The Clinical Spectrum, of Lym,phatic Disease | Klose Training

The Clinical Spectrum, of Lym,phatic Disease

KAVITA RAI>HAKRISHNAN AND STANLEY G. ROCKSON

Stanford Centerfor Ly mp hatic and Venous Disorders, Div is ion of Cm·diovascttla. r !Vledicine, Stanford University School of ivfedicine, Stanford, Calijo1·n ia, USA

Lympha tic disease is quite preva lent, a nd often not well clinica lly characterized . Beyond lym­p h ed em a, there is a b road array of human disease th a t d irectly or indirec tly a lter s lympha tic s t r u cture a n d function. T h e s y1npto m a ti c a nd obj ective presenta tion of th ese p atien ts can b e quite diverse. In thi s r eview, we h ave attempted to p r ovide a sys tem a ti c over view of th e s ubjective a nd obj ec tive spectrum of lympha ti c disease, wi th consider ation of a ll of th e cat egories of d isease that primar ily or secondar ily impair th e funct ion al integr ity o f th e lymphat ic system . Lymphed em a is d iscussed , a long w ith chrmnosom al d isorder s, lymp han giom a, infectious diseases, lympha n gi­ole ion1yon1 atos is, lipcden1a, heritable gene ti c d isorders, con1plex vascular n1alfortnations, prote in­losing enteropathy, and intestinal ly1nph an giectasia.

Key words: ch rom osom al disorders; lymphan gioma; lymphangiole iomyom atosis; p r o te in-losin g enteropathy (PLE)

Introduction

c ; iH~ n thc cen tral role oCt he kmph at ic s ~ ·stcm in c ir­

cu Lllon; m e tabolic. a nd immune-related homeostasis, it is not surpris ing th a t ge netic, clc, ·elopmental , and

acq uired disorde rs or this system manifest through a

broad a rray or prcclicta!Jlc sequelae. T he lymphatic­spt -c ific manifCsta tions range fi ·om blunted immune

re,ponses 1 and impai red metabol ic status1 to the a p­

pea rance or the debilitating a nd disfigur ing f(mn or re ~iona l s\\·ell ing genera lly termed (rmj;halnlla_:l

l .ymphat ic cl isca,e is q u ite IJIT\·alcm , a nd oficn not m ·ll clinically charactcrizcd. -L-I :\ cqui red d isease o f' the

lyn1 pharies mmt oficn takes tl!c lcmn of'lympha tic cir­

u t! a tory clisrup tion.typica lk resulting fi·om trauma. in­kl ·t ion. neoplasia, or fi ·01n iatrogenic causes_ :~.:; \\'hen

reg ional lymphatic flo"· is insu flicicnt to maintain tissue

hot n c·ostas is, inte rstitial fluid accumula tes and S11-clling

Cl h UL'S.

Bc·mnd h-mphedcma, there is a broad array of' hu­ll i.I n disease that direc t!~- or inclirecth- alters lymphat ic

structure and fimction. Not surprisingly; the symp­trn n atic (T ,\B l.E !) a nd objectiYe (T\Bl.E 2) prcswta­ti un of' these p atien ts ca n be quite c!i, ·e rse. D iagnosis

and cliflcremia l diagnosis poses distinct challenge.- . In

.\ ddtT:- ... !In ClllTl':-pcliHkl ln': Stil ll !t.:y c;. RCickscHI . ~I . D .. l) i, ·i:. icH I o f

C.:ldicJ\'<l 'ndar :\ k dirinL Fa lk COlrdicwa:-.rula r Rt>t:arrh Crmcr. Sta nli.Jrd { 'n iHT .. ity s,·hool of \lc·thr inc·. Swnli1rcl. C:\ ~ 1! 3 fJG . \ 'uice: + 1-G.)U-72.; ­; ·,;I : litx: + 1-fi.-10-i'l .->-1 :~ 9 ~) .

"lilt btl ll (£.!. ' ' nwd ... !.uli fll·d .c·d u

this rc, ·iell·. 11·e h an~ attempted to prrwicle a system­atic OH' IYic11· of the categories of' disease tha t primarih­

or scconclarily impair the fimctional integ rity of' the lymphatic system.

Lymphedema

Heritable congen ital lymphedema of the lo\\·er ex­tremities ,,-as first described by Nonne in 189! _'; In

189:2 , J\lil roy 7 described the fiimilial distribut ion of congenital !ymphcclcma, noting the im ·oh-e m ent of'

26 persons in a single fiunily. spanning six genera ­tions.:; Nonne- Milroy's lymphedema is charac­

terized b)' unilateral or bi lateral s\\·clling uf the legs,

arms, and/or {;ICC ll'ith gradual and irrcu :rsibk fi­brotic cha nges. :\clditiona l, d istinct , -a ria nts of herita­

b le lymphedema hm·e subsequently hcen desrribccL

In 1898, J\Ieigc reponed cases of lymphedema in

" -hich the age ol' onset 1ras afier pubciW. and which ofie n appea red alongside acu te ccllulit is.n In 196' t another Yariety of pubertal-onse t lympheclema9 11·as reported. in 11·hich the afTcclccl indi, ·iclual s hac! dis­

tichiasis (i.e., a n auxiliary set of cyelashcs).1'.1 Pa ­

tients with the Nonn c- :'vlilrm·'s syndrome, Meige 's syndrome, and the lymphedema-distichiasis syndrome tvpically prcsclll 11·ith pi tting edem a

that is commonly limited to the lt:gs. Although au­tosomal dominant transmission characterizes heri­table lymphcclcma . the molecula r mechan ism a ncl the pa thogenesis clifk r among the , -a rio us e ntities

iclcntif iecl.

Ann . N.Y. Acad. Sci. 11 31: 155-184 (2008). © 2008 New York Academy of Sciences. doi: 1 O. l 196/annals.14 13 .015 155

156

TABLE 1. Symptomatic correlates of lymphatic d isease

Symptom

Edema

fl cncased appe tite Rccurrcut \ ·umit ing

Di!Ticulty ;;;wallo\\·ing .Joint pa in

.\ lusck pa in Skin lc :-: ions

Back pa in Diarrhea

\\"eight loss .-\bclominal pain lnfcnil it,·

J aundice Sc,·cre irching

Dry C\ TS

:\b ">l' llt mrns{ruatinn Di ::.c olnrat ion of ur ine \ \ 'hcczing

Dyspnea

'\a use a

Hcmopt,·s is Increased appetit e Fn·cr Bloating .-\ bclominal diste nsion Sputu111 producti u11 Che>t pain :\"oi.">y respiration ()nc or nwrc bone fi·acturcs

Lymphatic disease

(;orham ·s d isease

Hcnnt·bm·s sy11clrome Intestinal l yrn phangicrta~ia

Klinc lc lter's syndrome Klippd - ·l·rcnaun<l\. synd rome J .ymphcclcma· dist ich iasis Lyntp hcdcJna- ltYJlOparatltyroid ism .\lcige 's disease (lymphedema tarda) .\Iii roy's d isease ~ curofibrOi ll a losis Prot ci Jt-los i1 1g cntcropatl1y

Stn,·an Trcn :s syndrome

Triploidy , ,·ndrome T urm.: r"s syndrome

YcllO\\' na il synclroJnc :\oonctn syndrome

:\ uonan ~yncl rome

IIJ tcstitJ allymphangicctasia :\annan synd rome

Blue rubber bleb t1C1·us " ·nclrollle ~oonan syndrome

:\oonan syndrome

Blue rubber bleb 11cvus sy11dromc \ lalrur c i syndromt.:

:\-curofi! Jnl rt Jel l osis

:\curufib ron1atosis 1Ittcs t inall~ ·n1phang icc tasia

ProtciJt -losing e n teropat hy

Pro tein-losing enteropat hy Proteill·losill.l?; enteropathy "Ji.Jr ll l'l' 's syndrOJllC

t\ agc uacs' synclrom c

. \ agcnaes · syndro me

'l 'untcr ·=' synd rome

Turner\ ='~ · nclrome

Filariasi"

Lympllailgi(llc ionlyo ,tiatosi:-;

I ~yn1phangiomatos i s

Pulmonary lytnphangicctasia Intest inal lymphangiectasia L; · Ill{J i la l lg"iolc i ntl l~ ·ott lc ttos i s

I .~ · lllJJIJ;tr tgiolcio i tl)·orttatos i :;

l )ulrnoJtat·~ · i ) " I l l f )lla!Ig"icc t~l s ia

L}-Ill j) llaiigi(,Jciorn;·oillCtlosis

Praclcr -\Vill i s,·llcln.lll ll' Filt·tri<lsis

Lyrnpli aJtgiolciOJll;·mnatosis L;·tl l!)ltttttgio lciut tl; ·oin atosis I .yn 1 pl1a ngiolciut nyo111 atu:-is I .ymp lwnginleinmyotna tosis

I.yitlpllangio l ci(ll l l ~·o,ttct t os i s

Cy:n ic angiomatosis

Annals af the New Yo rk Academy of Scie nces

TABLE 2. Objective disease

Facial abJwrmalitic:;

\ \ .ebbing ol"t hc neck

H ea rt m ur mu r

~ le n tal ret ardation

Distich iasis

Asc ites ··Sh ield chest"'

Short stature

.-\hsent/incomplf'tc puberty

Delayed puberty GyiJ CCOIIIastia

Holoproscnccpll;JI\·

I-11-potclorism

.\ licrophthalmia

.- \ 11ophthahn ia Rockcr-bo!tom feet Cutis aplasia O mpltalocTie .-\ pncic episodes :\ licroccphaly .\ [uscular hypoton ia I .ow-~ct rars

Ycl!m,· nai ls Enlarged !in:r Hypotonia f- h -pnmcntia Hypogonad ism O besity Rfdcs

Enlargccllymph 11odes L" ncqual arm / leg l3one cldfnmities

Hcmatuncsis ~ klcna

Rectal bleeding Vesicles Hyd rops li~ta li s

Hernia>

correlates of

Hcnnekcun ·s syndrome

:\oo1wn syndrome

Triploicly syndro me :\oonan syndrome Xoo nan sy ncl ron1c H ennr:ka m \ syn clro!lle

.:\ioona n syndro!llc

1.ymphcdcnw d ist ichi asi ... J> rotc iri- losirlg c r ttc t ·OJ><It! J~·

' I'u rnc r ~s syndrome

Edwards ' synclronw lntcstinallymphangiccta- ia \ lalliJCci\ syndrome T unH'I" .:-i sylldro tllt:

Klit~cl{· l ter"s sy11dromc · [ 'u r ncr's syndrome

Hcnnekam 's syndrom e

Klilldcltcr·s s\ · llclrtHII~

l ·:cl ,\-~\rd s ' :-; ynclrOJne

Pma u syndrom e

Palau syndrome Triplnidy >'·nclroll tc Pa tau syndrome

·I 'r ipluidy ~~·ndromc

Pata li ~ynd rnnH.:

J>atau synclroinc

Patau syndrome

Pawu synd ro m e

Ech,·arcls' wllclrome Ecl 11·arcls' sy11cl romc Triplnicly syndrome ·1 ·riploicly Wllcirome Ycllo"· nail sync! rom!'

:\ a_gcnacs ' syndro me

l'rackr \ \"illi syllclrumc l'rackr ·\Villi sy11cl romc l'radcr···\\"illi synd rome !'racier -\ \"illi syndrome Ly1 n pha ngiolciornyomatt l.'- is

J >tl l rnon~lr)· lynlphangicc t.t:- ia

f ·~ " lllj)\l :-t il_g i(lic iO J ll).OillC\(4 ;~i:;

.\lal1i•cr i's s\·ll clmmc \ [a!Tucc i's syndrome

Blue rubber bleb 11e1·us s~ · , clrome

Blue· rubber bleb ll c\·u.s "mlromc Blue rubber bleb 11Cn 1S sl·!l clroliiC I.yn1p hauginma c ircunl"l ·ri ptum

Cy~ ti c hy-g roma

Patau syncln"J lllC

Rodhokrishnan & Rockson : Clinical Spectrum o f Lymphatic Disease 157

lut tu mcruu.; Etmilie.; <tfllictcd 11·irh :\otliH.'--i\lilroy "s

tvrnph ,·clcma, the disorder has been linked to a mu­

.• t;ttion iu ll t+, the gene that encodes the va scular

endothelial gro" th t;tctor receptor 3 (VEGF.R-:1). t l In ­

. suflicicnt tvrosine kinase signaling by VEGFR-3 leads

. to rite l~tulty clcl·elopmctll of' aplastic: or hypoplastic

cr iphnallympha tic channels. 11

p i\ l utations leading to haploinsufTicicncy or the

nuclc< t! ' transcr ipt ion filc:tor, FOXC2 , have been

irnpli c<t tccl in the pathogenesis of lymphedcma­

distich ias is. 1 ~ i\lorc recently, the molec ular defect

. h<tS been linked to allllormal morphogenesis ol' the

Jvmphatic \·a!ve apparatus/ 1 which helps to explain

tfte cli nical pattCrll of lymph reflux tha t is observed

in the.'<' patien ts. Valve defects and abnormal pcri­

c1 tc / kmphatic enclotlwlial cell interactions charac ter­

i; e tit· · FO:\.C2 cldect of'lymphcclenw -clistichiasis.

