hershkovitz i et al. 1997. recognition of sickle cell anemia in skeletal remains of children

8/14/2019 Hershkovitz I Et Al. 1997. Recognition of Sickle Cell Anemia in Skeletal Remains of Children.

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Recognition of Sickle Cell Anemia in SkeletalRemains of Children

ISRAEL HERSHKOVITZ,1,3 BRU C E M. RO THSC HI L D,2

BRUCE LATIMER,1,4 O L I VI E R DU TOU R, 5 G E O R G E S L E ONETTI,5

CHARLES M. G REE NWALD,1 C HRI STI NE RO THSC H I L D, 2

AND LYMAN M. J ELLE MA11Th e Cleveland M useum of Natur al H istory, Cleveland , Ohio 44106-17672Art hri t is Center of Northeast Ohi o and Nort heastern Ohio U niversit iesColl ege of Medi cine, Youngstown, Ohi o 445123Department of Anatomy and Anth ropology, Sackler Faculty of M edicin e,Tel Aviv University, Tel Aviv 69978, Israel4Depart ment of A natom y, School of M edi cine, Case Western ReserveUniversity, Cleveland, Ohio 44106-49215U M R 6578 , C N RS Un i versi te de l a M edi ter r an ee, F acul te de M edecin ede M arseil le, 13385 M arseil le Cedex 5, France

K E Y W O R D S an emia; bone pat hology; children; iron defi ciency

A B S T R A C T The present study discusses in deta il the osteological chang esa s s o cia t e d wit h s ick le ce ll a n e mia in ch i ldre n a n d t h e ir import a n c e indiff ere n t ia l dia g n os is. P o s t erior ca lc a n e a l a n d s pe cifi c a r t ic ula r s u rfa c edisruptive meta carpal lesions a re dia gnostic for sickle cell anemia. Ca lvarialthickening, t ibial and femoral cort ical bone thickening, and bowing are ofmore limited utility in differential diagnosis. Granular osteoporosis, pelvicde min e ra l iza t ion a n d r ib broa de n in g a re n on s pe cifi c . L oca l ized ca lv a ria lba llooning,previously not described, ma y ha ve dia gnostic signifi cance. Bonema rrow hyperplast ic response (porotic hyperostosis) in sickle cell anemiap rodu ce s min ima l ra diolog ic c h a n g es con t ra s t e d wit h t h a t obs erv ed intha lassemia an d blood loss/hemolytic phenomenon.

Two other issues, t he osteological criteria for discriminat ing am ong theanemias and the purported relat ionship between porotic hyperostosis and

iron deficiency anemia, are also discussed. There is sufficient information toproperly diagnose the four major groups of anemias, and further, to establishtha t iron defi ciency is only indirectly a ssociat ed wit h porotic hyperostosis. Thehyperprolifera tive bone ma rrow r esponse (ma nifest a s porotic hyperostosis)t oblood loss or hemolysis exhausts iron stores, result ing in secondary irondefi ciency. Am J P hy s Ant hr opol 104:213226, 1997. 1997 Wiley-Liss, I nc.

A prevalent subject of study in palaeopa-t h olog y h a s bee n s t ru c t u ra l a l t era t io n s a t -tributed to anemia. The dat a a re frequentlyused to gain insight to broad biological pro-cesses (e.g., population migration and diffu-

sion of genes, origin of agriculture, and therelat ionship between economic tra nsit ion,evolutionary processes, etc.), in addition todefining the health of a specific populat ion(Hooton, 1930; Angel, 1966; El-Najjar et al.,1975; El-Najjar and Robertson, 1976; Lalloet al. , 1977; Mensforth et al. , 1978; Mens-forth, 1985; Walker, 1985, 1986; Palkovich,

1987; Hershkovitz et al., 1991). The validityof this a pproach is predicat ed on the a bilityto dist inguish accurately among the variet-ies of a n e mia . A lt h o ug h O rt n er a n d P u t -schar (1981: 263) suggested that differen-

t i a l d i a g nos is of a n e m ia i n d r y s ke le t a lspecimens may not be possible without con-sidering other va ria bles, including biochem-

*Correspondence to: I . Hershkovitz , Depart ment of Anat omyand Anthropology, Sa ckler Fa culty of Medicine, Tel Aviv U niver-sity, Tel Aviv 69978, Isra el. E-mail: ana [email protected] u.ac.il

Received 6 February 1996; accepted 16 J uly 1997.

AME RI CAN J OURNA L OF PH Y SICA L AN THR OPOL OGY 104:213226 (1997)

1997 WIL EY-L I SS, INC.


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istry, there may be reason for greater opti-mism. Subsequent studies (e.g., Rothschildand Sebes, 1981; Stuart-Macadam, 1987a,b;R e sn ick a n d N iwa y a ma , 1988; J oh a n s o n ,

1990; Rioja et al . , 1990; Babhulkar et al . ,1995; Bast ian, 1995) suggested addit ionalsigns, which appear diagnostic for specificvariet ies of a nemia.

The rarity of macroscopic descriptions ofthe skeletal impact of specific variet ies ofanemia s, based on exam inat ion of the entireskeleton of individual(s) with documentedcase histories, contra sts wit h the ma ny ra dio-logic reviews (e.g., Brit ton et a l. , 1960; Sha -hidi and Diamond, 1960; Burko et al. , 1961,1963; La nzkowky, 1968; S tua rt-Macada m,1987a ). As t he la tt er often empha size subtlefindings, i t seemed appropriate to exploremacroscopic correlates of such phenomena.The aim of the present study is to describe indeta il the osteologic chan ges in a child knownto have sickle cell anemia (SCA).

