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Fungal or parasitic: In an immunocompromised host, fungal or even parasitic joint
infections may occur and relevant studies must be sent from joint fluid/serum per
clinicalsuspicion.SBEwillsometimescauseanimmune-relatedarthritis,unrelatedto
directinfection. In the proper clinical setting (fever,heart murmur, embolic events),
bloodculturesareindicated.
Viral:Manyvirusescancausearthritis,includingthejointsofthefoot.Theseincludeviral
infectionslikehepatitisC,B;mosquito-borneviralillnesseslikedengue,chikungunya,
etc.DenguefeverisdiagnosedwithIgMimmunoassayELISA.Chikungunyamayhave
arthritisandarthralgiasymptomsmainlyinthebackandlowerextremityforweeksor
sometimesyears.Laboratorycriteriaincludeadecreasedlymphocytecountconsistent
withviremia.However,adefinitivelaboratorydiagnosiscanbeaccomplishedthrough
viralisolation,reversetranscriptionpolymerasechainreaction,orserologicdiagnosis.
LÖFGRENSYNDROME
Löfgrensyndromeisanacuteformofsarcoidosischaracterizedbyerythemanodosum(tender
rednodules),bilateralhilarlymphadenopathy,andpolyarthralgiaorpolyarthritis.Thearthritis
isoftenacuteandinvolvesthelowerextremities,especiallyanklejoints.Besidesthephysical
examfindingsofinflammatoryarthritisandimagingwithlymphadenopathy,serumangiotensinconverting enzyme, vitaminD(1,25)-OH, andcalcium levels are often increased;however,
noneoftheseabnormalitiesarespecific.
VASCULITIS–VASCULOPATHIES
Avarietyofvasculiticsyndromesmaypresentwithmanifestationsinthefeet.Onemajormode
ofpresentationisvascularinsufficiency.Thismayinitiallycauseclaudication,andmaylater
progress to pallor, cyanosis, ulceration, and eventually gangrene of the toes or feet. Often,
small-vessel vasculitis will present as a rash or palpable purpura. Hydrostatic forces are
thought to play a role in their preferential appearance in the lower extremities. Finally,
neuropathyresultingfrominfarctionofthevasanervorummayhavemajormanifestationsinthe
foot, and sometimes, the first presentation of it may be a foot drop. This is a medical
emergency.Immunologiccausesofvasculitisoftenhavecharacteristiclaboratoryfindings.For
example, activegeneralizedgranulomatosiswith polyangiitis(GPA), formerlyreferred toas
Wegener granulomatosis, is highly associated with antineutrophil cytoplasmic antibodies
(ANCA).
These antibodies cause a characteristic pattern of cytoplasmic granular staining with
immunofluorescence.Theantibodiesappeartobedirectedagainstproteinase3(PR3),aserine
proteasefoundintheprimarygranules ofneutrophils. C-ANCAisfoundin90%ofcasesof
GPAand is usually not present inothertypes of vasculitis. The titers ofC-ANCA parallel
disease activity of GPA. They are not as commonly found in the limited forms of GPA.
Antibodiesdirectedagainstmyeloperoxidase(MPO)produceaperinuclearpatternofstaining
referred to as P-ANCA. P-ANCAs are characteristic markers of systemic necrotizing
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2.
3.
vasculitis, and are seen in microscopic polyarteritis, idiopathic glomerulonephritis, and
Churg–Strauss syndrome. ANCA titers sometimes normalize posttreatment. Patients with
concomitantC-andP-ANCA may havelevamisole exposure, which is found inadulterated
cocaine.The mostcommon drugsthat producethis includepropylthiouracil, hydralazine, or
minocycline.
Atypical ANCAs directedagainsttargetsother than MPOand PR3 arefoundina wide
variety of conditions. These include inflammatory bowel disease, liver disease, chronic
infections, RA, HIV, and others. Mounting evidence directly implicates ANCAs in the
pathogenesisofvasculitis.