Chromosomal Disorders

C: it mmosomal disorders can lead tu the birth

of 1 iable incli1·iduab with multiple organic df'!(:cts

(T -\ t: l.l'. 3). · l'hese disorders arc uncommon; hence

the chromosomal basis can be readily m·crlookcd

or nt iscliagnoscd. Conf-irmaton· identification can be

arlt it'\Ccl onh- through duailed cytogenetic studies.

l\Lut \. ul' these cliwrdcr.; sc1·erch- distort 1\'lnpha tic

ftnH ·tion. Turne r's syndrome and Iilinefelter's syndrome arc linked to the sex chromosomes, 11·hile

Edwards ' syndrome and Patau syndrome arc

linked to autosomal chromosomes. Triploidy syn­drom e denotes the presence or an ext ra copy or all

the dmHl1ClSO!lles.

Turner's syndrome , first clescriiJcd in l93B. tl

is d tl' most comnwn sex-linked chromosomal aiJcrra­

tio tl in f(:malc ;; . 1-'' The patients clesnibecl h\· Turncr

liT I e later iclentificcl as !J a1·ing either a partial or

Ct >in plctc absence ol' one :\.-chromosome. :\ lore n'­

n ·:Hll-. the cla ss if-Ication f(H- Tumcr\ sntclromc has

b tT ll broade ned to include patients 1dw disp!a1· nw­

"lic·ism. or possess chromosum ;tl nmtplcmcnts. such

<h -1-;)_:\./ -Hi ,:\.:\.. 1'1 Patients 11·irh Tumcr's syndrome

~uc s!Jort in sta ture and typically p1·cscnt 11·ith amcnor­

rlt ,·: t. 17 This s\·ndromc is typically associated 11·ith go­

lladal clvsgcne.;is. leading to drastically reduced lcl'l~ l s

ni' the lrmalc sex hormones. lti :-.iconatcs 11·ith Tumcr's

s\· ndromc often display con genital J~mphedcma uf' the

ba nds and fi:et. 111 ."\ s a nmscqucncc of'tltc sex chrorno­

>ot nc loss, these patients arc at high risk f('Jr a , -ariet\·

of' dismclcrs, including diabetes, hypothnoiclism. os­

tcopurosis, and congenital heart disease. I l l Exogenous

acltnini stration of' estrogen;; and related dcril·ati\ ·cs has

lwt·n proposed as potc·ntial thcrap\· . .-\ chninistr;ttion of'

grt)ll·th hormone incrcast·s final height in kmalcs 11·irh

Turner's syndrotne but, paradoxical!); growth hor­

mone in conjunc tion 11·ith lo11·-c!osc es trogen therapy

clccrcascs the final he ight in these patients. 19

Klinefelter's syndrome, first described t11

19+2?' is a disease of' males, wit h an obserYccl fi·c­

qucm:y of' approximately I :G00. 21 I t is caused b~ - the

ptTscnc:e ol'morc than o ne X and/ or Y chromosomc.22

The syndrome is charactcri<:ed by hypogonadism that

presents with extremely Yariablc phenotypes. T he only

common symptorn is inkrtility.12 The genotypes arc

\·ariablc. including 47 ,XX'( -IB,XXY'( -Hl,XXX'(

'i9,XXXY'( and 49,XXXXY Clinical characteristics

include small testes, azoospermia, tall stature, and gy­

n ecomastia. These findin gs can be reconciled by the

hormmtal findin gs, namely, lo11· tcstostnonc lcl'l~ ls , a nd

absent fl:eclback inhibition !'rom testosterone, leading

to an a bundance of circulating FSH, LH, and estradiol

I C\·cls. 2~ In situat ions 11·herc cogniti\·e fi tcil itics arc af~ fcct ccl , a ndrogen therapy has sho1m promising results

in promot ing language clcH~lopmcn t and learning abil­

ities, and a more normal aclolescc:nt clc~\Tiopment. 11

Triploidy syndrome is estimated to occur in 15--20% of' spontaneous abortions clue to chromosomal

abnorm alities. Triploidy can result from an extra set

of maternal or paternal chromosomes, a.; well as fi·orn

clouiJlc fCrtilizatiutL D The f'c11 · li\-c birth s 11·ith this S\·n­

drmnc ha\'l' a short life span, a\·e raging 20 hours,2'1 al ­

though sun·i1·a! up to I 0.5 months has b een rcported .D

In most cases an enhtrgcd placenta results, along 11·irh

an edematous fetus, d:·splastic: cranial bones, ocula r cle­

f'ccts. and abnormalities in limbs, male genitalia, a ncl

\·arions internal organs.2';

Edwards' syndrome , abo knmu1 as trisumy l R.

11·as first clcscribccl in 196(J. ~ 1 After tr isomy 21, it is the

sccul\Clmost comnHHl autosomal tri somY, \l·ith a Jll'l ' \ ·a­

kncc of' I in fiOOO - HOOU lin~ births. Patients· a nomalies

include crania l abnorma lities. 11-chbing of the nLTk.

m a llo rmcd cars. allCl mental tTl<trda tinn .1 ; O nly .)

IU '~o or childre n SUt'l'ii 'C f(>r more than a yea r hccaUSl'

!Ceding di flicultics, cardiac a nd re na l m a lforrnation s.

and other dc!Ccts. T he clinical prese ntations or Ed­w ards ' and P atau syndrome ma\· appear similar

to physic ians \dtO clo not fi-cqttently c nc:otmtcr tlwsc

syndromes. Pa tau syndrome. or tri s omy 13 , is rare

<tlldthl· most letha l of' the 1 iahit' trisomies. :!t: The m e­

dian surYi\ ·al [(.ll' IH' 11horns i:; less th a n :1 clays. Tho ugh

clinical features of' patients \·an·. mental ddicicnc\· is a

consistent marker of' till' clisca.;c.1:: I-Ioluprosc ncephah­

is also associated 11·ith Pata u .;ynclrotnc. 11·hich disrup ts

mid litre ck\·clopmcnt. "11 Cardiac abnormalities ca n be

present:!'' and carcliopulmon<ttY arrest is a major cattst'

of' death .

TABLE 3. Chromosomal d isorde rs

I )i sca~c Ullldition

· l'urn('r's

:-. yndrulllt'

Symploms

Shun stature;

s\\-nllcn

h:lttds /ket "'

l>il'lh

\\'l'i Jf n:d I l<Tk;

droupin g-l·ycl ids;

"sltil'id-sll:tfH:<I" bro:td , !1 :11 chest: ;tb.>iCtll or

illUHIIJlivll'

,fn·t"!llj.llll<'ll\. '" flllill'l'l)'.

including sparse

puhir lli1ir and stn;_d\ bn·asts~

illkrtility

Dry eves

.:\I J ~nll

lllCI IStrualitHI ;

;-Jhs('Jll nurlllal

l!li )i :o.t lll\' ill

'"~~~Lna; painl'ul

Signs

(h·;t rian EL il1 1n·:

hypopla st il' or

ll~V<'I'l'IHl\ ' t ·x

n;1il s~ U!Hknk­

n·lopt ·d hrva .... t ..;

a11d g'l' llit:d ia;

m·hlwd neck:

short sta tu re.

lo\\' hair line in back; s itlli;lll

<Teas<· (a s iJJ gh­

<Tc ·;tsc· i11 tlw

paint); and

aiJJlOI'Illal bottr

clt·n·JoptllClll ur tltrdu·"

l.c-tbor;Hory

lindin ~s

t:tlzynH:s

( ~CilC I i(' <.\C'[( :U

illill' l"i i;\IHT

X-I inked dotnin;llll

inl~t·rit :l llt:l'

Pathology .-\ ss<a ·iatcd

COIH:]itiOIIS

:\b .... c11n· ul'onc :-. t·t I lydrnnrph rusis:

u l'g;t'llt'S t"run1 the pyduncphritis; shon ann ,,rotw

:\_ rhrO!liOSUllll"

iclic Jpat iJic

hyjJCI'll' llSiotl:

l'li:tbctcs :

I IS\l 'Op< HUSi~:

l'llllgl'ni tal

il 'ltlplu:dl'llla;

wci>IH'd neck; nail

dysplasia; high

pai:Hr; ' ""rt lintrtlt

tlll"t;te<trp:tl;

llc;tring loss;

hy j><Jtilyroidisnl ;

lin:r !intclioll

al>i!Onlw( itlt· s

l)i a~nosti t

rnt'lltods

Karyotype (only nne X )

L.:ltrasotlltd

(kidn<:l')

Erlto/iv!Rl ; audio!t1gy

l)jfJl:J 'CIIIi;,{

diag-n osi:-.

:\on\l:.tll

TABLE 3 . Continued

Disc·asc

ccmditiun Sylllpl011lS Signs

i .aiHlr~llory

findin gs

Kliuddtcr 's

syndronH·

(addition n l'

more titan I extra X aucl/ur

Y dlrtJ!l)USO il!t')

ln!C: nil ity ; l .<l('k ol' sc cu!Hi a ry Cytogenetic studies gy llt '('O trl O.l ~Hiil Sl' X Ua J

(clcn ·h)pmnn of' rh;tr:t l' lt·rist ics :

i>rt' itS IS ill lllah:s) Jacko!' (;1-!'iai/IJoci v I sn ual

h;tir: ltig·lt -piu.:hcd , ·oitT; ft- rn;t!t· tyjw

"1·1;" distrihuti<>n;

tt·sti r ula r

d ysg"L' ll t'Sis

Hormone tc ~ ti ng:

high plaslll<t l.'SH ,

I.H , cslrlldiul levels.

low plasrna

tcs lostc J·onl:

Increase in

ll:s tostcrnJH' i11

l'l'S(lOIISl' lO h(:G Incn.:a sc d urinary

g uJtac!l,tropil tS

(;d.mo rrna l l.l' ydi .~

cdlfttnnion)

StTutn ostcoca lcin

k1·ds dcc rcasl'd:

hydroxyl · proline/ ere at i1tin c:

ra ti11 incn: :tscd

( ill t'ITi.tSC cl

J'CSIII'jJtiOIJ )

dcncasccl dcpositi011)

liL'I H" t il· dd ~ · ~o:\

i l liH Til <lllCt' J>;tlh c, \o_!!;y

Snwll , linn lt's lcs

with st: minifi.:rous tuhul <t r

!Jy; t\i niz<Jlioll: sc lL ·n ,s is:

dq_{CIH'rtllr<J

I .cydig- n ·ll s;

hi s to!CJ~Y ol '

g'YIH.' t ' l)tll;J s tiL·

br(' a~ t s;

ltypcrplasi<t ol' intcnluctaltissul:

.\ s .... lH·i ;tt t:<.l

C.:UIH\itiOIIS

E\Iitra l val\'l:

probq>st·

V:tricOsl' , ·c iJJS

Di ·, \ ~UtiS\i t ·

n wdtu<.b

\-:( :c; lo ch:ltTI

tll itral l'<t l\'l'

proi<I( >St'

Radi(•gra phs HJ

det ect lower

holll' Jllincra[

d c ns il y1

r;tdi<miJ J<:Ir

syno los is.

t;turcJ([ontisrn

( .fmtimml

&. <1l Q V> <1l

.. .

