heredo-familial vascular and calcification · heredo-familial vascular andarticular calcification...

HEREDO-FAMILIAL VASCULAR AND ARTICULARCALCIFICATION

BY

J. SHARPFrom the Rheumatism Research Centre, University of Manchester,

and the Royal Infirmary, Manchester

(RECEIVED FOR PUBLICATION JANUARY 4, 1954)

This report concerns a family, several members ofwhich display an unusual type of calcification ofjoint structures and arteries, calcification and ossi-fication of ligaments, and juxta-articular and peri-osteal new bone formation.The full syndrome is a readily recognizable clinical

entity and appears to be rare, since only two previousreports of similar cases have been traced in theliterature. Magnus-Levy (1914) described a patient,a 47-year-old German female, who gave a historyof recurrent attacks of painful joint swellings,starting in her teens in isolated fingers and laterinvolving the hands and elbows. Each attack wasfollowed by firm enlargement of the affected joints.She later developed intermittent claudication in thelegs and evidence of heart failure. The joints of thefingers were enlarged, there was extensive thickeningand tortuosity of the larger limb vessels, and radio-logically there were calcifications in relation to theolecranon, patella, and finger joints, and the thick-ened vessels showed heavy calcification of an unusualpattern.

Levitin (1945) reported the case of a 24-year-oldAmerican serviceman who complained of painfulswelling of the joints of the hands and pain in oneknee of 2 weeks' duration. He also had painlessswelling of the finger joints and nodular thickeningof the arteries of the limbs and the tongue, but therewas no obvious abnormality of the peripheralcirculation. The radiological changes closely resem-bled those in Magnus-Levy's patient.

Case ReportsCase 1. A 47-year-old taxi-driver complained of attacks

of painful swelling in the hands and feet, stiffness of theback, and pain in the calves on walking.He gave a history that about 20 years ago he suddenly

developed pain and swelling of the dorsum of the righthand with heat and redness of the overlying skin. Overthe next few days the wrist and fingers became affected,the whole region being uniformly swollen. Moderate

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spontaneous pain was present, and movement of thewrist and lingers was excruciatingly painful. The attackgradually subsided in about 4 weeks, leaving slightresidual enlargement of the wrist and finger joints.Some months later, an identical attack occurred in theleft hand and similar milder attacks were noted sub-sequently in the feet and on one occasion in the rightelbow. He had not felt ill, and did not think that he hadbeen febrile during these episodes. The attacks, alwaysconfined to one site, occurred at irregular intervals ofabout 2 to 6 months, and each attack left further jointenlargement in the affected region with some limitationof movement. During the past 10 years or so, the attackshad been much milder, involving one or sometimes twoor three adjacent fingers, and small transitory painfullesions had developed at new sites, particularly over suchbony prominences as the ischial tuberosities and heels,and once over the manubriosternal region. In addition,he had noted occasional aching in the larger joints,particularly the knees and shoulders.About 10 years ago, following forcible extension of

the spine in a road accident, he was troubled for a fewweeks by aching in the thoracic region of the back, andsince then had noted progressive stiffening of the backand neck and had developed a slight stoop. Only in thepast few months had he had any further back pain, thistime at the base of the neck. Some 2 years ago, paintypical of intermittent claudication developed in thecalves, both being affected at the same time. The painwas initially brought on by walking about half a mile,but the pain-free distance has gradually decreased toabout 100 yards, the progression of symptoms on thetwo sides being exactly parallel.Although he had gradually lost about 2 stones

(12 7 kg.) in weight since the first symptoms, his generalhealth had remained good and he had no other symptoms.His only past medical history was of an attack of left-sidedophthalmic herpes zoster 11 years previously.

His sister, he said, had suffered similar attacks ofpainful swelling in the hands with residual enlargementof the finger joints. He knew of no other family historyof similar disease.Examination.-He was a healthy-looking, sparely-

built man, who stood with about 30° total flexiondeformity, due to a smooth, fixed lumbo-thoracic kyphos;

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ANNALS OF THE RHEUMATIC DISEASES

Fig. 1(a).-Case I, show-ing asymmetrical, largelybony enlargement of

finger joints.

