Brain Malformations Do Not Predict Hypopituitarism in Young Children with Optic Nerve Hypoplasia
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1 HORMONE RESEARCH IN PÆDIATRICS Originl Pper Received: Mrch 7, 2017 Accepted: June 20, 2017 Published online: August 22, 2017 Brin Mlformtions Do Not Predict Hypopituitrism in Young Children with Optic Nerve Hypoplsi Pmel Grci-Filion Hshem Almrzouki e Cssndr Fink, c Mitchell Geffner c, d Mrvin Nelson b, d Mrk Borchert, d The Vision Center, Children s Hospitl Los Angeles, Los Angeles, CA, USA; b Deprtment of Rdiology, Children s Hospitl Los Angeles, Los Angeles, CA, USA; c Deprtment of Endocrinology, Dibetes, nd Metbolism, Children s Hospitl Los Angeles, Los Angeles, CA, USA; d The Sbn Reserch Institute, Children s Hospitl Los Angeles, Los Angeles, CA, USA; e Deprtment of Ophthlmology, King Sud bin Abdulziz University for Helth Sciences, Jeddh, Kingdom of Sudi Arbi Keywords Hypopituitrism Pituitry glnd Septo-optic dysplsi Optic nerve hypoplsi Cerebrl mlformtion Abstrct Bckground: Optic nerve hypoplsi (ONH), leding cuse of peditric blindness, is ssocited with brin mlformtions nd hypopituitrism in the constelltion known s septo-optic dysplsi. Neuroimging is used to nticipte hypopituitrism, but with unconfirmed relibility. We report prospective findings on the ssocition of hypopituitrism with brin mlformtions. Methods: Children (<24 months) with ONH (n = 146; 87% bilterl) underwent bseline MRI nd nnul exmintions nd hormonl testing. Hypopituitrism sttus t ge 5 yers ws clssified. Results: A totl of 74% hd brin mlformtion(s). Hypopituitrism (69%) ws not ssocited with brin mlformtions (p = 0.351); this persisted fter djusting for the lterlity of ONH nd the timing of MRI (p dj = 0.869). No ssocition ws noted for bsent septum pellucidum (38%; p = 0.073), corpus cllosum bnormlity (51%; p = 0.625), nd mjor mlformtions (22%; p = 0.407). A mlformtion conferred positive predictive vlue of 71% (95% CI: 62%, 80%), nd negtive predictive vlue of 37% (95% CI: 22%, 54%). Overll, 10% (n = 15) of the cohort presented with trid of bsent septum pellucidum, corpus cllosum bnormlity, nd other mjor mlformtion; only hlf (n = 8) of these hd hypopituitrism. All 13 subjects with pituitry mlformtions mnifested hypopituitrism, conferring predictive vlues of 100% (positive) nd 34% (negtive). Conclusions: Hypopituitrism nd brin mlformtions re highly prevlent, but hve unrelted ssocitions with ONH. Brin MRI in infnts nd toddlers with ONH is n unrelible screen for hypopituitrism risk. Introduction 2017 S. Krger AG, Bsel Optic nerve hypoplsi (ONH), congenitl cuse of visul impirment, is recognized s spectrum disese of the centrl nervous system tht mnifests with brin mlformtions, neurologicl deficits, nd endocrinopthy [1]. Over the pst 40 yers, the popultion prevlence hs incresed 9-fold, ffecting s mny s 17.3 per 100,000 children younger thn 18 yers of ge [2]. E-Mil krger@krger.com S. Krger AG, Bsel Mrk Borchert, MD Children s Hospitl Los Angeles, The Vision Center 4650 Sunset Blvd., MS #88 Los Angeles, CA (USA) E-Mil chl.usc.edu
2 The phenotypicl heterogeneity of ONH hs led to dignostic terms tht center on the presence of brin mlformtions with purported ssocition for disprte outcomes [3 14]. Septo-optic dysplsi (SOD), the most prevlent term, originted from 1956 postmortem cse report of n symptomtic ptient with n bsent septum pellucidum ( septo-+ ) nd unilterlly rotted optic trct ( -optic ) [15]. In 1970, Hoyt et l. [16] first described the ssocition between ONH nd hypopituitrism, using the term SOD to scribe clinicl significnce to the bsent septum pellucidum. This report triggered reserch in risk ssocitions of brin mlformtions with hypopituitrism under the ssumption tht