The circulatory dynamics of polyostotic fibrous dysplasia

The Circulatory Dynamics of Polyostotic Fibrous Dysplasia* HENRY

D.

MCINTOSH,

M .D .,

D.

EDMOND MILLER, M .D ., I WILLIAM and J . LEONARD GOLDNER, M .D .

L.

GLEASON, M .D .t

Durham, North Carolina

T

Each patient was studied by right heart catheterization technics . Pulmonary artery, right ventricular, right atrial and systemic arterial pressures were measured in each patient by means of a Statham strain gauge coupled to an Electronics for Medicine carrier amplifier and photographic recorder . Cardiac outputs were estimated by the Fick principle (utilizing pulmonary arterial blood samples) at rest in all patients and during exercise in three . In five of the six patients, samples for oxygen content were obtained from several points in both the superior and inferior caval systems . Oxygen content of whole blood was determined by the technic of Hickam and Frayser [4] ; oxygen consumption was measured by a Beckman (Pauling) oxygen analyzer.

HE term fibrous dysplasia embraces a spectrum

of

pathologic processes having in

common a specific type

[13 . At one extreme is 1937 by Albright [23

of

skeletal involvement

the syndrome described in which includes the seem-

ingly dissociated manifestations

of

disseminated

(polyostotic) fibrous dysplasia, cutaneous pigmentation and precocious puberty among females ; at the other extreme is the tnomistntic lesion which may involve any part of the skeletal system [3] . Despite much speculation, the genesis and pathophysiology

of

the condition remains

obscure . The present investigation was designed to determine if the bony lesions of polyostotic fibrous dysplasia are accompanied by significant

CASE REPORTS AND RESULTS

circulatory alterations similar to those observed in osteitis deformans (Paget's disease)

Albright's Triad (Polyostotic Fibrous Dysplasia,

[22-26] .

Precocious Puberty and Pigmentation)

The study was suggested by fortuitous observaCASE I. A six year old Negro girl (I . M . D .) was admitted to the Duke Medical Center in February

tions made on a patient (Case n)§ with classic features of Albright's syndrome, cardiomegaly, and a systolic bruit over an area of extensive

TABLE I PERTINENT CLINICAL FEATURES

cranial involvement . MATERIALS AND METHODS

Age-

During a three-year period six female patients, ages six to sixty-eight years, with typical clinical and x-ray features of polyostotic fibrous dysplasia were available for hemodynamic studies . The clinical impression was confirmed by biopsy in four patients . (Table I .) Extensive clinical and laboratory studies excluded associated processes which might produce altered circulatory dynamics . (Table n .)

ase Case C No .

I

Raa and Sex

6,N,F 31,N,F 43,W,F

ev vs

§ Referred for study by Dts. William R . Lewis and Sidney Grossberg .

20,W,F 69,W,F 51,N,F

Unilateral Skeletal Lesion

Esseosially No Essentially Yes Essentially Yes

Yrecarious Pu-

betty

Yes Yes Yes

No No No

, gto son

Associated Disease

Yes

None None Acromegaly None None

No

YoWmyosi,is

Yes

Yea No Yes

Biopsy

Yes Yes No Yep

Yes No

* A, time of cardiovascular evaluation .

" From the Cardiovascular Laboratory, Department of Medicine and the Division of Orthopedic Surgery, the Duke Medical Center, Durham, North Carolina. This work was supported by Research Grants H-4807 and H-TS 5369 from the National Heart Institute and H-3582 and M-2109 from the Duke Medical Center for Aging, both of the National Institutes of Health, U .S . Public Health Serivec, grants-in-aid from the American and North Carolina Heart Associations and the Life Insurance Research Fund . Manuscript received March 3, 1961 . t Present address : Cardiopulmonary Laboratory, U .S . Naval Hospital, Portsmouth, Virginia . $ Research Fellow, American Heart Association . Present address : Section of Cardiology, Watson Clinic, Lakeland, Florida . VOL .

32, MARCH 1962

393



394

Polyostotic Fibrous Dysplasia-Mclntosh et al . TABLE

n

PERTINENT ACCESSORY CLINICAL FINDINGS

Serum Case No.

Age. (yr-)

Hemoglobin tgm. 31) Calcium (mg. %)

11

yr

6

1559

13 .0

10 .0

31 28 43 15 20 53 61 68 50 51

1959 1943 1958 1953 1958 1945 1953 1959 1957 1958

12 .0 15 .0 10 .5

9 .1 7 .6 8 .9 8 .9 9 .6 8 .8 8 .6 9 .3 9 .0 10 .4

13 .0 13 .0 13 .5 14 .9 11 .5 13 .9

Phosphate (mg, %)

Alkaline Phosphatase (Bodanaky units)

Protein-bound Iodine (isg . %)

61 .9

6 .2

2 .7 4 .0 3 .2 3 .4 3 .2 2,7 2 .5 2 .9 4,0 3,6

1959, because of severe bilateral genua valga which had progressed since the age of three . The breasts were prominent at birth . Vaginal bleeding was observed when the child was two years of age and on more recent occasions . The review of systems, past medical history and family history were not contributory . The blood pressure was 120/80 mm . Hg, pulse 90, respiration 18 . The cranium was symmetrical ; the fades was f1111 and moon-like . A caf€-au-lait pigmentation was present on the back . Discrete glandular tissue was present in both breasts . The heart was questionably enlarged . The second pulmonic sound was greater than the second aortic sound . No mur.murs were present. The labia majora were enlarged

Case L Cheat roentgenogram of a six year old Negro girl with the complete triad of Albright. The heart is probably enlarged for a child of this age. FIG . 1 .