HENOCH–SCHÖNLEINPURPURA
Henoch–Schönlein purpura (HSP) is a disease of the skin and other organs like kidney. It
causespalpablepurpura(smallhemorrhages),oftenwithjointandabdominalpain.HSPisa
systemic vasculitis (inflammation of blood vessels) and is characterized by deposition of
immune complexes containing the antibody IgA mainly in skin and kidneys. Along with
increased inflammatory markers, blood urea nitrogen, and creatinine, there is raised serum
levelsofIgA.Theplateletcountmayberaised,anddistinguishesitfromdiseaseswherelow
plateletsarethe causeofthepurpura.On biopsy,immunofluorescencedemonstratesIgAand
C3bloodvesselwall.
CRYOGLOBULINEMIA
Cryoglobulins are usuallyimmune complexes (rarelythey includeother serum constituents)
thatprecipitateatlowtemperatures.
Type I cryoglobulinemia is associated withmonoclonal Igs suchas those occurring in
Waldenström disease, lymphoma, or multiple myeloma. These are mostly of the IgM
subtype.
TypeIIcryoglobulinemiaiscomposedofamixofpolyclonalIgGsandmonoclonalIgMRFboundtoautologousIgG.
Type III cryoglobulinemia is the most common typeandcontains polyclonal IgGs and
polyclonalIgM-RFboundtopolygonalIgG.
ManypatientswithtypeIIorIIIcryoglobulinshavehepatitisCinfection.Thus,evaluationfor
hepatitis Cwith appropriate antibody tests is usually warranted. Hepatitis Cinfectionmay
causesmall-vesselvasculitis,oftenaffectingthelowerextremities.HepatitisB,endocarditis,
and many other infections may be associated with cryoglobulins. The typical presentation
includesapalpablepurpuraonthelowerextremitiesinnearlyallpatients.Ischemictoesmay
alsodevelop.PatientswithtypeIIandtypeIIIcryoglobulinemiawillhaveafalse-positiveRF.
Diagnosis requiresthe identificationof a cryoprecipitateintheserum. Bloodshouldbe
keptatbodytemperature(37°C)untiltheserumisseparated.Theserumisthenkeptat4°Cfor
48hoursandexaminedforaprecipitate.Theprecipitateisexpressedasa percentage ofthe
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serum volume, and may be further characterized by electrophoresis and immunofixation.
Complementactivation mayfrequentlybepresent onlabevaluation. Inaddition,evidenceof
glomerulonephritisandnephrosismaybepresent(e.g.,activeurinesediment,proteinuria,and
abnormalrenalfunctiontests).
DERMATOMYOSITIS/POLYMYOSITIS
Dermatomyositis andpolymyositis are characterized byinflammationofthemuscles, which
causesbothpainandweakness.Dermatomyositisisalsocharacterizedbyinflammationofthe
skin. Increased muscle enzymes are a hallmark, and muscle markers like creatine kinase,
aldolase, myoglobin, and lactate dehydrogenase are elevated. Sometimes, aspartate
transaminase and alanine transaminase are also increased as a result. Dermatomyositis is
associatedwithautoantibodies,especiallyanti-Mi-2antibodies,andtoalesserextentanti-Jo1 antibodies, which are more commonly seen in polymyositis. Myositis-associated and
myositis-specific antibodies including anti-Jo-1 andotheranti-synthetase antibodies may be
elevated.
SCLERODERMA
Scleroderma, also known as systemic sclerosis (SSc), is a chronic systemic autoimmune
disease characterized by hardening (sclero) of the skin (derma) with widespread vascular
dysfunction and progressive fibrosis of not only the skin but also internal organs. Limited
cutaneousSScmayhavefeaturesofCRESTsyndromeandonlydistalextremityinvolvement.
Anti-DNAtopoisomeraseI(Scl-70)antibodiesaregenerallyassociatedwithdiffusecutaneous
SSc (dcSSc). Anticentromere antibody is usually associated with limited cutaneous SSc.
AntibodiestoRNApolymeraseIIIarefoundinpatientswithdcSScandareatincreasedrisk
for scleroderma renal crisis. All patients with newly diagnosed scleroderma should be
appropriatelycancerscreened.