midline brin nd pituitry mlformtions shre common embryogenesis [8, 10 13, 16 18]. As reports emerged [4, 10, 11, 13, 14, 19 22], the definition of SOD expnded to encompss ONH nd ny mlformtion in the midline (involving the septum pellucidum, corpus cllosum, or pituitry glnd), nonmidline (holoprosencephly, schizencephly, hydrocephlus, etc.), nd/or hypopituitrism. The ssocition of hypopituitrism with brin mlformtions remins topic of debte. Despite improvements in neuroimging techniques, there hs been little progress in understnding the likelihood nd clinicl significnce of brin mlformtions in ONH, or their ssocition with hypopituitrism risk. There hs been wide vribility in the prevlence estimtes of both brin mlformtions (26 90%) nd hypopituitrism (10 100%) [3, 6 12, 22 33], mking ssocition rtes difficult to estimte. As some pituitry hormone deficiencies develop over time [34], ssocition rtes my be underestimted in cross-sectionl studies of children done t young ge. Further, the differences between selective versus brod inclusion criteri, imging modlity, nd d hoc versus systemtic testing of hypopituitrism complicte the reconcilition between studies nd generliztion to children with ONH. These inconsistencies hve resulted in vribility in recommendtions for the clinicl mngement of these children [9, 11, 12, 17, 22, 25 28, 30, 31]. This is prticulrly problemtic in young children, for whom the risk of undignosed pituitry dysfunction confers serious developmentl or even life-thretening consequences. We sought to fill this gp by leverging n observtionl registry of infnts nd toddlers dignosed with ONH who underwent nnul clinicl visits until the ge of 5 yers. Towrd this end, we nlyzed our prospective dt to determine the prevlence nd ssocition of brin mlformtions t bseline with hypopituitrism t ge 5 yers. Mterils nd Methods Prticipnts Since 1992, the Children s Hospitl Los Angeles is the site of multidisciplinry observtionl registry on ONH to centrlize systemticlly collected dt bout the disese sttus t the time of presenttion (bseline) nd nnully until the ge of 5 yers. Children with suspected ONH re referred from brod rnge of sources, including peditricins, endocrinologists, neurologists, nd vision specilists [29]. Prticiption in the registry requires presenttion prior to ge 24 months nd dignosis of ONH confirmed by ophthlmoscopy (M.B.). Methodology for the dignosis of ONH, clinicl protocols, nd the stndrdized dt collection hve been extensively published [29]. The evlution of pituitry function includes comprehensive endocrine testing t bseline (TSH, free T4, fsting AM cortisol, growth hormone [GH] surrogtes [IGF-1 nd IGFBP-3], LH, FSH nd/or testosterone in infnts <6 months of ge, nd prolctin) nd dditionl test results from the treting endocrinologist of the subjects. Since 2002, ll subjects without known hormonl problems hd nnul repet free T4, morning cortisol, nd t lest 1 provoctive GH test over the course of the observtion period. Auxologicl dt re collected nnully to monitor norml growth trjectory. Consistent with previously reported definitions [29], peditric endocrinologist (M.G.) scertined the subjects pituitry function bsed on clinicl evlution, lbortory levels, nd growth prmeters [35 37]. More specificlly, subject ws clssified s hving hormone deficiency if he/she were being treted with hormone replcement for GH, levothyroxine, hydrocortisone, nd/or desmopressin (t the time of enrollment), hd subnorml lbortory hormone levels for free T4, or hd subnorml stimulted pek serum GH or cortisol level fter glucgon provoction. The criteri for GH deficiency were defined s being treted with GH replcement t the time of enrollment s consequence of neontl pnhypopituitrism, stimulted pek serum GH level (<10 ng/ml fter glucgon), or height decelertion in the presence of subnorml levels of GH surrogtes. Dibetes insipidus (DI) ws dignosed on the bsis of filure to concentrte urine in the fce of clinicl hyperntremi or with wter deprivtion testing. Prticipnts underwent bseline neurordiology exmintion of the brin, if this hd not lredy been performed (noncontrst MRI with either 1.5 or 3 T hs been used exclusively since 2002). These ll included T1 nd T2 xil scns nd T1 sgittl scns of the brin. Specific scns with pituitry imging protocols were not routinely obtined. Of the 255 registry subjects enrolled s of My 2014, those tht reched the ge of 5 yers by the time of this study with bseline MRI were included. The Institutionl Review Bord t the Children s Hospitl Los Angeles pproved the registry, nd informed consent ws obtined from prent or gurdin of ll ptients. Mlformtions on MRI A neurordiologist (M.N.), who ws msked to the subjects clinicl chrcteristics nd to the originl MRI interprettion, reviewed the MRIs of the brin. The imges were specificlly reviewed for the presence of mlformtions involving the septum pellucidum, corpus cllosum, pituitry glnd, nd/or other prts of the brin (mjor nd minor). A corpus cllosum bnormlity ws scertined s either corpus cllosum hypoplsi or genesis. 252 Grci-Filion/Almrzouki/Fink/Geffner/ Nelson/Borchert
3 Pituitry glnd mlformtions were subdivided into bsent denohypophysis nd ectopic neurohypophysis. The bsence of the neurohypophysis (posterior pituitry bright spot) constituted n bnormlity only if the infundibulum ws lso bsent. Other mjor mlformtions tht were recorded included corticl heterotopi, schizencephly, gyrl mlformtions, cerebellr hypoplsi, white mtter hypoplsi, ventriculomegly, hydrocephlus, nd hypothlmic dysgenesis. Minor (or incidentl) findings were lso documented. Sttisticl Anlysis Descriptive sttistics summrize the clinicl chrcteristics of the registry cohort. Frequency (%) distributions of ctegoricl dt were compred between groups by χ 2 (or Fisher exct) test. Between-group differences of continuous dt, expressed s medin vlues (with interqurtile rnge) regrdless of distribution, were ssessed using the Student t test or nonprmetric nlog in the bsence of norml distribution. The reltive risk (RR) for brin mlformtions or hypopituitrism between groups ws computed by binomil log-liner regression [38]. The RR estimtes were djusted for lterlity of ONH nd the timing of MRI (prior to or fter registry enrollment). The probbility tht brin mlformtion cn ccurtely predict nd/or detect hypopituitrism ws lso estimted (sensitivity, prediction positive, prediction negtive). The sttisticl estimtes re presented with the corresponding 95% confidence intervls (95% CI). Sttisticl significnce ws defined s n lph of 0.05, using 2-sided lterntive hypotheses. Dt were nlyzed using Stt SE 11.0 (College Sttion, TX, USA). Results During the study period, 178 prticipnts were eligible (i.e., t the ge of 5 yers); 32 were excluded due to CT imging only, which left study cohort of 146 prticipnts (49% mle) with MRI findings. The medin ge t the time of MRI ws 8.3 months (interqurtile rnge ), nd 63% (n = 92) hd MRI before enrolling in the registry. A totl of 74% (n = 108) of subjects hd brin mlformtion. The prevlence ws similr regrdless of the timing of MRI (before vs. fter enrollment) (p = 0.650). Tble 1 lists the vrious brin mlformtion findings strtified on lterlity of ONH (13% unilterl). Compred to those with bilterl ONH, subjects with unilterl ONH were 61% less likely to hve brin mlformtion (95% CI: 0.37, 0.98). Individully, n bsent septum pellucidum ws eqully prevlent between lterlity groups (p = 0.516). Hypopituitrism by the ge of 5 yers mnifested in 69% of the cohort (n = 101); of