Basal Me,.bolc Rate I%)

Electrocardiogram

+13

8 .5 11 .5 4 .2 8 .0

+10 7 - 1

20

}18

61 4 .1 4 .2 1 .3 3 .8

21-Boor Pat Uptake (%)

30 30 22 14

I

Inverted Tvo-a Elevated S-TV :-s Horizontal axis Normal Normal Normal Normal Normal Normal Normal Normal Left axis deviation No change

and fine pubic hair was present . The vaginal epithelium was moist . Rectal examination revealed the uterus to be 3 by 1 cm . with a cervicouterine ratio of approximately 2 :1 . The child walked with an awkward gait due to knock-knee deformities . Pertinent accessory clinical findings are recorded in Table a . The 17-ketosteroid excretion on two successive days was 4 and 2 .9 mg. per twenty-four hours, Cytologic examination of vaginal secretions revealed precornified epithelium without basal cells . Roentgenograms of the skull demonstrated massive bony overgrowth of the cranium and facial bones . The heart was minimally enlarged ; the ribs and lungs were within normal limits . (Fig . 1 .) The left side of the pelvis was markedly deformed, being contracted and displaced medially . A pronounced varus deformity of the left femur was present . Numerous destructive radiolucent foci were present throughout the pelvis and proximal femors . These lesions were most prominent on the left but were also noted on the right . The bone age was about nine years compared to the chronologic age of six . A biopsy specimen from the left ilium confirmed the clinical impression of fibrous dysplasia . The electrocardiogram revealed inverted T waves in leads Vi, V, and V a, elevated S-T segment in lead V3, Vc and V4 and a horizontal axis . The pertinent catheter data are recorded in Table in and Figure 2 . Summary : This six year old Negro girl exhibited extensive skeletal involvement, pigmentation and precocious puberty. The heart was enlarged (Fig . 1) and the electrocardiogram revealed a horizontal QRS axis . The serum alkaline phosphatase of 61 .9 Bodansky units indicated extensive osteoblastic activity . The cardiac index was 5 .6 L ./minute/M2 . The iliac A-V oxygen difference was 1 .3 volumes per cent AMERICAN JOVRNAL OF MEDICINE



Polyostotic Fibrous Dysplasia--McIntosh et al .

AIK P04-619 B .U . B S A -77 C O -44 L /Min . OI-56L/Mm .

SKELETAL INVOLVEMENT

ART-VENOUS 0 2 DIFFERENCE . VOLS.%

395

AIK P0 4 -2 0 B . U . B.S .A . - 1 .52 M` C.O . - 71L/Min C . I .-47L/MIr/W

SKELETAL IVOLVENENT

ART-VENOUS 02 DIFFERENCE . VOLS.%

FIG . 2 . Case i, left ; Case iv, right . The shaded areas of the skeleton indicate the areas of osseous involvement . The A-V oxygen difference was determined by the difference of the oxygen content between a near simultaneous brachial arterial sample and a sample from the indicated site . Note that the patient (Case Iv) has unilateral involvement, except for the skull. The pigmentation was on the same side as the skeletal involvement . Unfortunately the catheter could not be introduced into the left iliac vein . Mk. PO, = alkaline phosphatase, Bodansky units ; B.S.A . = body surface area ; C.O . = cardiac output ; C .I . = cardiac index .

ach" of three years' duration . The mother and grandmother stated that the patient began menstruating at age six and had definite growth of breast tissue and pubic and axillary hair by the age of eight . A blow to the head at the age of ten was allegedly followed by a progressively enlarging protuberance of the right frontuparietal bones . Bilateral femoral osteotomies were performed for genua valga deformities at the age of twelve . The review of systems, past medical history and family history was otherwise not contributory . The blood pressure was 115/75 mm . Hg, pulse 98, respiration 16 . The cranium was large and triangular in shape with an irregular right frontoparietal pro-

present over the right carotid artery, right eye and right frontosphenotemporal region . This bruit and thrill disappeared during compression of the right carotid artery and diminished in intensity following occlusion of the right temporal artery . Light pressure over the right carotid artery converted the systolic murmur into a continuous murmur . Occlusion of the right carotid artery did not result in slowing of the heart rate [5,6] . The thorax was asymmetrical with a prominence over the right anterior portion of the chest. The heart was enlarged, the apical impulse being localized to the fifth intercostal space 10 cm . to the left of the mid-sternal line . The second pulmonic sound was greater than the second aortic sound and was slightly split . A third heart sound was present at the apex . A grade 3/4 systolic ejection-type murmur was audible over the entire preeordium, but was maximum over the pulmonic area . A 4 by 1 cm . cafe-au-lait pigmentation was present over the right mid-back and a similar I by 2 cm. lesion was present

tuberance . Funduscopic examination was within normal limits . A venous hum was present over the right jugular vein when the patient was sitting, but disappeared during jugular compression, turning the head to the right or during recumbency . In addition to the venous hum, a systolic bruit and thrill were