.r,·;':

TABLE 3. Continued

DiS< ';IS<;

<:ondition

Palau syndr(mH·

'I'rison1y

t:hronwstllll c I J

Edward<'

S}'fldr<HllC

(trisomy IH)

SymJHtJ!ll s

Cld"t lip/pabtc

bcial ckl(Tts

(ah:-wntur llJ ~ tlfiH ' fllcd 110:'-l t')

Hernias

Stop lnt'athing: pl)or l(·l'Ciing

l.abt1ratt1ry lindi ng~

Holtlprosc ncc j>hrdy (:ytug·c ltl·t ics (brain dt1Cs nut

divide cmnplt:tdy

into halves)

HYlHJidoriSit l

\ licrophthalmia

:\1u>pl1thahnia

Rnr kcr-i>ottorn ll:ct

\linopl11hal•nia

cutis aplasia ( l111ph ;docdc

:\pn('iL· t'pisodcs,

111arkcd t:rilurc to

thri\'l·; Sl'n:n.:

gro,,·th

n ·t;ln.latiotl.

nlt:lltal

n ·wnlatiutt:

II taJJ(>rt ll<ll iOIIS

(t' .g .. llliCnH.·cjJh;t Jy,

n :rchdla •·

hypopbsi<L, hy­

poplas i<~/ aplasia

ur curpus

callosurn. lr olo­

prosell<Tllllaly)

Prenat ally l' lS l l on

in terphase cells

C:on\'cntional

cytog-<·t tctic

studies

Ct·twti ~. · dc!l-n iJthtTililllCl'

Assoc iatl:tl

rut1ditions

( :arcliac clckct s

l'atcllt ductus

a rtvriosus

Ventricular septa l

dcll-ct

:\trial se ptal ckktt

Dex trocardia

Capillary

ltL'11l lutgiomata

PolycYstic

kidneys/ other

!"('II (II II ta\J{ lrTl"I<t ti<>ti S

l)j;\~liU S lic

llH: thods

Cardiilc \Tiltricubr EC:C liH· t·;tn li:tc septal clckct s "'ith ddi:ct>

P<>ly-,·al,·ul<tr

lH ·art disease·

l)ilkrnltia l

. \rt Itt '< 1gryJ>usis

------------------------------------------------------------------------------------------------------------------------·----

TABLE 3. Continued

l)isc<tse

condi tion

' l'riplo idy

syndn mH·

Symptoms Signs

Ccn('ral

dysmaturity; muscular

hypotonia ; l ar~c

postcrifH'

lillltanel;

liypcnduriSIII;

nlirn Jphtllalnlia;

coltlilon l ~\La ;

Clll<t ll t:ULI S

syr1 dacta ly

Abnormalities or th e

sk ull. Etcc, limbs,

genitalia (male karyo type),

\ ·arious intcrn;d

organs

l·i·tal hypoplasia ,

Jtlitr()st<>Jni tl,

low-se t t•ars

l .a lHJl'il ll)fY

filldings c('llt"ticddi:l'l

inht'rit ;Lt\ Cl' Pathology

T riploid cdll in ,·s

lllay hct\'<'

disappeared l'r01n

peripheral blood

so n· ici{'I H.:c of

triploicly r a n only·

l>c liH.111cl in the

n dt urcd ski n

li bmblasts

,\ ssoria!l·d

COIIditiuliS

At r ia l sr ptal dckcts;

p;ll cn t ductus <.trtcr iosus~

O\' L~ rridin g- auna:

hypoplastic ld't

ht:al'l syndrome:

tetralog-y or Fallot~ transposition ol '

g-rtat a ncrics

.Pulnlo!Htry

hypo plasia;

:t l>tJOrrnal lobation orlung

Thyroid hvpoplasia

Diagttosti c

mvtllllds

DillcTcntia l

di ;tg-nosis

162

Lymphangioma

Lymphangioma (T ·\ BI.J: +) is a congenital lym­phatic malformation th at ar is('S durin g <TniHYol ogic dvn:lopmcnt. Lymphangiont;tta ma,· ar is<' from scg­IIH'Ilt:i or l)mphatic \';bcuJ;tl· ti SS lll' th ;lt either biJ ap­propriately <IIJ<IStO illOSC, or may rcptTSL'Ill poniOilS of lymph :mcs that become grouped toget hc:r during dc­q·lopmcm. :;11 Lvmphangiomas arc norma II~ · clctcuccl 11·ithin the first :2 years of"lifl.·.:w The prcst·ncc ofmulti­pk or wicicsprcaci 1\-mphatic \'<1Setdar Illalkmna tions or this t\pc can be tcrmccl lymphangiomatosis. i\flU is th e most usdi.d diagnostic approach , since it permits ana l~ · sis or the 1\-mphatic ,;ys tcm within \·arious tissue layns. w Surgical excision is the common~\- employed therapeu tic approach. The lesions at·c classified by size and depth of form ario11, ,,·ich the smallct; superficial f(mn designated as lymphangion1a circumscrip­tum, 11·hilc the deeper lesions arc cJi ,·iclcd into cav­ernous lymphangion1as and cystic hygromas.

Ixmphang·ioma circumscriptum is characterized bv the presence of numerous superfic ial , ·csiclcs that are

ap proximately 1--:Z mm in diameter and often hllecl 11·ith clear fluicl.- '1 SubcuratH'Ous lymphat ic sacs arc rnnlll'C tecl , ·ia di l<llccl kmphatic chant 1cls tn th ese thin ­ll·alled \Tsiclcs. 11·ithou t cmmcnions 10 the no rmal kmphatic s , · srcm. ·;~ The defining prcst'lltation of lym­phangioma circumscriptum is th e oozing of colorless fluicl. :n

Ca,·crnous lympltang·iomas arc larg-e, loosely clc­finrd masses of sofi· tissue with lymphatic dilat ion in the dermis, subcu taneous tissue, and intermuscular se pta.:;n The owrlying skin generally remains unin­voked. al though skin changes, such as hyperplasia and hypr:rpigmen ta tion , may occur.

C.:ystir: hygromas, 11·hich arc fluicl-lillccl k sions, arc caused by the firilurc oCjugular lymphatic sacs to con­nect to and to drain into the jugular veins, thereby leading to the stagnation of lymphatic fluid. These sacs then enlarge. and the fluid the~' comain fills kmphatic , ·esscls <111cl cormcctiH' tissues, forming the cldini tiw lesion. The,· arc similar to ca,·ernous hm­phangiomas. although the hygromas arc often cn­,·:Jst·d " ·irhin a filnous capsulc30 They commonk occur ncar lymphat ico ., ·c nous junctions. and [()1\T fluid to accumulate in clilatccl kmphatics. leading to progn:ssin· kmpheclctna. ·'·; Cystic hygromas ;n-c commonk associated \\·ith othe r conditions, includ­ing Turnn\ syndrome. Klinddtcr's svndromc, and ,·a rious tr isomies.31

' Surgical excision is only ctnplm·ccl f(.>r supe rficial lesions. c ,·s tic hygromas that arc more deeply rooted requi re nonsurgical treatmen ts, indue!-

Annals of th e New York Academy of Scie nces

ing intralcsional i•~c:: tiot•1 ~,!· sclcrosi.ng agents. '> It ch <L~ bleonwctn .st and OK--1·32.3·' both of winch can ;11 ,1

· · · 'llcr regress ion of the hygromas. -

Infectious Diseases

L\·mJlhatic cksfunction can arise as a consr, 'Ll''tl · ' . i ' Ce

of invad ing pathogens. Lympha tic filariasis <ll ld lv111

_

phangiti ~· (T:\B l.t·: :) ) a1T t\1'0 such condi tions, itti !i;;tcd by organisms that inf'iltrmc and infh:l the lyt nphatic system. inhibit ing krnph flo11· and impairing liOrlllal im mune fi.mn icm.

Globally. 1uon: than 129 mill ion patients arc " !l lict~d by fi lariasis. This condition, fi·cqu<·rnh- disfiguri ng and disabling, is character ized by markedlY impairnl [\-111_

phatic function and lymphangiectasia. The prr· . .- ;:\l,~ncc o f' lymphatic fifari<1si s lags behind only malaria <t lld tu­berculosis in the magnitude of its impact on the ~lobal burden ofdiscase. :H; Patie nts arc inlixtccl by lilariar. or parasitic worms. which take up residence in til t· h:m­phatic structures. The oflSpring orfilariac circ ul<t t:~ in bloocl. :Jti The resulting compromi;;ed lvmph mio; me­diate aclcnoh-mphangit is. which resul ts in film " !' and stenosis of the lymph nodes and limits the l(_,l. tn;uion uf t1c11· hmph channels. \ \ 'h ik the common d inical pt'Cst·n tations often include hydrocele, lymp h,·dcma, and tropical pulmonaiY eosinophil ia. infCctccl pa ticnts ran remai n asy1nptmnat ic.-17 Diagnosis hinge' upon detection of mic rofi ilariac in Lilt' blood and lu,·aliza­tion of obstructing lesions in the hmphat it , using a combination of ultrasound and Doppkr. :il. Tradi­tional!;; treatment l1as ccntnccl arou nd alltip<~ras itic

mcclic;arions, including diethy lcarbamazine, ;tiht:nda­zole, and iH;rmcctin. :m. :;~ '.'Jcwcr approaches include antifi larial chemotherapy. a long with antibimit·:< such as cctracyclincs.·10

Lymphangitis is caused by rhc inflammation oi'lvm­phatic channels through ti ssue in fCnion. Pathogenic organisms include: bac teria , fi.m gi, \·iruscs, and proto­zoa:ft Patients present 11·ith fe, ·cr, chills, muscular pain, and hcaclachc .'1 ~ ·rhc distinguishing charactni-; tic of . this condition is the presence or erythematous. irn:gu­lar cu ta neous streaks in the ancctccl part of tl w body. The lym ph nodes can he enlarged and tcml<- r. ;r Pa­tie nts get Jcrally hm·c a histo ry of trauma. ofic 11 tninot; or skin inlectior t. .u The trea tment ;tpproaclt ll l<t nclatcs the utili:.:ation of appropt·iatc al!tim icrohiak 1

:

Lymphangioleiomyomatosis

r .\'lllj>hanQ:iolciomnmratosis (J •. \i\ l j' is characterized . " . . { by the spread or abnormal Sl\loolh 11ll! S(' lc eel !, L:\ :'-•

._ "" '7 " '7 :- ';' n· "'( =- ;:;- "'( "l ·:FQ

TABLE 4. lymphangioma

I )isc·a,<·

('OIH.Jitioll

l.ymphang·i<Hna ( 111\COill ll H HI.

JJ (llllariO itl :tlOIIS1

CO llgcJlit ;d

lll tdlin·tuations of

knq>hatic sy, tnll th:tt i11vol\'<· skin ;llld

sula:utaJH'IJ\lS ti :-.sucs;:

superficial \T:\idcs

l .ymphangio111a cirnnn"rrip tull l (nHHc

dctv·sca t• ·<l)

( :m·L'I"IIOU S

lymJlll ;lngi,mla

Syn 1p1oms

\'('rntnnts clla ltges;

dt'a r

Sig-ns

Pe rsistent , llltdtipll' dustl ' l s

of tran:-,lw.:cnt n :sidc:-.

that nmta in ck:lr lyn>ph

lluid

Solitary rubbery noduk Superficial saccular

\\·it!t nu skin rhan~cs clil:.llions front umlcrlyin~

knlpl t<>tic \'\:ssd s th"t

occupy t><lpilla and I""" 11pward aga inst til {'

ov~·rlyin~ ("pidlTJnis

- ~ "-' -

I .;tiHJrattJry

li11dings

~ ~

Fannr \'11 1-rdatcd

; ulli .~nt is prcsc 11t i11

IH: IlJrtngitJtl\a ~ hut

ncg:Hin· or \n:a kly

po~i tivc in lyt llJ ll l(lllg"itllll il "\

~. Q ,., = 2- " 2.. 2. ~· ~ ~ -

( ;nwt ic

ckkc:t I >iag11ustic

inhcrit&liHT P;!thulc1g-y nH ·t l1ucb

Voidt ·' rcpn·s<·t~t \IR I biop, ,·

dilatl'd h-mph ch;untds tlt:tt cttu sc ·

till' dermis to np:u1<l. Thl' htlll<'ll is lilh-d

ll' ith lyll·lph:nir llnid and uill'tl <"CHJtctills

n:d blood n ·lls,

\ytnJ>IHI<")'ll'S ,

lllarrop lta ~t's,

llt 'U tl'll pilils: lit It'd IJ\· llitt l'llclothclial n ·lls

l .arg('. irrcgtt lilr

dJannds in n·tirular

dnmis, litll·d I"·

sin ~lt- layer nl' <·ndothdial n ·lb

,.., ""

F. ,.,

I ):tbska 's lc 1\\· - .~ ntth­

ang icJsan:oJn il:

E?

