Beta thalassemia major is rare in Serbia. Previo-usly incurable, affected patients now live to adult-hood with regular blood transfusions. The impro-vement in supportive treatment over recent deca-des has given rise to many more patients sufferingfrom the associated metabolic complications ofanaemia and iron overload, such as osteopenia

and other skeletal changes. We present two patientswith severe beta thalassemia major from early child-hood, who encountered pathological long-bone fractu-res during the clinical course of their disease. One suf-fered a distal femoral diaphyseal fracture, and the sec-ond a distal tibia fracture. Both fractures occurred inosteopenic bone and were managed non-operativelydue to the patients’ general medical condition. Despiteintense medical intervention, both patients died fromdisease progression within one year of their fractures,aged 23 and 24 years. As life expectancy rises it is anti-cipated that an increased number of beta thalassemiamajor patients will suffer pathological long-bone andother osteoporotic fractures. These fractures appear toboth herald and contribute to a general clinical deteri-oration of this disease. Advances in stem-cell technolo-gy may hold the key for a definitive cure.

Key words: Beta thalassemia major, osteopenia,long-bone fracture

INTRODUCTION

Thalassemia is a genetic disease which affects the pro-duction of one or more globin chains (alpha, beta, ga-

mma and delta), resulting in a depletion or loss of he-moglobin function. The disease has several clinical enti-

ties including thalassemia minor (a mild heterozygoustrait/carrier state), thalassemia intermedia (a severe hete-rozygous disease), and thalassemia major (homozygousdisease), the most severe.

Thalassemia major is most prevalent in people of Medi-terranean, Arab and Asian origin. In Serbia the most com-mon disease form is the thalassemia trait, which typicallypresents with iron resistant microcytic anaemia and occas-sionally with jaundice. The major form of thalassemia israre and affects only very few cases per year. After the in-troduction of typed, filtrated transfusions of packed redblood cells (PRBC) and chelating agents (deferoxamine),the survival of patients improved1. However, an increasi-ng number of patients suffer from the secondary metabo-lic effects of the disease, including osteoporosis and its re-lated fractures2-5.

CASE REPORTS, MATERIAL AND METHODS

First patient, VP born in 1981, was diagnosed with betathalassemia major and the Lepore hemoglobin variant atthe age of 18 months. He was treated with intermittentblood transfusions and subcutaneous deferoxamine infusi-ons, and underwent splenectomy at the age of 9 years. Hisearly childhood development was not significantly affec-ted. In 1999 he was referred to our Institute because of adeteriorating condition. On examination he was found toha-ve many clinical features of secondary hemosiderosis,including bronze skin hyperpigmentation, hepatomegaly10 cm below the right costal margin (RCM), hypogo-nadism, and diabetes. Laboratory analyses demonstratedsevere anemia with leukoerythoblastic differential andsigns of liver decompensation due to secondary hemo-siderosis (AST 95U/L, ALT 60U/L, AP 130U/L, gGT35U/L, LDH 598U/L) with markedly elevated ferritin7420 mcg/L (normal limit 500 mcg/L). The patient wascommenced on regular transfusions of filtrated PRBC, re-ceiving 3-4 PRBC bags per month, and had severalcourses of defero-xamine. Withnin 4 years his ferritin lev-els rised to 8500 mcg/L, with further progression of hepa-tomegaly (15cm below the RCM); though liver functiontests had not deranged further.

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Thalassemia major. A report of two cases with severeskeletal involvement

A.Le{i}1, A. Bogdanovi}2, V. Sudji}1, N.Suvajd‘i}-Vukovi}2,HDE Atkinson3, M.Bumba{irevi} 11Institute for orthopaedic surgery and traumatology, CCS,School of Medicine, Belgrade2Institute for hematology, CCS, School of Medicine, Belgrade3North London Sports Orthopaedics, Department of Traumaand Orthopaedics, North Middlesex University Hospital,London, UK.