over the upper left thigh . Surgical scars were noted over the lateral aspect of both knees . Pertinent accessory clinical findings are recorded in Table H. A radioactive iodine uptake or proteinbound iodine determination was not obtained because of recent x-ray contrast studies. Roentgenograms of

bilaterally, while the left subclavian A-V oxygen difference was 4 .3 volumes per cent . CASE n . A thirty-one year old Negro woman (F . S .) was admitted to the Duke Medical Center in December 1957 for evaluation of "gas on the stom-

vor . 32, HATCH 1962



396

Polyostotic Fibrous Dysplasia-Mclntosh et al. 0

In

~~

O

a

i II I



c

In

m

iCo

m

M

Fir. . 3 . Case u . Chest roentgenogram of a thirty-one year old Negro woman with the complete triad of Albright . The heart is enlarged . The involvement of the ribs by the fibrous dysplasia can be noted on the right.

i

F

E

A

the skull revealed irregular bone changes with thickening of the diploe . There were numerous areas of rarefaction as well as areas of increased density . The entire skull was thickened and there was considerable sclerosis of the sphenoids with widening or destruction of the entire sells . A roentgenogram of the chest confirmed the clinical impression of cardiomegaly . (Fig . 3 .) The ribs showed irregular widening and zones of thickening throughout, but more noticeable on the right. Irregular thickening and radiolucent areas were present throughout the pelvis and the tong bones . A biopsy specimen from the right tibia confirmed the clinical impression of fibrous dysplasia . The pertinent catheter data are recorded in Table n : and Figure 4. During the catheterization 3 nil . of indocyanine green dye* was injected into the pulmonary artery and a dye-dilution curve was obtained from the brachial artery with and without occlusion of right common carotid artery . (Fig . 5 .)

d

U

eC

d

4

g E. 5 w z F

e

I

I

C

c

? I

Summary : This thirty-one year old Negro woman exhibited extensive bilateral skeletal involvement and pigmentation . She gave a history of precocious puberty . A systolic bruit and thrill were present over the right carotid artery, right eye and right frontosphenotemporal region . The heart was enlarged . (Fig. 3 .) The serum alkaline phosphatase was 8 .5 Bodansky ./minute/M2 L units . The cardiac index of 6 .6 . was distinctly elevated . The rapid recirculation of dye demonstrated by dye-dilution curves

* Generously supplied as "Cardio-green" by Dr. John H . Brewer, Hynson, Westcott and Dunning, Inc ., Baltimore, Maryland . AMERICAN

JOURNAL

OF

MEDICINE



397

Polyostotic Fibrous Dysplasia -McIntosh et al .

_56

-22 --2 .6 (Artery) -4 5 19

IPUImOomy Artery)

-L7

-25 -44 5 .5

AIK P04 -8 .5 BA B.S .A . - I .36 M° C0 .-8&L/Min . C L -66 L /Mint

SKELETAL INVOLVEMENT

ART-VENOUS Oy DI

AIK P04-4 .2 B .U. B S. A . - 185 Me C .O. - 54 L /Min . C I - 29'~/W /

ERENCE .VCLS .%

SKELETAL INVOLVEMENT

ART-VENOUS 0, DIFFERENCE . VOLS .%

Pte . 4. Case n, left ; Case m, right. In Case n there was extensive bilateral skeletal involvement- The iliac A-V oxygen difference was equal bilaterally . The cardiac output was not increased in Case in . Note the tendency toward unilateral involvement in this case. There was a 3 .2 volumes per cent oxygen difference between the blood draining the involved and uninvolved side of the pelvis .

(Fig . 5) was compatible with an arteriovenous communication .

sure was 120/80 mm . Hg, pulse 76, respiration 14 . The thyroid gland was diffusely enlarged . The cardiovascular system was within normal limits . The labia minnra and majora were hypertrophied ; the clitoris

Polyostotic Fibrous Dysplasia with Precocious Puberty CASE m . A forty-three year old white female school teacher (S . K . L .) was first seen at the Duke Medical Center in 1943 at the age of twenty-eight for evaluation of suspected acromegaly . Two years previously her hands and feet enlarged ; the forehead, nose and mandible became more prominent and a masculine hair distribution developed . The menses became irregular .

Ifie patient gave a history of bloody vaginal discharge sporadically from one year of age until regular menses were established at the age of eleven . Pubic hair appeared at age nine . At the age of twenty-one a basal metabolic rate was said to be minus 40 per cent and she was given thyroid extract which was continued until her admission to the Duke Medical Center . She denied knowledge of skeletal disease . The past medical history, review of systems and family history were otherwise not contributory . In 1943, when first seen in this Clinic, the patient was described as a large, heavy-set, hirsute white woman with prominent orbital and supraorbital ridges, a broad nose and a protruding mandible . The hands and feet were large and broad . The blood presvot . 32, MARCH

1962

RESTING

I

e rmebgeey ; 3 aalm onoryim lmonory Artery

ml. corn Plmonary+rreeri

Sampling Site . :

Brachial Artery

Brachial Artery

Hear/ Rote :

84/min . 9 .0 L ./min .

93/min .

Ccrd, c ovtput

71 L./min .

Fin . 5 . Case n . Polyostotic fibrous dysplasia . There was a 1 .9 L./minute decrease in cardiac output during occlusion of the right common carotid artery, the side with the. systolic bruit . The pulse rate increased rather than decreased as would be expected (Nicoladoni-Branhan sign) [5,6] . The pressure required to occlude the artery was painful to the patient . Both curves show an early recirculation of dye .

