benign familial hematuria

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1969;44;590PediatricsMelvin I. Marks and Keith N. DrummondBENIGN FAMILIAL HEMATURIA

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( R ece ived Janua ry 24; a ccep ted for pub lic atio n A p ril 1 7 , 19 69 .)A id ed by Term G rant M T -1579 from the M ed ica l R esearch C ounc il o f C anad a.PR ESEN T ADDRESS : ( M .I.M .) D epa rtm en t o f Ped ia tric In fec tious D iseases, U n iversity o f C olo rad o

M ed ica l C enter, D enve r, C olo rad o .ADDRESS FO R REPR INTS : ( K .N .D .) R en a l Labo ra to ry , M on trea l Ch ild ren s Hosp ita l R esear ch Inst i tu te ,

2300 Tupp er S tree t, M on trea l, P .Q ., C anada .PED IATR ICS , V o l. 44 , N o . 4 , O c tober 196 9

59 0

B E N IG N F A M IL IA L H E M A T U R IAM e lv in I. M a rks , M .D ., C .M ., and Ke ith N . D r u m m o n d , M .D ., CM ., F .R .C .P . (C )

Th e Rena l Lab csra to r!,r, M cG ill U n ivers ity-M on trea l C h ildren s H osp ita l R esearch Ins titu te , M on t rea l

ABSTRACT . A sym ptom a tic per sis ten t r en al h em a-tun a of 6 m onth s to 8 years d ura tion w as ob-served in seven of eigh t sib ling s. T here w a s nofam ily h isto ry of ren al d isea se o r dea fne ss, a ndother fam ily m em bers exam ined show ed no rm a lur ina lyses; n on e o f th e o the r k nown form s o f he red -i tary renal d isea se w e re detecte d . A bno rm alit ies o frenal fun ction o r gen era l phys ical hea lth and de-ve lopm ent w ere no t d etec ted . R ena l b iop sies w ereperfo rm ed in the tw o pa tien ts w ith the long es t h is -to ry o f h em atu ria (7 and 8 y ears ). L igh t and im -m unofluorescen ce m icrosco p ic stud y o f rena l tissue

rev ealed no ab norm alitie s o f g lom eruh i o r in te rsti-tia l tis su e.T h is fam ilia l cond ition is charac te rized by per-siste n t m ic roscop ic h em atu ria w ith ep isod ic gro sshem atu ria and a favo rab le long- te rm prog nos is . A l-though the pa thog enesis is unc lea r, an imm uneprocess do es no t appear to be in vo lved . M icro -sco p ic exam ina tio n of the u rine of fam ily m em bersin hem a turia w itho u t an obvio us e tio logy is w a r-ran ted . Pedia trics, 44:590 , 1969 , HEMATUR IA , HE -RED ITAR Y R ENAL D ISEA SE , FAM ILIA L H EMATUR IA ,RENAL B IOPSY .

A LTHOUGH hem atu r ia is a com m on m an i-fe sta tion o f activ e o r ser iou s rena l d is-

o rde rs , it m ay , in som e in stances , be o f le ssse r ious im port. R ecen tly a fam ilial rena ld iso rde r w as d escr ibed in w h ich recu rren to r pe rsis ten t hem a tu ria is p resen t w ith ou tev id en ce of p rog re ssiv e rena l d isea se .1 T hep re sen t rep ort d escr ibe s a fam ily w ith th isd iso rd er in w h ich seven o f eig h t sib lingssh ow ed p ersis ten t h em atu ria w itho u t c lin i-cal o r lab o rato ry ev idence o f im p aired rena lfu nc tion . L igh t and imm unofluo re scencem icroscop ic s tu d ie s w ere don e on rena lb iop sy tissue from tw o of the p atien ts . T hem oth er h ad n o ticed th at h er ch ild renpassed d ark urine o n num ero us occasio ns,u su ally un re la ted to illne ss , and thu s so ugh tm ed ica l ad v ice a t o u r ho sp ita l.

