Medullary unidentified bright objects in Neurofibromatosis type 1: a case series

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1 D Amio et l. BMC Peitris (2018) 18:91 CASE REPORT Open Aess Meullry unientifie right ojets in Neurofiromtosis type 1: se series Alessnr D Amio 1, Feeri Mzio 1, Lorenzo Ugg 1, Rento Cuoolo 1,5*, Mrio Cirillo 2, Clui Sntoro 3, Silverio Perrott 3, Dniel Melis 4 n Arturo Brunetti 1 Astrt Bkgroun: In Neurofiromtosis type 1, ererl Unientifie Bright Ojets re well-known enign entity tht hs een extensively reporte in the literture. In our se series, we wish to fous on further possile lotion of suh lesions, the spinl or, whih we hve efine s meullry Unientifie Bright Ojets. These hve een, to our knowlege, srely esrie in previous works. Cse presenttion: We report the ses of 7 ptients with meullry Unientifie Bright Ojets in Neurofiromtosis type 1 tht we hve followe for up to 9 yers in our Regionl Referrl Center for Neurofiromtosis. In ll of our ptients, these lesions were ompletely symptomti n reporte on Mgneti Resonne exms the ptients unerwent for other linil initions. Conlusions: The im of our work is to inrese wreness of the possiility of meullry Unientifie Bright Ojets in Neurofiromtosis type 1 ptients, whih n simulte neoplsti lesions, suggesting more onservtive pproh in these ses. Keywors: Neurofiromtosis I, Unientifie right ojets, Spine, Mgneti resonne imging, T2-hyperintense lesions Bkgroun Neurofiromtosis type 1 (NF1) is rre (prevlene of 1 in 2700 neworns) utosoml ominnt geneti isorer [1]. It is ignose on the sis of linil riteri suh s the presene of utneous spots (fé-u-lit), frekling in the xillry or inguinl regions, neurofiroms (plexiform or otherwise), Lish noules, opti piloity stroytom, sphenoi wing hypoplsi or plsi, long one ysplsi n/ or pseuorthrosis, n positive fmily history (NIH riteri). On Mgneti Resonne (MR), NF1 presents wie spetrum of ltertions whih involve oth the white n gry mtter in the whole CNS [2 5]. Spinl neoplsms in NF1 ptients n e oth extrmeullry (neurofiroms n mlignnt peripherl nerve sheth tumors) n intrmeullry (stroytoms, epenymoms n gnglioglioms). We report seven ses of NF1, followe t our referrl enter, * Corresponene: rento.uoolo@gmil.om 1 Deprtment of Avne Biomeil Sienes, Feerio II University, vi Sergio Pnsini 5, Nples, Itly 5 Nples, Itly Full list of uthor informtion is ville t the en of the rtile who shre intrmeullry ltertions hrterize y multiple foi of high signl in T2WI similr to unientifie right ojets (UBOs) normlly reporte in the rin of NF1 ptients [6, 7]. Therefore, meullry UBOs (mubos), lthough rre fining, must e onsiere in the MRI fetures of ptients with NF1. Cse presenttion Cse 1 An 8-yer ol hil with two oler rothers presente with glol evelopmentl elys, genu n uitus vlgum, n ilterl lufoot with seonry git isturne. He ws ignose with NF1, presenting with more thn six fé-u-lit spots (> 5 mm), inguinl n xillry frekling, one lrge hiry pth on the hn n vsulr mlformtion on the right leg. The neurologil exm ws negtive. He unerwent n X-ry exm of the spine, euse of mil soliosis, showing slloping of the posterior wll of T6-T9 verterl oies for whih we performe n MR exm of the spine. The MR sn showe three intrmeullry hyperintense lesions The Author(s) Open Aess This rtile is istriute uner the terms of the Cretive Commons Attriution 4.0 Interntionl Liense ( whih permits unrestrite use, istriution, n reproution in ny meium, provie you give pproprite reit to the originl uthor(s) n the soure, provie link to the Cretive Commons liense, n inite if hnges were me. The Cretive Commons Puli Domin Deition wiver ( pplies to the t me ville in this rtile, unless otherwise stte.

