Idiopathic avascular necrosis of the femoral heads in five members of a Moroccan family

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JointBoneSpine79(2012)504–506

Available online at

www.sciencedirect.com

Case report

Idiopathic avascular necrosis of the femoral heads in ﬁve members of a Moroccan family

Jihane Sekkat

^∗

, Ouafaa Rachidi , Saadia Janani , Ouafaa Mkinsi

ServicedeRhumatologie,CHUIbnRochd,Casablanca,Morocco

a r t i c l e i n f o

Articlehistory:

Accepted25May2012 Availableonline5October2012 Keywords:

Avascularnecrosis Femoralhead Idiopathic Family

a b s t r a c t

Avascularnecrosis(AVN)isidiopathicinabout40%ofcases.Thepathophysiologyofavascularnecrosis remainsincompletelyelucidated.Here,wereportacasethatunderlinestheroleforinheritedfactorsin AVNofthefemoralheads.IdiopathicAVNofthefemoralheadsoccurredinfivemembersofthesame family(awoman,hertwopaternalaunts,hermalepaternalcousinandherfemalepaternalcousin)ata meanageof42.4years(range,33–58years).StandardpelvicradiographsshowedArletandFicatstage 4AVNinthreepatientsandstage3intwopatients.Noneofthepatientshadahistoryofglucocorticoid therapy,alcoholabuse,ortrauma.Allfivepatientsunderwentinvestigationsforacause,includingblood cellcounts,alipidprofile,coagulationtests,testingforantinuclearantibodies,hemoglobinelectrophore- sis,ultrasonographyoftheabdomen,andstandardradiographsofthelonglimbbones.Theresultswere normalornegative,rulingoutknownhereditarycausesofAVNsuchassicklecellanemiaandGaucher disease.ManycasesoffamilialAVNofthefemoralheadhavebeendescribedinpatientswithsicklecell anemiaorGaucherdisease.However,onlyfivefamilieswithidiopathicfamilialAVNofthefemoralheads havebeenreported(threeintheUSandtwoinTaiwan).Allthepatientsinthesefamilieshadisolated bilateralAVNofthefemoralheadswithoutAVNatothersites.

1. Introduction

Avascular necrosis (AVN) is deﬁned as cell death in both compo- nents of bone, i.e., bone tissue and bone marrow. This incapacitating condition occurs chieﬂy in adults between 30 and 60 years of age.

The treatment is mainly surgical.

AVN of the femoral head contributes 3% of all cases of hip disease. Although its prevalence is unknown, 15 000 cases are estimated to occur each year in the US. Glucocorticoid therapy is the main cause of nontraumatic AVN, followed by alcoholism, decompression sickness, systemic lupus erythematosus, sickle cell anemia, and other less common causes. Familial AVN seems very rare.

Most of the reported cases of familial AVN were associated with Gaucher disease, sickle cell anemia, or familial thrombophilia. In the absence of these three conditions, familial AVN is exceedingly rare. Here, we report an unusual case of bilateral femoral-head AVN in ﬁve members of the same family who had none of the known causes.

∗ Correspondingauthor.

E-mailaddress:jihane.sekkat@gmail.com(J.Sekkat).

2. Cases

2.1. Index case

A 33-year-old woman with an unremarkable medical history was admitted for isolated mechanical pain in both hips of 4 years’

duration. She had no history of glucocorticoid therapy, alcohol abuse, trauma, deep sea diving, or thrombosis. Both hips were painful upon mobilization. Motion-range limitation was found in all planes, being most marked for internal rotation, ﬂexion, and abduction.

The plain pelvic radiograph showed AVN of both femoral heads.

The lesions were stage 4 in the Arlet and Ficat classiﬁcation scheme.

The following investigations were performed: blood cell counts, test for antinuclear antibodies, hemoglobin electrophore- sis, serum lipid proﬁle, coagulation tests, ultrasonography of the abdomen, and plain radiographs of the long limb bones.