Fig. (b).-Case 2, show-ing more marked similar

changes.

he had between a quarter and a half of the normal rangeof neck movement. Chest expansion was 3 * 5 cm.The texture, temperature, and sweating of the skin

of the extremities was normal. The joints of the fingers(Fig. la) showed striking bony enlargement, and aroundthe fifth metacarpo-phalangeal and fourth and fifthproximal interphalangeal joints of the right hand, whichhad been the site of a mild flare-up some weeks previously,there was also slightly tender soft tissue thickening;the remaining hand joints were not tender. There wasmoderate mechanical limitation of finger movement buthand function was good. The first carpo-metacarpaljoints were not enlarged, but their motion was slightly

limited and accompanied by crepitus. The wrists showedmoderate restriction of movement and there was a slightflexion deformity of the elbows. The sternoclavicular andmanubriosternal joints were slightly enlarged and tender,and the movement of both shoulder girdles was slightlyrestricted. The toes were normal apart from dorsalsubluxation of the outer metatarso-phalangeal joints onthe left. The tarsi showed a valgus deformity and slightlimitation of movement. There was slight bony enlarge-ment of ankles and knees with crepitus on motion of thelatter. Hip movement was full and painless, and straight-leg raising was to 900 on each side. Both ischial tubero-sities were slightly tender.

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HEREDO-FAMILIAL VASCULAR AND ARTICULAR CALCIFICATIONPalpable nodular thickening of

the radial, brachial, femoral, andleft superficial temporal arterieswas present; dorsalis pedis andposterior tibial pulses were absenton both sides, these vessels beingimpalpable. The retinal vesselsappeared normal. Oscillometryshowed greatly diminished pulsa-tions in both calves and in theupper limbs the flush of reactivehyperaemia (Pickering, 1933)appeared at the tips of the digitsof the left hand in 4 seconds, andat the tip of the right thumb in 5seconds and of the right fingers in7 seconds.There was some pallor of the

conjunctivae; no abnormality wasnoted in the viscera or lymphglands. Apart from anaesthesiaeover herpes scars, in the left frontalregion, no abnormality was de-tected in the nervous system.

Fig. 2(a).-Case 1, rac

Radiological Investigations.-The thickened phalappearances were most unusual.The hands (Fig. 2a) showed en-largement and rather widely-spacedtrabeculation of the ends of themetacarpals and phalanges withasymmetrical deposition of newbone, mainly at a short distancefrom the articular surface; theshafts of the phalanges appearedthickened probably because of theincorporation of periosteal newbone which was evident on several(particularly on both the fifth prox-imal) phalanges. This irregular newbone formation resulted in the falseappearance of "erosions" of severalmetacarpal heads (notably the rightfifth), and of the bases of both fifthproximal phalanges. The jointspaces proper were normal through-out, but in some of the terminalinterphalangeal joints the growthsof new bone had approximated Fig. 2(at the joint margins, giving aspurious appearance of narrowing. Amorphous deposi-tions of calcium were present in close relation to almostall the finger joints. The appearance suggested that thecalcification was in some cases intra-articular and inothers in joint capsules (Fig. 3a, overleaf). Calciumdeposits were present in relation to both first carpo-metacarpal joints, and there was deposition of irregularnew bone on the lower ends of both ulnae. Radiographs(Fig. 5a, overleaf) confirmed the subluxation of the outermetatarso-phalangeal joints on the left, and suggestedenlargement of the metatarsal heads and bases of the

ldiographs showing enlargement of bone ends, periosteal new bone onlangeal shafts, and capsular and intra-articular calcification.

-Case 2, radiographs showing more severe changes.

proximal phalanges. There was definite erosion of theheads of the left third, fourth, and fifth metatarsals,with probable narrowing of the fifth metatarso-phalangealjoint space. Calcification, of lesser degree but of the sametype as the fingers, was visible in relation to severalmetatarso-phalangeal and interphalangeal joints, andfaintly calcified vessels were visible in both first inter-osseous spaces. Irregular new bone was present on bothmedial cuneiform bones, and, in the lateral view, bonyspurs were present on the plantar surface of each oscalcis. Anterior and posterior tibial arteries on both sides

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Fig. 3(a).-Case 1, enlargement Fig. 3(b).-Normal control.of area indicated by arrow in Fig.2(a), showing bony enlargement

and articular calcification.

showed heavy clumpy calcification. New bone waspresent on both femoral condyles (Fig. 4a), and faintspotty calcification in relation to the lateral compart-ment of the right knee. The striking feature of thefilms depicting the knee joints was, however, the grossclumpy calcification of both popliteal arteries, and thefainter calcification of an unusually tortuous longsaphenous vein on the left side. Radiographs of the calvesshowed that the calcification continued in the anteriorand posterior tibial and peroneal arteries.New bone formation was evident on the epicondyles

of the left humerus, there were small soft tissue calcifica-tions in relation to both elbow joints, and on each sidethe proximal portion of an interosseous artery wasfaintly calcified.New bone was also present on the upper aspect of

the right greater trochanter (Fig. 6a); the hip jointsappeared normal. The pelvis was asymmetrical and wastilted backwards because of the kyphos, and both iliaappeared to be more vertical than normal, and to bethickened above the acetabulum. There appeared to benew bone formation over both ischial tuberosities, and,on the left, this partly surrounded a translucent areawhich may in part have resulted from bone erosion. Theleft sacro-iliac joint appeared fused, whereas on the rightsome joint space was retained, though the margins weresclerosed and irregular. A good joint space was visible atthe symphysis pubis, where the appearances otherwiseresembled those of the right sacro-iliac joint. Clumpy

Fig. 4(a).-Case 1, radiograph illustrating new bone on femoralcondyles, faint calcification in relation to lateral compartment ofright knee, heavy calcification of popliteal arteries, and faint calci-fication of left long saphenous vein. (Two lead pellets also present

near right knee.)