MATERIALS AND METHODS

The skeleton (H TH 1784) of a 6-yea r-oldboy with splenomegaly and peripheral andcentral thrombotic phenomena, secondaryto sickle cell a nemia (1928 Lakeside Hospi-tal record no. 122388), was examined at theC l ev el a n d M u se um of N a t u r a l H i s t or y,wh e re t h e s k elet o n is n ow h ou s ed in t h e

Ha ma nn-Todd collection.Th e s ke le t on w a s com p le t e, w i t h a l le piph y s e s. M a c ros cop ic e xa min a t ion wa sperformed, especially noting cha nges in ca l-varial bones, facial architecture and sinuses,long bones and ribs. Autopsy x-rays werecompared to those taken of isolated bones.The morphometrical char a cteristics of HTH-1784 used to assess developmental problemswere derived from thr ee sources: 1) measu re-ments taken directly from the bones [claviclele n g t h , s c a p u la h e ig h t a n d bre a dt h , t h re em ea s u r em e nt s on e a ch r i b, i n n om i na t eh e ig h t a n d widt h , s ize o f v e rt e bra l c a n a l ,

size of basivertebral foraminae and cranialm o du l e (m a x i m u m l en g t h m a x i m u mbre a dt h ba sion-bregma height/3) follow-ing methods described in B ass (1987), 2)metrica l informa tion recorded by Todd fromthe cada ver (e.g. , head measurements), a nd3) me t r ica l in forma t io n f rom t h e h os p it a lrecords (stature and weight). Comparat ive

growth da ta were obta ined from H erskovits(1924), S imm ons a nd Todd (1938), a nd Sim -mons (1944).

Our genera l control group (aged 4 t o 16)

comprised of 24 skeletons of children andsuba dults from th e Ha ma nn-Todd Osteologi-cal C ollection (HTOC) a nd 26 children fromthe collection of the D epart ment of Ana tomya n d An t h r o po lo g y, Te l Av iv U n iv e rs i t y(TAU OC). As only fi ve children, a ged 6, ofthe contr ol sample (tw o from t he HTOC a ndthree from t he TAUOC ) were a vailable, totest the correspondence of the HTH-1784child measurement s to his age cohort, linearregression analysis was performed. Linearregression along with the 95% confi denceinterval w as computed using measurementsta ken from all ava ilable children w ithin the4 to 9 year a ge interva l. To avoid deviat ion oflinearity, no measurements from older chil-dren w ere included. Each mea surement of theHTH-1784 child w a s th en compa red a ga instthe respective predicted mea n a t each a ge.

A special ma croscopic exa mina tion of ca l-canei from all suba dults (47) an d 200 a dultsfrom the Ha ma nn-Todd collect ion wa s alsoperformed.

RESULTS

Skeletal alterat ions were predominantlyt h os e re fl e ct in g bon e ma rro w h y p erp la s ia

an d va scular compromise (e.g., thr ombosis).The ma jor cha nges observed in t he skeletonare described below, from a regional perspec-tive.

The skull

General thickening of the calvarium waspresent (Fig. 1). A marked ectocranial sur-fa ce disrupt ion (porotic hyperostosis), involv-ing large areas on both sides of the sagit tals u t u re , wa s l imit e d t o t h e p a rie t a l bo n e s(Fig. 2). The thickening of the diploic spacewas limited (on anteroposterior and lateralx -ra y v iews ) t o f ron t a l a n d p a riet a l bon e s,

sparing th e coronal suture r egion, but withmild thickening of the orbital roof. Endos-teal resorption of the externa l d iploic platein the parietal region was so extensive thatit resulted in its virtual effacement, with theexception of a multila mina ted ba lloonedarea in the parietal bone (described below).Slight perpendicular tra beculae w ere noted

214 I . H ERS H KO VITZ ET AL.


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in this a rea, probably representing a n earlyh a ir-o n -e n d re a c t io n . Th e in n e r t a ble

showed no signs of porosity on macroscopicexamination, or thinning on radiologic ex-amination, although a generalized granulartexture was noted. The skull size (cranialmodule) wa s within the ra nge (95% confi -dence limits) of t he regression of th e contr olgroup age mean, and sha pe abnorma lity wa slimited to th ose in th e diploic plat e, as noteda bove. Todds records on th e ca da ver (ma xi-m u m h ea d l en g t h 194 mm; ma x imu mh e a d widt h 138 mm; auricular height 117. 5 m m ) a l so i m pl y t h a t h ea d s iz e i swithin the normal range.

Marked ectocranial ballooning (as dis-

t inct from bossing, see Discussion) wa spresent in the par ieta l, fronta l and tempora lbones. While ectocra nial texture w as unaf-fected in those regions, macroscopic exami-nation revealed hyperpigmented (blue-black)punctua te ectocra nial discolorat ions from0.1 to 0.4 mm in size. Present at a d ensity of2040 per cm 2, t hese spots w ere limited in

distribution to the regions of marked ectocra-n ia l ba l loon in g. Tra n s i l lu min a t ion of t h e

ba llooneda rea s revealed increased densit ys im i la r t o t h a t n ot e d i n a r e a s of p or ot i chyperostosis.

F a c ia l a rc h i t ect u ra l re la t ion s h ips we renormal. No pathological changes were ob-served in the maxillary or frontal sinuses.The hard palate was thickened with accen-tuation of vert ical trabeculae. The linguala s p e c t o f t h e ma x il la ry a lv e o la r a rc h wa sthickened (34 m m), producing a medial swelling adjacent to the molar teeth. Theman dible wa s robust , with very slight supra-lingula periostea l new bone deposition.