these, deficiency ws isolted to GH in 33 subjects. A brin mlformtion did not correlte with hving hypopituitrism (p = 0.351). The lck of ssocition persisted fter djusting for lterlity Tble 1. Chrcteristics of the ptient cohort (n = 146) n % Gender Mle Age t consent, months 8.3 ( ) Lterlity Unilterl Hypopituitrism b Growth hormone deficiency c Hypothyroidism Cortisol deficiency Dibetes insipidus Age t MRI, months 12.4 ( ) Brin mlformtion Absent septum pellucidum Corpus cllosum bnormlity d Pituitry glnd mlformtion e 13 9 Absent pituitry glnd 1 1 Ectopic neurohypophysis 9 6 Absent neurohypophysis f 5 4 Mjor mlformtion b Corticl heterotopi 10 7 Ventriculomegly 7 5 White mtter hypoplsi 7 5 Schizencephly 6 4 Gyrl bnormlity 5 3 Cerebellr hypoplsi 4 3 Hydrocephlus g 3 2 Hypothlmic dysgenesis 1 1 Dt re presented s the medin (interqurtile rnge). b Frequency counts re not mutully exclusive; multiple pituitry hormone deficiency occurred in 66 subjects. c Growth hormone sufficiency in 7 subjects could not be confirmed with stimultion test. d Corpus cllosum bnormlity includes 5 subjects with genesis. e Pituitry glnd sttus could not be determined in 1 subject. f Absent neurohypophysis ws defined s nonvisulized bright spot nd bsent infundibulum. g Includes 1 subject with Dyke s diverticulum. of ONH nd timing of MRI (p dj = 0.869). A brin mlformtion conferred positive predictive vlue of 71% (95% CI: 62%, 80%) nd negtive predictive vlue of 37% (95% CI: 22%, 54%) for hypopituitrism. Specific Brin Mlformtions Hypopituitrism did not correlte (Tble 2) with findings of bsent septum pellucidum (p undj = 0.188), bnorml corpus cllosum (p undj = 0.268), or other mjor mlformtions (p undj = 0.636). The lck of ssocitions persisted fter djustment for lterlity of ONH nd timing of MRI (p dj = 0.073, p dj = 0.625, nd p dj = 0.407, respectively). Brin Mlformtions nd Hypopituitrism in ONH 253
4 Tble 2. Risk of hypopituitrism t ge 5 yers ssocited with specific brin mlformtions Hypopituitrism, n (%) Undjusted Adjusted b no (n = 45) yes (n = 101) risk rtio c 95% CI risk rtio c 95% CI Any brin mlformtion 31 (29) 77 (71) , , 1.28 Absent septum pellucidum 21 (47) 35 (35) , , 1.02 Corpus cllosum bnormlity 20 (44) 55 (55) , , 1.16 Mjor mlformtion 11 (24) 21 (21) , , 1.16 Combintion d of mlformtions 7 (16) 8 (8) , , 1.12 Pituitry glnd mlformtion e 0 (0) 13 (13) The hormone sttus is presented s yes for hypopituitrism nd no for norml hormone levels. b Adjusted for lterlity nd the timing of MRI (prior to vs. fter enrollment). c No bnormlity is the referent. d Combintion denotes n bsent septum pellucidum, corpus cllosum bnormlity, nd mjor mlformtion. e Pituitry glnd sttus could not be determined in 1 subject. Tble 3. Absence of the septum pellucidum nd the risk of dditionl brin mlformtions Septum pellucidum, n (%) Undjusted Adjusted intct (n = 90) bsent (n = 56) risk rtio 95% CI risk rtio b 95% CI Corpus cllosum bnormlity 38 (42) 37 (66) , , 2.03 Mjor mlformtion 14 (16) 18 (32) , , 3.76 Pituitry glnd mlformtion 8 (9) 5 (9) , , 2.90 Intct septum pellucidum is the referent. b Adjusted for lterlity nd the timing of MRI (prior to vs. fter enrollment). A pituitry glnd mlformtion ws present in 13 subjects, ll of whom mnifested hypopituitrism (Tble 2), including 2 with DI. The positive nd negtive predictive vlues of pituitry glnd mlformtion for hypopituitrism were 100 nd 34% (95% CI: 0.26, 0.43), respectively. Among those with n ectopic neurohypophysis (n = 8), the infundibulum ws bsent in ll but 1 subject in whom the neurohypophysis ws prtilly descended. Among 133 subjects with n intct pituitry glnd, 66% (n = 87) hd hypopituitrism, including 12 with DI. There were 4 ptients in whom the bright spot of the neurohypophysis ws not