AUTOINFLAMMATORYDISEASES
Autoinflammatorydiseasesareagroupofgeneticallydiversebutclinicallysimilardisorders
characterized by recurrent fever associated with rash, serositis, lymphadenopathy, and
musculoskeletal involvement. These fevers occur in the absence of any infections or
malignancy. These include familial Mediterranean fever (FMF), tumor necrosis factor
receptor-1 associated periodic syndrome, etc. Some people consider Still disease an
autoinflammatorydiseaseeventhoughithassomefeaturesofthatofRA.Itischaracterizedby
quotidian(daily)fevers,arthritis,andanevanescentrash.
Inflammatorymarkers,suchasCRPandESR,areelevatedduringdiseaseflaresandmay
sometimes be abnormal between episodes in these diseases. Genetic tests for various
autoinflammatory diseases like FMF are available. Commonly, ferritin and IL-18 are
substantiallyelevatedinthesediseases.
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2.
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HYPERCOAGULABLESTATES
A number of hypercoagulable states may present in muchthesame wayasthe vasculitides.
These include disorders of coagulation related to deficiency of factor C, factor S, and
antithrombinIII.Factor5Leidenmutationmayalsoleadtoahypercoagulablestate,especially
in the homozygous form. Specific coagulation assays should be performed when these
conditionsaresuspected,particularlyifthereisafamilyhistoryofcoagulopathy.
GENOME-WIDEASSOCIATIONSTUDY
Agenome-wideassociationstudy(GWAS)isanexaminationofmanycommongeneticvariants
indifferentindividualstoseeifanyvariantisassociatedwithatrait.GWAStypicallyfocuses
on associations between single-nucleotide polymorphisms and traitslike major diseases by
comparing patients with disease to that of normals, thus providing insights into associated
molecular mechanisms. RA, SLE, ankylosing spondylitis, and some other autoimmune
rheumaticdiseasesarecomplexgeneticdisease,wherethereisevidenceoffamilialclustering,
but not ofMendelianinheritance. Disease-associated loci identified to date reveals greater
sharing of risk loci among the groups of seropositive (diseases in which specific
autoantibodiesareoftenpresent)orseronegativediseasesthanbetweenthesetwogroups.The
natureofthesharedanddiscordantlocisuggestsimportantdifferencesandsimilaritiesamong
thesediseases,andhelpsidentifynewtherapeutictargets.Thiswouldhelpdiagnosediseases
intheat-riskpopulationandalsotodeveloptargetedtherapiesinthefuture.
3
NODULES
In addition to gout and RA, hyperlipidemia may cause skin nodules. Type II
hyperlipoproteinemia may present with Achilles tendinitis and tenosynovitis. Asymmetric
oligoarticularsynovitishasbeen describedintypeIVhyperlipoproteinemia.Cholesteroland
triglycerideprofilesareusefulintheevaluationofthesedisorders.
From this discussion, it is clear that laboratory testing is an invaluable part of the
diagnosticprocess. However,itisbestusedonlyinadirectedfashionand only aspartofa
completeevaluationthatincludesahistoryandphysicalexamination.
REFERENCES
Maksymowych WP, Boire G, van Schaardenburg D, et al. 14-3-3η autoantibodies: diagnostic use in early rheumatoid
arthritis.JRheumatol.2015;42(9):1587–1594.
Navarro-CompánV,deMiguelE,vanderHeijdeD,etal.SponyloarthritisfeaturesforecastingthepresenceofHLA-B27
or sacroiliitis on magnetic resonance imaging in patients with suspected axial spondyloarthritis: results from a cross-
sectionalstudyintheESPeranzaCohort.ArthritisResTher.2015;17:265.
KirinoY,RemmersEF.Geneticarchitecturesofseropositiveandseronegativerheumaticdiseases. NatRevRheumatol.
2015;11(7):401–414.
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SELECTEDBIBLIOGRAPHY
ARAGlossaryCommittee. Dictionary of the Rheumatic Diseases: Vol II: Diagnostic Testing. New York,NY: Contact
Associates;1985.
KelleyWN,HarrisED,RuddyS,etal,eds.TextBook ofRheumatology.Philadelphia,PA:W.B.Saunders;1997.
KhanMA,KellnerH.Immunogeneticsofspondyloarthropathies.RheumDisClinNorthAm.1992;18:837.
McCartyGA.Autoantibodiesandtheirrelationtorheumaticdiseases.MedClinNorthAm.1986;70:237–261.