Fig. 4(b).-Case 2, radiographs showing similar changes.

calcification was visible in vessels in the pelvis and upperthighs, probably the gluteal, femoral, and profundafemoris arteries and some of their branches; these vesselsappeared rather wider than normal.The appearance of the lumbar spine on antero-

posterior projection (Fig. 7) resembled the "bamboospine" of advanced ankylosing spondylitis, but, in thelateral view (Fig. 8a), in spite of extensive ligamentousossification, there was none of the characteristic squaringof the vertebral bodies, and the vertebral plates appeared

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HEREDO-FAMILIAL VASCULAR AND ARTICULAR CALCIFICATION

to be duplicated. Theanterior aspect of thelower abdominal aorta wasfaintly outlined by a finestreak of calcification. Mul-tiple small calcificationswere visible in the upperabdomen, probably invisceral vessels. There waswedging of the eighth thor-acic body (Fig. 9a) andanterior osteophytosis ofthe adjacent bodies at theT8/9 space. The T9/10space was fused anteriorlyat, or just anterior to thedisk margin. At the pos-terior ends of the diskspaces, there appeared tobe bony continuity betweenmost of the vertebralbodies. Calcification wasvisible in the disk sub-stance of the T6/7 spaceand, in lesser degree, in theT9/10 and T1O/11 disks.

In the cervical spine theupper disk spaces werenormal, but the C2/3 spacewas almost sealed an-teriorly by beak-shapedovergrowths of the corre-sponding bodies, resemb-ling osteophytes. At the sitecorresponding to thesegrowths on the antero-inferior margin of thefourth cervical body, asmall, oval amorphouscalcification was lying incontact with the vertebra.Apart from slight spondy-losis at the C7/TI level, thecervical spine appearedotherwise normal. Exten-sive clumpy calcificationwas visible in vessels, prob-ably medium-sized arteries,in .the front of the lowerneck.The skull was normal.

The pineal body was calci-fied. Multiple calcifications,probably within costal car-tilages were seen on theradiograph of the chest butthere was no definite calci-fication of the pulmonaryvessels. Therewaserosion ofseveral ribs, ofthe type seenin coarctation of the aorta.

C : A~..Fig. 5(a).-Case 1, radiograph showing subluxation of outer metatarso-phalangeal joints and erosion ofouter metatarsal heads of left foot, small calcifications in relation to metatarso-phalangeal and inter-

phalangeal joints, and faintly calcified first metatarsal arteries.

Fig. 5(b).-Case 2, showing slight porosis of outer metatarsal heads and extensive articular calcifications.

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Fig. 6(a).-Case 1, radiograph showingasymmetry of pelvis, new bone formation onright greater trochanter and ischial tubero-sities, fusion of left and narrowing of rightsacro-iliac joint with sclerosis and irregu-larity of the margins of the latter and of thesymphysis pubis. Heavy calcification isvisible in gluteal, femoral, and profundafemoris arteries and some of their branches.

Fig. 6(b).-Case 2, radiograph of pelvis,showing similar but less marked asymmetry,periosteal new bone on greater trochantersand anterior superior iliac spines, and heavycalcification of iliac, femoral, and profunda

femoris arteries.

Labor-ator-y Investigationis.Haemoglobin 70 per cent. (104

g./100 MI.).Haematocrit 35 vols./100 ml.Mean corpuscular haemoglobin concentration 30 per

cent.White blood cells 8,600/c.mm.Differential count normal.Serum calcium 9-6 mg./100 ml.; Serum phosphorus 3-1

mg./100 ml.; Serum alkaline phosphatase 17 units/100ml. (on two occasions); Serum uric acid 3-1 mg./100ml.; Serum cholesterol 110 mg./100 ml.; Serum bilirubin0-5 mg./100 ml.; Serum thymol turbidity 2-4 units.

Plasma cholesterol 597 mg./100 ml.; Plasma alkali reserve71 vols. COJ100 ml.; Serum albumin 3-8 g./100 ml.;Serum globulin 2 5 g.f/100 ml.

Serum protein electrophoresis: albumin normal,a1globulin normal, a2globulin moderately increased,P globulin moderately increased, y globulin normal.