visulized despite visible infundibulum: 3 hd hypopituitrism, including 1 with DI. Concomitnce of Brin Mlformtions Tble 3 describes the ssocition of brin mlformtions with the bsence of the septum pellucidum. The gretest ssocition ws with mjor mlformtions (RR dj = 2.06) followed by corpus cllosum bnormlity (RR dj = 1.53), but not pituitry glnd mlformtion (RR jd = 1.02). There were 15 subjects with the mlformtion trid historiclly linked with SOD (bsent septum pellucidum, corpus cllosum bnormlity, nd other mjor mlformtions); of these, only hlf (n = 8) mnifested hypopituitrism (Tble 2). Discussion The concurrence of brin mlformtions nd ONH hs been extensively reported, lbeit with significnt vribility in rtes nd ssocition with hypopituitrism. In young ptients with ONH, findings of brin mlformtions hve been scribed prognostic vlues to determine the need for endocrinologicl evlution [9, 11, 12, 17, 22, 25 28, 30, 31]. The speculted significnce of brin mlformtions for hypopituitrism stems from the notion tht SOD is distinct entity tht bestows high risk for hormone deficiencies. Using the only existing prospective registry of young children with ONH, we demonstrte tht brin mlformtions re pervsive in young children with ONH nd re n unrelible screen for hypopituitrism risk. The corresponding type I nd II error 254 Grci-Filion/Almrzouki/Fink/Geffner/ Nelson/Borchert
5 rtes of brin mlformtions for the detection of hypopituitrism re 69 nd 24%, respectively. Our cohort of ONH hd predominnce of bilterlly ffected cses, similr to previous reports [6, 10, 17, 22, 26, 29, 31]. A dignosis of ONH in one or both eyes ws not ssocited with incresed prevlence of bsent septum pellucidum, but bilterl disese ws ssocited with higher risk of other brin mlformtions. Unilterl cses were not protected from brin mlformtions, nd in fct, nerly 50% of the unilterl cses in our cohort hd t lest 1 identified brin mlformtion. This refutes previous reports tht brin mlformtions re exclusive to bilterl ONH [9, 12, 26, 28, 31]. Corpus cllosum bnormlities, not bsence of the septum pellucidum, were the most common brin mlformtions in these children with ONH. Notwithstnding the prefix of septo- in SOD, n bsent septum pellucidum remins inconsequentil to morbidity. An bsent septum pellucidum in isoltion, or coupled with corpus cllosum bnormlity nd/or mjor mlformtions, did not confer risk of hypopituitrism (Tble 2), nor did ny combintion of structurl bnormlities with the exception to the pituitry glnd. Our findings dd to the mounting evidence refuting the clinicl significnce of the (bsent) septum pellucidum in ONH [10, 12, 24, 30 32]. Absence of the septum pellucidum hs been scribed clinicl significnce in ONH, due in prt to its ssocition with other mlformtions such s corpus cllosum hypoplsi [8, 12, 31, 39]. The septum pellucidum forms by the fusion of leflets stretching between the developing corpus cllosum nd hippocmpl commissure, beginning t round 12 weeks of gesttion [40]. Corpus cllosum growth continues following birth, nd my thus be hypoplstic without ffecting the septum pellucidum. Agenesis of the septum pellucidum is thus corollry of plsi, but not hypoplsi, of the corpus cllosum. Severl homeobox genes influence this process, the dysregultion of which lso leds to holoprosencephly, nophthlmos, nd pituitry plsi [41]. Becuse of this, the constelltion of findings historiclly clled SOD [16] hs been presumed to implicte this geneticlly controlled sequence [17, 18]. However, bsence of the septum pellucidum is commonly seen in cses of ONH when the corpus cllosum is norml or merely hypoplstic (26 nd 46%, respectively, in our cohort), nd in otherwise neurologiclly norml individuls [39, 42]. In such cses, bsence of the septum pellucidum