2 D Amio et l. BMC Peitris (2018) 18:91 Pge 2 of 5 on T2WI lolize in the ervil n thori trts. The lrgest of these lesions ws lolize in the ervil trt (C1-C6) n presente tumor-like pperne n ws initilly ignose s low-gre glil neoplsm. Sine the ptient in t present ny new symptoms t the time of the exm, wit-n-see pproh ws hosen. Three months lter, follow-up MR exm of the spine ws performe, showing prtil spontneous regression of the ervil spine lesion n stility of the two other T2WI-hyperintense spinl lesions. On the susequent MR follow-up exms one nnully for three yers n then innully for 6 more yers, the ervil lesion showe further spontneous regression n then ws unhnge through the en of the stuies (Fig. 1). All of the MR exms inlue post-ontrst T1WI, n none of the lesions ever showe enhnement. In the light of these oservtions n eviene of linil stility, the initil hypothesis of low-gre glil neoplsm ws none n the lesions were relssifie s meullry UBOs. Cse 2 This ptient ws 12-yer-ol femle with norml evelopment n growth. She ws the only hil of helthy ouple. At the ge of five, she presente with ysphgi, txi, typil fè-u-lit spots n frekles, thus linil ignosis of NF1 ws me. The susequent rin MR exm showe multiple ererl n rinstem T2WI-hyperintense, non-enhning lesions, whih were ignose s UBOs, iffuse fornix thikening, rinstem enlrgement n unilterl nonenhning opti nerve gliom. An itionl noulr lesion, whih presente enhnement on post-ontrst T1WI, ws foun in the right ereellr hemisphere n ws ientifie s piloyti stroytom. Aitionl exms, inluing ophthlmologil n enorinologil essys revele no further normlities. The posterior foss neoplsm showe linil n riologil progression t further exmintions n the ptient unerwent surgil removl of the lesion t the ge of nine, with n improvement of the ysphgi n txi. She then evelope pinful orsl soliosis for whih X-rys of the spine were performe showing only shisis of the posterior rh of S1, leing to spinl MR to exlue the presene of neurofiroms. We foun multiple smll intrmeullry lesions whih were hyperintense on T2WI, h lurre mrgins, lote mostly in the entrl meullry region n in the ervil spine, some of whih presente tumor-like pperne. None of these lesions showe enhnement on post-ontrst T1WI. After two-yer MR follow-up, ll of the lesions remine unhnge n were ignose s meullry UBOs. Cse 3 A 28-yer-ol femle with norml evelopment n growth presente for re. At the ge of twelve she ws ignose with NF1, inherite from her fther, n ws note to hve lumr soliosis ssoite with lower lim length symmetry, Lish noules, multiple utneous neurofiroms, utneous ngioms n frekles. The neurologil exm ws negtive. A rin MR exmintion revele ilterl pllil UBOs. She evelope pinful orsl soliosis for whih she unerwent spinl MR exm showing three T2WI n T1WI-hyperintense spinl lesions lolize in the thori spine with tumor-like pperne. None of these lesions showe enhnement on post-ontrst T1WI. During the 9-yer MR follow up, these lesions remine stle without the onset of ny new neurologil symptoms. Therefore, they were ientifie s meullry UBOs (Fig. 2). Cse 4 A mle ptient who h positive fmily history for NF1 (fther) ws evlute. He ws 14 yers ol t the time of the first exm in our institution. He presente with utneous neurofiroms, mroephly, n short stture. In ition, ilterl opti nerve pllor ws e Fig. 1 Ptient numer 1. Sgittl Turo Spin-Eho T2-w sequenes: lrge intrmeullry hyperintense lesion (C1-C6) t the time of ignosis (), showing regression t 1 () n 2-yer () follow-up, n stility fter 3 () n 5 yers (e). Other smller lesions with similr fetures re evient in the D10-D11 () region tht were less evient in the lst ontrol

UBOs, non-enhning ilterl opti glioms n piloyti stroytom of the left thlmus. The exm lso showe smll T2WI-hyperintense spinl lesion t the level of C1.