The results were normal or negative. Thus, this patient had no evidence of any of the main causes of AVN including hyper- corticism, alcoholism, decompression sickness, systemic lupus erythematosus, sickle cell anemia, vascular thrombosis and Gaucher disease.

The patient declined total hip replacement surgery.

doi:10.1016/j.jbspin.2012.06.012

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J.Sekkatetal./JointBoneSpine79(2012)504–506 505 Table1

Informationonthefamilyoftheindexpatient.

Case Age(y) Sex Relation History PelvicX-ray(ArletandFicatstage) Treatment

1 33 F Indexcase None 4bilateral Declined

2 58 F Paternalaunt None 4bilateral Declined

3 47 F Paternalaunt None 3bilateral Noresources

4 30 M Paternalcousin None 3bilateral Noresources

5 42 F Paternalcousin None 4bilateral Totalhiparthroplasty→favorablecourse

Table2

Geneticstudiesofidiopathicavascularnecrosisofthefemoralheads.

Study Gene Polymorphism Results RiskofAVN

[2] 3families,65sporadiccases COL2A1 G3665A

G3665A G2306A

Positive Mutationsinallthefamilialcases Nomutationsinthesporadiccases

[5] 2families COL2A Positive

[6] 59patients,234controls PAI-1 4G/5G Positive 4G/4Ggenotype,P=0.001

FactorV Al691GLeiden Negative –

Prothrombin G20210A Negative –

MTHFR C677T Negative –

36patients,235controls PAI-1 4G/5G Positive 4G/4Ggenotype,P=0.009

MTHFR,prothrombin C677T Positive C/TMTHFRheterozygote,P=0.0l4?

GPIIIa G20210A Negative –

PLA1/A2(Leu33Pro) Negative –

[7] 66patients,300controls MTHFR C677T Positive TTgenotype,OR(95%CI)=3.2(1.2–8.7)

[8] 72patients,300controls FactorV G1691ALeiden Positive Aallele,OR(95%CI)=5.7(1.8–17.5)

63patients,282controls FactorV G1691ALeiden Positive Aallele,OR(95%CI)=2.7(1.2–5.8)

38patients,282Controls FactorV G1691ALeiden Positive Aallele,OR(95%CI)=3.1(1.4–6.6)

Prothrombin G20210A P=0.006

[9] 103patients,103controls eNOS ecNOS4a∧ Positive Allele4a,OR(95%CI)=4.3(1.35–13.62)

AVN:avascularnecrosis.

2.2. Family study

Table 1 reports the information obtained on the family, and Fig. 1 shows the pedigree. The investigations for a cause were repeated in the four other family members with femoral-head AVN. The results were normal or negative, indicating a diagnosis of idiopathic AVN.

Fig.1.Avascularnecrosisofbothfemoralheads,stage4intheArletandFicat classiﬁcationscheme.

3. Discussion

Risk factors that contribute to the development of AVN fall into two main groups: environmental factors and genetic factors.

3.1. Environmental factors

Environmental factors are dominated by hypercorticism fol- lowed by alcoholism; decompression sickness; systemic lupus erythematosus; fat embolism; hypersensitivity reactions (e.g., transplant rejection); thromboplastin release in a variety of situations such as cancer, pregnancy, and head injury; and hypoﬁb- rinolysis.

3.2. Genetic disease

Genetic disease associated with AVN includes familial thrombophilia, Gaucher disease, sickle cell anemia and other hemoglobinopathies.

None of these factors was found in any of the ﬁve family mem- bers.