more likely indictes seprtion from the developing corpus cllosum due to fctors not necessrily under genetic control. Our study identified pituitry mlformtion in 9% of subjects, within the lrge prevlence rnge of 6 64% reported in the literture [6, 9, 12, 17, 27 29, 31, 32]. Specific pituitry imging protocols were not utilized in this study. Thus, quntifiction of denohypophysel mss could not be performed, nd it ws not possible to determine whether the nterior pituitry glnd ws smll, lthough it ws present in ll subjects. On the other hnd, the neurohypophysel bright spot ws clerly visible in 95% of subjects. Since this is not likely to be flse-positive finding, it is lso unlikely tht imging protocols cused spuriously low prevlence of neurohypophysel bnormlities. While pituitry mlformtion ws highly predictive of hypopituitrism, the converse cnnot be sid for structurlly intct pituitry glnd. Our reported specificity of pituitry glnd mlformtion for hypopituitrism (34%) is lower thn some erlier reports. In previous studies of vrious brin bnormlities, smpling ptients tht underwent neuroimging nd cliniclly selective, or one-time, endocrinologicl testing my help explin discrepnt rtes [3, 8 12, 14, 16, 22 28, 30 32]. For exmple, ptients with identified hypopituitrism my be more likely to get pituitry imging, while ptients with identified pituitry mlformtion re more likely to get frequent hormonl testing. Most reports used brod criteri for mlformtion nd hve considered bsence of the neurohypophysel bright spot in isoltion s sufficient [8, 12, 13, 17, 27, 28, 30 32]. Since visuliztion of the posterior pituitry bright spot on MRI my be influenced by secondry fctors, such s hydrtion sttus nd plsm glucose levels [43], the lck of bright spot in isoltion will rtificilly inflte the rte of pituitry glnd mlformtions. Even so, brodening our definition to include ll subjects with nonvisulized bright spot incresed the prevlence of pituitry glnd mlformtion to only 12%. It seems incongruous tht n bsent neurohypophysis would predict denohypophysel dysfunction insted of DI [8, 12, 27], which only occurred in 10% of the cses reported by Rmkrishnih et l. [30] nd in 11% of this cohort. Furthermore, the prevlence of hypopituitrism (75%) nd DI (25%) in our subjects with nonvisulized bright spot is consistent with the prevlence in the overll subject popultion nd rgues ginst true ssocition. In contrdistinction to previous reports [12, 27, 44], 13 (out of 15) of our subjects with DI hd visible posterior pituitry bright spot, vlidting the structure-function mismtch noted by others [31, 32, 45]. The high prevlence of hypopituitrism (66%) with n intct pituitry glnd on MRI reinforces the importnce of monitoring Brin Mlformtions nd Hypopituitrism in ONH 255
6 hormone levels, despite norml neuroimging, until norml endocrinologicl sttus cn be concluded with confidence. Mny strengths of this registry endorse the generlizbility of our findings to the mngement of young children with ONH. The min strength over previous reports is the use of prospective, systemticlly collected dt in subjects enrolled ner-sequentilly prior to ge 24 months from brod referrl bse [29]. The prevlence of brin mlformtions nd hypopituitrism in our cohort ws higher thn tht in most other reports on ONH, with only 12% of our subjects not hving brin mlformtion or hypopituitrism. Ahmd et l. [46] reported similr findings in cohort of ptients with ONH, nd in tht study CT ws the predominnt imging modlity. The lck of ssocition of brin mlformtions t bseline with hypopituitrism by the ge of 5 yers, despite the high prevlence of both, is not likely the result of scertinment bis, detection, or low sttisticl power. Differences from previous reports include the exclusive