Shoulder girdle

The size and shape of clavicles (length 97.9 mm) and scapulae (height 89.9 mm;bre a dt h 67. 2 mm) w e re w it h in t h e 95%con fi de n ce l imit s of t h e re g res s ion of t h econtrol group mean age. Slight porosity wasp r es en t i n t h e m e t a ph y s ea l r e gi on s ofclavicles and vertebral region of scapulae. A

Fig. 1. Midsagitt al section of the skull. Thickened fronta l, parieta l an d occipita l bone diploic space,with lamellar ra diat ions (hair-on-endph enomena ) noted only in superior as pect of parieta l bone.

215S I C K L E C E L L A NE M I A I N C H I L D R E N


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minimal a mount of new periosteal bone wasnoted along a 1 cm swath, distributed on theventral a spect of the entire vertebral ma rgin

of the scapula e.Upper limb

All epiphyses a nd a rt icular surfaces weref ree of p a t h o log ica l p roce s se s on ma c ro-scopic examination. Porosity was noted inthe proximal hum eral meta physes, both r a-dia l me t a p h y s e s ( dis t a l s ig n ifi c a n t ly mo reaffected tha n proximal), and the dista l ulnarm e t a p hy s es . S l i gh t b on e d ep os it i on w a snoted in areas of tendon at tachment, alongthe radial and ulnar diaphyses (ulnae moreaffected than radii) . Intracort ical bone re-sorption and mild endosteal scalloping were

noted on x-ra y examina tion.M a cr os cop ic e xa m i n a t i on of h a n d a n dw r i st b on es w a s u n r em a r k a b le , w i t h t h eexception of cortical disruption of the distalart icular aspect of the left second metacar-p a l . A s l ig h t p eg -l ik e a p p ea ra n ce of t h edistal epiphyses of the proximal a nd middlep h a la n g es wa s n ot e d. M e t a c a rp a l les ion s

included a m argina l erosion a nd a subchon-dra l defect. The lat ter a ppea red as a 0.5 mms eg m en t of or d i n a r y cor t i ca l b on e , s u r -

rou n ded by a n u n dermin in g ly t ic zon e a p -p ro x ima t e ly 2 mm in dia me t e r a n d 1 mmdeep. Endosteal and intracort ical bone re-sorption with minimal linear periosteal newbon e f orma t io n we re n o t e d o n t h e ra dio-graphs.

Thoracic cage and vertebrae

The ribs of HTH-1784, compared to thecontrol group, were thicker (third rib: A-P(mid-shaft) 4.5 mm, Circum. 23.8 mm;fourth rib: A-P 5. 1 mm, Circ u m. 24.2mm) throughout their entire length (third

r i b con t r ol : X A-P 4.20; S . D .A-P 0.67;

Xcircum

121.74; S.D .circum

2.76). En dos-tea l sca lloping and int ra cortica l bone resorp-tion, with slight trabecular coarsening, werenoted on the ra diographs. All vertebra e wereof s t a n d a r d s iz e a n d s h a pe . Va s cu la r f o-ram ina (especially t he ba sivertebral) werela rg e , 5 4 mm (Fig. 3). A slight porositywa s present on the ventral surfaces of lum-

Fig. 2. Superior view of skull. P ar ietal bone porotic hyperostosis.



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bar vertebral bodies. A lateral x-ray of thevertebra e revealed osteopenia with a coar senedappeara nce of the residual body tra beculae.

Pelvis

Th e t wo in n omin a t e s we re h ig h (129.0

mm) and na rrow (80.0 mm), with the iliumla cking the ty pical mus hroomsh a pe. Whilethe a rea (product of length a nd w idth) of thea l a e w a s n ot i ncr ea s ed ov er t h a t of t h econtrol group, the alae were 20% thickert h a n n or m a l . A l a r g e c or t i ca l d ef ect w a spresent in each iliac acetabular (art icular)surfa ce, penetrat ed by lar ge vascular fora mi-nae. The pubic and ischial bones were unaf-fected.

Lower limb

Minimal periosteal r eact ion wa s noted onboth femoral diaphyses. Metaphyses, epiphy-

s es a n d a r t ic u la r s u rfa c es we re f re e of a n ysign of pat hological process or developmen-ta l disturba nces. Two enlar ged diaphysealnutrient foraminae were present in each ofthe femora. Tibiae a nd femora w ere slightlybo we d a n d fl a t t e n e d a t mids h a f t ( F ig . 4) .Cort ical thickening wa s observed ra diologi-cally on the ant erior aspect.

Ma croscopic foot/a nkle a bnorma lities w erelimited to the ca lcanei. Disruption in surfaceintegrity was noted at the superoposteriora s p ect (F ig . 5), p os t e rior t o t h e a re a ofat ta chment of t he joint (ta localcanea l) cap-sule. This region of compromised surface

integrity wa s located ant erior to the area ofattachment of the Achilles tendon and asso-ciat ed bursa e. Eleven smooth-wa lled sur-f a c e p e rfora t io n s, of i rreg u la r s ize , we relocat ed an terior to a 1.5 mm d eep, 2 mm 3mm, cresent-sha ped depression. A1 m m 2mm fra gment of cortical bone wa s present a tthe base of that depression, with its ma rginspart ia lly undermined. The surrounding r e-gion had been smoothly excavated. Underly-ing the 0.5 to 0.7 mm smooth-walled perfora-t ions was a cyst ic area , approximately 3 mm(diameter), with smooth ma rgins. A dot-dash pat tern of surface discontinuity was

noted on the superoposterior surface of thecalcaneus, between the insertion area of theta localcan eal joint capsule an d t he a nteriorAchilles bu rsa .