<h-rnmt it is

!Jt'I'JH'tif(,rnlis: IJ l'l' (>t'S

silllplc:-\; IH 'I'pcs zosllT:

lipOlll:>'; lyttq>ha tlg" it ·,·tas i;t:

tJJ aligttant tttdatHJtlla:

tl u·ta s tati~· rarc i tHH l ta

oi'thl' >kill: tlt·urofil>nlttlat<Jsis: Stt·\,·an ' J'n'\'<'s

"Y 'Jd rollll'

" f1

" -,~~.-

l I

I

TABLE 5. Infectious diseases

I )iscasc

condition

l .ylllphatic fibriltSis

Sv111ptntns

h·\'l-r: in g-uinal or

< t~iiLnY

ll·nq>lwckttt>i>aLill·; tl' stindar and/or

inguinal pain~ skin c:•..:liJ\i ;tti on ; and

lintb or ge ni tal

•: dnua; c:loucly,

1nilk-lik(' urine

J·: , · ~ ~ till'nl 4 llllUS

nll;_tiH ' UllS stJ'(·aks;

!Cwr, ,-hills.

Illalaisc; lH·;tdacill· ; ;ultl rexia ; tnyalg ia:

rcn.' nt skin traurna

Sign ~

Episodic at lac ks or kvtT associtttt'(! with inflcurunatiou o[· tln: inguinal lylllph lltlllcs 1

tl· stis. splTillatic cord,

lvn>pht·clcn>a. or a

combination u!"dtcsc~ ailscrss

f{Jnnation a t nodes; n :llnlar

in\':1si1111 witl1 plasmt1

cells/ t'osinophils/ tll:tc­

rophag~ s with hyperplasia or lyrnpl~<llic cndothdium;

ly111 phatir damage and rhronir

Jcak<tt{C of prolc:in-ridt [ymp!J in the: tis ~·au:s; thickening ol' skin and chronic infl:nions

contribute to the appcarattcc

nl' clcpltatlt i; ~:.; i s

Eryllu·tllatous and itTt'gular

linear stn:aks cxtt·nd !i·o1n

prim;wy inknion sitt· tow<trd

draining reg ional nuc.ks; ll'llCkrncss and I'H·at; blistering ol' skin: lyn1pll nodes swolkn

ancllcnckr; rhildn·n may lw 1(-hrik I lat ·hvcardic

l.~1hn ratory

findings

l)t'tcniun ol'

lllitTo(il;tria<: 111

IJin"d

C:IH: inlitrk('(l

knkot·ytosisj ;n>rl bluwl rultun·

( lc ~ tdiJJg- < · (lgc

cuhun· or

aspi ra tion uf" pus)

Fil >rosis or all<·nn:l lymph nodes:

stenosis of'

lymphmics with lin>itcd c:o ll aL<·ra l chantH·I f(H·tn ;Jtilln ;

Utl<ttlcous changl·s:

lt)'j)t'rk<.: ratosis.

c-tcanthosi s, lymph alld l ~tlly ti ss Ut'~ loss or das\ in 1-ibc:rs, ;u td

fibrosis

:\ sscJriatl·cl

COilditiOII S

lbctcriod /llttlg~t l

lympl >admitis:

rl'hq>sitlg·

cellulitis

Di;tg nosti('

lltl·thods

C:hcsl radiog;r;tph

l'it r;t~ou tHI

(h-n>ph«L ic

olbtruction of'

ingui 11 al and ~(Til((i\

lv n q>l~<llics )

l .y1uph node or skin

noduk biopsy

Uilkrcnlial

:\n ~6<H.:dt' tll<.l ;

;tstlnna;

1-ludgk iu's

cli sc;, tsc:

linlrocclc:

lcprow: lvn>plwckn>a: lyntj)lllllnct

(non-

Hodgkin 's);

\l ilruy 's dis l - ~l Sl'.

sc n>­

tal/tcstic.:u l"r ll'<lllllli-l

Con tart dennatitis

f(adhokrishnan & Racksan : Clinical Spectrum of Lymphatic Disease 165

cell>. through both the pulmonary mtnstillum and the a.--: ial lymphatics, leading to the cys tic destruction of till' lung alo ng with hmphatic wall thickening.;.' ( f..\11 1.1: G). L:\ i\1 is also charaCLerized hv the prese nce of puhnonar>· cysts and angiomyolipomas, tumors com­prised of LA\ f cell> adipose llssue, and under.de,-cl­opcci blood , ·essels:'·' LA\ · I 1s an extremely rare cl!scase, f(Ju !ICI iniC11-cr than I in a million indi,·iduab. It affects nHiinly women of ch ildbearing age:'" The chief symp-101n; and clinical presentations associated with L:\ i\ I nrc pulmonarv. including pneumothorax, progn:ss i, ·c cly>JH lca , chylous pleural drusions, cough. hemopty­sis. and chyloptysis:H "ion-pulmonary f-ind ings include Junphangiolciomyomas, the large c)·s tic masses com-1;10nlv fou nd in the abdominal and retrope ritoneal rc­giom, and chylous ascites. The pulmonary cysts can be de tected through high-resolution chest tomography. TI 11· kcv diagnostic tool is tissue biopsy of either the lu ngs or lymphatics with immunohistochemical sta in­inf! lor the antigen Hi\IB-ki .'1; The target of th is anti­gen is the melanoma-related glycoprotein l 00 , which is <:pec ific I(J r L \ i\ I cells. Trea tment is often fix used on preventing or minimizing pneumothorax through plcmodesis and pk urcctomy:IB Additionally, emboliza­tion of' angiomyolipomas is pcrlormccl if necessary. Be­cause L \;\·I presents in young kmalcs and is found to bt · heightened in the presence of' increased estrogen, it 11 <1s bclic,·cdthat progesterone would ha,·c therapeutic clli-ns. Holl'l'HT, it has been siHJ\1'11 that progesterone cu1 only slo11· the progress ion of the disease, while also producing numerous negat in~ side dfects.-I<J .. -,o Curren! r,·search is fi>cused on determining 11·hcthcr rapamn·in may be helpful in treating angiomyolipomas. ·II

Lipedema

Lipcdcma (T.·\ BI.E 7) \\·as first described b\· :\l ien and Hines'-" in 19-W as a bilateral, gradual accumulation ,f fatty deposition in the lo" ·cr ext remit ies and but­t ucks. '-'~ The bod>' habitus su pcrf'icially resembles that ofbilatnallo\\·cr extremity lymphedema, although the inHJh'emcnt of'thc two limbs is substant ially more sym­metrical than in lymphedema, and there is almost al­\,·ays sparing of the fCet. The condition is found al­most exclusively in ft·malcs . Af1i:' t'ted individuals often descr ibe a litmily history of' large lcgs.--'3 Lipcdema is l'urthcr characterized by the prese nce of normal cuta­neous architecture, lack ing the fibrotic changes often seen in I ~ ·mpheclema.'~'~ \Iallcolar fat pads inlipcclcma patients arc prominent, 11·hilc they arc normal in lym­phcclcnla patients. Furthermore, the edema is char­:\rtcristically 110n-pitting.'·.:; Patients of'tcn complain ol'

se,·en.' pain in, nr ac hing ot; the lt.>11Tr extremities. uftcn below the knees .. -,:; Histologic sampling rl'veals edematous adipose cells that arl' sometimes hvpcrplas­tic.:' '' The chid' diagnostic f-inding that distinguishes lipcdema fi·om lymphedema is the presence or normal dynamic lymphatic li.111etio n by lymphosc intigraphy.:.:; Hom:\·cr, the microlymphatic function can become distorted in lipcdcma, and a component of secondary lymphcclcma ol'ten supervenes. The usual clements of' complex dccongesti, ·c physiotherapy, 11·hich han~ an ameliorating cllcct upon lymphedema. adcllittk: , ·alue fi.>r patients 11·ith lipedcma .''1; Suction lipectomy is a promising treatment that has been demonstrated to significantlv reduce the size ol' cxtrcm itics.--,r;

Heritable Disorders

There is an array of syndromic heritable disorders that arc associated " ·ith dysfunct ion of the lymphatic system (T.·\ Ili.E 8). Often , these syndromes are also as­sociated \\·ith abnormal fi1c ial and mental dC\-cJop­mcnt. Because these disorders arc ra re, insights into the expression of disease arc often limited or incom­plete. A useful organizational schema is to classif~ · the disorders by their autosomal rccessi, ·e (Hennekam's syndrome , the Prader-Willi syndrome, and Aa­genaes' syndrome) or autosomal dominant (Noo­nan syndrome, Adams-Oliver syndrome , and neul-ofibromatos is) modes of genetic transmission.

Autosomal Recessive Hennekam 's syndrome \\·as first described in

1989 f(Jilo\\·ing the study or an inbred fiimih- fi·mn a small fishing tom! in the :\cthcrlands. T he condi­tion is characterized by lymphangiectasia, st'\·cre lYm­phedema. fiJCia l abno rmalities. and mental rctarcla­tion:ii Since the original descript ion of the syndrome, only 2-J. patients baH~ been diagnosed " ·ith this con­clition; nc, ·c rtheless, since these descriptions span II widely separated countries, the genetic anomaly is bc­lic,·edto be diiTusc. '>B The filcial clisfiguration represcn­tati,·e of this syndrome includes a fl at bee and nasal bridge, small mouth , car defects, and wiclci>' spaced eycs.:>i Gabrielli el a{. have proposed that these fil­cial anomal ies mai be the conseq uence of jugular lymphatic obstruction. '-''1 Such lymphatic obstruction would result in fiH:ial lymphedema \\·ith rcsultam cu­taneous oYcrdistcntion , and f~1ci a l distortion. O thers ha,·e theorized that the associated intestinal lymphang­iec tasia might p romote protein loss, thercb,· caus ing peripheral edema , ascites, and the loss of lymphocytt's and ,·itamins,''B all of which arc seen in patients with

TABLE 6. Lymphangioleiomyomatosis and lymphangiomatosis

D isL·asl '

nJilditiutl Syrnptut ns

[.ym]>lt a Jtg icJ- l)ys jllll '<t; hnn<JJ>tysis:

ki(HIIYtllll;t tu s is t·\ty\tl plysis;

l .ym phangitnna­

tosis

nausea. hloati ll_!!,", abdomill;d

dist('usio11 : roug h;

SJ>llltllll

t>roductiOit ;

\dttTzin~; chest

pain MUI'g'li11g in the chest

Pn·sc11t s in \a u·

dtildlwod; can

orcur in <Ill)' t iss ue

iu whic h

l\'lup hatics a rc

non nally l(allld;

p rcdilcnioll li>r

tltorac ic ~llld llt'Ck

ilt\'Oin:rn cnt;

wht'L"Zl'S

(rnisd i;tgnoscd ;ts

asthma)

Sip;11s

Rttks: ]>lll'U­

tnotilurax:

chv lo tho-

chy lo us

pkural

drusions;

ly<ll ­

phadt·IH>p<I­

thy

Ct' IH' lic c.kkct

inlwritatt tT

Sporadic

Pa tltol og-y

1\ ltdtip\" lymphilllg"itJill as

(ln: ll-tlill (·rcntiate<l

ly111phati c tissu<' tlt at

prl'Sl'!lt a s multicy:•aic or

SJHIIlg'l' - \ikl' (H'C llll lll iil liOll S;

l)l·n ig n prol ill:r~Hiuus ol"thl·

ly nlJ.lhatic chanllcl s \\'ith

abnormal co!H JC<.:t ions {(I

th" lycupha lic system); :tt JastunJosin g- ~ IH_lothdial

linl·d .spacTs along

pu l1uonary lvmphatic

I'< Hilt'S <H."l' ()lli[><tllil·d by :J.-.y ttJJJH'tric:ti!y sp:tcctl IJU IH.!It..:::; of spindle cell s

:\ ssuLi: ttnl

l'OilclitiOI\S

R{'md h;unanwnas;

lymphcdcnm;

ci Jyi<JjWricotrditttlJ ; ,·ys tit ·

soli tiss ue n~asst·s _; uttTinc

fihru ids; pulmon ary

ill'lllO rri Jag:c;

lll'll tosiclt: ros is

l'cricardial Ill' plcucal

dl'usions; chylous

cll "usio tts; cllyit>f>tysis;

lt CilHlfll)"Sis;

cl tylnlll'rit·arcl i ti ll 1;

chylous a sc ill·s;

j>n>tcin-wastirtg

t.'lllcn >pathy; pcripltcral

lyn tl>hcdcnta

ltt'tlli lty]l<'rtl'Op!ty;

lyil1J>!Jtl!l t:t"l iit; dissc 11t i t l~ tt cd

iltl!':l\"i tSCU/;u · Ctl<~gltloj>ality ;

cocxisr.t.:.llCc of lyric lJ(H i e

Biupsy:

lliag- n<)stic

mct hocls

O pc 11 l.un~

'1'1 ·; tnsbrollchial + H iV! B·I·:>

sta i11i11 ~ (LAM cell s)

"l 'i ssut· biopsy uf" it l\ ·u lvcd

lycnphat ics () thn:

H iglt-r('solutic>ll

CO! lljltltt ·rizc(l t(Hnog raplty

(H RCTI"I' tiHlr;tx/abdonll'l t

Pu lmonary li.111niu n I('St

(a irllo\\" obstruction ~;,

impaired gas transkr) ( :Jwst radiog rap h

llollt' biopsy

lylllJ >I JangiogTotplly

dtvs L radiog"t"ap h

CT imagi 11~

:-.JRI

ll illiTcllt ial

.-\stlu n; t: SIHHllaJH ·(nts

!HlL"U Jnotlt nrax:

~·tnplty s l · tn a:

tuberous scle rosis;

i11tcrstit ia l

pullllnt ta ry lih r(lsis:

pulmonary

lympll:tttgicuasi<J:

i>rutll·ltic)litis:

kiOtll)'OS<t i"("(Jill <.l

'\ st lt r11 a

.-- -~ .. 2: z

~ ~ r.