398

Polyostotic Fibrous Dysplasia-Mclntosh et al . and gradual progression of radiolucent lesions in several ribs on the left . No gross evidence of sarcomatous changes in the radiated fibrous dysplasia lesions in the base of the skull has developed [7,8] . The patient was readmitted to the Duke Medical Center in July 1958 for re-evaluation and elective cardiac catheterization . The general appearance was as previously described . The blood pressure was 125/85 mm . Hg, heart rate 72 . The thyroid was not enlarged . The cardiovascular system was within normal limits . There was no abnormal pigmentation . Pertinent accessory clinical findings are presented in Table n . The moderate anemia was thought to be due to iron deficiency, but of insufficient degree to result in circulatory alteration . The previously described skeletal defects were again noted . Data obtained at catheterization are presented in Table in and Figure 4 .

Fro. 6_ Case nr. Note the marked involvement of the left ilium and femur. The iliac A-V oxygen difference was 5 .5 volumes per cent on that side compared with 8.7 volumes per cent on the right .

was prominent . No abnormal pigmentation was present . Pertinent accessory clinical findings are recorded in Table it. The visual fields were normal . The glucose tolerance curve was normal . Roentgenograms of the skull revealed increased density in the region of the sphenoid sinuses with hyperostosis of the frontal bones . The dorsum sellae was not enlarged and there was no evidence of destruction . The heart was not enlarged . Cystic areas were present in multiple ribs on the left and the first rib on the right . A large radiolucent area was present in the left ilium . (Fig. 6 .) No significant changes were observed in the right pelvis or lower extremity . An old fracture line with irregularity of the inferior cortex of the left femoral neck was noted, together with areas of decreased density and sclerosis in the metaphysial region . A wide area of bone destruction was present in the trochanteric region . The shaft of the left femur was bowed laterally and the entire cortex was irregular. The left tibia was wider than the right . The attending physicians concluded that the patient had polyostotic fibrous dysplasia as well as acromegaly . In an attempt to arrest the latter condition 3,300 r were directed to the pituitary . Re-evaluation one year later showed slight constriction of the visual fields bilaterally and during the next two years an additional 13,800 r were directed to the pituitary . Careful re-evaluation of the visual field suggested that the constriction of the fields was not that characteristically seen with a pituitary tumor, but was probably due to fibrous dysplasia tissue compressing the optic nerves . The patient was followed closely for the next fourteen years and remained essentially asymptomatic except for severe frontal headaches . The skeletal lesions showed little change except for the appearance

Summary : This forty-three year old white woman experienced precocious puberty, and exhibited essentially unilateral skeletal involvement but had no abnormal pigmentation . In addition she presented features compatible with acromegaly . The serum alkaline phosphatase at the time of the cardiac catheterization was 4 .2 Bodansky units . The cardiac index was within low normal limits, 2 .9 L ./minute/M 2 . The iliac A-V oxygen difference on the left (side of major involvement) was 5 .5 volumes per cent ; the right iliac A-V oxygen difference was 8 .7 volumes per cent . Polyostotic Fibrous Dysplasia and Pigmentation CASE rv . A fifteen year old white girl (E . M . H .) was admitted to the Duke Medical Center in 1953 for treatment of an incomplete fracture of the right femur . A roentgenographic survey revealed extensive involvement of the right half of the skeletal system by localized areas of radiolucency, thinning and irregularity of the cortex . Pertinent laboratory data are recorded in Table ii . The fracture was treated successfully by excision of the fibrous tissue in the subtrochanteric region, bone grafting and insertion of a Vitallium® screw . Microscopic examination of the tissue obtained at surgery confirmed the clinical impression of fibrous dysplasia . There was no evidence of precocious sexual development . The patient has had no further symptoms referable to her disease and is leading a normal unrestricted life . She was readmitted to the Duke Medical Center in November 1958 at the age of twenty years for the purpose of cardiac catheterization . The past medical history, review of systems and family history were non-contributory . The physical examination revealed a well developed, well nourished white girl . The blood pressure was 120/60 mm . Hg, pulse 86, respiration 16 . AMERICAN JOURNAL OF MEDICINE