Urine: albumin free, neutral or acid, specific gravity1,020, centrifuged deposit normal, culture sterile;Urea clearance 97 per cent. average normal; Plasmaurea 30 mg./100 ml.; Urine amino-acid nitrogen382 mg./24 hrs; Urine amino-acid paper chromato-graphy, normal pattern; Urinary calcium excretion191 mg./24 hrs (on ward diet giving an approximatedaily intake of 1,200 mg. calcium).

Blood Wassermann reaction negative.

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HEREDO-FAMILIAL VASCULAR AND ARTICULAR CALCIFICATIONof the affected finger joints with a little limitation ofmovement. She thought that a course of gold injectionsgiven about 13 years ago was of benefit, and during thepast 10 years or so the attacks had been much milderand confined to isolated finger joints.Some 10 years ago she also developed typical inter-

mittent claudication simultaneously in both calves onbrisk walking. Shortly after this, she began to lose weight,became pale and breathless, and noted an increase of achronic, slightly productive cough to which she had beensubject for a number of years. Eventually, 7 years ago,

4 ^ b'pernicious anaemia was diagnosed, liver injections weregiven with apparent benefit, and she regained her normalweight. In spite of the improvement in the anaemia,the claudication persisted, and the distance she couldwalk briskly without pain had gradually decreased toabout 200 yards.Her first symptoms in the feet were noted 2 years ago;

these consisted of aching across the dorsum of the fore-foot on walking and attacks of burning discomfort in

A r Eo |the soles in bed. The latter attacks were particularlysevere in winter; they were eased by movement of thefeet and relieved by walking about.She had never had any trouble with the back, and had

:.V_:, noted no other symptoms other than occasional hotflushes since the menopause 3 years ago. In her pasthistory she recalled "growing pains" in the lower limbs,which ceased at about 10 years of age, but no seriousillnesses.

Fig. 7.-Case 1, radiograph of ankylosed lumbarspine with extensive ligamentous ossification.

Electrocardiogram normal.Blood sedimentation rate varied between30/200mm. and 16/200mm.(Westergren)during 6 weeks' observation.

Rose's serum differential agglutination test(modified Ball, 1950) at weekly intervals,gave negative results on the first twooccasions and positive results on fouroccasions thereafter.

Arteriography via right brachial arteryshowed all digital arteries patent.Case 2. Sister of Case 1, a housewife,

aged 50 years, stated that at the age of 19shehad pain in the manubriosternal regionfor aboutone month, particularly on cough.ing or sneezing. Her next symptomoccurred 20 years ago, when she developeda painful swelling involving the whole rightupper limb, and the swelling subsided inabout 3 weeks. During this attack she wasnot ill, and she was disturbed only by thepain. An identical attack occurred inthe left hand 2 weeks later, and subse-quently she had similar attacks in thehands at intervals of one to two years,both hands being sometimes affected ^simultaneously. These attacks sometimes Fig. 8(a).-Case 1, lateral radiograph Fig. 8(b).-Case 2, similar view, show-sinvlvthneous figers, anda after eac of lumbar spine, illustrating duplicated ing only slight porosis and minorinvolved the fingers, and after each vertebral plates and lack of squaring osteophytosis of vertebral bodies.attack she noted some enlargement of vertebral bodies.

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Fig. 9(a).-Case 1, lateral radiograph of thoracic spine, showingwedging of 8th thoracic body, bony continuity between severalvertebral bodies posteriorly, anterior osteophytosis at T8/9 andfusion at T9/10 spaces, and calcification in substance of disks T6/7,

9/10 and 10/11.

Examination.-She was a pale, well-nourished woman,bearing some facial resemblance to her brother, Case 1.Her hands (Fig. Ib), which were of normal temperature,colour, and moisture, were strikingly similar to his,with even more marked non-tender enlargement of thefinger joints, the asymmetrical bony excrescences in somecases extending beyond the joint limits; there was flexiondeformity of the terminal interphalangeal joints of bothfifth fingers, and moderate limitation, apparentlymechanical, of the others. The metacarpo-phalangealjoints showed rather less bony enlargement than theinterphalangeal joints, and there was slight rubbery softtissue thickening of both. Slight bony enlargement ofboth first carpo-metacarpal joints was present, with somecrepitus on movement. The lower ends of the right radiusand ulna and of the left ulna to a lesser extent wereenlarged, and there was slight limitation of wrist move-ment. The external condyle of the right humerus feltslightly enlarged; both elbows lacked 5-10° extension.Both shoulder girdles were considerably limited inmovement, scapulo-humeral movement being full. In the

Fig. 9(b).-Case 2, radiograph of thoracic spine, showingcalcification at disk margins and a small deposit in the

substance of disk T8/9.