O n e o r more n u t r ien t f ora min a ( e) w e represent on 90%of superoposterior calcanea ls u rfa c es in 200 a du lt s . Th re e o u t of 47s u ba du lt s h a d mu lt ip le s ma ll f o ra min a e a t

Fig. 3. P ostero-superior view of thora cic vertebrae. Enlar ged basivertebra l foramina e.



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t h is lo c a t io n , wh ile t h e re ma in de r h a d n osurface alterat ions (other than those at tr ib-uted to deteriorat ing processes within thes t o ra g e dra we rs ) . T h e v e ry t h in n a t u re o fcalcaneal surface bone occasionally allowsdeteriorat ing processes within the drawersor post-depositional deteriorat ing processesin a rc h a e olog ica l ma t e ria l . Th e la t t e r wa sdist inguished from changes of necrosis onbas is of broken, unremodelled tr a beculae.

Developmental assessment

No discrepancy was found between biologi-cal a nd chronological a ge. The biological a geof HTH-1784, assessed from the teeth andbones (U belaker, 1987, 1989; Demirjian ,1 9 8 0 ) , w a s 6 t o 6 . 5 y e a r s , s i m i l a r t o h i schronological age (6 years). The comparisonof of the st a tur e (1,212 mm) a nd w eight (29.5

kg) (hospita l an d Todd records) of HTH-1784with tha t of children his a ge (dat a collectedat the beginning of the century) showed noevidence of developmental delays. The meansta ture of children 6 years old, at the begin-n in g of t h e 20t h ce n t u ry, v a r ie d ( a mon gstudies) from 1,157 m m (S.D. 52.0 mm) to1,177 mm (S.D . 42.8 mm) (Her ksovits, 1924;Sim mons a nd Todd, 1938; S imm ons, 1944).Our observations on the epiphyses (as de-scribed above) confi rmed tha t HTH-1784

had no developmental disturbances.DISCUSSION

The birth of th is child, 12 year s a fter thefi rs t cl in ica l re port of s ick le c el l a n e mia(Herr ick, 1910), fortuit ously a llowed identi-fication of the etiology of his splenomegaly.Th is f u lfi l le d t h e a p riori re q u ire men t in

Fig. 4. Medial view of right femur and tibia. Bowed femur an d tibia.

F i g. 5. S u p er i or v ie w of l ef tcalcaneus. Surface disruptions inre g ion be twe en the i nsert i on ofthe Achilles tendon and articularsurfac e ( for the tal us) . Mul t i pleforamena a re present on the calca-n e a l s u r f a ce , a n t e r i or t o a l a r g ed i sr u p t ed a r e a . Th e l a t t e r c on -t a i n s w h a t a p pe a r s t o b e n or m a ls u r f a c e b o n e a t t h e b a s e o f t h ehole.



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clinical diagnosis that a phenomenon mustbe re c o g n ize d a n d be c o difi e d a s dis t in c t .While molecular a na lysis (to distingu ish be-tw een t he SS and SC variet ies of sickle cell

a n e mia ) wa s fi rs t re port e d ( G ra h a m, 1924)during the lat t er port ion of his short l ife, i twa s u n a v a i la ble c l in ic a l ly du rin g h is l i f e -t ime. G iv e n t h e s imila r i t ies bet we e n t h eosseous impa ct of SS a nd SC disease (Roths-ch ild a n d Se bes , 1981; R e s n ick a n d N i-wa yam a, 1988), a bsence of tha t informa tionis of l imited importance. I t is possible thatthe polymerase cha in rea ct ion a mplifi cat ionof DNA extracted from the skeleton couldpotentially resolve the type of sickling dis-ease tha t w as present , should its pert inencebe demonstra ted.

A m a jor p r ob le m of a s t u dy t r y in g t oe st a bl is h dia g n os t ic c r it e r ia , ba s e d on t h eskeleton a lone, is whether all a typical bonyresponses observed are a result of the dis-ease under investigation (in this case SCA).In the following discussion w e try to ma tchour osseous fi ndings wit h dat a (mainly ra dio-logica l) obta ined from reported cases of sicklecell an emia. We omitted from our fi na l list ofdiagnostic criteria bony lesions for which acorrelation could not be identified, althoughsuch correla tions rema in a possibility.

Recognition of SCA in th e skeleton shouldbe carried out in tw o successive stages: thefi r s t , t o i d en t i fy t h e c a s e a s a p a t h ol og ya s s o c ia t e d wit h t h e h e ma t o p o ie t ic s y s t e m(use Ta ble 1); t he second, to t ry to ident ifyth e disea se its elf (use Ta ble 2).

Through the present case we demonstratethe a pproa ch above. The fi rst q uestion is: Dowe ha ve sufficient osteologic evidence tocon clu de t h a t H TH -1784 h a d a p roblemassociated with the hematopoietic system?Wha t a re other possible explana tions for th eobserved pat hological chan ges?

General differential diagnosis

Although diseases of the hematopoietic

s y s t em a re k n own t o a f fe ct t h e bo n es in avery chara cterist ic ma nner (Table 1), fewar e a ctually exhibited. Furt her, the classiccharacterist ics are rarely present in youngindividuals (aged 9 year s).

The best indications for hematopoietic dis-eases a re to be found in t he skull (Ta bles 1a n d 2 ). Th e m os t p r om i n en t os t e ol og i c

ch a n g e s in t h e s k ull of H TH -1784 w e reparietal osteoporosis, parietal, frontal andtemporal bone ba llooning,a nd pa rieta l an dfrontal diploic space thickening. While po-

rotic hyperostosis was clearly present (Fig.2), the ha ir-on-end ra diologic a ppea ra ncewa s subt le an d difficult t o recognize. This isin a ccordan ce with clinical recognition of itsra rity a nd limited severity (28%) in sicklecell anemia (Ca rroll and E van s, 1949; Eh ren-preis and S chwinger, 1952; Sebes a nd Diggs,1979).