Nolle B, Specks U, Ludermann J, et al. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener
granulomatosis.AnnInternMed.1989;111:28–40.
PagetS,PellicciP,BearyJF,eds.Manual ofRheumatologyand OutpatientOrthopedicDisorders.Boston:Little,Brown;
1993.
SammaritanoLR,Gharavi AE,LockshinMD. Antiphospholipid antibodysyndrome:immunologicandclinicalaspects. Semin
ArthritisRheum.1990;20:81.
SchumacherHR,ed.PrimerontheRheumaticDiseases.Atlanta:ArthritisFoundation;1993.
SchumacherHR,ReginatoAJ.Atlas of SynovialFluid Analysis and Crystal Identification. Philadelphia:Lea &Febiger;
1991.
SoxHCJr,LiangMH.Theerythrocytesedimentationrate:guidelinesforrationaluse.AnnInternMed.1986;104:515–523.
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T
his chapter focuses on skeletal dysplasias and metabolic bone diseases with
manifestations in the feet. Although a strong association between osteoporosis and
fractures has not yet been established, the contribution of this condition (which is quite
commoninpostmenopausalwomen)torecurrentfracturesandtheirhealingprocessshouldnot
beoverlooked.Inaddition,otherrareorpossiblyunderrecognizedmetabolicbonediseases
suchashypophosphatasia(HPP)andPagetdiseasemayincludefootlesions.Oftentheastute
clinicianmayrecognizethepresenceofaskeletaldysplasiainapatientwithanalreadyknown
orevennotknowdiagnosisandthenappropriatelyreferthispatientforfurtherevaluationand
management.
SKELETALDYSPLASIAS
Severalsyndromesassociatedwithskeletaldysplasiasmaymanifestwithabnormalitiesofthe
feet. Oftentheseare hereditary, andidentificationofaprobandpatientmayhavesignificant
implicationsfor the whole family. A carefulclinicalinspection andexaminationaswell as
evaluationofradiographicabnormalitiesmayleadtotheidentificationofabroadersyndrome
thatmayrequireamultidisciplinarymanagementapproach.
Geneticdisordersoftheskeleton are aclinicallyandgeneticallyheterogeneous group of
disorders of bone and/or cartilage characterized by abnormalities in growth, development,
and/or homeostasis of the human skeleton.1 They include the osteochondrodysplasias
(primarilyaffectingboneand/orcartilage),thedysostoses(affectingasingleboneorgroupof
bones),thebrachydactylies(primarilyinvolvingthehandsandfeet),andthelysosomalstorage
diseases.Althoughrelativelyrareindividually,theskeletaldysplasiashaveanestimatedbirth
prevalence of nearly 1/5,000.2 It is now apparent that there are over 450 distinct genetic
disordersoftheskeletonthatmustbedistinguishedforspecificgeneticcounseling,prognosis,
andtreatment.Oftheseconditions,316areassociatedwithoneormoreof226differentgenes.
Osteopoikilosis
Osteopoikilosis (“spotted bones”) is an autosomal dominant condition with an interesting
radiographic appearance that may commonly affect the tarsal bones. If associated with
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connective tissue nevi and dermatofibrosis lenticularis disseminata, the disorder is the
Buschke–Ollendorffsyndrome.3DeactivatingmutationsintheLEMD3genewereidentified.
4
Osteopoikilosis (OMIM #166700)is usuallyanincidentalfinding. Thebonelesions are
asymptomatic,butifnotunderstoodcaninitiateacostlyinvestigationformetastaticdisease.
5
Familymembersatriskshouldbescreenedwitharadiographofawristandkneeinearlyadult
life. Joint contractionsandlimb length inequality mayoccur,especiallyinindividuals with
accompanying changes of melorheostosis (discussed below). The nevi usually involve the
lower trunk or extremities andare smallasymptomaticpapulesoryellow or whitediscs or
plaques,deepnodules,orstreaks.
3
There are numerous, small, usually round or oval, foci of osteosclerosis. Commonly
affectedsitesaretheendsoftheshorttubularbones,metaepiphysesoflongbones,andtarsal,
carpal,andpelvicbones.Lesionsremainstablefordecades.Bonescanisnormal.