/PRIKAZ SLU^AJAUDK 616.155.194-06:616.7DOI:10.2298/ACI1002099L

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In August 2004 the patient suffered a spontaneous stressfracture of the distal femoral diaphysis. There had been noprodromal symptoms or prior clinical skeletal problems.The patient had delayed bony union and ongoing pain fol-lowing conservative management in plaster cast (Figures1, 2). Radiographs showed rarefaction of the cancellousbone, loss of cortical thickness and widening of the intra-medullary canal (Figure 3). Similar osseous changes werealso noted in both humeri. The lumbar spine was osteo-penic and the L2 vertebra had loss of height.

The patient’s condition continued to deteriorate, with amore prominent anemia and increased transfusion dema-nds, with further deterioration in liver function. The pati-ent died in July 2005 at the age of 23 from progressive he-patic failure.

Second patient, ZV born in 1976 had the Yugoslav-defi-ned beta thalassemic homozygous mutation and the He-moglobin Lepore variant, and was diagnosed with betathalassemia major at the age of 2. She underwent splenec-tomy at the age of 16 in an attempt to reduce the numberof hemolytic crises, and was included in the 1996 trial wi-th hydroxyurea (350mg/d) and sodium butyrate.

She was referred to our Institute in 2000 at age of 24,with a severe deterioration in her general health, signs ofhepatic insufficiency and severe endocrine dysfunction(insulin dependent diabetes mellitus and amenorrhea).The patient had also recently developed severe bony painin the axial skeleton and in all four limbs from bone mar-row hyperplasia (Figure 4), and had sustained a fractureof the distal tibia immediately prior to hospital admission.The fracture was treated with manipulation and plastercast immobilization, but failed to show any signs of bonyunion by 3 months. On admission her Karnofsky indexwas 30% and ECOG performance was 3. She had severehemolytic anemia as a part of the thalassemia syndromewith leukoeryhtroblastic differential. Ferritin levels werenot determined due to technical reasons, and transferrinsaturation was 81%. She also had hepatomegaly 7cm be-low the RCM, with deranged liver tests, ALT 32U/L,AST 55U/L, AP 97U/L, LDH 650U/L. She developed adeep vein thrombosis in her injured leg shortly after admi-ssion, despite thromboprophylaxis, and died from hepaticinsufficiency at the age of 24.

Both patients had small stature, and were below the 5th

centile for height. Neither had trophic changes or legs ul-cers, or a prior history of skeletal problems, and both haderythroblastosis without particularly marked rises in alka-line phosphatase.

DISCUSSION

The underlying mechanisms of skeletal involvement inthalssemia are complex5,6 . Patients suffer hemolysis andsubsequent tissue hypoxia, as a result of their globin dys-function. As other regulatory mechanisms are preserved,patients develop intramedullary bone marrow hyperplasiain reaction to this hypoxia. It is now recommended thatpatients be transfused to hemoglobin levels of 110-120g/L to decrease tissue hypoxia and erythropoietin secreti-on1,7,8. Splenectomy is also indicated in severe forms ofhemolysis.

Hemosiderosis of the hypophysis, pancreas and otherorgans, secondary to hemolysis and multiple PRBC trans-fusions, leads to many endocrine and metabolic changes.These endocrine changes affect the process of ossificationand lead to delays in bone maturation, premature epiphy-seal fusion, a decrease in cortical bone thickness, abnor-malities in remodeling and arthralgia3,4,5 . Some have su-ggested treating thalassemic osteopenia with dietary supp-

FIGURE 1A,B

RADIOGRAPH DEMONSTRATING THE DISTALFEMORAL DIAPHYSEAL FRACTURE. AP (A) ANDLATERAL VIEWS (B)

FIGURE 2A I 2B

RADIOGRAPH OF THE DISTAL FEMORAL DIAPHY-SEAL FRACTURE AT 6 MONTHS SHOWING THE DE-LAYED UNION. AP (A) AND LATERAL VIEWS (B).

100 A. Le{i} et al. ACI Vol. LVII

lements such as 1200mg calcium daily (in the adolescentpopulation), vitamins D, B6, B12, and K together withphysical exercise and training3,4. Hormonal treatment (es-trogen, testosterone) is indicated where there is hypogona-dism, and calcitonin and bisphosphonates when treatingosteoporosis6.