C AS E P RE SE NTA TIO NST ab le I p resen ts in fo rm a tion on th e af-

fec ted m em bers o f th is fam ily . T hey w ereasym p tom a tic and th ere w as n o h is to ry o fstrep tococca l in fec tion , rena l traum a , exp o-su re to tu be rcu lo sis , b leed in g d iso rde r , o redem a in any of the p atien ts . W e w ere u n-ab le to d etec t an y unu sua l env ironm en ta lc ircum stan ces. C ases 2 and 4 had been

treated fo r u rina ry trac t in fec tion s; how -eve r , h em atu ria an teda ted and fo llow edth ese in fec tion s. T he ch ild ren w ere o f ave r-age in tellig en ce an d w e ll d ev e loped . P hys i-cal exam ina tio ns, in clu d ing b lo od p re ssu re ,w ere unrem ark ab le excep t fo r a pe rfo ra tedrigh t ea rd rum in C ase 6 asso cia ted w ith anip silate ral 20 decib e l co nduc tive h earinglos s . Th e u rina lyses o f each of the a ffec tedsib lings revea led m ic ro sco p ic h em a tu ria inexcess o f 50 red b lo od ce lls pe r h ig h -p ow erf ield in cen tr ifug ed sp ec im ens o n num erou soccasio ns; g ran u la r and red b lood ce llca sts w ere seen in all ch ild ren excep t C ase7 . There w as n o pyu ria , am inoac idu ria , o rbac te ru r ia . Tw en ty -fou r-hou r u rine p ro te inde te rm ina tions , m ax im um urin e co ncen tra -tion , a r id ac id ify ing capacity w ere n orm a l.T he b lood u rea n itrog en and serum crea ti-n in e w ere no rm al in a ll, as w ere the c rea ti-n in e c lea ran ces in the fou r p atien ts te sted .In trav en ous py elo g ram s, vo id ing cysto u r-e th rog ram s, B 1 g lobu lin lev e ls , co ag u la tionstu d ie s , and o ph th alm olog ic exam in atio nsw ere un rem arkab le . F ive o f the sev en pa -tients had norm a l aud io g ram s; C ase 4 had au n ila tera l 40 decib el neu rosen so ry h earinglo ss , and C ase 6 a conduc tive d e fec t a s p re -

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T A B L E I

AFFECTED S IBL iN GS IN FAM ILY

C a s eVumber

34

6

Age(yr)

11109S643

Sex

MFFFIFF

F ic. 1 . Two no rm al g lom e ru li from C ase 2, PA Ss t i o rig ina l n l(Ig n if lcd tio n , y :3 00 .

ART ICLES 59 1v iou sly m en tioned . In add itio n , a ll p atien tshad a norm a l hem og lob in concen tra tion ,w h ite b loo d cell co un t, e ry th rocy te sed i-m en ta tion ra te , an tis trep to lysin 0 titer , to ta lse rum pro te in and e lec trop hore sis , se rume lec tro ly te s , ca lc ium , pho sph orus, and u ricacid .

R E N A L B IO PS IE SPercu tan eo us ren al b iops ie s w ere don e in

C ases 2 and 3 , sin ce these pa tien ts had thelo ngest know n dura tio n of h em a tu ria . Th etissue w as f ix ed in 2% g lu ta ra ldehy de , p ro -cessed fo r ro u tine ligh t m ic roscop y , andsta ined w ith h em a toxy lin ph io x ine sa ffron( H PS ), pe rio d ic acid -S ch iff ( PA S ), an dp e riod ic ac id silve r m eth en am ine ( PASM ) .P a rt o f the tis sue w as im m ed ia tely fro zenin isop en tane preco o led to 7 0# {176}Cn dr yice an d proces sed fo r im m unofluo re scen cem ic roscop y as desc r ibed prev iously .2 T h istissue w as sta ined fo r hum an im m unog lo bu-lin G (IgG ), B 1 g lobu lin (B 1 , a lb um in ,and fib r in . In each b iop sy the re w ere 2 0to 2 5 g lom eru li ava ilab le fo r lig h t m ic ro s-copy and 8 to 10 g lom eru li ava ilab le fo rimm unoflu o rescence m ic ro scopy . Th erew ere n o ab norm a litie s s een in the g lom eru lio r in terstitia l tissu e, an d the re w as n o gb-m eru la r o r in te rstitia l flu o rescence fo r IgC,