5
Dermatofibrosislenticularis disseminataconsistsofunusuallybroad,markedlybranched,
interlacing elastin fibers in the dermis; however, the epidermis is normal.3 Foci of
osteosclerosisarethickenedtrabeculaethatmergewithsurroundingnormalboneorareislands
of cortical bone that include haversian systems. Mature lesions appear to be remodeling
slowly.
OsteopathiaStriata
Osteopathiastriata(OMIM#166500,autosomaldominant)featureslinearstriationsattheend
of long bones and the ileum. Like osteopoikilosis, it is usually a radiographic diagnosis.
Gracile linear striations are found in cancellous bone, particularly withinmetaepiphyses of
majorlongbonesandtheperipheryoftheiliacbones.Carpal,tarsal,andtubularbonesofthe
handsandfeetarelessoftenandmoresubtlyaffected.Thestriationsappearstableforyears.
Bonescanisalsonormal.
5
Melorheostosis
Melorheostosis(OMIM#155950),fromtheGreekwordsforlimb,flow,andbone,refersto
“flowinghyperostosis.”Theradiographicappearanceresembleswaxthathasdrippeddowna
candle. About 200 cases have been published6 since the first description in 1922.
7
Melorheostosisoccurssporadicallyandmayaccompanyosteopoikilosis.
Melorheostosistypicallypresentsduringchildhood,usuallywithmonomelicinvolvement;
bilateral disease is characteristically asymmetrical. Cutaneous changes may overlie the
skeletal lesions and include linear scleroderma-like patches and hypertrichosis. Fibromas,
fibrolipomas, capillary hemangiomas, lymphangiectasia, and arterial aneurysms can also
occur.8Softtissueabnormalitiesareoftennotedbeforethehyperostosis.Painandstiffnessare
themajorsymptoms.Affectedjointsmaydevelopcontractures,andleglengthdiscrepancycan
follow premature fusion of epiphyses. Bone lesions seem to advance most rapidly during
childhood.Inadultlife,melorheostosismaynotalwaysprogress.9Nevertheless,painismore
frequentwhenthereiscontinuingsubperiostealboneformation.
Dense,irregular,andeccentrichyperostosisofbothperiostealandendostealsurfacesofa
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singlebone,orseveraladjacentbones,isthehallmarkofmelorheostosis.6Anybonemaybe
affected,butthelowerextremitiesaremostcommonlyinvolved.Bonecanalsodevelopinsoft
tissuesnear skeletal lesions,particularlynear joints. Melorheostotic boneis hyperemic and
“hot” during bone scanning. Serum calcium, inorganic phosphate (Pi), and alkaline
phosphataselevelsarenormal.
Melorheostosis features endosteal thickening during growth and periosteal new bone
formationduring adultlife.6Affectedbones arescleroticwiththickened,irregularlamellae.
Marrowfibrosismaybepresent.6Intheskin,unlikeintruescleroderma,thecollagen ofthe
scleroderma-likelesionsappearsnormaland hasthereforebeencalled linearmelorheostotic
scleroderma.
10
Pachydermoperiostosis
Pachydermoperiostosis (hypertrophic osteoarthropathy: primary or idiopathic; OMIM
#167100)causesclubbingofthedigits,hyperhidrosisandthickeningoftheskinespeciallyon
thefaceandforehead(cutisverticisgyrata),andperiostealnewboneformation,particularlyin
thedistalextremities.Autosomaldominantandrecessiveinheritancewithvariableexpression
is established.11 In 2008, autosomal recessive pachydermoperiostosis was elucidated by a
loss-of-function mutation within the gene that encodes 15-hydroxyprostaglandin
dehydrogenase.
12
Men seem to be more severely affected than women and blacks more commonly than
whites. Age at presentation is variable, but usuallyit is during adolescence. All principal
features(clubbing,periostitis,andpachydermia)troublesomepatients;othershavejustoneor
two. Clinical manifestations emerge over a decade and can then abate.12 Progressive
enlargement of the hands and feet may cause a paw-like appearance, and there may be
excessive perspiration. Acro-osteolysis can occur. Fatigue and arthralgias of the elbows,
wrists,knees,andanklesarecommon.Stiffnessandlimitedmobilityofboththeappendicular
and the axial skeleton may develop. Compression of cranial or spinal nerves has been
described.Cutaneous changesincludecoarsening,thickening,furrowing,pitting, andoiliness
of the skin, especially the scalp and face. Myelophthisic anemia with extramedullary
hematopoiesismayoccur.Lifeexpectancyisnotcompromised.