Thalassemia major typically develop enlargement of thecenters of ossification of the frontal bones leading to thi-ckening of the skull (caput quadratum), and earlier ossifi-cation and premature fusion of the epiphyses, affecting lo-ngitudinal growth; the humerus is typically more affectedthan the femur9. The spine is also commonly affected byscoliosis, kyphosis, and osteoporosis. Despite supportivetreatment fractures are common affecting around 30% ofpatients (with 20% suffering multiple fractures) 2 . The fe-mur and tibia are the most affected bones, with two peaksin the incidence of femoral fractures (at 5-12 years and14-17 years) 8.

Thalassemia patients with bone pain should undergo ra-diography. Our patients were found to have typical decre-ases in the cortical bone thickness, and dilated meta-phy-ses. Patients may also have "punched-out" osteolysis, Er-lenmeyer bone deformities, Schmörl nodes and bony de-formity angulations and bone shortening (our X-ray of hu-merus). Fracture lines are generally transverse, and bonescintigraphy and MRI can reveal microfractures, especi-ally around the ankles9,10. Differential diagnoses should

also be borne in mind, such as vitamin D resistant rickets,osteomyelitis, leukemia, lymphoma, and metastases.

Fractures in thalassemia major patients are preferablymanaged non-operatively as the bone is often not strongenough to be accommodate the implants11; obvious exce-ptions include femoral neck fractures where internal fixa-tion is more appropriate. Though callus formation is un-usual, the bone healing time is generally normal or sligh-tly prolonged. This is not the case in patients with severeanemia where delayed union may develop (as was seen inour two patients). Refractures are common, though boneremodeling can be good, and osteotomies can be perfor-med for residual limb deformity.

FIGURE 3

RADIOGRAPH OF THE TIBIA SHOWING RARE FRAC-TION AND CORTICAL THINING OF TIBIA

FIGURE 4

RADIOGRAPH OF THE HUMERUS, WITH DEFORM-ITY AND CORTICAL THINING DUE TO BONE MAR-ROW HYPERPLASIA

Br. 2 Thalassemia major 101

Our patients’ long-bone fractures coincided with theirgeneral clinical deterioration, and both died of hepatic fai-lure within a year despite intensive supportive care. It thusappears that these fractures may both herald and contrib-ute to a terminal phase in beta thalassemia. It is hoped thatthe significant morbidity and mortality associated with se-vere form of this disease will be resolved through advan-ces in stem cell grafting and better other supportive andchelating treatment with new oral agents.

SUMMARY

BETA TALASEMIJA. PRIKAZ DVA SLU^AJA SA FRAK-TURAMA DUGIH KOSTIJU

Beta talasemija je retka u Srbiji. Pobolj{anje suportivneterapije u pro{lim decenijama, dovelo je do toga da sveve}i broj ovih pacijenata ima problem sa udru‘enim meta-boli~kim komplikacijama anemije i o{te}enja gvo‘djem,kao {to su osteopenija i prelomima. Prikazujemo dva paci-jenta sa te{kim oblikom beta talasemije, koja je dijagnos-tikovana u detinjtsvu, a kod kojih je do{lo do patolo{kihpreloma dugih kostiju u toku njihove osnovne bolesti. Je-dan pacijent je zadobio prelom distalog dela femura, adrugi prelom distalne tibije. Oba preloma su nastala na os-tepeni~noj kosti i bili su le~ena neoperativno, zbog op{tegstanja pacijenata. Uprkos intenzivnom le~enju, oba pacije-nta su preminula zbog progresije osnovne bolesti, u uzra-stu od 23 i 24 godine. Kako se du‘ina ‘ivota pove}ava,mo‘e se zaklju~iti da }e se u budu}nosti pove}avati brojpacijenata sa beta talasemijom kod kojih }e nastajati pato-lo{ki prelomi dugih kostiju, kao i drugi prelomi zbog os-teoporoze. Ovi prelomi su uzrokovani lo{im stanjem paci-jenta, ali i dovode i do daljeg klini~kog pogor{anja bole-sti. Napredak u tehnologiji mati~nih }elija je klju~ za defi-nitivno le~enje ove bolesti.

Klju~ne re~i: beta talasemija maior, osteopenia,frakture dugih kostiju.

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NAPOMENA: Izrada rada je potpomognuta projektom Ministar-stva za nauku i tehnolo{ki razvoj Srbije

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