Radhakrishnan & Rackson: Clinical Spectrum of Lymphatic Disease 167

z -·~ -

~ ~ -c

·~ ·r.

~

.¥ ~ ~

t,; -

:..

·~

:;,

~ ..

;: _::: .. :r. - -:;

:.0:· ::

} -~

i --:0: ·

'-' ·~ :" ·r.

- ~

:r. --

·~ --~

~ g ·"

~ ?. -

thi~ syndrome. Interestingly. difll:renn:s in presctll<llion

and sym ptoms arc 1·ast , sugges ting difl"c rcntial cxprcs­sivity or a single gene. :,:;

The Prader- Willi syndrome shares 11·ith Hcn­nckam's syndrome the attri butt ·~ of f~tci a l a noma h­and mental reta rdation . Patie nts ge nerally also mani­

fi:st neona tal hypotonia. hypogonadism , hyperphagia ,

and small hands and fcct.1'0 A short , young ,,·oman

\\"ith nlan>· or these characterist ics was first clescribccl in l8G4, but Andrea Prader ollicially desc ribed the syndrome in l 95GG1 This syndrome is an example of

ge nomic imprinting, 11·here the clinical expression of the d isease is dependent on the parent fi·om 1d10m the abnormality 11·as in herited . The syndrome has bee n

linked to chromosome l :l , and is paternally inhcritecl. 1 '~ If the abnor mal chromosome comes from the mother.

then the phenotypic expression dill i:: rs, a condition de­

scr ibed as Angelman's syndrome. Aagenaes' s yndrome is another autosomal re­

ccssi\T lymphatic cond ition. It consists o f cho lcstatic lil"l:r disease in conjunction with generalized lym­phcclcma .t>:l The edema is most commmtly knmd in

the lo11·er extremities, as 11-cll as in the hands and scro­

tum.' i:l This syndrome 11·as fi rst studied by Aagenaes

in 1968, and most patients 11"!10 bear the diagnosis arc fi·mn a single reg ion in southwestern :\"or11·ay. 1

i ·l i\·Iost

patients follow the general pattern oriymphedema pro­gress ion and simultaneous cholcstatic regression wi th

agc.1' ·1 The pathology of the t1w componen ts or the

disease is distinct, wi th the l in~ r disease attributed to <>ian t-cell transf(mn a tion , and the !l·mphcdcm a to

lymphatic 1·essel h~voplasia6·1 Symptoms include itch ­ing and jaundice, and there is o lten a gro1nh delay du ring childhoocL1'·1 0Jutri tional and , ·ita m in supple­ments hal"l: bee n shmm to hm-c therapeutic \ ·al uc fc1r

patients.1i-l

Autosomal Dominant In 1883 a m edical student , Kobylinski. described

a young patien t 11·ith a 11 ebbcd neck. This is the first

docu menta tion or the Noonan syndrome, a con­

genital syndrome consisting of a webbed neck, m en­

tal retardation , short stature,0 '' and cardiac defects, pa rticula rly pulmonary , ·ah-e stenosis.1;li Addi tionally,

many pa tients ha1·c lymphatic , ·esse! dysplas ia, neona­

tal lymphedema, intesti nal or pulmonary lymphang­iec tasia . and cystic hygromas.' ':; An alysis of patients

wi th this condition r<Tcals tha t the ge netic abnormal­ity can e ithe r occur sporadically or as an autosomally

dominant form of genetic transmission. Coll ins and Turner found that while the sporadic muta tion was clistributecl c\·cnly among socioeco nom ic g roups, the

Jiuni lial mu tat ion 11·as predominantly J!nt ncl at no tlg

TABLE 8. Heritable disorders

Disease

c.:uuditiou

i\d;un s Oli\'(:1'

synclronH'

Dd(·cts nl'tht· sc;dp

a nd rraniurn

associ<ltnl with

di stal limb

+. 111omalil's and

OCCilSi(l ll <L i

llll'lllal

rctard ttticJJl

l .;d_)()rat<>ry

lindings

Ccn<·tic dcll-n

iJJhcrittlllCl'

1VIost aut(JSOillai

dUillillallt ; SOI1ll'

sporadic

tllllUS(llll<tJ

J'Ct"t 'SS I\T

Patholugy :\ SS<H.' i<.tt<·d

corulitioJlS

Cardiovascular

system :

'li ·tra lo!-.'Y ol'bllot and jlllilllOilC.li'Y

;ttn:s1;1

H ead a nd neck:

!\rr:utia ol'thc llal

l>ollt'S wiLI1

normal hones of'

the cranial h;-ts(' :

hvpoplaslic lilCit:s

and micrun:phaly Hand a nd foot:

Hypuplastic nails;

sin1plc sylldactyly; bot!)' syncbn yly:

(J"i \II S\TI'SC

J'('c\urtitH1 ckkns: t·ctnl{Ltctyly; polnlactyk;

l> raci Jy<Ltuvlv

Spine: Ckcas ioJJal

spina bifid:t

Skin: .\plasia cutis

cungcnita u!"tlw

S('<t lp

Nervous system:

J· l)•dnHTjlh:dtJS,

t ., , il c ·r>s~ ·

l)i ;tgnustic.: n1cthods

RaclitlgTi.lJ>Its;

c.:C.:IIOl'ardiogr;J­

plw

l) ilkn:nt ial

TAB

llist:<tSC l'll lldi ti OJI

0:ootmn

syttdroml·

_:\;cun)­

libromatosis

:\ ag-c n tH·s·

sy1tdrunu:

(ch o lcstasis

\\'ith lll i:tla h­

so rptioll )

Sy1nptotns

I h:tT< ·asf·d

<tppct it c; rn.:qll(.;ll t or

lim.:d[•l

VCll ll it ing;

dysphagia; sn ·erl' join! o r

tnusck pain

Cnlli:c-c<>l<Hnl

ntacular ll·siuns;

f'n:ckling in non ­

s\ttt-cxp<lscd

areas: bac k pain

Pn:dt~ rnin i\ n liy lll

f\<J nvcg- ian

patients;

jaundirl'; scnTc

pruritis

Si~II S

hoci>d aiHlurtllalit ics,

\\:ebbing of' thv

neck: cltcst

dcf( H·mitit·s;

IH'art Inurmur:

rncnt:d

n:t;trdatitHI

\Jt:Urt>fiJ )!'Oill<lS;

optic glioma;

l lamart<HIItts

011 II"IS;

di stinctin:

bony ](·siuus

Hc.:patOit lcgaly

lindings

' l 'ltro tnlwcytnpclli;t ;

J)l'Oiortgcd

ttCl i\ 'tll ccl partial

tlo rOinl•oplasti•• ti me

:\utosonwl

d01ninant or

Sj)Ot'<H:J ic

;\ull>sn m al

tlontinanl (no

Eunily history Ill

!"l O ' ~~ ~ ); h i~h

mutalion rate

Vasculop;othl' (art('l' iaJ S(CIIOSCS

due tt> irnimal

cdlular

pn>l il( ·ratitn>): lilmmtusnd ;tr

hypcrpbsia ol' arteries kads to

rr not! ~trtc ry

s tcno~ i s :

n :n:br;d

inl~trctio1t;

~uH: urystn (rare)

Po ss ibly aulOs<Hli <.tl (;{' IHTalizc<l

ITL'CS~IVL' Jylllphat ir

a11omtdy

(lynlpl o-cdl'ltta dlll· tc J

lyn1ph \'i'SS<' i hypopl; os ia): gi;un-cdl

hl'patitis with fihrusis of' portal

Iran

}>ttltnottary

valvular st <"nosis;

cryplon·hi{lisnl

lyrnpht·dt•Jtlll;

osteoporosis; ,·as('td it is

Jlrogn:ssivc

ltigl t-li ·cquctn:y

s(·t ls < Jl'illl'll ra I hea ring loss;

pleural drusiu11s;

hydrops lc·ta li s lnlpaircd

n:spinlt iun (H'

dcg-lu itit ion;

itttcrstitial

J>t llm<mary

lihrosis: renal artery stenosis;

U'l\:bra l inl~1n: tion~ short

stature ; sco liosis:

!tyj>cncnsion

dc, ·clupnlclltal

delay H epa tic t irrhosis;

g" I'O\\'th

n:tardati<H I;

rickets;

pco·iphera l

lleumpathy: r('CUI" rt 'lll

cellul itis;

hyperlipidemia:

bleed in~ (\·it:u n in K

cklicicllcy)

Bln:dill )'; diatlH.'Sl'S (bnorXl dt·f i('it·t Jcy);

ka ryotype to

di stin guish linn1

Turner's syndrollK (X( )): clcnro- and t·~ ·htll'<trdi ugra­

phy: audiulogit'

n ·; tlu:ttiOit

~1RI c·r irnagin~

l .ivt'l' biopsy

(J.;iatH-cdi

tl':tJISfC.H 'lll :tlitlll S)

·ru nll'r sy nd nnnl·:

'1'risomy ~ I :

Escuhar

syndnmH·

r:onlinurd

I

TABLE 8. Continued

Disease.·

nmclition

Ht'IIIH:bm's

synclrc, tn t

SytnpttllllS

I-:<f,·nJ:! ; IOI('ial

:tfHHtlidics

moc.kr~ ttc

dc·vcl<Jillll<'llla l pruhh-llls

Signs

l x n•p lieclt: lll a: l yntplwt t~iecta­

sia; bcial

<lltutna lies; dcl ; t~Td OilS(' \ o! '

puberty; llHJCicratc

tnvrnal

rct:trdatitH t

l .al lora tory

lindi n .~s

I· Iypog·;·untn :t­

g lob ulitt c ttti :t

l-l ypualhunti <lclllia HyJ)tH.·; tlt·c.·tt ti:t

l.nt kopenia 11·itli

lymphop• ·•• ia

Ccnctit· dl'kct

inlwrita tH'c·

ln ""'' rcp"rt "I' I II Elm ilia! ca:-.c:...

cqu;;tl sex rt tt it' ·

int:n·:tscd

pan:nt:d

t' Uil S: tllg'llitt it ~.