IC, alb um in , o r f ib r in ( F ig . 1 and 2).F A M IL Y H IS T O R Y

The fam ily is o f S co ttish an cestry w ithn o consan gu in ity , h is to ry o f ren al d isease ,o r hea rin g o r v isua l d efects . T he m o the rh ad a urin ary trac t in fec tion d uring 4 preg -n an c ies . A s sh ow n in F igu re 3 , s ev en o f thee igh t sib ling s w ere a ffected ; the youngest,age 11 m onths, has a n orm al u rin a lysis atthe tim e of th is repo rt. T he p aren ts , a pa -te rna l u nc le, a m a terna l aun t, an d tw o m a-te rna l cous ins h ad norm a l u rina lyses.

D I S C U S S I O NTh is is the secon d rep ort in w hich be -

n ign fam ilia l hem a tu ria has been spec ifi-ca lly desc rib ed and the firs t in w hich im -m uno flu o rescence s tud ie s have b een done .In 8 of the 10 fam ilie s d esc r ibed byI s fcConv i l le , et a!., an atitosomal dominan t

Duration ofI fematuria Biopsy

(documented by F indingsurinal yses)

7y r7 yr N o rm al8 yr N ormalyr5y r6tt6m o

pa tte rn o f in he ritance w as su ggested , h ow -eve r, in o ur fam ily an d in tw o of M cC on-v ille s fam ilie s , ne ithe r pa ren t w as affec ted .

S ix o f the seven b io psie s in M cC onv illess tudy w ere n orm a l b y ligh t m ic ro scopy , andon e show ed m oderate p ro life ra tion and en-la rgemen t o f the m esan g ia l ce lls o f m ost o fthe g lom eru li. O ur pa tien ts b iops iesshow ed no abnorm a lity by ligh t o r im m u-nofluo re scence m icroscop y , sugg esting th a timmun e m echan ism s a re no t o pe ra tive inth e pa th ogenesis and p ro v id in g fu rthe r ev i-den ce fo r the b en ig n na tu re o f th is d iso r-de r . A youb and V ern ie r3 foun d nonspecif icchanges o r n o abnorm a lities in the b io psie sof five p atien ts w ith h isto r ies sug gestive o ffam ilial hem a tu ria; fam ily m em bers w ereno t stud ied . A varie ty of rena l les ions h av ebeen descr ib ed in pa tien ts w ith no nfam ilia lrecurren t hem atu ria. T hese chang es inc lude



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59 2 FA \IIL IA L HEM A TUR IA

Ftc .. 2 . G lom eru lu s f rom Case 3 stain ed fo r hum anlgG . A U glom eru li ex am ined w ere negativ e f o rbo th IgG and B g lob u lin . O rig in al m agn if ication ,

x 300 .

f ocal or segm ental m esangial p ro lif e ration ,o r fo cal g lom eru litis .4 6 E lec tron densein cml)rane deposits hav e been describ ed insev eral o f these patien ts .7 T he sign if icanceo f these lesions and the long -term prognos isin su ch in s tances is no t e stab lished ; how -ev er, it is generally f e lt that recurren t orpers isten t hem aturia w ith fo cal g lom eru litisis a ben ign cond itio n .