feet there was a little slightly tender soft tissue thickeningof the outer metatarso-phalangeal joints and additionalslight bony enlargement of both first metatarso-phalangealjoints. The bases of the first and fifth metaiarsals on eachside were enlarged. The tarsi were normal, but there wasslight limitation of movement at the right ankle. The rightAchilles tendon was a little thickened and tender, andthere were palpable bony spurs on each os calcis lateralto the insertions of the Achilles tendons. The bonesaround both knee joints felt rather prominent and weregenerally tender, and there was palpable irregularity ofthe upper outer aspects of both patellae. Terminal kneeflexion was slightly painful on both sides. Hip movementwas full and painless.The lumbar spine was somewhat straightened and

there was a slight thoracic kyphos. In the thoracic andlumbar regions, the range of movement was between aquarter and a third of normal, and in the cervical region,rotation was about a quarter of normal, movements inother directions being much less restricted. Chest expan-sion was 6 25 cm.

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HEREDO-FAMILIAL VASCULAR A ND A RTICULA R CALCIFICATIONNThe brachial pulse was absent in the left antecubital

fossa, and a finely nodular cord was palpable at theusual site of the artery. Both radial pulses were of poorvolume, and the femoral and ankle pulses were absent,but these vessels were not palpably thickened. Otherpulses and vessels appeared normal. Oscillometryrevealed greatly diminished pulsations in both thighs, andthe flush of reactive hyperaemia was delayed in all thefingers and in the left thumb.

There was slight conjunctival pallor and a littlecyanosis of the lips and nail beds. There was no atrophyof the skin or significant lymphadenopathy. The heartwas clinically slightly enlarged to the left, and a softapical systolic bruit was heard. There was neither venousengorgement nor oedema, and the lungs and abdomenshowed no significant abnormality. The feet were pinkand the toes warm and rather dry. Cutaneous sensationwas impaired over the right forefoot and in the tips ofthe toes on the left, and vibration sense was also slightlyimpaired over the right great toe. Slight wasting of themuscles of the right thigh was present without notableweakness. No other abnormality of the nervous systemwas detected.

Radiographs of the hands (Fig. 2b) showed changesidentical with those in Case 1, but more severe. Thefeet (Fig. 5b) showed similar but more extensive peri-articular calcifications and slight porosis of the outermetatarsal heads. No calcification was visible in themetatarsal vessels. The knees (Fig. 4b) showed a littlesoft tissue calcification in the region of the femoralcapsular attachments and severe arterial calcification,which continued in similar degree in the left anteriortibial artery as far as the ankle and in other calf vesselsto a lesser extent. Faint calcification was visible in atortuous right saphenous vein.There was a little fluffy new bone on the outer aspects

of both greater trochanters and anterior superior iliacspines (Fig. 6b), but the sacro-iliac and hip jointsappeared normal. The pelvis showed a lesser degree ofasymmetry of the type seen in Case 1. Heavy clumpycalcification was visible in the iliac, femoral, and pro-funda femoris arteries, which appeared widened, and insome of their larger branches.The lumbar spine (Fig. 8b) appeared somewhat

porotic with large disk impressions and small osteophyteson several vertebral bodies, but there was none of thebridging and gross ligamentous ossification seen inCase 1. The abdominal aorta was not calcified, butclumpy calcification was visible in two vessels in the upperabdomen, probably the left renal and gastro-duodenalarteries.

Calcified deposits were visible at the margins of mostof the disk spaces in the thoracic region of the spine(Figs 9b and 10); in some situations these lay internal toosteophytes, and several of the deposits appeared to beunconnected with vertebral bodies. The appearancessuggested that the deposits had occurred in the outerlayers of the annulus fibrosus and there appeared to bea small deposit also in the substance of the T8/9 disk.The heavy calcifications lateral to the spine in Fig. 10were in costal cartilages and no abnormal calcification

Fig. 10.-Case 2, radiograph of thoracic spine, showingmarginal disk calcifications. In the lowest space theseare unconnected with vertebral bodies. The heavycalcifications lateral to the spine are in costal cartilages.

was visible in the lung fields. Faint spotty and linearcalcifications were visible in the arch and upper partof the descending thoracic aorta.

In the neck, the hyoid bone, and thyroid and cricoidcartilages, and the anterior aspect of the lower tracheawere calcified. The lower disk spaces were slightlynarrowed, with spotty calcification, and there was osteo-phytosis of the lower vertebral bodies. Spotty calcifica-tion was also present in several vessels, probably arteries,in the front of the neck.Radiographs taken 16 months previously showed that

several of the calcifications about the finger joints hadincreased appreciably in size while others had decreased;there had been no definite change in the radiographicappearances of the feet or pelvic vessels.