IH J \ '('l"t ic;d

trcutstn iss itlll:

c'tHl Sis tcllt \\'it it :tli{ ( J~( J\ ll <'tl

I'CLT SS I\'t'

l':ttiH Jiugy

:\s:..<Jl' ittt \'tl

CtHHii ticHJS

l'apillae ncr\' i optiri

Slig·ht tortuosity o r

the \'(· in s

Yel low Jltacula

( :c,ndttcliCH l

clca l'n css

Nar ro \\' upper

thorax

Cong·cnita l ht'an

dcll ·ct

Urn bilic;d li cmi ;cs

C1mLractun·s

S\·1\d;cctyk

Brain cyst

Pyloric s tt"nosis

1-lc~tr in ~ loss

Blollcl \ '<·ssd

~liHHil al i c s

:\toni c scizun·s

[ )i a~ tt ost i l·

11 1!'\!Jods

:\ ltt li utnl·try

I lil li- rl'luia l

TABLE 8. Continued

l)ist·asL'

condition

J>radcr \Villi

syttdnmw

Sym JHoll ls Sig ns

\:col\atal Hypto 11ia; hypotonia ~ li:tus hypnrnt·tHi;t;

sm all l i1 r h ypo~onadis rn ;

)!;<'stationa l ;tgL·: 11hcsity UJldcsccii (It·d

tes tes; dcl;.tyt"·d t1ltJ[() ]'

dcq·\opmctlt

slow Ill l'!lt<tl

dt ·\·c·lop tlll:Jlt

, ·cry stncdl

ha11cls ancl i(Tt

in cumparisun

tu hod)· rapid

weight ~a i 11~

ins;!li;Iblc

appetitt·, !(HHl

cr;tnng :

al n 1< lltcl-sh;qJ<:cl

l'Y<'S; IL<l\TO\\-'

l> il.rontal skulL

tnorh icl ohl'sity:

skl'ict;tl (linli>) ahnonn rditit ·s,

:-; t ri tH'

L -tboratory

find ings

Ccnctic IL'St ing,

induding­dtrolllf)Sll l llfll

analysis l( ll·

llH: tll)l ttiUII

patterns i11

P\YS n·g·ion;

SoudJCI'll blot hyi>ricliza­tion /l'CR; analysis !(J r

underly ing llllitl itrL: I tl <t\

disomy;

fiiiOJT SCl' ll( in situ hybriclizat inn

(FlSI-1 ) can run fir m

pn:natid

diagnosis; e\ ·:..duat ion fiJr

IJy[)ogu llttdistn:

ll \L'~lSUI'C I11 L' JI IS

of' insul in-l ik!'

gT! J\\·th Etllor-1

(IC F-1 ) and

ICFBI'-:1: ;!SS('SSJnnll ot'

ti i)TOi<l l adn· JJ al

and pitu itary

statu s

Ccnrtic dd~ · <: t

iJt!t r ri t; ttH 'l·

Gc11omic

itttprintiltg-:

dilkrl'lt t i~tl g~·nc

r~prcssi t,tt

based up()n

parent o l'ori_!_!,"i!l

(loss ol' p;lt<'I'Jial

g t ' lll' 01'

rna l CI' JJ a!

d ison>y)

l>;ILitolugy

:\ss{H:iatcd

cun ditions

C:arcliupuiJ lltJittt ry

COIII!JI'Ullli s c;

di:dwtcs;

ortll!J jll'ti ir

problnns

Di;tg'JHJS!il·

nH·lltods

C:ran i;d 'd Rl (to c \·od uatt · f(>r

lt yjll>J>i tllit:Jrisn l): seria l du: d-l-IHTgy X-rav

ahsn rptiollll'l r~ ·

(DEX:\ ) SG\11!\ ill g

!{It· d c- tcc­

tionhnouituring {)r o :; tc O[H) rosis;

scoliosis sttJ<.'!i('s:

cht·st X -ray;

abdom inal

ul t t'<L S OIHJgT<q> il ~·;

( :T a nd

g·;tStru intl' SLill Ctl

trnag-u1g

J) ilkrt· llti al

d iag-nosis

lnl:uJt iJ,·

II~THlltHtia:

IH 'Oilatal ~c ps i s :

<k\"l·ll l\ >llH' Jltal

d!'by/ nH'Iltal n· t :lrd ~ tti < JJl,

ohc~i t)~ ;Ht d

!t~ · \ll l g"< ·,,l:· tdi s J Jl:

.\!b right

ill' rccl itary t IStt·t 1dyst rnpl1y·: llardr:t-Bi,·cll

SY JldJ'<li'J'l(· ;

Cohen

~Y ' 'cln11nl';

B<n:jt"su n­

h,rss nJ:tll­

l .elun;J\11'1

syJu\ rt JIIIL';

Soll!l' p; ni t ·Jil S

" ·ith Fr;1gik X

syndnm1c ;

Poss ihk tiq or

l p dele tions

172

lower g roups.1;; In order to ascertain the pathophys­

iology of rhc condition, patients were lymphang io­

g raphically inn~s tiga tccl. The documented abnormal­

ities included lymphat ic ~ ·csscl aplasia and hyvop la-. sia and diminished lymph a tic fl ow-';:; It has be en

hypothesized tha t the m :hbcd nec k phenotype results

fi ·0111 the regression of cy~tic hyg romas when h-m­pha tic oh~rruc tion is a llel ·imecl r ;.; .-\clditionallr em­

bryo nic kmphcclcma may p t-c\·c nt proper migration

of ti ssllt:s d uring del"ciupment. leading ro the a noma­

lies. such as the cryptorchidism. hypertclorism, and

lcl\\·-sc t cars that a re comn1un in these patients.6.i

Prenatal diag nosis is oflen accomplished ultrasono­

g raphic;illy. 11 ith detection of c:1·stic l11·gromas and edema. c,s

Adams-Oliver syndrome comprises congenital

c utis aplasia, or abse nce of all skin layers, 11·hich gener­

ally ma niiCsts as scalp and skull defects, a long with dis­

tal limb a bnonnalities.6H Although paticms often hm·c

scn're ckkcts o f the skull , ce ntral nerYous -ystcm de­

fects han~ not been reponed. Intelligence and intellec­

tual clcl-clopment is normalf;9 iVhile the most common

mode o f inhcritance is a uto. omal dominant.'0 spo radic

cases and a utosomal reccssi1-c inheritance have also

bern clocum en tcdw Some afkcrcd indi,·iduals al so

kt\T <tssociatccl ca rdiac clclc:cts. Poust i cl a!. ha1·e pos­

tula ted that the ge netic clckct decreases the stabil ity

of embryonic b lood \Tssc ls, the reby· disrupting \·ascu­

lar dr~ ·clopmcnt. particu larly in the cranial ITrtcx and limbs.';9

Neurofibromatosis is a single-ge ne disorder or

the ne tYOus system . The responsible gene has been

mapped to ch ro mosom e l 7. il. ' 2 The protein im·oh-ed

is n(' ttrof1brom in , a tum or suppressor. and an inhibitor

of cellu lar g ro11·th and difTcrentiation in neurons, g lial

cell s, a nd Scll\\·ann ce ll: . i:J T his loss of inhibition IT­

suits in uncontrolled cell ;rro11·th of centra l a nd periph­

era l nciYOUS system cells , and ca n lead to the lonna­

tion of the tumors (neuroftbromas) when both alleles

o f the gene a rc lost, as 11·cll as non-tumor manifesta­

tions if a single a lle le is mutatccl n Clinical charac­

te rist ics include hype rpip:m e n ted maculcs, ncurofi bro­

m <lla. and benign intracranial calcification s . ~+ :\"cu­

rofibromatos is i,; inherited in an auwsomal domin a nt

manner, but clinica l expression 1·a rics g reatly. i ·f C sc­

fi.d cliagnostir m odalities incl ude :\IRI and CT imag­

ing. Currently, clinical trials arc under 11·ay to a:rcr­

tain the ellen of p irfc nidonc. an antillbrotic com­

pound. on the neurofibromas, \\'hilc other inH' stigators

arc attemp ting to d e1dop new methods of measur­

Ing the gro" ·th of neurofibromas through volumetric :\IRI. 7:'

;o....___ --------····-.

Annals of fhe New York Academy of

Various d isorders represent the result of

deve lopmen t of, or insult to, the blood , .,,snda lymphatic vascula r svstcms ("L\lll.E 9). Th ,·, (· r

oltl'll han· a superficial component. a nd Jl n' , cnt . . l . . f I k. . I r· f" as lr-regu anues o t 1c s ·111, lilt u: orm o nnclu J,., or les

1·

S. 1 1 1 r· l 1· · · · ons lllCC l l(" pat 10 ogy 0 t ll'SC COil ( !liOns IS CC>!ll[) [" : tcateu

thcrapi cs arc foc used upon alleviating th, · de rrnal ' flict ions. af.

Cystic angiomatosis is a congenital co nc[·1r· · ton ofunknm,·n ctiolo(!:v. defined b1· thc rxcscnr ·.· ,, (' 1111 c·•· __ . · · · mcr-ous cystic skele tal lesions. '' The lesions a rc

round or o1·al. and the1· van' ll"iclek in size. · ·\ ltllo h . . . . . , : .· ug thc cltmcal course IS \'a ned. th e lestons mn:q frequent!

presrnt during the first Jew dccaclf's of life . . ;: The crsti~ les ions m ay be duc_ tc~~li latccl blood vessels m ly lllpl;atic · channels, or both. ' 6

· ' ' The c1·sts a rc encircled lw a g lc, Aat layer of endothelia l cell . iG Patients '

1rith soft ti ssue masses, and som etimes hm c pain . \\·e lling due to pathologic fnlc turc. ; ; . i 9.Hf ' Cyst ic

g iomas are easily cle renablc on rad iograph, since

represent a reas of" destro~~d bone that are <harply de·

f'in ecl by· a sclerotic rim ." Biopsies, often in alTectcd

areas _of the rib. are pcrf()rmed to co nfir m the diag­

nosis.'" Chemothe rapy and raclio tht·ra py k t1·e hecn ·

a ucm ptccl, but gcncrall y ha1·e bent inclll:rtual. iii

Maffucci's syndrome 11·as first ck't.-ribed in ,·

18R I : since then , fC\\Tr than 200 case., It a" · been re­portcdg 1 The syndrome is characte ri zed iJ,· the pres­

ence ufhard subcuta neo us euchond rom as ;u td hcman­giomasll2 clue to mesoderm al dysplasia .:ll :\ i<>,;t ofthes~ ··_­tumors are ben ign, \\'i th a 15- 20%, inciden< "<" ofmalig- .

nant tra snsformation a~ Dyschondroplasia . improper

formation of bone in cartilage, is scc n.R·; .\ lalTucci's

syn drome often impairs lymphatic syste1n !\merion,

leading to edema and secondary infi::ctinn.1' ·, :\lost indi­

, ·iduals affiictccl with this syndrome are plwnotyp·

normal at birth ; lesions appear during child hood and·

may progressi1·cly 11·orsen. 11:;

DifTuse hemangiomatosis is d efined b,· the

c nce of non-malignant. 1·isreral hema ng i01nas rlmt fi.:c:t at least th ree o rgan sy$tc m s8 ti The lesions

attr ibuted to a conge n ita l clcfi:ct. The , ·asctd,t r h tomas are postulated tu arise as a ronsequ,· ncc of

fic icncics in pericyte;; in tll<' 1·asntlar 11·all ' u' T his

clitio n is extremely rare. 11·ith kwer than 71)

cases.11 1 Al l clescrii>ecl patient s !tan· k sions PI" t!ll' skin,

l. l . l I . . I . a.- Ther­tH' r, Jr<llll , ungs. anc gas trmntesuna tra c<-. I . . I l . f" I -ts been apy \\"ttl cor[lrostero!c s anc ullc r eron-Ci 1. .

l Ri ·r··t I . f' t f. J , , ·' srJor~>c attnnptec . 1e mcc JanJsm o t 1e aw>ra m t c

to these medications is not known Bi

_i -; ::.; ,.., -c::;

~

' / --/ ;:; ;=, 5· 0 " " §

u. "' -, ;_ 'f ::: "" ~ "; ;:; .. ' .. ("')

,, "

TABLE 9. Comp lex vascular malformat ions

l)iscast·

rond itiu11

P roteus syndronw

\!a ll'ucci 's

syndrol!H'

Symptoms

Partia l gig·cutti sm;

lung l ~H:c ; wide

tl asal bridg-t': l llll Ut h n pl'll at

l'l' '\ t ; uppl'r body

\\'as ting;

lc<ll'llittg

clisabilitic::;;

<>CCasiOII a l

SClZlii'CS

Signs

Cttt <ulcous a nd

suiKttlatH"<Hls

le si on s~

in cluding

\ "(lSt:U ial"

rnai i (H·nlat i< >n s~

lipunws; hyp('r­

pigtnt·ntatiOil ;

and srn:ral

I yj)t"S 01" rlt'Vi

Sul 't. hl uc-co lorl'd E11cho11droma'

growths in diswl wit h multipk

aspl'cls or t·xtn:mitics;

short stat ure;

urH:qtw l

ctnn/kg ll' nglh

angiomas; bony

rkl(">rlt li L i~ ·s;

da rk, irrq.!,'ula rly shaped h t tll iLtlg"iont<ts

~ ·

cj ;

:./1

;::; - ·- .~

5 ~ ~ · r.

l .ahora tury

linding-s

"' 0

,.., :::- "' :..- r: "'- .-- - , .. / - ~

~

~ ";

1 ; '"" "' ~ ::::>.. -

(;l'lll ' ti(" ddi:ct

inl lt'l'itcu!l'c l)atholog-y

Son JCHic CortJH:cli\'t· ti ssuC'

mosa icism for a 11cv i l'l'Scn tblc tltliiL inatJI,

ll ll idt• tttilit·d

kthal lll!Jsaic istn

Spr•radic. lllauill:s ls t'<t rl y inlik (~

·I :) )Tars) ; 2:) 1XJ

o t' ca~l'S ~ liT

CIH tgcnital

tig-l ltly

l'tll'llJmCLt.:c.l.

col lagc Lt-ridl

('0!111U'li\ 'C

ti%ul' :

cpidnmal ll c\·i g-e nerally l~ \: hihit

a rombi11atinn oi' liyp<· rkeratosis,

pa rakeratosis, a('a nthosis, ami

papiii<J Jn;Jt< JS is

TlmHnbiofitn I(H·mwithill

\ 't·sst"ls and

dc\·c lop into

phlcboliths: Il lest· appl':tr as

calcil·i<'d

micrn-n·ss<·ls;

ch01 1dro sar-

("(Jill itS

d iag-nosl'd l.1y poorly dilkrcllll iatul pl<·i(>lllOI'[l lli< ·

dt<Jt t drot·ytr~

"--

n '"' ;:::. ' · -": "' :r.