Polyostotic Fibrous Dysplasia--Mclntosh et at . A large "coast of Maine" cafe-au-lait pigmentation was present on the right cheek and extended onto the neck . A smaller lesion was present 3 cm . to the right of the first lumbar vertebra . The heart was not enlarged . The second pulmonic sound was louder than the second aortic sound . A soft grade 1/4 systolic murmur, which varied in intensity with respiration and position, was present at the apex . The remainder of the physical examination was within normal limits . Pertinent accessory clinical findings are presented in Table u . Roentgenograms of the skull revealed thickening and increased density throughout the occipital region . The outer table of the . right parietal bone was markedly thickened . The sphenoid sinuses were obscured by the increased density of the gar, rounding bone . The fifth right rib posteriorly was widened and the cortex thickened . The pelvis and hip joint on the right revealed several large radiolucent areas . The cortex of the right femur was thickened and cystic areas were present in the proximal aspect . A Vitallium screw was present in the neck of the femur with no evidence of bone absorption . Irregular cystic areas were present in the mid-position of the right fibula and right radius . The bones of the left extremities and hemipelvis appeared essentially normal . Data obtained at cardiac catheterization are presented in Table m and Figure 2 . Summary : This twenty year old white girl exhibited essentially unilateral skeletal involvement and, as has frequently been reported, extensive pigmentation on the same side of the body [2,9-13] . There was no history of precocious puberty . The serum alkaline phosphatase at the time of the cardiac catheterization was 2 Bodansky units . The cardiac index at rest was elevated (4 .7 L ./minute/Ms .) . The iliac A-V oxygen difference on the left (side of major involvement) was 3 .4 volumes per cent . The catheter could not be directed into the right iliac vein . CASE v . A sixty-eight year old white retired school teacher (I . R . L.) was struck on the face as a child . Shortly thereafter a bony protruberance developed on the left mandible . This lesion progressed in size, and at the age of thirty-one a portion of the left ramus of the mandible was removed . She was told that the lesion was a "cancer ." There was no recurrence of the mass for thirteen years . During her second pregnancy, at the age of forty-four, a similar protruberance developed on the left maxilla . Exacerbation of the process (i .e ., fibrous dysplasia) during pregnancy has been previously reported [10,11] . This lesion increased in size and prompted the patient to visit the Duke Medical Center for the first time in 1945 at the age of fifty-five . She denied signs of precocious puberty . She had VOL .

32,

MARCH

1962

399

had two full term normal deliveries, the last at fortyfive years of age . She complained of pain in the left hip and leg which was said to be the result of a "dislocation" of the hip in childhood . The past medical history, review of systems and family history were non-contributory . At the time of the first admission to Duke Hospital, there was a 6 by 6 cm ., slightly tender exostosis of the left maxilla which also involved the left half of the hard palate . The left leg was 7 cm . shorter than the right with associated limitation of flexion of the left hip . A 4 by 3 cm. caf€ au laic lesion was present on the back to the right of the first lumbar vertebra . Pertinent laboratory data are presented in Table n . Roentgenograms of the ealvarium revealed a sclerosing osteitis with thickening of the bone of the entire base of the skull from the mastoid process to the region of the frontal bone extending to the parietal boric . The medial wall of the left orbit was also markedly sclerosed . Both rami of the mandible were involved by the process and contained multiple cystic areas, the cortex remaining intact . Bony trabeculations were visible in these cystic areas . Multiple radiolucent areas containing trabeculations were present in the left ilium, ischium and pubic bones . An old fracture of the neck of the left femur with overriding was present, resulting in considerable shortening of the extremity . Cystic changes extended to the mid-portion of the shaft . Less extensive cystic areas containing trabeculations were also present in the right ilium and shaft of the right femur. A biopsy specimen from the left maxilla was compatible with fibrous dysplasia . \o specific therapy was recommended . The mass on the left maxilla continued to enlarge and resulted in mal-occlusion of the teeth . The patient was therefore readmitted to the Duke Medical Center in 1953 for resection and plastic reconstruction of the mandible . The results of the physical examination were unchanged from the previous admission . Pertinent laboratory data are recorded in Table it . Except for the facial lesions there was no evidence by roentgenographic evaluation of progression of the osseous process . She was readmitted to the Duke Medical Center in March 1959 for cardiac catheterization. At that time she stated that she had been essentially asymptomatic except for episodes of nervousness and rapid heart action. The nature of the arrythmia was unknown . Skeletal lesions were quiescent. The past medical history, review of systems and family history was non-contributory . The blood pressure was 160/80 mm . Hg, pulse 84, respiration 16 . She presented a rather grotesque appearance because of the deformity of the calvarium . A large defect was present in the frontal region of the skull. The previously observed pigmentation was unchanged . Funduscopic examination was within normal limits . The thyroid was palpable, but not enlarged, and contained a nodule in the right lobe . The heart



400

Polyostotic Fibrous Dysplasia-Mclntosh et al .

AIK P04-3.8 O.U B .S.A. - 1 .6 Ma C .O. -63L/MM . . C . I . - 3.9 L./Min./M=

SKELETAL INVOLVEMENT

ART-VENOUS 0, DIFFERENCE, V0L5%

AIK PO.-4 .2 8.U. 8.SA. - 1 .3 M 2 GO, - 60 L /Min . C. I . - 46 L ./Min/M :

SKELETAL INVOLVEMENT

ART-VENOUS 0, DI FERENCE . VOLS%

Fm . 7 . Case v, right . This sixty-eight year old woman had a cardiac index of 4 .6 L./minute/Ms. Case vi, left. This patient had extensive involvement of the left ilium. The iliac A-V oxygen difference was 3 .4 volumes per cent on the left compared with 5 .6 volumes per cent on the right . was not enlarged . The second aortic sound was greater than the second pulmonic sound ; the second sounds at the base were split. The mitral first sound was accentuated . No murmurs were present . The liver was palpated 2 cm. below the right costal margin and the spleen was enlarged 3 cm . below the left costal margin . There was a moderate lumbar scoliosis . The left leg was 7 cm . shorter than the right. Pertinent laboratory data are recorded in Table n. In addition, results of routine liver function studies were within normal limits . Roentgenograms of the entire skeleton showed no evidence of progression of the process when compared with films obtained fourteen years previously . Pertinent hemodynamic observations made at the time of the cardiac catheterization are recorded in Table us and Figure 7 . Summary : This sixty-eight year old retired school teacher had extensive cranial and long bone involvement and pigmentation, but no history of precocious puberty . The serum alkaline phosphatase at the time of the cardiac catheterization was 4 .2 Bodansky units . The cardiac index of 4 .6 . ./minute/M2 was L elevated . Polyostotic Fibrous Dys¢lasia