3 D Amio et l. BMC Peitris (2018) 18:91 Pge 3 of 5 Fig. 2 Ptient numer 3. Sgittl Turo Spin-Eho PD-w (), T2-w () n Turo Spin-Eho T1-w, efore () n fter () i.v. ontrst injetion, sequenes: 3 tumor-like orsl spinl lesions whih show high signl on PD, T1 n T2-w imges without enhnement on post-ontrst T1w sequenes note for whih he unerwent rin MR, showing multiple UBOs, non-enhning ilterl opti glioms n piloyti stroytom of the left thlmus. The exm lso showe smll T2WI-hyperintense spinl lesion t the level of C1. The susequent spinl MR exmintion onfirme the isolte ervil tumor-like lesion on the right sie of the or whih showe no enhnement fter golinium injetion n with well-efine mrgins (Fig. 3). This lesion lso h high signl intensity in ADC mps. Follow up exms in the next two yers showe no signifint vrition in the hrteristis of the forementione lesion. Fig. 3 Ptient numer 4. Sgittl Turo Spin-Eho T2-w (), Spin-Eho T1-w (), xil Turo Spin-Eho T2-w () n xil ADC mp (). A well-efine, T2-hyperintense, T1-hypointense tumor-like lesion lolize on the right sie of the ulo-meullry juntion. It presents high signl intensity on the ADC mp ue to intrmyelini eem

4 D Amio et l. BMC Peitris (2018) 18:91 Pge 4 of 5 Cse 5 An 8-yer-ol mle with no fmily history of NF1 ws evlute n foun to hve norml psyhomotor evelopment n growth. He presente typil fetures of NF1 n mil k pin for whih spinl MR exm ws performe. It showe four smll tumor-like lesions of the spinl or whih were moertely hyperintense on T2WI. These lesions were rely visile in sgittl sns, ut xil imges etter efine the presene n hrteristis of the forementione lesions. None of these lesions showe enhnement on post-ontrst T1WI n they showe no evolution in the follow up exm one yer lter. Cse 6 This 11-yer-ol mle ptient h no fmily history for NF1 ut h glol evelopment elys n mil ongenitl hypotoni. At the ge of two months he ws ignose with NF1, presenting with typil fè-u-lit spots, mroephly n frekles. A rin MR exmintion, performe t the ge of 10, showe prerolni piloyti stroytom for whih the ptient unerwent surgery. A spinl MR exm ws performe euse of the onset of pinful orsl soliosis. It showe four tumor-like lesions of the spinl or n of the onus meullris whih were hyperintense on T2WI n showe no enhnement on post-ontrst T1WI. A follow up exm fter 6 months showe no vritions. The neurologil exmintion i not revel ny fol efiit. Cse 7 A 7 yer-ol mle ptient ws ignose t the ge of 18 months with NF1, presenting typil fè-u-lit spots n frekles, without fmily history for this pthology. Neuropsyologil evelopment n growth were norml. He unerwent the first MR exm t our institution s he presente persistent hehe n reution of the visul uity, showing low-gre stroytom lolize in the tegmentum of the mirin using triventriulr hyroephlus. An inientl lesion of the ervil spine ws etete for whih spine MR ws performe. Three tumor-like, T2WI-hyperintense lesions were etete, none of whih showe enhnement on T1WI fter golinium injetion. All of these were stle t follow-up MR exms fter 12 months. Disussion In previous stuies, rin UBOs hve een vriously efine: hmrtoms, ltere myelintion, or heterotopis [8 10]. In the only histologil nlysis of these lesions, vuoles (5 100 μm) hve een oumente in the myelin sheth. This ws orrelte to intrmyelini eem. A reution in the ellulrity of the white mtter ws seen s well, together with n inrese prolifertion of glil ells [11]. More reent stuies hve onfirme this fining y using non-invsive MR tehniques whih showe moifition of the mirostruturl omprtmentliztion with n inrese of extrellulr-like intrellulr wter, n inition of intrmyelini eem, in UBOs onfirming the previously mentione histologil finings [12]. In NF1, intrmeullry lesions re more frequently low-gre stroytoms (15% of