Severe periostitis thickens tubular bones distally: typically the radius, ulna, tibia, and
fibula, andsometimes themetacarpals, tarsals/metatarsals,clavicles,pelvis,skull base, and
phalanges.Clubbingisobvious,andacro-osteolysiscanoccur.Thespineisrarelyinvolved.
Ankylosis ofjoints,especiallyinthehands andfeet,maytrouble older patients. Themajor
challenge indifferentialdiagnosis is secondaryhypertrophic osteoarthropathy(pulmonaryor
otherwise). Here, however, the radiographic features are somewhat different, featuring
periosteal reaction that is typically smooth and undulating.13 In pachydermoperiostosis,
periostealproliferationisexuberant,irregular,andofteninvolvesepiphyses.Bonescanningin
eitherconditionrevealssymmetrical,diffuse,regularuptakealongthecorticalmarginsoflong
bones,especiallyinthelegs,causinga“doublestripe”sign.
Nascent periosteal bone roughens cortical bone surfaces and undergoes cancellous
compaction so that centrally it can be difficult to distinguish histopathologically from the
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originalcortex. Theremayalso be osteopenia oftrabecular bonefrom quiescent formation.
Mildcellularhyperplasiaandthickeningofbloodvesselsisfoundnearsynovialmembranes,
butsynovialfluidisunremarkable.
14
FIBROUSDYSPLASIA
Fibrousdysplasiaofbone(FD)(OMIM#174800)is anuncommonskeletaldisorderwitha
broadspectrumofclinicalpresentation.Onone endofthespectrum,patientsmaypresentin
later life with an incidentally discovered, asymptomatic radiographic finding that is of no
clinicalconsequence.Ontheotherendofthespectrum,patientsmaypresentearlyinlifewitha
disabling disease. The disease may involve one bone (monostotic FD), multiple bones
(polyostotic FD), or the entire skeleton (panostotic FD).
15–17
FD may be associated with
extraskeletal manifestations, the most common of which is areas of cutaneous
hyperpigmentationcommonlyreferredtoascaféaulaitmacules.Theselesionsvarywidelyin
size but have characteristic features that include jagged, “coast of Maine” borders, some
relationshipwiththemidline,andsometimesfollowthedevelopmentallinesofBlaschko.FD
canalsobeassociatedwithhyperfunctioningendocrinopathies,includingprecociouspuberty,
hyperthyroidism, growth hormone (GH) excess, and Cushing syndrome. FD in combination
withoneormoreoftheextraskeletalmanifestationsisknownasMcCune–Albrightsyndrome
(MAS).
18–21
Arenaltubulopathy,whichincludesrenalphosphatewasting,isoneofthemost
commonextraskeletaldysfunctionsassociatedwithpolyostoticdisease.22Morerarely,FDmay
beassociatedwithmyxomasofskeletalmuscle(Mazabraudsyndrome)23ordysfunctionofthe
heart,liver,pancreas,orotherorganswithinthecontextoftheMAS.
24
FD is caused by missense mutations of the GNAS complex locus on chromosome
20q13.3.
25–27
GNASencodesthealphasubunitofthestimulatoryGprotein(Gsα)involvedin
the cyclic adenosine monophosphate (cAMP)-dependent signaling pathway. The mutation
impairs the intrinsic GTPase activity of Gsα, leading to persistent stimulation of adenylyl
cyclaseandaberrantproductionofcAMP(gain-of-functionmutations).28MutationsofGNAS
associatedwithFDandrelateddisordersareneverinheritedandcouldtheoreticallyoccurat
anytimeduringpostzygoticdevelopment.However,thereisinvolvementofapluripotentcell
as the initial target of the disease, thus explaining how the mutation can be transmitted to
derivativesofallthreegermlayersandbebroadlydistributedinpatientswithsevereformsof
thedisease.Atthesametime,differencesinthesizeandviabilityoftheclonearisingfromthe
original mutated pluripotent cell could account for the variability of theclinical phenotype
observedinthemajorityofFDpatients.