Reports of femoral-head AVN in twins or families suggest a

role for genetic factors. Several mutations have been identiﬁed in

studies of idiopathic AVN (Table 2) [1,2,3]. Most of these studies

focused on genetic polymorphisms affecting the coagulation and

ﬁbrinolysis system. Three studies demonstrated a positive correla-

tion between the factor V Leiden mutation (a common risk factor

in thrombophilia) and idiopathic AVN [6]. Other studies indicate

a role for mutations affecting genes involved in thromboembolic

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506 J.Sekkatetal./JointBoneSpine79(2012)504–506

: unaffected male : unaffected female : affected male : affected female Fig.2. Pedigreeshowingtherelationshipsamongtheﬁveaffectedfamilymembers.

disease, such as plasminogen activator inhibitor-1 (PAI-1) [4] and 5,10-methylene-tetrahydrofolate reductase (MTHFR) [5].

The ﬁrst study that did not focus on the coagulation system found evidence of a role for the gene encoding endothelial nitric oxide synthase (eNOS) [7]. This enzyme controls the production of nitric oxide, which induces vasodilation and inhibits platelet aggre- gation. A polymorphism in the eNOS gene was shown to be involved in the occurrence of idiopathic AVN [7].

A genetic study in three US families with bilateral idiopathic femoral-head AVN showed autosomal dominant transmission over four generations (Table 2) [2]. All three families had mutations in the gene for type 2 collagen (COL2A1) on chromosome 12q13. In two families, the mutation resulted in substitution of serine for glycine at codon 1170 in a GXY repeat in COL2A1. In the third fam- ily, the glycine-to-serine change occurred at codon 717 of COL2A1.

No COL2A1 mutations were identiﬁed in patients with sporadic AVN [2]. Another study investigated two families from Taiwan with bilateral femoral-head AVN transmitted on a dominant basis over four generations [3]. Again, the genetic study identiﬁed mutations in COL2A1.

The mutations in COL2A1 (which encodes the main component of joint cartilage) may result in impaired cartilage performance responsible for abnormalities in the underlying bone, which in turn may lead to AVN. AVN did not occur at sites other than the femoral

heads in any of the ﬁve previously studied families or in our family.

Transmission occurred on an autosomal basis in the ﬁve previously studied families. However, the pedigree in our family is not consis- tent with autosomal dominant transmission. We did not perform genetic tests. Tests for recently implicated abnormalities in IL-33 would be of interest (Fig. 2).

Disclosureofinterest

The authors declare that they have no conﬂicts of interest con- cerning this article.

AppendixA. Supplementarymaterial

Supplementary data (Table S1) associated with this article can be found, in the online version, at doi:10.1016/j.jbspin.2012.06.012 and at http://www.sciencedirect.com.

References

[1]HadjigeorgiouG,DardiotisE,DardiotiM,etal.Geneticassociationstudiesin osteonecrosisofthefemoralhead:minireviewoftheliterature.SkeletalRadiol 2008;37:1–7.

[2]LiuYF,ChenWM,YangRC,etal.TypeIIcollagengenevariantsandinherited osteonecrosisofthefemoralhead.NEnglJMed2005;352:2294–301.

[3]ChenWM,LiuYF,LinMW,etal.Autosomaldominantavascularnecrosisof femoralheadintwoTaiwanesepedigreesandlinkagetochromosome12q13.

AmJHumGenet2004;75:310–7.

[4]Glueck CJ, Fontaine RN, Gruppo R, et al. The plasminogen activator inhibitor-1gene,hypoﬁbrinolysis,andosteonecrosis.ClinOrthopRelatRes 1999;366:133–46.

[5] Zalavras CG, Malizos KN, Dokou E, et al. The 677C–>T mutation of the methylene-tetrahydrofolatereductasegeneinthepathogenesisofosteonecrosis ofthefemoralhead.Haematologica2002;87:111–2.

[6] KosterT,RosendaalFR,deRondeH,etal.Venousthrombosisduetopooranti- coagulantresponsetoactivatedproteinC:LeidenThrombophiliaStudy.Lancet 1993;342:1503–6.

[7]KooKH,LeeJS,LeeYJ,etal.Endothelialnitricoxidesynthasegenepolymor- phismsinpatientswithnontraumaticfemoralheadosteonecrosis.JOrthopRes 2006;24:1722–8.