Cr a nia l ballooning (sw elling) is differentfrom cranial bossing. The latter is a nor-mal phenomenon which occurs in both chil-dren and adults. Lateral dome-shaped pro-trusion of the t empora l regions and regionsa r ou n d t h e a n t e r ior p a r t of t h e s u pe ri ortemporal l ines are commonly seen in chil-dren. However, they ar e usually n ot a ssoci-a t e d w i t h ch a n ges i n t h e t e xt u re of t h ee ct ocr a n i a l p la t e , or w i t h a n i ncr ea s e i ndiploic space.

Ax ia l ma n if e s t a t ion s in H TH -1784 in -cluded slightly enlarg ed ribs, hypervas cular-iza t ion of v ert e bra e a n d in n omin a t e (a la e )thickening. Absence of vertebra l endplat eindentation is not surprising, given the sub-jects a ge. Vert ebra l cha nges (Fig. 6) a re seenin less than 10%of individuals with sicklecell a nemia (Reynolds, 1966; Ka klama nis,

1984; J oha nson, 1990), t heir occurren ce lim-ited to those who have reached the age of 8y ea r s (K a r a y a l ci n e t a l . , 1976). G r a d u a lindentat ion of adjacent vertebral end platesmay produce a fish-mouth appearance onlat era l x-ra y (Fig. 6). Discontinu ous indenta -t ion can produce an H -shaped vertebralappearance (Reynolds, 1966; Cassady et al. ,1967; K a k la ma n is , 1984; R e sn ik a n d N i-wayama, 1988).

Appendicular skeletal changes predomi-nantly affected the lower extremities. Thefemora and t ibiae ma nifested slight bowingan d cortical bone thickening, but no obvious

narrowing of the medullary cavity. Cort icaldisruption was noted on the superior borderof the calcanei, between the site of Achillest e nd on i n se rt i on a n d t h e t a l a r a r t i cu la rsurface.

Considering the nature of the osteologicchanges in HTH-1784, it is no wonder thatthe diagnosis of anemia in skeletons of past



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TA BL E 1. Osteological changes associated wi th di seases of th e hematopoietic system, by bones

C h a ra ct er is t ics Th a la s se mi a S ick le ce ll S econ da r y i ron d efi c ie ncy P r im a r y i ron d efi c ie ncy

SkullC a l v a r i a 1262%4

Granular osteoporosis 18% Focal pseudo-radiolucent areas 6,7 R

Calva rial thickening

Thinning of outer and inner table 25% Widening of diploe space Porotic hyperostosis Ha ir-on-end(porcupin e qu ill) a ppea r. (x-ra y) R R5 RDiffuse calcification (chalky appearance)6

FaceLa r g e h e a d Lat eral displacement of orbits Sunken nasa l bridge High, prominan t cheek bone (rodent fa cies) Maxillary sw elling Enlarged upper a lveolar r idge

Mandible (alveolar bone)Increased radiolucency Coarsened trabeculae1

SternumSternal widening R Sterna l cupping3 8%

PelvisDemineral ization 32% R R

Protrusio acetabuli 20% Patchy sclerosis 24% Coarse tra beculation 5% R RMedullary hyperplasia Avascula r n ecrosis 1%

VertebraeOsteoporosis R C odfi sh vert ebra R 10% S q u a r ed o ff e nd p la t e d ep r es si on (H -v er t eb r a e) R Enlarged basivertebral foraminae. C olla pse (compression fra ct ures) R S h a p e ch a n g es : i ncr ea s e d w i d th r ed u ce d h ei gh t R Sclerosis (dense ban ds)

Tubula r bonesDemineral ization 62% R RThinned cortex R RWidening medullary space R RMicrofractures Pa thologic fractures R Widening of metaphyses and epiphyses

Retarded bone age

Delay closure of growth plate Prema ture part ial epiphyseal plat e closure Growth deformity

prox. humeral epiphyses2 prox. femoral epiphyses 2 distal femoral epiphyses2 distal t ibial s lant 2 39%

Bone infarcts Bone-within-bone appear ance (osteonecrosis) Enlargement of nutrient foramina Coarse tra beculation 15% R RPatchy sclerosis 27% Osteomyelitis Lace-like appearance of external surface Elongation (pseudo-Marfans syndrome)

RibsBroadening of posterior aspect 32% R RD em inera liza t ion () 26% R RCoarse tra beculation 4% R RSclerosis 32%

Linear density (rib-within-rib) Cortical erosions (and thinning)

Denti t ionDisorderly teeth eruption Malocclusion of jaw s (maxillery overbite) Structura l abnormali ty of the teeth

The da ta presented in Table 1 a re derived from num erous publications; for references, see Table 2.1 Sur rounded by osteoporosis with coarse tr abeculae, produces a step-ladder a ppeara nceis occasionally revea led on x-ray.2 After the age of 10 years.3 Childhood phenomena.4 Number expresses relative population frequency.5 R ra re (manifest in less tha n 1%).6 Only in individuals 50 years.7 Radiolucent areas correspond to hyperplastic bone marrow surrounded by dense sclerotic bone (not lytic areas).