T he on set o f asym p tom atic hem aturiaearly in lif e w ithout pro te inu ria o r o therabnorm al laboratory stud ies and the f ind ingof sim ilar f ind in gs in o ther f am ily m em bersshould suggest a d iagnos is o f ben ign fam il-ial hern atu ria. It is im p ortan t to ex c lu de , in -so f ar as is possib le, the cond ition o f h ered-itary nephritis w ith d eaf ness, w h ich has a

Eb I iiI i i#{225}F IG . 3. Family ped igree. A f f e cted m em bers indi-

cated b y cro ss-hatched areas; N T -not tested .

m ore serio us p rogno sis. espec ially in af -f ec ted m ales. T h e p rogno sis in b en ign f a-m ilial hem aturia appears to b e ex ce llen t, assugges ted l ) )T th e course observ ed ov er ap ro long ed perio d of f rom 5 to 8 y ears inf ou r o f ou r patien ts w ith th e com ple te ab-sen ce o f an y de tectab le renal parench ym aldam age in th e tw o patien ts w ho w ere b i-o psied . A lthough pro longed ob serv atio nex tend ing ov er sev eral d ecades w ill benecessary to pro v ide a f inal asse ssm en t o fth e se rio us ne ss of th is conditio n , the p resen tdata sugg es t that th is is a d is tin c t en tity sep-arable f rom o ther f orm s o f h ered itary renald isease in w hich th e p rogno sis is le ss f av or-able.

SPECULATI ONA w id e v ariety o f fam ilial o r h ered itary

form s o f renal d isease is now recogniz ed . Ina num b er o f these d iso rders, ex traren al ab -normali t ie s ( in v o lv ing , f or ex am ple , the ey es,sk in , sub cu tan eous tissu e, sk ele ton , or audi-to ry apparatu s ) m ay be p resen t, dependingon the specif ic hered itary n ephropathv inques tion . Progressiv e k idn ey dam age w ithth e dev elo pm ent o f renal insu f f icien cy isth e usual cou rse in m o st f orm s of h ered itaryn ephropathy ; in som e in stances th is ou tcom eis les s lik ely in the f em ale than in the m ale .

T he p resen t report describes a f am ilialnephropathy characteriz ed by recu rren t ep -isodes o f gross hem aturia w ith in terv en ingpers isten t m icro scopic renal hem atu ria af -f ec ting sev en of e igh t sib lings o f bo th sexes .N o ev iden ce o f progressiv e renal dam agew as seen , and the ch ildren w ere all in goodhealth . A f am ilial tendency to red bloodcells leak ing f rom gbom erular cap illarybasem en t m em branes appears to b e the so leabno rm ality . S tud ies w ith f am ilie s such asth is m ay e luc idate the un ex p lained m echa-n ism by w hich a v arie ty o f non spec if icstim u li m ay lead to ex acerl)ationS of grosshem aturia in patien ts v i th d if f e ren t f o rm so f renal gom eru lar d isease .

SUMMARYA f am ily is describ ed in w hich sev en o f

e igh t sib ling s show ed persisten t hen iatu riaov er a perio d o f 6 m onths to 8 y ears. R enal



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A R T I C L E S 59 3b iops ies f rom tw o of the patien ts w ith he-m atu ria fo r 7 and 8 y ears, resp ectiv ely ,w ere no rm al by ligh t and im m unof lu -orescence m icroscopy . C om ple te laborato ryev aluatio n rev ealed no ev idence o f im -paired renal fu nc tion in any of th e patien ts.B en ign fam ilial hem aturia appears to be ad istinc t en tity separable f rom other f orm so f h ered itab le renal d isease w h ich hav e ale ss f av orab le prognosis.

R E F E R E N C E S1 . M c Co nv ille , J. M ., W est, C . D ., and M cA dam s,

A . J.: Fam ilial and no n f am ilial ben ign hema -tuna. J. Pediat., 69 :207 , 1966 .

2 . Dnux nm ond , K . N ., M ichael, A . F., Good , R . A .,and V ernie r, R . L .: T h e neph rotic sy ndrom eof childhood: immuno log ica l , clin ical andpathologic correlation s. J. Clin . Inv es t., 45 :6 2 . 0 , 1966 .

3 . A y oub, E . M ., and V ernie r, R . L .: B en ign re-

curren t hem aturia. A m er. J. D is. Ch ild ., 109:2 1 7 , 1 9 6 5 .