use of MRI techniques for the dignosis of brin mlformtions, stndrdized seril endocrine testing [1] to overcome limittions of point prevlence estimtes [17, 26, 31], nd focus on cses dignosed erly in life which re more likely to hve more severe findings [6, 12, 14, 19, 26, 27, 31]. One limittion of our study is tht we my hve slightly underestimted the prevlence of GH deficiency nd hypothyroidism since evolving hypopituitrism hs been reported in children with ONH [34]. For our reported prevlence of GH deficiency, we re somewht ressured tht our cpture rte ws high bsed on dt from the GENESIS GH registry in which the men ge of initition of GH tretment in 165 subjects with SOD ws 3 yers, with rnge of yers [47]. Severl limittions re worth noting. Our study findings re restricted to ptients with ONH nd cnnot be generlized to hypopituitrism risk in ptients with congenitl brin mlformtions without ONH. We lso included MRI scns tht were obtined prior to enrollment source of potentil bis. The rte of hypopituitrism ws slightly, but significntly, higher in those subjects tht hd MRI scns performed prior to enrollment, suggesting tht erly clinicl mnifesttions of hypopituitrism my hve contributed to erly suspicion of the dignosis. Nonetheless, bsence of ssocition of brin mlformtions with hypopituitrism ws independent of MRI sttus t the time of enrollment. Lstly, exclusion of cses from our registry tht presented fter the ge of 2 yers limits generlizbility to very young children with ONH. Nevertheless, these findings reduce the complexity of clinicl decision mking in ptients with ONH dignosed in erly life. In clinicl prctice, we generlly see ptients every 4 6 months (more frequently in younger children), which would llow erlier detection of reduced growth rte nd the initition of lbortory evlution. While we conclude tht brin mlformtions re not predictive of hypopituitrism in this popultion, they re known risk fctor for seizures nd developmentl dely in this condition [11, 12, 29, 31], nd their erly identifiction my be importnt for predicting nd/or preventing dverse outcomes. For exmple, corpus cllosum hypoplsi is ssocited with 3-fold incresed risk of cognitive deficits [29]. Since 1970, investigtions of ONH hve used brin mlformtions nd lterlity s the criteri for dignostic subtype nd risk of hypopituitrism [6, 7, 10, 12, 13, 18, 28]. This study demonstrtes tht infnts with unilterl ONH lso hve high risk for hypopituitrism, lbeit less thn bilterlly ffected infnts. Brin mlformtions re common in children with ONH nd re unrelted to hypopituitrism; both mnifest independently in the ONH disese spectrum. All infnts nd toddlers with ONH should be considered t high risk for hypopituitrism regrdless of findings on neuroimging. Acknowledgments This reserch ws supported in prt by the Prevent Blindness Americ Foundtion, the One Smll Voice Foundtion, nd grnt No. UL1TR000130, Children s Hospitl Los Angeles, from the Ntionl Center for Advncing Trnsltionl Sciences (NCATS) t the Ntionl Institutes of Helth. Disclosure Sttement The uthors hve no conflicts of interest to report. References 1 Grci-Filion P, Borchert M: Optic nerve hypoplsi syndrome: review of the epidemiology nd clinicl ssocitions. Curr Tret Options Neurol 2013; 15: Ter Fhnehjelm K, Dhl S, Mrtin L, Ek U: Optic nerve hypoplsi in children nd dolescents; prevlence, oculr chrcteristics nd behviourl problems. Act Ophthlmol 2014; 92: Morishim A, Arnoff GS: Syndrome of septo-optic-pituitry dysplsi: the clinicl spectrum. Brin Dev 1986; 8: Grci-Filion/Almrzouki/Fink/Geffner/ Nelson/Borchert