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populat ions is so difficult. G ra nula r osteopo-rosis, pelvic deminera lizat ion and rib broad -ening are quite nonspecifi c. Calvar ial t hick-e n in g a n d t ibia l a n d f e mo ra l c o rt ic a l bo n ethickening and bowing are more limited indifferential diagnosis. Osteomalacia, Pagets

dis e a s e , a n d a c ro me g a ly c a n a ls o p ro du c ethis pa tt ern. Loca lized calvar ial ba llooningis of unknown differentia l significa nce a t thist ime. Differential diagnosis should includeleukemia, osteomyelitis, treponematoses, he-m o ph i l ia , j uv en i l e r h e u m a t oi d a r t h r i t i s(J RA), skeleta l dyspla sia (e.g., t richorhino-phalan geal syn drome), rickets, tha lassemia

and other disorders result ing in hemolysis(e.g., glucose-6-phosphate dehydrogenase de-ficiency), and secondary iron deficiency ane-mia (see next section). Osteomyelitis, w hichoften occurs in individuals with sickle cella n e mia (B u rk o e t a l . , 1963; L a g u n doy e ,

1970), is easily recognized because of theassociated distort ion of bony ar chitecture(Resnick and Niwayama, 1988; Rothschildand Martin, 1993). The limited periostealreact ion and its distribution in HTH-1784contra sts with more extensive involvementin treponemal disease (Ortner a nd P utsha r,1981; Resnick and Niwayama, 1988; Roths-

TA BL E 2. Osteological changes associat ed w it h di seases of th e hematopoietic system1

C ha ra ct erist ics Th a la ssemiaSickle

cellSeconda ry iron

defi ciency2Pri ma ry i ron

deficiency 3

OsteopeniaGeneralized osteoporosis Central vertebral endplate depression Localized osteolysis Mottled osteolysis

Growth di sturbanc eEpiphyseal shortening Epiphyseal closure delay Tibiota lar deformity

Avascular necrosisCollapse of articular surface Cortical discontinuit y Widened, fla ttened epiphysis Epiphysio-meta physeal overlap Femora l hea d collapse/mush room sha pe Proximal humeral collapse

MicroinfarctsCentral metaphyseal plate depression Trian gular epiphyseal deformity4 J uxta -ar ticular 10%

Ca lcaneal surfa ce lesion 9% Sclerosis Medullary canal infarct

Hand foot syndrome5 17% Lytic areas in tubular bones Thinn ed cortices Shortening of digits Subperiosteal new bone format ion P at chy ra diolucency/moth-eaten appear an ce Focal ost eosclerosis

Osteomyelitis

1 Derived from Cooley and Lee, 1926; Cooley et al., 1927; Moseley, 1929a,b; Moore, 1929; Diggs et al., 1937; Caffey 1937, 1952; Carrolland Eva ns, 1949; Ehrenpreis a nd S chwinger, 1952; Prowler a nd S mith, 1955; Ca rroll, 1957; Trowell et a l., 1957; Eng , 1958; Sherma n,1959; Barton and Cockshott, 1962; Burko et al., 1961, 1963; Robinson and Rodnan, 1965; Sarnat, 1962; Moseley, 1963, 1974; Watson etal., 1963; Hewett and Van Nice, 1964; Currarino and Erlandson, 1964; Argen and Sullivan, 1966; Soni, 1966; Aksoy et al., 1966;Reynolds, 1966; Reynolds, 1983; Diggs, 1967; Ca ssady et a l., 1967; Lanzkow sky, 1968; Lagund oye, 1970; Pa tel, 1973; Mourshed a ndTuckson, 1974; Kanyerezi et al., 1974; Espinoza et a l., 1974; Palmer, 1975; Sha ub et a l., 1975; Kara ylcin et a l., 1976; Keitel et al., 1976;Worrall and Butera, 1976; Leichtman et al., 1978; Gratwick et al., 1978; Sebes and Diggs, 1979; Rothschild and Sebes, 1981; Dorwartand Schumacher, 1981; Levine et al . , 1982; Lee et al . , 1981; Ba ker a nd Demos, 1982; Zimmerman and Kelley, 1982; D ardel a nd

Gerst er, 1983; Gorriz et al., 1983; La wson et al., 1981, 1984; Exar chou et al., 1984; Ka klama nis, 1984; deCeulaer et al., 1984; Fink etal., 1984; Keller, 1982; Redma n a nd Nelson, 1985; Scutellari et al., 1985; St uar t-Macada m, 1987a; Ha nker a nd Amstutz, 1988; Resnickand Niwa ya ma , 1988; Orzincolo et a l., 1989; Hernigou et al., 1989, 1991; Korovessis et a l., 1990; J ohanson, 1990; Arman et a l., 1992.2 E.g., hemolytic anemia or blood loss induced marrow hyperplasia.3 Hypoplastic bone marrow.4 Peg-in-a-holedeformit y, noted only in older children a nd a dults.5 Known also as sickle cell dactylitis, a phenomenon noted in children aged 6 months to 2 years. It is very rare after 6 years of age,representing disappearance of red marrow from the small bones of the hands by this a ge.