:-§._ r; .. ;:::

AsstH.: itltcc l

tonditions

EttdlOit(!J"OJll OLS

clc\'!·l"jl i'ro lll llH'SOdl'l'lll i:d

dysplasia; unt·quallcg

h-u gtlt ; Jl a tho ltJg it·

fi·tu ' ttll"CS.

malunion oJ' f"ractun.:s: c hon­

dtlJSa t·f( Jrn;t,

ll elll<lngioso tr­cunta,

lytl lJ >II:ttlg"itJs;Jr­

coma

r , 7-

"' --·

- ---7"' "'- "'

Diag-nostic

nu·thods

l{ ;ldit lg_TH j)ILs:

CT/\IRI

C:T/ \liZ! hone

biopsy ii'

L'llt' honcln'lll:Ls n ·okl·

f .

7-;; ;;. "'- 2-

. ~ :···

llilll·n· JJti al

diagnosis

~! l' u ro l"illi "UI Jt ; \!(J~ i s

Klippel ' l 'n :nau 11ay ··

\\'dwr :-;ynd,·oJnr ·

K:t posi\ sarcom;:t:

Klippd ' I'n·nau 11ay ·

We bel·

syt1dron1t::

J>rntt·us

sych1n1 Itlt:

( .'rmlinun/

(')

5' r;· 3..

.g> (1) r'\ :; c 3 0 ..., ,...

'<: 3 "0 ::J" 9. r;· CJ c:;;· (1)

0 V> (1)

J~"' r

TABLE 9 . Continued

Uisvasc

ronditinn Symptoms

Blue rubber bi<- h \l ultiple skin

ra·nrs ll:sinns: syt 1clron1l' protuiH·ntnt,

dark bltw,

I'Oill!>l'l'SsibJt:

bkhs

Laboratory

find ing-s ( :CIIet ic clckn

inhcr i t ~liHT

Lesions are l·"t-cal or n tlt blood: Sporadir, asytnptullta ti <'~ ( :HC :; :-.tTtTn l(w c-t utnsotllal

hut may IH· iron dt'li cil·ta·y dom in;.ull painfld or flfH'tllirt ; jnhcrittliH:t: also

lt'tHic r ; urin;dysis rl'pOrtC'd

liypt:rhidrosis of (IH.: lll;tlul'ia lll<l)'

ski n U\"(Tiyin~ he CIUSl'c\ by the k sion; bladder lcsi<u ") l:ttig·ue (frorn

blood loss) : lt l'ntatnnt:s is,

rnclc.: na. or l'rank

r.-ctal bleeding;

joint pain:

bli ndness

(ccn·bral or ccrt bdlar canTI HHll:lS that

IH'JlHUTitag'l'

into tltTipital

lolws)

Vas('u lar tissttt·

with tun uous,

blood-filled t·ctatir \ '(·sst.·ls.

lined by sing lt­laycr or <"I!(l<>tliC!i u< n. with

S UI")"()Ur!ditl~

thin ("01\IH:("(i\ 'C

tissw· ;

dystrophic calcilica tion

tnay be pn:sc nl

Ass<>riatc.:d

cottditicms

l) iagnnstic

lll t; thocls

l111a~ing-:

rad iographs c-t n: uscrul ill ~uspcrlcd bont or joint involn:me11t

\lRl ;

t'IHlosn>J>Y l(n·

g<J" LnJiittc-stitlal

ll" ~: iu11 s

Dilli.:n· nti al

diagnus i~

Kaposi's

sarnl ltl:t :

Klippel ' l 'n·naunay

\\'chn syl l( lrnJn(':

\lall"ucci 's

syndnu1u: : \ 't'IHHIS \;tkt ·s

TABLE 9 . Continued ----------·---------------···-· -·-·-··----I ) i sc~I St'

CllrtditiCI II

J) iili tsc

lu·tJlang·io­

llJatosis

( :ystic an­

gi tJnl tttosis

Syn1ptoms

:\t·un;tt: ll

pn·ttHmittlry

linding-s: SJll a ll

red Jnacuk;

1 c\aJJ~ i ~ -c t; tsi:1.

fH · blue macu ll'

atthr:

\Jnn :tl lp;ioJJi a

Sltt '

Soil tissue rnassl's,

local izt·d pain

and S\\'dling­rt"ialcd ID

pathologic

li ·;n:turc

:\it·, 11 ~ttta l ,·isccral.

ll!Jil - lll<lli ~llillll

I H'lll :l ll g"iC HII<J S :

\';ISL'Ubr

[ J;ttllflrttHll llS

lh-spnca wit h o r

\\' itiHHH

cy:lllosi:-;, a:-~citt ·s,

splctH HJH 'ga ly,

lt t'j)::l t<JJncg:t l y:

a n l'rllia ; soli.

tissw· masst·s

I .; dJora to tY

find ings

( ;l'IH'tir dl'krt inher itance

( :ong-cnit:d

ddccl

l .csiuns ha\ 'L·

dila!nl lhil i·W:t )) ,·c[

channels lined

by a single l;tyt-r

oJ"fialll'IICd

endothelial cdls. with li·w fi,c ;Ji

.i\l'('i\S of'

t: lltlothcl ial

proJi ll.Tctti01 1; 1\U othvr ce llu lar

hypcrpl;Jsia ur

plc1 1ll10rphism;

wtll-lili·ITied

vascu lar

chanuds:

ctbtl tJrnJ;t l

capill a rivs

coursin~ in tiH·i r

normal situation

throug-h musdc

s ug-~cs t s that

lt c!llangi<Htla s

arc lntlll<trtoma~

:\ SSI )L·i:ttn\

l:tllldi titHlS

'l 'lt nHlliJo<:y t< lJ.H'II i;t

~tnd IH' Ill <lll ,t!)<mJ;t:

JH ICI\l l \UI l10r:tx: sc l<·n,sis:

gotsln litt lt:st i1ml

ill'Illlll'rllagt·:

anemia~ n : ntral

ll LT\ 'OUS S)'StCll1

i ll \ ' {)1\-{'(lH'lll~

hydwtTf>I J;tltJs:

ll l' llHIITilagc;

heart fiti l urc ~

st·a rring-;

uln: r~ 1t i cuJ

Vascula r mal - Dilated. cawrnuus O slvr Wcbvr

fC 1nnatiun or thin walled Rendu

umgl' Hital

ungm

\':tsc ul a r

di<II IIH" ls lincd

by flat

endothelial n·ll s

(s in1 il ar to 1..-\\1 )

i )i;\ }!, 1\U~ ti<'

tlll'llJOds

\ )it1'~·1 vul i cd

1 ) ia~llosis

Radiolog-ic: round tw i\·lultiliH:al I .a np;('rh ;uJs

o\·o id g('ograph ic n :ll hi stim ·~ · tos i s~

OS(l'O [ytiC ksiO IIS

with scle rotic

horchTs, link·

n·!'lidu;d central

tr:tbn: ulatinn, 110

ptTiuStl·al n·ac ti o11

ur signirlraut

111atri:x I(H· tua tiot l

hy pc rpa r;H lty ru idisll 1;

lll<.' tas t;, ttir can·itwtn c t ~

lyn1phoma;

lll<t !'i llll'Ylllsis:

sarcoidtlsis:

[Jhak< Jt'llalt>sc·s:

.\ lall'tt('(' i\ syndrollH '

( .(mfinul'rl

CJ ;:;;· Cll Q

"' Cll

TABLE 9. Continued

I )iscasc

l'O IH iition

Klipp.-! ' l 'rcnaun;ty

:-.ylldl'(lllll '

S~ lllp!OltiS Sign -.

Capil lary IH' lllallg iolll;l/pt•l t ­

\\' it tl' s tain: distillt 'l.

liw ·~ tr lu,nkr: 111 ' \ ' li S

1\;ulltlH: u:-.: la rgt· .

iallTaJ. SII JWrl iciaJ

n·in hq.!; innin g :11

I(HJt/lu\\t'l' kg to

entry poi Ill itt tilt·

t!li ,!.!,'l t/gllltt•;t\ :ll'l':l: luHt\·/ ,. .. nfi ti :-.:-uc.:

hyJH'rlniJ!ill ': li tllb iJ\'jHTll'lljl ill·/ lt-ngth di -.,cn·pancies

:\ ss1 •cia tt·c I <:tHiditiull :'-1

[ .ytnphnknttl: spi11a bilida: liyposp;uli;ts;

polydaclyh' ; syndact\·1,·:

tllig,ldactyly;

ili'JH'rh i<ln iSis; llyfH·rtrit·l!t):-i is:

pan·stht·sia;

<kcakifiration 11 f

ill\ 'Oivn.\ IHJnL" s;

d1ronic \ 'CIIou :-.

in s utl icivlll'Y~

dcnll<lt it i:..: pour

'''ot11 1d healing:

ulrl'ratitJJI:

thnmtbo~ i s : t'lllholi

J)iagnostic

method=--

lloppkr tllt r;asoltllcl:

dilkrnnia1ion ol' \ '<t St.:tt\ar lUI rH lfS

11-om \·a sc ular

nta li(>rJnalions

C'l'/:v!Rl dkcti\·c·

li~r· \ 'isualizing· ('Xll'Tll oi' lt·sinns

and infih raliun o( ' d eeper t issul's

Pla in lillll nldi(Jgrttt>ll~·:

ll'l('.;tSUI't: II H'Ill ol'

long- bones

Culm llupplcr

ulll·a ­

S!llliH:I/dupkx

S(' tl llllill ~:

visualizt'

pai<"ll<'}' oi'd!' C"Jl \ 'l.'IHHt:'i system

:'\!Jgic>gTCIJl/1)'

J) ilkrcn li<d

diagnosis

\ Ldl'uci syndronw:

i>nH<:liS

syriCir<ltlH·

TABLE 9. Continued

Discast:

('OilditiO!I

C)·stic

il)')2,TOillaS

SyinJ>lwns

Sing-le or Inuhiplc lluid-tilkcl

lcs iuns th a t

orrur at sites t)r

lymph<u ic--

Vt; llO l.I S

COI Ifll'l'litlll;

priillarily in nc..:ck :tnd axi ll a

Si~Il S

l .ylllph<:<kma

Hydrops ft:tali s

1.;\ IJnratory

finding-s

HYjl<Jjlr<JtciJICilJia

c;,~ !Wlic dd(·ct

ilthcrilant:l' PaLh(J[tJgy

Congenital: D ilated ,

<t lll<JStHll Ctl disurg;;Inizc(l

!T('{'SS \\'<' \ylllph cha l lll{'b

due lo l ~ lil un: or ly111ph sacs tn

t' stahlish ve nous

drai1t ct~c

:\s~<H · iatcd

CUIH.[i tioiiS

' I 'urncr's syndrome;

C\U[OSOillai

t riscut 1 ics (t risorny

:! I): Klill ckltcr\

syiHirOIII(';

Noonan

sytld!Ull'lt' ;

P rot('liS

syndnunc:

hcn·cli t<IIY

lyrnjJIH ·t it 'lil a;

dll.ts io11 s: pkura. ()t·rit ·:trdi tllll,

ahdonwn

Diag-JJ Oslic nH:thods

Chest X-ray:

c\·aluatc rnecli ­

ast illu m / ch('st

:\ !RI: l'valuation ol'

LI H· cystic n ullponrllt or hygr<llll<l

C:T to detect hii:Jr

i l lVol\l:llH.'Ill

DiiJl.rcnlial

diagnosis

l-I c ltla llginll las;

\yTIIJ>il<tllg illlll;tS;

\·asc ular

llJ:tif(H'HlHliu n :.; : lll'Ck

twnors;

t' ll t't'phalort'k: 11\l'lliflgnn: lc;

hrant·hial cyst:

lipoma: lotryll.WJCclc: t hyro~lossal du('t cys t;

dcn nuid cyst:

t<Tcltolll~ l (ran·)