Laboratoryv Investigations.Blood sedimentation rate 12/200 mm. (Westergren);

Haemoglobin 84 per cent. (12 4 g./100 ml.); Haemato-crit 43 per cent.; Mean corpuscular haemoglobinconcentration 29 per cent.; White cell count 4,700/c.mm.; Differential count normal.

Serum calcium 10 1 mg./100 ml.; Serum phosphorus 3 3mg./100 ml.; Serum alkaline phosphatase 12 units/100ml.; Serum uric acid 1 2 mg./ 100 ml.; Serum cholesterol210 mg./l00 ml.

Urine normal.

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ANNALS OF THE RHEUMATIC DISEASESOther Members of the Same Family

As this was clearly a familial syndrome, thefamily history of these patients was investigated insome detail. The parents of Cases 1 and 2, whowere first cousins (Fig. 11), had both died fromcerebro-vascularaccidents. Thefather was knownto be hypertensivein his later years,and his only sisterdied from a stroke

85 v 83

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9 @ 9 9 9 9 d

77 5 58 68 84 83 81 4 1

Q79

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brachial and radial arteries were observed; the otherlimb vessels appeared normal. Moderate limitation ofspinal movement and mild osteo-arthritic change in theperipheral joints were present. Radiographs of the hands,right forearm, feet, pelvis, lumbar and cervical spine, andchest showed evidence of disk degeneration and osteo-

67 d 9 60+

+ +

60+ 67 48 70

72 I 66

72 68 66

at the age of 48 years. | , .INone of the earlier gen-eration appeared to havehad any changes in the 43(joints similar to those of 60 54Cases and 2. (4) (3)We were able to ex-

amine clinically and lradiologically nine othere 9

members of the family, 30 24 17

apart from Cases I and2. These are included in L __ -

the dotted area of Fig.11. Some manifestations of the familial disease werefound in two brothers of the original patients, andin two children of Case 2. Brief records of these fourcases are given below.

Case 3, the elder brother, aged 54 years, had alwaysenjoyed good health.Examination.-The only abnormalities noted were

slight tortuosity and doubtful thickening of the rightbrachial, radial, and both posterior tibial arteries andmild hypertension. Radiographs disclosed no significantabnormality in the hands, feet, pelvis, or lumbar andcervical regions of the spine. Spotty calcification, muchless dense than in Cases 1 and 2 was visible in thepopliteal, posterior tibial, and proximal portions of theperoneal arteries on each side, and in the left first meta-tarsal artery.

Case 4, the eldest brother, aged 60 years, gave a historyof recurrent attacks of low back pain since the age of40 years and of angina of effort in the past 2 years.

Examination.-Severe hypertension and striking tor-tuosity and thickening of the right superficial temporaland right brachial and, to a lesser extent, of the left

d.(6)

I (i) CASE NUMBER

AGE

a.j2+DEAD50 47(2) (I)

Fig. 11.-Genealogical tree.

7 20 15 7

L) (5) J

arthritis in the spine, and early osteo-arthritic changein the joints of the hands and feet. The heart was con-siderably enlarged. Faint spotty calcification was visiblein the first and second metatarsal and right ulnar arteries.

Case 6, son of Case 2, now aged 27 years, gave aa history of symmetrical claudication in the calves onrapid walking since the age of 16 years. No abnormalitywas noted on physical examination. Oscillometryrevealed diminished pulsations in the left calf. The radio-graphic appearances of the hands, feet, and cervicalspine were normal. The pelvis showed the same type ofasymmetry as Cases I and 2, and there was a slightcompensatory lumbar scoliosis. Faint calcification- wasvisible in both short saphenous veins; these were nottortuous or varicose.

Case 6, son of Case 2, now aged 27 years, gave asuggestive but not definite history of intermittent claudi-cation in the calves on severe effort, also starting at theage of 16 years. No abnormality was noted on physicalexamination, or in the radiographs of the hands, feet,calves, pelvis, or lumbar and cervical spine. Oscillometryof the calves gave normal readings.

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HEREDO-FAMILIAL VASCULAR AND ARTICULAR CALCIFICATION

The five other members of the family who wereexamined were symptom free and appeared normalon examination. All were normotensive and showednegative results in the serum differential agglutina-tion test. None had calcification of joint structuresor of blood vessels in the hands, feet, pelvis, lumbaror cervical spine, or calves, but both the daughtersof Case I and the daughter of Case 4 showed pelvicasymmetry of the type seen in Cases 1 and 2.

Mode of Inheritance.-The most probable modeof inheritance is by a rare recessive gene, Cases I

and 2 being homozygous and presenting the fullsyndrome, and Cases 3-6 being heterozygous anddeveloping the syndrome in an incomplete form.On this hypothesis, the children of Case 1 shouldalso be heterozygous and should develop theincomplete syndrome in due course, and some of thechildren of Cases 3 and 4 may also be heterozygous.The occurrence of the pelvic asymmetry in childrenwho are otherwise at present unaffected may besignificant in this respect.