4. Fe rris , T . F., G o rden, P., K ashgarian, M ., andEpste in , F. H . : R ecurren t hem aturia and f ocalnephrit is. N ew Eng. J. M ed., 276:770 , 1967 .

5. W es t, C . D ., M cA dam s , A . J., and N orthw ay ,J . D . : Focal glom erulonephritis in ch ildren. J.Pediat., 73 :184 , 1968 .

6. G erv ais, M ., and D rum m ond , K . N . : C hro n ic be -n ign recurren t hem atu ria in ch ild ren . ( A b s t. )C anad ian S oc ie ty o f N eph ro logy , S econd A n-n ual M ee ting , V ancouv er, B .C ., p . 7 , January1969 .

7. S in ger, D . B ., Hi l l , L . L ., R osenb erg , H . S .,Marsha l l , J., and S w enso n , R .: R ecu rren t h e -m atunia in ch ild hood. N ew Eng. J. M ed ., 279:7, 1968 .

Acknowledgmen tW e ackn ow led ge wi th gratitu de th e coope ration

and assis tan ce of D r. F. W . W ig lesw o rth , D irector,Departm en t o f Path o logy , Mont rea l ChildrensHo sp i t a l .

HO W O F TE N S HO ULD O NE TAKE A BATH ?Dur ing the V ic to rian era, ch ild ren , if bathed

at all, u sually f ound S atu rday ev en ing th e daychosen by the ir paren ts. D aily bath ing w as notcons idered necessary , and m igh t ev en be harm -f u l. A good ex am ple o f m id-eig h teen th cen turym edical adv ice w ritten fo r ch ild ren abou t th ism atter is g iv en b e low :

A late w rite r in the M edical and S urg ical Jou r-nat utters the op inion that once a w eek is of tenenough to bath e the w ho le body fo r th e purpose oflu xury or clean lin ess . Flann el w orn nex t to the sk inat all seaso ns is p ro per, and is in f in ite ly m orehealth fu l than all the daily baths now so fash ion -able.

T he oil w hich is secre ted b y th e sebaceou sg lands o f th e sk in , se rv es the pu rpo se o f lu bricat-ing its su rface. N ow if this secre tio n is constantlyrem ov ed as fas t as ex ud ed, i ts d estined obje ct isth ereby de f eated . T h e ex cre tory duc ts o f th e per-spiratory glands , an d th e g lands th em se lv es, re -quire th is unctuou s m atter o f th e sk in , to k eepth em in h ealth and actio n . If v ery f requent bath-ing o f th e w ho le body is p rac ticed , it m ust b e ob -

v i o u s t hat th is m atte r cann o t b e lon g p resen t toperform its o f f ice. A s to the ass im ilatio n o f f unc-t ion s of th e sk in and lungs, it w ill be apparent,t hat w hen the sk in ac ts im perf ec tly , o r ceases toact at all, th e lung s hav e an ex tra am ount o f du tyto perf orm ; and it is generally in ju st su ch casesth at engorg em ent tak es p lace, constitu tin g in f iam -mation o r pneumonia .

W hile a great num ber o f health statis ticians at-trib u te th e in crease o f m odem lo ngev ity to th is andt hat cause , w e be lie v e that the bene f its o f ch eapf lann el, linen and cotto n cloth es are ov erlo ok ed.W e can w ell understand how necessary it is f o rsav ag es to bath e once a day , bu t not those w hoen joy th e lux u ry of clean lin en. W e are no believ ersin ex traord inary w ate r in du lgence , bu t w here th epoin t is, o f prudential d epartu re f rom nece ssaryand health fu l b ath ing , is the im po rtan t ques t ion .

NOT ED BY T . E . C ., JR . , M.D .REFERENCE

1. Pinck n ey , C .: T he B ook of U sef u l K now ledge:or In terestin g Fac ts. B oston : C . C . P. M oody ,pp. 171 -173, 1851.



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1969;44;590PediatricsMelvin I. Marks and Keith N. DrummondBENIGN FAMILIAL HEMATURIA

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