( ,'outinunl

--

..__

178

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Annals of the New York Academy of Sciences .. '

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IIHHH!f ~ - ~ .i

- ~i - r1;i~~~~~ :;:: - ~ """

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-~r. --;,; ~

~

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:';,JhH~l~ ~

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'-/ :.:;=

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t~ ~ ~ .§ "9 ~ ::: ; ~ ~ ~ - ..... .... - .., .,,

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ces Rodhakrishnon & Rockson: Clinical Spectrum o f Lymphatic Disease 179

Gorham's disease is the uncontrolled gro11·t h of ;Jl >il-!11aJigtJa!ll \·ascuJar channds that lead lO !)·sis or the alkctcd honcmt.::~' The condition is assoriatt·d with ,11 1 ~iomatosis of blood an cl lymphatic n·sscls. 11 ~ 1 The shn ulclcr~' 1 ' and pcki s ~ 11 arc most fi·cqucntly aflt:Clccl in thi' clisC'ase. Chylous pcricard ial and plcmal cirusiom ;ur associated ,,·ith this cunclition, ami chylothora:-: can so111 ctimcs result fi·01n dilation oflymphatic I'('Sscls 11·ith rcl lu:-: into pleural ca1·ityH9 Treatment in\'C>ln:s surgery,

11·ith resection or hone reconstruct ion. ancl radiation. a"

Proteu s syndrome is a congenital m·ergrCJII'th or nu tnen> us bocly tissues and cdllinesY1 :\'amcd for th e character in Greek mythology 11'110 had the ability to

change his shape at wilL this condition is polymor­phil· in nature. ~n It is characte rized by subcutaneous nu nors, hyperostosis, hypnplastic connect i1-c tissue in tht' soles and palms, pigmented nc1·i, and partial gi­gantism of hands or f cet.~'~·~': 1 Cell components appear normal, although there arc signs of h~1xrplasia or dis­organization ofccllsY~ The cond ition is rare, with onl~· a !l-11· hundred estimated afTi ictcd persons. It is spo­radic and mosaic. in that indi,·iduals han· certain cells " ·ith mu tations and others that a rc normal. ~' 2 There is nttTc ntll' 110 molecu lar marker i('lr this condition , 11·hi•·h is often miswken for Klippel-Tren aunay syn drome (KTS), M a ffuci 's syndrome, or neu­rofibroma tos is , among others. Since orthopedic c01 nplications often arise, particularly scoliosis, treat­me nt is generally surgical or takes the l(mn of phl'~ical th rrapy. Dl Future directions 11·ill im·ol\'(: characteriz­ing the molecular defect responsible for the condi­tion. thcrcl.Jy pm·ing the \l'ay for accurate diagnosis and pharm acologic thcrapyY2

Klippel-Trena unay syndrome represents a combination of vascular malfcm nations, inrl ucling cap­illarv anomalies (port 11·inc stain), 1·aricose veins, and the hypert rophy or bone and soft tiss uc.~H While Klippcl- Trcnaunay syndrome generally manifests in a single cxtn:mit); it can also a llcc t multiple limbs or the entire body. ~'+ Histologicalh; the condition mani­li.·st, as dilated telangiectatic n·sscls in the upper dermis 11·hid1 do not spon t<UJcousk regrc,;s.''·-,

Recent studies to pinpoint the genetic abnormality leading to this cond ition have been insightful. Some Klippcl -Trenaunay syndrome patients hmT a mu ta­tion in the VGFQ ge nc, 11·hich , analogously to , ·ascu­lar o_·ndothclia l growth I~Ktor is an angiogenic fitrtor. lhc.<c mutations arc either chromosomal transloca­tions or poilll mutations, and both tend to enhance the dl(:n of the protein.% The condition is phcno­typil ·ally di1'C!'sc, and th erefore it is hypothesized that it is genet ica lly heterogeneous as 11·ciL and that other 1\Clli's may also be implicated. % Complications ar is-

ing l'rom KlippeJ .. Trenaunay s1·ndrnmc include pain and lymphedema. Doppl rT ult rasouuds arc employed to distinguish l-\.lippcl Trcnaunay synd rome from he­mangiomas. 11·hilc C:T aud .\liZ ! is used to cktcrminc the ck pth of tissue im'Uln·mL·nt. ' '7 ! ' ~ ' Lymphosc intig­raphy is employed when the lymphatics arc thoug·ht to lw inH>kccl, 1"l ' particularly when patients present 11·ith lymphedema. Trcatmclll is aimed at prm·iding symp­tomatic relief in the for m ofclc,·;Hion and compress ion stockings for cdcma. 1 " 1 · 1 "~

Blue rubber bleb n evus consists nf'1·asndar nc1·i of' the skin and hemangiomas of' the gastrointesti nal tran that lead to hemorrhage and atll'mia. 11 n The name arises fi·om the fi1ct tha t the nevi me blue and rub­bery, and also soft and eas~·to compress. 101 The n ·nous malfcmnations arc either congenital or present in the first \Tars of life, and progress in both size and number m-er timc. 10:L I<f> The condition is sporadic , though cer­tain instances of autosomal dominant inheritance hm·e been rcportcd .111:; Dcfimnities of surrounding bone mm· occur as the resul t of increased pressure fi·01n hcmangiomas. 101

; Treatment inrludcs transfusions and iron rcplaL'Cml'nts 11 13 f(Jr gastrointc.- tinal blood loss. and endoscopy i, cmplon·d fi)l' less-itt1·asi1·e treatnu·nts, such as sclerotherapy, f()r the lesions. 11 '·-, Pharmacologic treatments including corticosteroids ami interferon-a ha\'(' been f(nmd incfl(-ct i\'l·: lesions regress, bu t the n return once trcatmem is stoppcd. 1

" :'

Protein-Losing Enteropathy and Intestinal Lymphangiectasia

Loss of' lymphatic fluid and plasma protein 11·ithin th e lumen of the gast rointestinal tract can lead to edema and hypoproteinemia (T.\ BJ.I : l 0). These phe­nomena arc encountered in a 1·a rict y of afflict ions, in­cluding protein-losing enteropathy (Pf .E) and intestinal lym phangiectasia . The mechan isms that predispose to this kmn or protein loss arc not yet ftdll · unckrstood: hOIIT\·cr, patients 11·ith PI.E typicalk ha\'l' local km­phat ic obstruction ami stasis, 1"' ,,·bile thmw wit h km­phangiccta> hm·e dilated kmphatic \Tsscls in the in­testinal 1·illi. 111B

Protein-Losing Enteropathy Pat ients 11·i th PLE hm·c excessive pro te in loss into the

gastroi ntestinal lumen leading to liypopmtcincmia. 1''

7

I'LE is associated ,,·ith numero us disordcrs, including inflammatOr)· bo11'cl disease, infl.:ct ion, celiac disease, imestinallymphangicctasia, thoracic duct obstruct ion , ami cardiac disease. 109 Gcncrall}; obstruction of lym­phatic vasculature yields increased hydrostatic pressure throughout the lymphatic system of the gas trointestinal

180

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Annals of the New York Academy of

tract , resu lting in lymph stasis. Prote in-rich 1 .

fluid is CO!Jscqucntly lost within the lumen rl(· the trointcsti na ltract through the lactcals in thv in micro,·illi . Protein loss in paticms with Pf J~ is selective, in con tradist inction to glomerular eli . . · ·

110 seases where loss is sizc-dejJcnclcnL and indud,., j)l· · · ,,· . .. . <~srn · proteins, albumin, globulim, and transfe rrin. l !i9 If! a f. II . I· . . f' I . Oss o a )Utn ln excecc s Its rate o syn t ll'Sls, ccl,· 1na

ups. Other clinical manikstat ions include <t,c itcs. .. <~nd pleural and pcricardial ctli.tsiom.

Diagnosis ofi:cn relics upon of the characteristic labo ratory

which include: hypoalbuminemia teinur ia ; reduced plasma concentrations

gamma globulins, cholesterol, and alpha-!

trypsin ; lvmphopcnia: and malabsorption of

a nd bt-solublc vitamins. 109 Whil e int rmcnous[\,:

adm inistered radioact i\ 'C macromolecules, such

Cr-5 I, In-Il l, and I- 125, arc used to lag . quantif)' protein loss, IO!l abdom inal scintigraphv can

additionally demonstrate sites or protein lo ~" - ;u;' The

most commonly employed diagnost ic tool is the measu remcn t of endogenous proteins. ,-\s an f' :-;ample, both fecal concentrations and clearance o i· alpha-!

an titrypsin arc rnuch higher in PLE paticnh than in

una[kctcd individu als . Rccommcndcclmedical care depends on the under­

lying cause. For patients with lvmphatic oll'truction, se\Trcly reducing dietary bt intact , along ,,·it h >upplc­

mentation of medium cha in triglyccriclcs, C<ll l reduce .

the hydrostatic pressure within the lymphatic svstcm

and thereby decrease protein loss. l ntra\Tnous albu~

min replacement , 111 small bcl\\·cl resect ion, 1 1 ~ or high­

close steroid therapy may also prove bcndicial 1 13·

11·1

For patients wi th congenital hea rt disease, rec \· nt stud·

ics suggest that hepari n may reduce leakage of protein

into the intestinal lumen. 111

Intes tinal Lymphangiectasia Intestinal lymphangiectasia is a rare condition char­

acterized by severe edema, thickening of sm ail -boweL · · \\·all , PI .E, asc ites, and pleuralcO'usion. 11 :' Ifhm phatic

fluid and proteins a rc lost into the gastroi n testin al tract,

patients ma\· present with generalized edema clue to . h)llOprotci ncmia. lOB The conditio n may lx primary,

resul ting fl-om a congenital lymphatic vasrul<Ir disor­

der. or scconclarv. as a conscCILit:ncc of inflan nnatorY ' ' ' • ' ' ' . llti

o r neoplastic mnJh·c m ent of the lymphatiC sy,;tcin .

T he pa thogenesis remai ns unclear. Yang and Jung

propose that in testin al lym phangiectasia may develop when lymphatic obstruction involves a segmen t of the boweL 117 Holt proposes that dila ted intcst in al!YilljJh<lt­

ics may rupture, producing a leak of lymph into the

~-.. -~""· ""-"'· "'·-<"'~·~~~"'- '"'*1!'!.-4"'2A~:PI!'!."~¥"'-"'""'"'"'"-1!!!11!!!2f.l._!!l£11!1"""""·"'-"'*e:'"""'.....,...,.....,. __ ~=-----. -..--~·

flees

l<ttic ~<I S ­

. ina[ 101!­

.hl'S,

''lla ·In,, 'I C[ ­

,Lnc[

Il ion itics, 1 >ro-

of .1\J ti­

Ln ILISJv

11 as

and can

The the

nplc. d1 a- l

'· il in

lclcr­·t ion, pple­ducc ·,tl'll1

.t!I JU­hig;h-1'.1 11

'lltCI\1

d wr­'loll·cl

rhat ic

trac t, Ill' to

!lli.lf)~

di,or­;a wry

111; l ll

.Jung ., ,·lop

,,r the

1phat· ill dw

((adhakrishnan & Rackson: Clinical Spectrum of Lymphatic Disease 181

intes tinal lumen. tlu 'l )'pically dilata tion of lymphatic channels in the intestinal 1·illi leads to a malabsorp­tion offill because long-chain f~uty acids can no longer be adequ ately processed by these abnormal lymphatic I'C:O!Wb.IOB

CT imaging is ofte n crnploycd in th e diagno­sis ,rr intest inal lymphangiectasia. The images rc,·ca l clifl'use, nodular thickening or the bowel wall ll'ith asr i lt'slt~• and hypo-dense strea ks in the small bowel, reflect ing the markcdk clil atccl lymphatics. llll Replace­!l1n1l of' dietary long chain fflll)' ac ids 11·ith a medium chain triglyceride formu la reduces intestinal protein

losses. 1111

Conflicts of Interest

The authors eke! are no conOicts or interest.

References

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~ ________ .. __ .,_ - ·

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1 ·

. . C<(S· a syndrome cha raelt:nzcd by fat l q:~~·5 C\ lld (lrtho:;h7· · ·

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. .

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llLI.I .. !..'\ .. E. Roc:JII-.. EJ S"·' "· t1 rtf. ~()[Ill. . o(' the locus ll>r ch()lrsta:-i s-lymph('c.kma ~y ndronH.' tAn·

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Rodhakrishnan & Rockson: Clinical Spectrum of Lymphatic Disease 183

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