-Lazaroff J, Fletcher BD. Idiopathic infantile

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Idiopathic infantile arterial calcification in two siblings: failure of treatment with diphosphonate

arterial calcification: roentgen diagnosis of a rare cause ofcoronary artery occlusion. Pediatr Radiol 1973;1:224-8.

8 Maayan Ch, Pelag 0, Eyal F, Mogle P, Rosenmaan E, BarZiv J. Idiopathic infantile arterial calcification: a casereport and review of the literature. Eur J Pediatr 1984;142:211-5.

9 Meradji- M,- de Villenieuve VH, Huberi'J, de"Bruijn WC,Pearse RG. Idiopathic infantile arterial calcification insiblings: radiologic diagnosis and successful treatment.J Pediatr 1978;92:401-5.

10 Milner LS, Heitner R, Thompson PD, et al. Hypertensionas the major problem of idiopathic arterial calcification ofinfancy. JPediatr 1984;105:934-8.

11 Witzleben CL. Idiopathic infantile arterial calcification-amisnomer? Am J Cardiol 1970;26:305-9.

12 Scholler GF, Yu JS, Bale PM, Hawker RE, Celermajer JM,Kozlowski K. Generalised arterial calcification of infancy:three case reports including spontaneous regression with

long-term survival. J Pediatr 1984;129:257-60.13 Retbi JM, Casasoprana A, Gabilan JC, Dehan M,

Rosenstein-Retbi J. Idiopathic arterial calcification ininfancy. Eur J Pediatr 1978;129:55-60.

14 Gower ND, Pinkerton JRH. Idiopathic arterial calcificationin infancy. Arch Dis Child 1963;38:408-11.

15 -Moran JJ.' Idiopathic arterial calcification of infancy: aclinicopathological study. Pathol Ann 1975;10:393-417.

16 Marrott PK, Newcombe KD, Becroft DM0, FriedlanderDH. Idiopathic infantile arterial calcification withsurvival to adult life. Pediatr Cardiol 1984;5: 119-22.

17 Rosenbaum DM, Blumhagen JD. Sonographic recognitionof idiopathic arterial calcification of infancy. Am J Radiol1986;146:249-50.

18 Bickel E, Janssen W. Arteriopathia calcificans infantum.Arch Kinderheilk 1963;169:274-85.

19 Russell RGG, Smith R. Diphosphonates: experimental andclinical aspects. J Bone Joint Surg 1973;55B:66-86.

BRITISHCARDIACSOCIETY

NEWSLETTER..

The Council of the British Cardiac Societyhas endorsed the suggestion for a regularnewsletter in the journal. This will appearmonthly, or at least in most issues. We hopethat members will write to the president or toany of the council about matters of specialinterest or concern; views will be publicisedin the newsletters whenever it seems appro-priate to do so. But more important, thenewsletter will give the officers of the societyan opportunity ofkeeping members informedof recent discussion and decisions. In thesedifficult days we will have no shortage oftopics.The council will continue to guide the

society in all matter of importance, but thecommittee structure will be enlarged andstrengthened. The Joint Training and Man-power Group that was set up last year willliaise closely with the Specialist AdvisoryCommittee-and indeed will have somemembers in common. The Audit Committeeis also already in existence. Both of thesebodies have representation from the Cardio-logy Committee of the Royal College ofPhysicians of London. We will also havegroups with responsibility for datamanagement, for liaison with technicians,and for public relations. Others may follow asand when the need arises. We will give moredetails in the next newsletter.The meeting in Torquay seemed to go well,

and it proved a popular venue. We areconfident that Glasgow and Harrogate will beequally successful. The question now iswhether or not members wish to have some

meetings in London. We will be seeking yourviews.

Anxieties about staffing and training con-tinue. We believe that the new proposals fortraining set out in the May issue ofthe journaland discussed at the business meeting inTorquay are important if we are to maintainstandards that are comparable to the best inEurope. But at the time ofwriting we have notachieved final agreement with the RoyalCollege of Physicians of London or with theDepartment ofHealth. In order to strengthenour case-especially with regard to regis-trars-we were asked by the college to pro-vide up to date information on staffing levelsat consultant and senior registrar level in timefor a meeting of the Manpower Group inJune. We accepted the importance of this, butit gave us a little over two weeks to conductthe 1990 biennial survey that was originallyscheduled for July: previous surveys havetaken up to a year for information to becompleted. To compound our problem, thegroup at the Univesity of Sussex who helpedwith previous surveys was not available onthis occasion. Richard Vincent (now directorof the Trafford Centre for Medical Researchat the university) stepped into the breach, andtogether we had a fraught fortnight. We had asteep learning curve: we apologise to ourmany friends who may have felt harassed andwho endured a number of procedural errorswhich would not have occurred were it not forthe unseemly haste of the work. We aregrateful for all the patient help that was given.We must mention a small printers' error in

the publication on the proposed pattern offuture training that we failed to pick up atproof stage. The text referred to a period ofthree years after registration for generalprofessional training: the table showed onlytwo. The text, of course, was correct.We have heard criticism that cardiologists

have little enthusiasm for audit. We believethat we have led the field in this area. Thepacemaker database was a pioneering effort,and the angioplasty register will be of com-parable importance. Our own surveys of

staffing and facilities are a type of audit, andour specialty was the first to conduct these.Some of the working parties set up by thesociety had a major component of audit (forexample that on "Cardiology in the DistrictHospital"). The Joint Audit Committee ofthe Cardiology Committee of the RoyalCollege of Physicians and the Society is nowactively pursuing new areas of interest. It willexamine the management of acute coronarydisease initially as a pilot study in five districthospitals; a register is being set up todocument complications of angiography alsoin a few centres at first but with plans for earlyexpansion; visits by consultants have beenarranged between departments in tworegions-early experience in parts of SouthEast Thames have proved rewarding andpopular. Perhaps we have not been makingenough noise about our activities, and per-haps our newsletters about our activities willhelp to correct this.

DOUGLAS CHAMBERLAINPresident, British Cardiac Society

NOTICES

British Cardiac SocietyThe Annual Meeting will take place at theScottish Exhibition Centre, Glasgow on 30April to 3 May 1991.

Electricity and the heartThe 6th Einthoven Symposium will be heldon 19 October 1990 in Leiden. The sympo-sium, co-sponsored by the Netherlands HeartFoundation and the European Society forCardiology, will be on electricity and theheart. Information from Mrs J Rust, PhiaBerghoutlaan 21, 2343 PM Oegstgeest, TheNetherlands. Telephone (+ 32) 71-17.35.53.

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