ptients) [13]. Rre ses of epenymoms (4 ses) [14] n gnglioglioms [15, 16] hve lso een reporte in NF1 ptients. These lesions re lmost lwys symptomti, single, hve n inhomogeneous signl, often enhne in post-ontrst T1WI n usully show progression in follow-up exms. To our knowlege only one previous report of meullry lesion in ptient with NF1, nlogous to those herein oumente in our ptients, hs een pulishe s of this te. The lesion, in line with the knowlege of the time, ws efine s hmrtomtous spinl or lesion [17]. We report seven itionl ses presenting suh lesions lolize in ifferent segments of the spine, minly in the ervil segment, esriing their MR fetures n long-term linil n riologil follow up. In our experiene, ptients more frequently h multiple symptomti meullry lesions, with tumor-like pperne, lwys hyperintense in T2WI, hypo, iso or slightly hyperintense in T1WI, n were never enhning in post-ontrst T1WI. At follow up exms they were stle, exept for one ptient in whih spontneous prtil regression ws oumente (Tle 1). For these Tle 1 Summry of the ptients ngrphil t n neuroriologil fetures Age Sex T1WI T2WI CE Lotion (n ) Follow-up (yrs) Cse 1 8 M Hyperintense Hyperintense None ervil (1), orsl (2) Regression (9) Cse 2 12 F Isointense Hyperintense None ervil (3), orsl (2) Stle (2) Cse 3 23 F Hyperintense Hyperintense None orsl (3) Stle (9) Cse 4 14 M Hypointense Hyperintense None ervil (1) Stle (2) Cse 5 8 M Isointense Hyperintense None ervil (2), orsl (2) Stle (1) Cse 6 11 M Isointense Hyperintense None ervil (2), lumr (2) Stle (0,5) Cse 7 7 M Isointense Hyperintense None ervil (3) Stle (1) M mle, F femle, CE ontrst enhnement, n numer, yrs. yers

5 D Amio et l. BMC Peitris (2018) 18:91 Pge 5 of 5 hrteristis, nlogous to those of rin UBOs in NF1 ptients, we hve lssifie the spinl lesions of our ptients s meullry UBOs (mubos). The limittions of our stuy re the smll numer of ptients n the sene of histologil onfirmtion of our ignosis ue to the enign nture of the lesions whih in t justify iopsy espeilly in reltion to their meullry loliztion. For these resons we hope to expn the popultion for future stuies. Even if sreening for mubos is not n inition for routine spinl MR exms, MR stuies of the spine my e one in se of other symptomti lesions. Knowlege out these enign mubos is ritil for the orret interprettion of the imges n proviing pproprite prognosti informtion. Conlusions The presene of mubos might hve een severely unerestimte in the pst ue to the symptomti nture of these lesions. In ll our ptients the ignosis ws me inientlly in spinl or rin MR exms they unerwent for onurrent symptomti onitions (pinful soliosis, rin lesions). The im of our work is to inrese wreness of the possiility of mubos in NF1 ptients whih n simulte neoplsti lesions, suggesting more onservtive pproh. Arevitions CNS: Centrl nervous system; MR: Mgneti resonne; mubos: Meullry unientifie right ojets; NF1: Neurofiromtosis type 1; NIH: Ntionl Institute of helth; T1WI: T1-weighte imges; T2WI: T2-weighte imges; UBOs: Unientifie right ojets Aknowlegments Not pplile. Funing The uthors reeive no funing for this reserh. Avilility of t n mterils The tsets use n/or nlyze uring the urrent stuy re ville from the orresponing uthor on resonle request. Authors ontriutions All uthors ontriute sustntilly to the pulition, in orne to the ICMJE guielines. In prtiulr: ADA n MC re the peitri neuroriogists who reviewe ll the MR exms. AB is the supervisor n he of eprtment tht overviewe ll the imging work one for the pper. FM, LU n RC re the riology resients who ontriute to ollet n nlyze the t, reserh the iliogrphi referenes n ontriute to the writing of the pper. DM n CS re the peitri neurologists who follow the ptients whose ses we reporte. They hve ollete the