It is possible that forebears other than the parentsof Cases 1 to 4 may also have been heterozygous andthat the incomplete syndrome may sometimes cause

little if any disability and be compatible withlongevity.

DiscussionThe main features of these six cases and of the

two previously reported are summarized in theTable. The full syndrome affecting joints, juxta-articular bone, periosteum, and blood vessels asmanifested in Cases 1 and 2 is a distinctive clinicalpicture. The history is usually characteristic, and theirregular, apparently largely bony, enlargement ofjoints, particularly of the fingers, and the nodularthickening of the peripheral arteries are striking.Radiologically, the changes in the joints and largerarteries are unmistakable. The spinal appearancesin Case 1 in some views suggest ankylosing spondy-litis, but it is quite exceptional to see such a degree ofspinal change in ankylosing spondylitis withoutcomplete fusion of the sacro-iliac joints and squaringof lumbar vertebral bodies; the appearance ofduplication of the lumbar vertebral plates is mostunusual. Furthermore, the appearances in thethoracic spine of Case 2, which might reasonably besupposed to represent an earlier stage of this change,bear no resemblance to those of ankylosing spondy-

,LE

SIX CASES COMPARED WITH THOSE PREVIOUSLY REPORTED.

Present InvestigationsSeries Msgnus-Levy Levitin Pre-sentInvestigations

(1914) (1945) Case I Case 2 Case 3 Case 4 Case 5 Case 6

Age.47 24 47 50 54 60 20 27

Sex.F M M F M M F M

Consanguinity

SibsAffected.--

Descendants Affected ?

Clatidication 0 0 ?

Arteries -t -- -.> o Limbs - - ---- --<, ~~~~Veins... ____ ._ ___.___ __-________ _ __

on Visceral Arteries . ?

.oi Aorta .

Pulmonary Vessels

Blood Pressure (mm. Hg) "200" 160/110 115/85 180/100 170/105 235/125 120/70 140/80

Limbs .

Joints Involved -- ---- ---________________.

Spine

Blood Chemistry Normal Raised Normalalkalinephos-phatase

Albuminuria.. Trace -

D.A.T. . .I~~~~~

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litis, and the sacro-iliac joints are radiologicallynormal.The change in severely affected arteries, as might

be expected from the radiological appearances,appears to be of a distinctive type. Levitin (1945),who biopsied a posterior tibial artery in his patient,found the media and intima fibrosed and grosslydistorted with bizarre calcified patches containingdeeply acidophilic hyaline bodies or granules usuallyembedded in the calcified plaques which projectedinto a considerably natrowed lumen. Occasionalsmaller deposits were also present in the adventitia.This patient was the only one of the four showing thefull syndrome who was without intermittent claudi-cation, in spite of heavy calcification of all the mainarteries of his lower limbs.

Calcification of the arteries and around the jointsbut sparing the viscera, the common site of metastaticcalcification, has been described in association withadvanced renal failure (Albright and others, 1937;Hubbard and Wentworth, 1921), but both thesecases showed evidence of hyperparathyroidism andgrossly abnormal biochemical findings in the blood,and neither showed any overgrowth of bone. Noneof the three patients with this syndrome so inves-tigated showed evidence of metabolic disturbancesof this kind, which implies that the calcification isof the dystrophic variety, that is, secondary toa primary disturbance in the tissues.The syndrome can be distinguished both by its

natural history and by the anatomical location of thedeposits from the other well-recognized forms ofdystrophic calcification divided by Steinitz (1931),on clinical grounds, into the two categories ofcalcinosis universalis and calcinosis circumscripta.The former occurs most frequently in children, andextensive calcium deposition is found in the skin,subcutaneous tissues, muscles, fasciae, and tendons,usually associated with the development of jointcontractures and ulceration of the superficialdeposits. Its prognosis is grave, the patient usuallysuccumbing to intercurrent infection after a pro-longed enfeebling illness (Brooks, 1934), althoughremission and recovery do occasionally occur(Weber, 1914; Kennedy, 1932; Craig and Lyall,1931). In calcinosis circumscripta, mainly a diseaseof adult women, deposits occur most commonlyin the skin and subcutaneous tissues of the upperlimbs, especially of the fingers, but without par-ticular relation to joints; it is commonly associatedwith reduced circulation in the extremities andsclerotic changes in the fingers.