29
The pathology of FD is characterized by the development of fibro-osseous lesions that
replacenormalskeletalstructuresandimpairnormalskeletalfunctions.
Thesitesofskeletalinvolvement(the “map”ofaffectedtissues)areestablishedearlyin
patientswithFD.Ninetypercentofthecraniofaciallesionsareestablishedbeforetheageof5,
and75%ofallsitesofFDareevidentbytheageof15;theimplicationisthatessentiallyall
clinically significant disease is present very early in life, probably by the age of 5.
17
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PathologiceffectsofGsαmutationsinosteogeniccellsaremostpronouncedandevidentduring
thephaseofrapidbonegrowth,andaccountforthefactthatchildhoodandadolescencearethe
periodsduringwhichthediseasemostcommonlypresents,isthemostsymptomatic,andisthe
periodofpeakrateoffractures.
30,31
Themostcommonpresentingfeaturesarealimp,pain,or
afracture.Anybonecanbeaffectedincludingthefeet,althoughmostcommonlytheribs,long
bones, and craniofacial bones are affected, whereas lesions in the spine and pelvis are
typicallylesspainful.32Pathologicfracturesofweight-bearinglimbbonesareamajorcauseof
morbidity.Deformityoflimbbones,whichisacommonfinding,iscausedbyexpansionand
abnormal compliance of lesional FD, fracture treatment failure, and occasionally local
complications such as cyst formation.29 Malignancy in FD is rare (less than 1%).33 Rapid
lesionexpansionanddisruptionofthecortexonradiographsshouldalertthecliniciantothe
possibilityofsarcomatouschange.Osteogenicsarcomaisthemostcommon,butisnottheonly
typeofbonetumorthatmaycomplicateFD.
DiagnosisofFDmustbeestablishedbasedonexpertassessmentofclinical,radiographic,
andhistopathologicfeatures.Markersofboneturnoverareusuallyelevated.22Theextentofthe
skeletaldiseaseis bestdetermined with totalbodybone scintigraphy,whichcanbe usedto
assess the skeletal disease burden and predict functional outcome.34 Patients should be
referred to an endocrinologist for screening and treatment of the metabolic derangements
associatedwithFD,especiallyhypophosphatemiaandGHexcess.
MutationanalysismaybehelpfulindistinguishingFDfromunrelatedfibro-osseouslesions
of the skeleton, which may mimic FD both clinically and radiographically (osteofibrous
dysplasia, ossifying fibromas).29 Multiple nonossifying fibromas, skeletal angiomatosis, and
Ollierdiseasemaysometimesenterthe differentialdiagnosis. Distinctionfrom theseentities
reliesonhistologyandmutationanalysis.
AcromelicandAcromicricDysplasias
Acromelicdysplasiaandacromicricdysplasia(AD)arebecauseofinheritedmutationsinthe
gene for fibrillin-1 (FBN1). Fibrillin is a fibril-forming extracellular matrix protein with
importantrolesinthedevelopment,growth,andmaintenanceofskeletalelements.
35
Themostwell-knownofthesesyndromesisMarfansyndrome, whichisassociatedwith
handoffvalueswithforefootabductionandlowering ofthe midget(pes planus). Individuals
withMarfansyndrome(OMIM#154700,autosomaldominantinheritance,1in5,000)display
major disease features in the skeleton: tall stature and arachnodactyly, scoliosis and chest
deformities, joint hypermobility and muscle wasting, pes planus, and craniofacial
abnormalities, including a highly arched palate. Multiple features in other organs
(cardiovascular,ocular,skin,lung,andcentralnervoussystem)arealsopresent.Prevalenceof
skeletalfeatureschangeswithaging.Inchildren,pesplanusprevalencedecreasedfrom73%
to65%betweenages0and6years.
36
Theacromelicdysplasiagroupincludesthreeraredisorders:Weill–Marchesanisyndrome
(WMS), geleophysic dysplasia (GD), and AD, all characterizedby short stature, short and
stubbyhandsandfeetthatareshorterthanexpectedfortheirheight,stiffjoints,delayedbone
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