linil history n t of the ptients. SP is the supervisor n the he of the neurologil eprtment where these ptients re followe. All uthors re n pprove the finl mnusript. Ethis pprovl n onsent to prtiipte Not pplile. Consent for pulition The legl gurins of every ptient gve onsent for the exeution of the MR exm n to pulish the informtion. In the only se regring n ult sujet, the ptient provie the onsent herself. Imges were ll nonymize prior to inlusion in the pper. Competing interests The uthors elre tht they hve no ompeting interests. Pulisher s Note Springer Nture remins neutrl with regr to jurisitionl lims in pulishe mps n institutionl ffilitions. Author etils 1 Deprtment of Avne Biomeil Sienes, Feerio II University, vi Sergio Pnsini 5, Nples, Itly. 2 Deprtment of Meil, Surgil, Neurologil, Metoli n Aging Sienes, Seon Università egli Stui i Npoli University, vi Costntinopoli 104, Nples, Itly. 3 Regionl Referrl Center for Neurofiromtosis, Deprtment of Womn, Chil, Generl n Speilisti Surgery, Seon Università egli Stui i Npoli University, vi Costntinopoli 104, Nples, Itly. 4 Deprtment of Trnsltionl Meil Sienes, Feerio II University, vi Sergio Pnsini 5, Nples, Itly. 5 Nples, Itly. Reeive: 12 July 2016 Aepte: 19 Ferury 2018 Referenes 1. Evns DG, Howr E, Gilin C, et l. Birth iniene n prevlene of tumor-prone synromes: estimtes from UK fmily geneti register servie. Am J Me Genet. 2010;Prt A 152A(2): Moore BD 3r, Slopis JM, Jkson EF, et l. Brin volume in hilren with neurofiromtosis type 1: reltion to neuropsyhologil sttus. Neurology. 2000;54(4): Cutting LE, Koth CW, Burnette CP, et l. Reltionship of ognitive funtioning, whole rin volumes, n T2-weighte hyperintensities in neurofiromtosis- 1. J Chil Neurol. 2000;15(3): Steen RG, Tylor JS, Lngston JW, et l. Prospetive evlution of the rin in symptomti hilren with neurofiromtosis type 1: reltionship of mroephly to T1 relxtion hnges n struturl rin normlities. AJNR Am J Neuroriol. 2001;22(5): Greenwoo RS, Tupler LA, Whitt JK, et l. Brin morphometry, T2-weighte hyperintensities, n IQ in hilren with neurofiromtosis type 1. Arh Neurol. 2005;62(12): Rosenum T, Engelreht V, Krölls W, et l. MRI normlities in neurofiromtosis type 1 (NF1): stuy of men n mie. Brin n Development. 1999;21(4): DeBell K, Poskitt K, Szuek J, et l. Use of "unientifie right ojets" on MRI for ignosis of neurofiromtosis 1 in hilren. Neurology. 2000;54(8): Brffmn BH, Bilniuk LT, Zimmermn RA. The entrl nervous system mnifesttions of the phkomtoses on MR. Riol Clin N Am. 1988;26(4): Smirniotopoulos JG, Murphy FM. The phkomtoses. AJNR Am J Neuroriol. 1992;13(2): Bognnno JR, Ewrs MK, Lee TA, et l. Crnil MR imging in neurofiromtosis. AJR Am J Roentgenol. 1988;151(2): DiPolo DP, Zimmermn RA, Rorke LB, et l. Neurofiromtosis type 1: pthologi sustrte of high-signl-intensity foi in the rin. Riology. 1995;195(3): Billiet T, Mäler B, D'Aro F, et l. Chrterizing the mirostruturl sis of "unientifie right ojets" in neurofiromtosis type 1: omine in vivo multiomponent T2 relxtion n multi-shell iffusion MRI nlysis. Neuroimge Clin. 2014;4: Tortori-Donti P, Rossi A. Peitri Neuroriology. Brin, He n Nek, Spine. Springer 2005; Cheng H, Shn M, Feng C, et l. Spinl or epenymom ssoite with neurofiromtosis 1: se report n review of the literture. J Koren Neurosurg So. 2014;55(1): Hyshi Y, Nk M, Mohri M, et l. Gngliogliom of the thorolumr spinl or in ptient with neurofiromtosis type 1: se report n literture review. Peitr Neurosurg. 2011;47(3): Giussni C, Isimli G, Mssimino M, et l. Gngliogliom of the spinl or in neurofiromtosis type 1. Peitr Neurosurg. 2013;49(1): Ktz BH, Quener RM. Hmrtomtous spinl or lesion in neurofiromtosis. AJNR Am J Neuroriol. 1989;10(5 Suppl):S10.

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