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ch ild a n d R ot h s ch ild , 1995), e ve n i f t h esa bre-shin rea ction wa s not considered indifferentia l diagnosis. Although fungal dis-ease (e.g., histoplasmosis) can cause digitalperiosteal reaction (Resnick and Niwayama,

1988), pelvic demineraliza tion, rib broaden-in g , c a lv a ria l t h ick en in g a n d ba l loon in g ,t ibial and femoral cort ical bone thickeningand bowing, posterior calcaneal and art icu-lar surface meta carpal lesions do not occur(Hewett an d van Nice, 1964; Diggs, 1967;Lagundoye, 1970; Karayalcin et al . , 1976;Leichtma n et al., 1978; Rothschild a nd Sebes,

1981). Similarly, the various fibrous dyspla-s i a p r od u ce c h a r a c t e r i st i c, w e l l -d e fi n e dchanges in skeleta l morphology an d interna lstructure (Resnick and Niwayama, 1988),

quite different from the deminera lizat ion,rib broadening, calvarial thickening, t ibialand femoral bowing, posterior calcaneal andart icular surface metacarpa l lesions seen inHTH-1784 (Diggs et al. , 1937; Hewett andvan Nice, 1964; Lagundoye, 1970; Karayal-cin e t a l . , 1976; L e ich t ma n e t a l . , 1978;Rothschild and Sebes, 1981). Rickets is rela-t ively easy to dist inguish from sickle cellanemia . E piphyseal a nd m etaphyseal cup-ping, widening a nd fr a ying, ricketic rosar y,an d pseudofra ctures (on x-ra y) (Resnick an dNiwayama, 1988) characterist ic of ricketswere not seen in HTH-1784, while general-ized rib broadening a nd posterior calcanea lerosive disease a re not seen in r ickets.

M a j or e ros ive dise a s e, a x ia l (e .g . , zy g -apophyseal or sacroiliac) joint erosions, fu-sion of axia l (cervical zy ga pophysea l) a nd/orperipheral joints, and micrognathia are allsigns of juvenile rheumatoid arthrit is , andare not found in HTH-1784 (Resnick an dN iwa y a ma , 1988; B u ik s t ra e t a l . , 1990).Pr ematur e epiphyseal closure an d/or bal-looned epiphyses occur in juvenile rh euma -toid arthrit is , tuberculosis and hemophilia(Resnick and Niwayama, 1988; Rothschildand Martin, 1993). While subchondral ero-sions may occur in hemophilia, absence ofe pi ph y s ea l ov er g r ow t h a n d i n t r a o ss eou scysts (pseudotum ors) in HTH-1784, elimi-nate this diagnostic consideration.

Differential diagnosis among thehematopoietic diseases

E v e n i f a l l t h e re q u ire me n t s n e e de d t odiagnose (in an archaeological skeleton) adisease of the hema topoietic syst em ar e met(Table 1), the challenge of identifying theactua l disease st ill exists.

Co mpa rin g ou r obs erv a t io n s o n H TH -

1784 to known osteologic changes associatedwit h dis ea s e of t h e h e ma t o poiet ic s y s t e m(Ta ble 2) exemplifi es t he challenge of spe-cific dia gnosis. Much of t he dia gnostic list(e .g . , g r o wt h dis t u rba n c e , m icro in f ra c t s ,han d-foot syndrome, etc.) wa s not demon-strated in HTH-1784. Observation of suchch a n g es i n a s in g le i n d iv id u a l w i t h S C A

F i g. 6 . L a t e r a l x -r a y v ie w of t h o ra c ic v e r t eb r a e .Growth pl ate i nde ntat i on pat t e rns produce fi sh-mouthappearance of disc space (central portion of figure) andH-shaped appear an ce of vertebra e (superior a nd inferioraspects of fi gure).



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under age 9 is infrequent in clinical popula-t ion s . H owe v er , t h o s e p re se n t ma y be o fgrea t va lidity (see Ta ble 2) in differentia tingSCAfrom other hematopoietic diseases.

Of the osteologic changes manifested byHTH-1784, only th e posterior calcanea l a ndart icular surfa ce metacar pal lesions appeardiagnostic for sickle cell anemia (Diggs etal., 1937; Hewett and van Nice, 1964; Lagun-doye, 1970; Karayalcin et al. , 1976; Leicht-ma n e t a l . , 1978; R ot h s ch ild a n d Se bes ,1981). As specific alterat ions are noted in

on ly 14% of in div idu a ls wit h s ick le ce llanemia (Rothschild a nd Sebes, 1981), a noverall picture must be utilized in differen-tial dia gnosis [unless individual fi ndings ar epathognomonic (e.g. , calcaneal lesions are

present)]. The calcanea l lesions noted insickle cell a nemia a re quite distinct from thebroken, unremodelled trabeculae of storageor post-depositional processes and forami-nae occasionally noted in otherwise appar-ently healthy suba dults.

Tha lassemia classically produces such a g-gressive marrow hyperplasia, that the hair-on-end phenomenon is relat ively common.This is in contrast to its rarity in sickle cellan emia (Carr oll and Eva ns, 1949; Ehrenpreisand Schwinger, 1952; Diggs, 1967; Sebesa nd D iggs, 1979). As fa cial bone involvement

is s e e n o n ly in t h a la s s e mia (R e sn ick a n d

Niwa ya ma , 1988), it is an importa nt dia gnos-t ic fi nding when present . Ha nd-foot-syn-drome, which occurs in 17% of individua lswith sickle cell anemia, is not diagnostic, asit also occurs in thalassemia, fungal infec-t ions, rickets, leukemia an d perha ps juve-nile rheumat oid a rthr itis (B urko et a l. , 1963).

Permeative cort ical lesions and radiolu-cent metaphyseal bands (on x-ray), so char-a c t er i st i c of l eu k em i a (R e sn i ck a n d N i -wayama, 1988), were not seen in HTH-1784.

Infa rction of long tubula r bones and ca lca-n e i a p p e a r o n ly in s ic k le c e l l a n e mia a n d

allow confident dia gnosis when present. Thelimited occurrence of t his phenomena re-q u i r e s a n a l y s i s o f t h e o v e r a l l n a t u r e a n dpa tt ern of osseous cha nges (Ta bles 1 a nd 2),if confident diagnosis is to be obtained. Thediagnostic significan ce of th e reported fi nd-ings a re indicat ive of sickle cell anemia , an dnot a sickle cell tra it . The lat ter is not know n

to produce bony changes (Resnick and Ni-wayama, 1988).