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Trns Am Ophthlmol Soc 1981; 79: Brkovich AJ, Frm EK, Normn D: Septooptic dysplsi: MR imging. Rdiology 1989; 171: Brodsky MC, Glsier CM: Optic nerve hypoplsi. Clinicl significnce of ssocited centrl nervous system bnormlities on mgnetic resonnce imging. Arch Ophthlmol 1993; 111: Kufmn LM, Miller MT, Mfee MF: Mgnetic resonnce imging of pituitry stlk hypoplsi. A discrete midline nomly ssocited with endocrine bnormlities in septo-optic dysplsi. Arch Ophthlmol 1989; 107: Mrglith D, Tze WJ, Jn JE: Congenitl optic nerve hypoplsi with hypothlmic-pituitry dysplsi. A review of 16 cses. Am J Dis Child 1985; 139: De Morsier G: Etudes sur les dysrphies crnio-encephliques. III. Agenesis du septum lucidum vec mlformtion du trctus optique. L dysplsie septo-optique. Schweiz Arch Neurol Psychitr 1956; 77: Hoyt WF, Kpln SL, Grumbch MM, Glser JS: Septo-optic dysplsi nd pituitry dwrfism. Lncet 1970; 1: Meht A, Hindmrsh PC, Meht H, Turton JP, Russell-Eggitt I, Tylor D, Chong WK, Dttni MT: Congenitl hypopituitrism: clinicl, moleculr nd neurordiologicl correltes. Clin Endocrinol (Oxf) 2009; 71: Webb EA, Dttni MT: Septo-optic dysplsi. Eur J Hum Genet 2010; 18: Ptel H, Tze WJ, Crichton JU, McCormick AQ, Robinson GC, Dolmn CL: Optic nerve hypoplsi with hypopituitrism. Septo-optic dysplsi with hypopituitrism. Am J Dis Child 1975; 129: Mosier MA, Liebermn MF, Green WR, Knox DL: Hypoplsi of the optic nerve. Arch Ophthlmol 1978; 96: Menezes L, Aicrdi J, Goutieres F: Absence of the septum pellucidum with porencephli. A neurordiologic syndrome with vrible clinicl expression. Arch Neurol 1988; 45: Roberts-Hrry J, Green S, Willshw H: Optic nerve hypoplsi: ssocitions nd mngement. Arch Dis Child 1990; 65: Mser N, Grnt DB, Stnhope R, Preece MA: Dibetes insipidus with impired osmotic regultion in septo-optic dysplsi nd genesis of the corpus cllosum. 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Dev Med Child Neurol 2012; 54: Grci-Filion P, Epport K, Nelson M, Azen C, Geffner ME, Fink C, Borchert M: Neurordiogrphic, endocrinologic, nd ophthlmic correltes of dverse developmentl outcomes in children with optic nerve hypoplsi: prospective study. Peditrics 2008; 121:e653 e Rmkrishnih RH, Shelton JB, Glsier CM, Phillips PH: Relibility of mgnetic resonnce imging for the detection of hypopituitrism in children with optic nerve hypoplsi. Ophthlmology 2014; 121: Birkebek NH, Ptel L, Wright NB, Grigg JR, Sinh S, Hll CM, Price DA, Lloyd IC, Clyton PE: Endocrine sttus in ptients with optic nerve hypoplsi: reltionship to midline centrl nervous system bnormlities nd ppernce of the hypothlmic-pituitry xis on mgnetic resonnce imging. J Clin Endocrinol Metb 2003; 88: Hddd NG, Eugster EA: Hypopituitrism nd neurodevelopmentl bnormlities in reltion to centrl nervous system structurl defects in children with optic nerve hypoplsi. J Peditr Endocrinol Metb 2005; 18: Atpttu N, Ainsworth J, Willshw H, Prulekr M, McPherson L, Miller C, Dvies P, Kirk JM: Septo-optic dysplsi: ntentl risk fctors nd clinicl fetures in regionl study. Horm Res Peditr 2012; 78: M NS, Fink C, Geffner ME, Borchert M: Evolving centrl hypothyroidism in children with optic nerve hypoplsi. J Peditr Endocrinol Metb 2010; 23: Ahmd T, Borchert M, Geffner M: Optic nerve hypoplsi nd hypopituitrism. Peditr Endocrinol Rev 2008; 5: Fink C, Vedin AM, Grci-Filion P, M NS, Geffner ME, Borchert M: Newborn thyroidstimulting hormone in children with optic nerve hypoplsi: ssocitions with hypothyroidism nd vision. J AAPOS 2012; 16: Vedin AM, Grci-Filion P, Fink C, Borchert M, Geffner M: Serum prolctin concentrtions in reltion to hypopituitrism nd obesity in children with optic nerve hypoplsi. Horm Res 2012; 77: Greenlnd S: Model-bsed estimtion of reltive risks nd other epidemiologic mesures in studies of common outcomes nd in csecontrol studies. 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