vi . A fifty-one year old married Negro housewife and school teacher (G . M . T.) was in good health CASE

until 1950 when, at the age of forty, "flu" developed characterized by malaise, fever and a cough . She was referred to the Radiology Department of the Duke Medical Center solely for a gastrointestinal series . No history, physical examination or other studies were recorded . Fluoroscopic and roentgenologic examination showed a large pleural effusion at the base of the left lung, and moderate fluid at the base of the right lung. (Fig . 8 .) The heart was considerably enlarged in all diameters . No lesion of the gastrointestinal tract was demonstrated . The symptoms gradually subsided and in 1951 she was able to resume her activities as a school teacher . In 1955 weakness developed in the lower extremities, gradually progressing to involve the muscles of the trunk so that she was unable to sit erect or walk without assistance . She was admitted to the University of North Carolina Memorial Hospital, Chapel Hill, North Carolina on October 10, 1956, for evaluation . Pertinent physical findings recorded in the records of that hospital* included a blood pressure of 160/80 mm. Hg, pulse 80, respirations 20, temperature 37 ° c . Fine crepitant tales were audible over the lower third of the lungs posteriorly . The heart was enlarged 1 cm . to the left of the mid-clavicular line in the fifth left interspace . A grade 3/4 systolic murmur was audible over the entire precordium, maximum to the left of *Kindly supplied by Dr . Louis Welt, University of North Carolina School of Medicine, Chapel Hill, North Carolina . AMERICAN JOURNAL OF MEDICINE



Polyostotic Fibrous Dysplasia-Mclntosh et ¢l .

40 1

aken in 1950 ; right, taken in 1958 .

the sternum in the third intercostal space. This murmur was poorly transmitted into the neck . The liver was enlarged 3 cm . below the right costal margin, There was no pitting edema . The patient was unable to raise herself to a sitting position or to arise from the squatting position . No evidence of muscular atrophy was apparent . No other abnormal neurologic findings were noted . There was a hard bony protruberance over the left eye which had been present since childhood . A roentgenogram of the chest revealed cardiomegaly and pulmonary congestion . (Fig . 8 .) A dysostosis of the left fifth rib was present . Roentgenograms of the skull revealed an irregular expansion of the calvarium on the left, involving the occipital and parietal areas . The outer and inner tables were intact . Within the calvarium were areas of radiolucency with irregular sclerotic bone. Similar lesions were present in the left ilium and ischium as well as the left humerus and the left tibia . No lesions were present in the right half of the body . These lesions were compatible with polyostotic fibrous dysplasia . No specific therapy other than the ingestion of digitoxin and the restriction of sodium was recommended . The patient's condition did not improve, and she was admitted to the Duke Medical Center for study in July 1957 . The history and physical examination were essentially as previously noted. Pertinent laboratory data are recorded in Table n. A muscle biopsy specimen was thought to be compatible with polymyostitis . During the first eight days of hospitalization, the patient had a low grade fever . In view of the muscle biopsy she was given prednisone, 10 mg . per eight hours. She promptly became afebrile and improved symptomatically . The administration of digitoxin and restriction of sodium were continued . The improvement was most gratifying. Her muscle strength increased so that she was able to resume her VOL .

32,

MARCH

1962

duties as a school teacher . Symptoms of congestive failure subsided and she gained 30 pounds of weight . The anemia disappeared and the dose of prednisone was gradually reduced to 5 mg. twice daily . The patient was readmitted to the Duke Medical Center for re-evaluation and cardiac catheterization in June 1958 . The blood pressure was 170/85 mm . Hg, pulse 100, respiration 16 . Funduscopic examination revealed grade 2 hypertensive changes . The neck veins were not distended . Fine crepitant rales were present posteriorly at the base of both lungs . The heart was enlarged 1 cm . beyond the mid-clavicular line in the fifth intercostal space . The second aortic sound was greater than the second pulmonic sound . A grade 3 114 systolic murmur was audible over the entire precordium, but was maximum in the aortic area and was transmitted into the neck . The liver was palpated 3 cm. below the right costal margin . There was no edema of the ankles . No specific muscle weakness could be demonstrated . No pigmentation was present . Pertinent laboratory data are recorded in Table n . Roentgenograms of the skeleton revealed no changes from those previously reported . The chest roentgenogram is reproduced in Figure 8 . Pertinent catheterization data are presented in Table in and Figure 7 . Summary : This fifty-one year old Negro woman had extensive unilateral skeletal involvement but no pigmentation or history of precocious puberty . The nature of the illness that occurred at age forty is unclear. The chest roentgenogram at that time showed considerable eardiomegaly and evidence of congestive failure . (Fig . 8 .) She recovered from that illness, however, without residual symptoms . An unclassified polymyositis then developed as well as signs



402

Polyostotic Fibrous Dysplasia-McIntosh et al .