Tables 1 an d 2 summa rize th e osteologicchanges a ssociat ed wit h iron defi ciency (pri-

ma ry a n d s e con da ry ). I ron de fi c ie n cy a n e -mia must be considered separately, as theosseous changes appear related to the pri-mary disease (bone marrow hyperplasia sec-on d a r y t o h e m ol y t i c a n e m i a , i n eff ect i v eerythropoiesis, or response to blood loss)(Fairbanks and Beutler, 1995), rather thanto the iron deficiency. Disorders stressinghemat ologic homeosta sis (e.g., hemolyticanemia, ineffective erythropoiesis, blood losssecondary to parasitic infections) result in ahyperplast ic ma rrow response. The la t tertypica lly progresses until essentia l nutr ients/cofactors a re consumed.

Any relationship between iron deficiencyan d porotic hyperostosis t eleologica lly mustbe indirect. After all, the very presence of theha ir-on-end phenomenon a nd porotic hy-perostosis identifies hyperplastic bone mar-row. The dia gnosis of iron defi ciency a nemiaimplie s t h a t t h e re is in a de q u a t e iron f orblood cell production (Fairbanks and B eut-ler, 1995). Thus, iron defi ciency producesh y p ore ge n era t iv e ma rro w (F a irba n k s a n dB eutler, 1995), th e opposite of porotic hy per-ostosis. Finch (1970:412) ha d clea rly demon-stra ted t he effect of limited iron supply . . .

in limiting marrow proliferation. Althoughiron defi ciency can not produce porotic hyper-ostosis, the conditions that produce porotichyperostosis can induce iron deficiency ane-mia . A n y p ro ce ss t h a t in cre a s es ma rro wactivity increases consumption of basic nutri-e n t s (F a irba n k s a n d B e u t ler , 1995). I rons t ore s a re t y p ica l ly t h e mos t ra p idly de -pleted, resulting in iron deficiency and sec-ondary iron defi ciency a nemia. S evera l suc-ces si ve s t a g es of i ron d efi c ien cy a r erecognized: Init ially decrement in storageiron occurs, w ithout decline in level of func-tiona l iron compounds (iron depletion). After

iron stores are exha usted, la ck of iron limitsproduction of hemoglobin and other act ivecompounds that require iron as a constitu-ent or cofactor, a nd iron-deficient an emiadevelops (Fairba nks a nd B eutler, 1995).

Clearly, HTH-1784 did not exhibit any ofthe bony chang es a ssociat ed with prima ry orsecondar y ir on defi ciency disea ses (Ta bles 1



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and 2), w hich leave us with the S CA optionas t he most likely diag nosis.

In the present study we discuss in detailthe osteologic cha nges a ssociat ed wit h sickle

cell anemia in children and the way they canbe used in differentia l diagn osis. Our resultss h o w t h a t p o s t e rio r c a lc a n e a l a n d s p e c ifi cart icular surface disruptive metacarpal le-sions are the most diagnostic for sickle cella n e m i a . Tr a d i t i o n a l d i a g n o st i c f e a t u r e s(comm only used by a nt hropologist s for SC A),such as ca lvar ial thickening, tibia l and femo-ral cort ical bone thickening, a nd bowing a reprobably of more limited use in differentialdiagnosis. Phenomena such as granular os-teoporosis, pelvic demineralization, and ribbroadening are quite nonspecific. Localizedcalvarial ballooning, not previously de-scribed, may have dia gnostic significance aswe ll. B o n e ma rro w h y p erp la s t ic re s pon s e(porotic hyperostosis) in sickle cell anemiaproduces minimal ra diologic changes con-t ra s t e d wit h t h a t o bs e rv e d in t h a la s s e miaa nd blood loss/hemolyt ic phenomenon.

In t he present study efforts ha ve also beenmade to establish osteologic criteria for dis-criminating among the four major groups ofanemia s, based on the literature.

Th e import a n c e of p res e nt in g a s in glecase of SC A derived from the fa ct tha t bonelesions a t tributed t o one an emia or a notherare reasonably common in prehistoric andearly historic skeletons. With this pa per, w eadd to the relat ively sparse literatur e on thema croscopica lly visible bony cha nges a ssoci-ated with a documented case of sickle cella n e mia . F in a l ly , t h e re is n o do u bt in o u rmind th at one of the challenges to paleopa-thology mirrors that of forensic investiga-tionthe desire for a clear unbr oken th rea dof evidence. Such opportunit ies are ra re,and therefore each such case deserves in-depth analysis. HTH-1784 validates perspec-tives based on the archeological record andprovides an opportunity for future diagnos-t ic verificat ion.

ACKNOWLEDGMENTS

This research was carried out during thesabba tical of one of the aut hors (I .H) at theCleveland Museum of Na tura l History. I t ispart of collaborative research project entitle Dynamic Pat tern in Human Skeletal Biol-

ogy between the Laboratoire dAnthropo-logie B iologique, Fa culte de Med ecine deMa rseille, U nivers ite de la Medit erra nee,Fra nce; Depart ment of Phy sical Anthropol-

ogy, Cleveland Museum of Natural Historyan d Department of Ana tomy, Ca se WesternUniversity, Cleveland, Ohio, USA; ArthritisCent er of Nort heast Ohio, Youngstown , Ohioand Department of Anatomy and Anthropol-ogy, Sa ckler Fa culty of Medicine, Tel AvivUniversity, Israel.

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