Localized calcifications of tendino-capsular struc-tures around joints, particularly the shoulder joint,are occasionally encountered; similar deposits have

been noted less frequently at other sites, such as thewrist and finger joints, and sometimes at severalsites in the same patient (Maseritz, 1935; Sutro andCohen, 1941; Cooper, 1942; Vasko, 1946; Seiden-stein, 1950). Hamilton (1951) suggested the descrip-tive title calcinosis localisata for this condition;the deposits may be asymptomatic, but are oftenrevealed in radiographs taken to investigate acutepainful swelling of the affected parts, the radio-graphic appearances resembling a minor form of thejoint changes seen in the patients described above.In calcinosis localisata, however, the depositsfrequently disappear after these acute episodes;this disease seems to have no familial incidence nordoes vascular calcification occur in associationwith it.

ConclusionThe familial syndrome of calcinosis of the joints

and arteries here described is remarkable in that thecalcinosis is associated with periosteal bone pro-liferation and ossification of ligaments. It is thereforebest regarded as a distinct entity until the mechanismsof dystrophic calcification are more fully understood.

Dystrophic calcification is probably due to aspecific change in connective tissues, but it is notclear which connective tissue elements are con-cerned, and the nature of the disturbance is un-known. Future studies on the tissues of these patientsmay help to elucidate the problems of the site andmechanism of abnormal calcification and ossificationin connective tissue.

SummaryIn a family resulting from the marriage of first

cousins, two of the four siblings display calcificationof joint structures and arteries of an unusual typetogether with juxta-articular and periosteal new boneformation.The son and daughter of one of these and the

remaining two siblings appear to have a milder formof the syndrome affecting the blood vessels only.The disease appears to be a rare and distinct

heredo-familial form of dystrophic calcification.

I am greatly indebted to Professor J. H. Kellgren formuch helpful advice, to Dr. H. Harris for assistance in theinterpretation of the genetics of the syndrome, and toDr. Robert Ollerenshaw and the staff of the Departmentof Medical Illustration for reproduction of the figures.

REFERENCESAlbright, F., Drake, T. G., and Sulkowitch, H. W. (1937). Btull.

Johns Hopk. Hosp., 60, 377.Ball, J. (1950). Lancet, 2, 520.Brooks, W. D. W. (1934). Quart. J. Med., n.s. 3, 293.Cooper, W. (1942). J. Bone Jt Surg., 24, 114.Craig, J., and Lyall, A. (1931). Brit. J. Child. Dis., 28, 29.Hamilton, A. R. (1951). J. Bone Jt Surg., 33B, 572.

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HEREDO-FAMILIAL VASCULAR AND ARTICULAR CALCIFICATIONHubbard, R. S., and Wentworth, J. A. (1921). Proc. Soc. exp.

Biol. (N. Y.), 18, 307.Kennedy, R. L. J. (1932). J. Pediat., 1, 667.Levitin, J. (1945). Radiology, 44, 489.Magnus-Levy, A. (1914). Dtsch. med. Wschr., 40, 1305.Maseritz, I. H. (1935). J. Bone Jt Surg., 17, 1017.Pickering, G. W. (1933). Brit. med. J., 2, 1106.Seidenstein. H. (1950). J. Bone Jt Surg., 32A, 413.Steinitz, H. (1931). Klin. Wschr., 10, 1132.Sutro, C. J., and Cohen, L. J. (1941). Arch. Surg., 42, 1065.Vasko, J. R. (1946). J. Bone Jt Surg., 28, 638.Weber, F. Parkes (1914). "Proc. XVII Int. Congress of Medicine,

London, 1913", Section 13, Pt 2, p. 179. Oxford UniversityPress, London.

Calcification vasculaire et articulaire her6do-familialeRESUME

Dans une famille de quatre enfants nee de l'union decousins germains, deux d'entre eux sont atteints decalcification des structures articulaires et arterielles d'untype rare, associee a la neoformation osseuse, juxta-articulaire et periostique.

Les deux autres, ainsi que le fils et la fille de l'un desplus gravement atteints, semblent presenter une formeplus benigne de ce syndrome car chez eux l'atteinte neporte que sur les vaisseaux sanguins.

11 s'agit ici probablement d'une forme heredo-familialerare et distincte de calcification dystrophique.

Calcificaci6n vascular y articular heredo-familiarSUMARIO

Dos de los cuatro hijos, frutos de la union de primoshermanos, presentan una calcificaci6n de estructurasarticulares y arteriales de un tipo raro, asociada conneoformaci6n 6sea, yuxta-articular y periostea.Los dos demas, asi como un hijo y una hija de uno de

los precitados parecen sufrir de una forma mas benignade este sindroma, que en ellos afecta s6lo los vasossanguineos.

Se trata sin duda de una forma heredo-familiar, raray distinta, de calcificaci6n distr6fica.

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heredo-familial vascular and calcification · heredo-familial vascular andarticular calcification...

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