of congestive heart failure . Serum alkaline phosphastase was 3 .8 Bodansky units . At the time of the catheterization she had cardiomegaly and significant pulmonary hypertension . Despite the evidence of congestive failure, the cardiac index was 3 .9 L ./minute/M' . The iliac A-V oxygen difference on the left (side of major skeletal involvement) was 3 .4 volumes per cent ; the right was 5 .6 volumes per cent . COMMENTS

These six patients had extensive disseminated fibrous dysplasia . Cranial involvement was present in all, producing obvious distortion of the facies in four (Cases it, III, v and vi) . Only one patient (Case it) had extensive bilateral involvement . Five of the six patients had mixed arteriovenous oxygen differences less than 4 volumes per cent . The cardiac index was 3 .9 L ./minute/ M 2 . or greater in five . No previously recognized systemic cause was found to explain the increased flow in these patients . The increased cardiac output could be the result of (1) anxiety, (2) increased metabolic demand as a result of the polyostotic fibrous dysplasia, or (3) increased vascularity, i .e ., arteriovenous shunts, most likely in the bony lesions . Anxiety did not seem to be a factor during the studies . In no patient was the oxygen consumption or respiratory minute volume increased above normal values . If the increased flow were due to increased metabolic activity, the arteriovenous oxygen difference across involved bone would be large . If, however, the increased flow were due to arteriovenous shunting, the oxygen difference would be narrow . Both patients with bilateral pelvic and femur involvement (Cases i and it) had an iliac A-V oxygen difference of 1 .7 volumes per cent or less bilaterally . The iliac A-V oxygen difference in one patient (Case nt) on the left (side of major involvement) was 5 .5 volumes per cent ; on the contralateral side, 8 .7 volumes per cent . Another patient (Case vi) had major involvement in the left pelvis . The iliac A-V oxygen difference on that side was 3 .4 volumes per cent ; on the contralateral side, 5 .6 volumes per cent . These findings strongly suggest that arteriovenous shunting occurs in regions involved by fibrous dysplasia . That the bony lesions contained functioning A-V fistulas is suggested by the presence of borderline or definite cardiac enlargement in

three patients (Cases t, n and vi) (Fig. 1, 3 and 8) ; by a systolic bruit over an area of extensive cranial involvement in another (Case n) ; and by the horizontal QRS vector of the electrocardiogram in a six year old girl (Case I) . The biopsy material obtained in these patients was carefully examined to determine the degree of vascularity . The vascular pattern was extremely variable . Some areas of the tissue were avascular ; elsewhere there were numerous thin-walled sinusoidal capillaries . These findings are similar to those reported in the literature [7-3,12,14,15] . Fries [15] observed that when the deposition of bone proceeded more rapidly, the vascularity was more abundant ; areas consisting of more fibrous tissue and less bone were less vascular . These studies would suggest that the lesions of polyostotic fibrous dysplasia contain functioning A-V fistulas which are capable of increasing regional blood flow and occasionally cardiac output . The increased flow may occasionally result in cardiac enlargement and possibly contribute to congestive heart failure . Circulatory alterations accompanying polyostotic fibrous dysplasia have not been emphasized in the English literature . No report of a cardiac catheterization was found in over 150 case reports of polyostotic fibrous dysplasia which were reviewed . Cardiomegaly, demonstated before death, was reported in only two cases [16,17] . One of these patients had associated hyperthyroidism [16] . Only five autopsy reports were found [9,18-21] . The heart was enlarged in three of these cases, but other primary causes could be invoked to explain enlargement in all three . Similar hemodynamic alterations to those observed in this study have been reported in Paget's disease (osteitis deformans) [22-26] . The increased vascularity apparently is more extensive in Paget's disease than in fibrous dysplasia . This vascularity has been repeatedly emphasized in reports of biopsy and autopsy material and has been demonstrated by arteriograms [22,23,26] . In fact, Paget [27] in his original description in 1877 pointed out that the skin temperature was increased over affected bones . Edholm and Howarth [24] found the cardiac output increased in patients with Paget's disease only when the process was active (alkaline phosphatase above 45 King-Armstrong units) or extensive (greater than 35 per cent of the skeleton involved) . The present series is too AMERICAN JOURNAL OF MEDICINE



Polyostotic Fibrous Dysplasia-Mclntosh et al . small to make any such correlation in polyostotic fibrous dysplasia . The series is large enough, however, to demonstrate that increased flow does occur through bone invaded by fibrous dysplasia . SUMMARY Six patients with polyostotic fibrous dysplasia were studied clinically and by cardiac catheter technics . Cardiac enlargement was present in three

of

the six patients . The resting cardiac index exceeded normal values in five of the six patients . Selective venous sampling revealed narrow oxygen differences across areas

of

A-V

extensive

skeletal involvement.

of A-V

It is concluded that the osseous lesions fibrous dysplasia

contain functioning

fistulas . Polyostotic fibrous dysplasia may be accompanied by high output cardiac failure . It is concluded that polyostotic fibrous dysplasia is accompanied by circulatory changes qualitatively similar to those found in Paget's disease (osteitis deformans) . Acknowledgment : We wish to express our appreciation to Drs . Norman Berry, James Bacos, and Howard K . Thompson, Jr . who assisted in several of the catheterizations ; to Miss Anne Stallings, Mrs . Henry Dixon, Mrs . Clyde Gilbert and Mrs . Dudley Price; and to Mr. Elon Clark, Director . Medical Illustrations Department, Duke Medical Center . REFERENCES 1 . LICHTENSTEIN, L. Polyostotic fibrous dysplasia . Arch . Surg ., 36 : 874, 1938 . 2 . ALBRIGH'r, F ., BUTLER, A. M ., HAMPTON, A . 0 . and SMITH, P . Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction with precocious puberty in females . New England J. Med., 216 : 727, 1937 . 3 . PRITCHARD, J . E. Fibrous dysplasia of bones. Am . J. M. Se ., 222 : 313, 1951 . 4 . HICKAM, J . B . and FRAYSER, R. Spectrophotomctric determination of blood oxygen . J. Biol. Chem., 180 : 457, 1949 . 5 . NICOLADONI, C . Phlebarteriectasic dcr rechten oheren Extremitat . Langenbeck's Arch . f. kfin . Chir ., 18 : 252, 1875 . 6 . BRANHAM, 11, II . Aneurysmal varix of the femoral artery and vein following a gunshot wound . Internat . J. Song,, 3 : 250, 18907 . ALLDREDGE, R. H. Localized fibrocystic disease of bone : results of treatment in 152 cases . J. Bone & Joint Surg ., 24 : 795, 1942. 8 . MORCENSEN, E . G . Fibrous dysplasia of bone . Report of an unusual case with endocrine disorders . Aria med. 5'candinao., 161 : 453, 1958 . VOL . 32, MARCH 1962

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9 . ALBRIGHT, F., ScowLLE, B. and SULxOwITGH, H . W . Syndrome characterized by osteitis fibrosa disseminate, areas of pigmentation, and gonadal dysfunction . Endocrinology, 22 : 411, 1938 . 10 . DOCKERTY, M. B ., MEYERUING, H . W. and WALLACE, G . T . Albright's Syndrome. (Fibrous dysplasia of bones with cutaneous pigmentation in both sexes with gonadal dysfunction in females .) Proc . Staff Meet, Mayo Clin ., 19 : 81, 1944. 11 . HUNTER, D . and TURNBULL, H . M . Hyperparathyroidism : generalized osteitis fibrosa ; with observations upon the bones, the parathyroid tumors, and normal parathyroid glands . Brit. J. Surg., 19 : 203, 1931-32 . 12 . FALCONER, M . A., CoPE, C. L . and Roan-SMITH, A . H. T. Fibrous dysplasia of bone with endocrine disorders and cutaneous pigmentation (Albright's disease) . Quart . J. Med., 11 (as .) : 121, 1942 . 13 . NELLF.R, J. L. Osteitis fibrosa cystica (Albright) . Am . J. Die . Child., 61 : 590, 1941 . 14 . VALLIS, J ., POLAK, M. and ScHAJovscz, F . Fibrous dysplasia of bone . J. Bone & Joint Surg., 32a : 311, 1950 . 15 . FRIES, J . W. The roentgen features of fibrous dysplasia of the skull and facial bones : a critical analysis of 39 pathologically proven cases . Am . J. Roentgenol., 77 : 71, 1957 . 16 . HIRSCH, I . S . Generalized osteitis fibrosa . Radiology, 12 : 505, 1929. 17 . MURRAY, R . C ., KIRKPATRICK, H . J . R . and PORRAI, E . Albright's syndrome (osteitis fibrosa disseminata) . Brit. J. Surg., 34 : 48, 1946-47. 18 . STERNBERG, W. H . and JOSEPH, V. Osteodystrophia fibrosa combined with precocious puberty and exophthalmic goiter : pathologic report of a case. A .- J. Dis'. Child ., 63 : 748, 1942 . 19 . HARRIMAN, D . G. F. and MILLER, J . H . D . Fibrous dysplasia with skeletal lipoid granulamatosis ; case with necropsy . J. Bone & Joint Sarg ., 36B : 95,1954 . 20 . WIGGINS, J . C. Polyostotic fibrous dysplasia with extraskeletal features (Albright's syndrome), case with postmortem observation . North Carolina M. J., 16 : 520, 1955 . 21 . JERVIS, G . A . and SCHEIN, H . Polyostotic fibrous dysplasia (Albright's syndrome), case showing central nervous system changes . Arch . Path ., 51 : 640,1951 . 22 . EDHOLM, () . G-, HOWARTH, S . and MCMIGHARL, J . Heart failure and bone blood flow in osteitis deformans . Clin. Sc ., 5 : 249, 1945 . 23 . HOWARTH, S . Cardiac output in osteitis deformans . Cin. Sc ., 12 : 271, 1953 . 24 . EDHOLM, 0 . G . and HOWARTH, S . Studies on the peripheral circulation in osteitis deformans . Clin . Se., 12 : 277, 1953 . 25 . LEQVIME, J . and DENOLIN, H. Circulatory dynamics in osteitis deformans . Circulation, 12 : 215, 1955 . 26 . SORNB£RCER, C. F. and SMEDAL, M . I . Mechanism and incidence of cardiovascular changes in Paget's disease (osteitis deformans) : critical review of literature with case studies, Circulation, 6 : 711, 1952 . 27 . PAOET, J. On a form of chronic inflammation of bones (osteitis deformans) . Tr. Med. chir . Soc. Land., 60 : 37, 1877 .