Ultrsound Ostet Gynecol 1999;13:274 280 Fetl crniofcil structure nd intrcrnil morphology in cse of Apert syndrome R. K. Pooh, Y. Nkgw, K. H. Pooh*, Y. Nkgw* nd N. Ngmchi Deprtment of Ostetrics nd Gynecology nd Clinicl Reserch Institute, Ntionl Zentsuji Hospitl; *Deprtment of Neurosurgery, Ntionl Kgw Children s Hospitl, Kgw, Jpn Key words: PRENATAL DIAGNOSIS, ULTRASOUND, APERT SYNDROME, INTRACRANIAL MORPHOLOGY, FETAL PROFILE ABSTRACT Apert syndrome is chrcterized y crniosynostosis, midfcil hypoplsi nd ilterl syndctyly. We document in detil the intruterine nturl history of Apert syndrome y seril sonogrphic exmintion. Ultrsound exmintion of 19-week fetus reveled n norml ppernce of the skull. The susequent exmintion including trnsvginl rin scnning demonstrted deformed occipitl prt of the cererum nd lterl ventricles, frontl ossing, low nsl ridge nd n norml ppernce of the fetl hnds nd feet. The distortion of the fetl profile ecme progressively worse with dvncing gesttion. Towrds the end of pregnncy, nterior prominence of the cererum, ventricles nd corpus cllosum ws demonstrted nd mild non-progressive ventriculomegly ws seen. The femle 3152-g neworn with the typicl fcil ppernce of Apert syndrome, ilterl syndctyly of the fingers nd toes nd isolted cleft plte ws delivered t 37 weeks. Postntl threedimensionl computed tomogrphy scn demonstrted the fusion of the coronl suture nd wide mid-line clvril defect, nd crnil mgnetic resonnce imging confirmed the prentl sonogrphic findings. Although the kryotype ws norml, genomic DNA nlysis of the firolst growth fctor receptor 2 reveled Ser252Trp, which is specified in the muttionl sis of Apert syndrome. The time course of the prentl findings in this cse my help increse understnding of the intruterine nturl history of Apert syndrome. INTRODUCTION The fetl skull consists of severl crnil ones with open spces such s the coronl, sgittl, lmdoid nd metopic sutures nd nterior, posterior nd nterolterl fontnelles. The sutures nd fontnelles re preserved despite development of the crnil ones during pregnncy. If ossifiction of the skull occurs premturely, the sutures re oliterted nd this is known s crniosynostosis. This nomly my e isolted or my form prt of syndrome such s Apert syndrome. There hve een severl reports on the prentl ultrsound detection of crniosynostosis ut no description of the longitudinl sonogrphic chnges in the fetl profile nd intrcrnil morphology tht occur. We document the prentl course of fetus with congenitl crniofcil normlity. CASE REPORT A 25-yer-old Chinese primigrvid with n unremrkle medicl history registered t our hospitl t 11 weeks of gesttion. An ultrsound exmintion using LOGIQ 400 mchine (GE Yokogw Medicl System, Tokyo, Jpn) with 5.0-MHz trnsdominl proe nd 6.5-MHz trnsvginl proe ws performed t 14 weeks nd 5 dys of gesttion nd reveled single fetus with iprietl dimeter (BPD) consistent with dtes nd norml ppernce of the spce of the coronl suture. The norml ppernce of the fetl skull ws noted t second exmintion t 19 weeks (Figure 1). On the next visit, for further sonogrphic exmintion t 20 weeks of gesttion, the fetl cheek ws seen to e slightly prominent for the gesttionl ge (Figure 1). Seril sonogrphic exmintions were performed therefter. Figure 2 shows the chnges in the intrcrnil structure which were detected trnsvginlly. Although norml ppernce of the corpus cllosum ws detected t 20 weeks (Figure 2), the nterior prominence of the corpus cllosum nd the cvum septum pellucidi ws demonstrted in lte pregnncy (Figure 2). From 20 weeks, the occipitl prt of cererum, lterl ventricles nd surchnoid spce ppered to e deformed y oppression from the posterior direction (Figure 2c). The nterior prt of the cererum nd ventricles ecme prominent in lte pregnncy (Figure 2d) ut did not chnge significntly Correspondence: Dr R. K. Pooh, Deprtment of Ostetrics nd Gynecology, Clinicl Reserch Institute, Ntionl Zentsuji Hospitl, 2-1-1 Senyu-cho, Zentsuji City, Kgw no. 765 8507, Jpn CASE REPORT 274 Received 6 4 98 Revised 19 8 98 Accepted 30 11 98
Figure 1 The norml ppernce of the fetl skull ws noted in the reech-presented fetus t 19 weeks of gesttion (). The fetl cheek t 20 weeks ws mildly prominent for the gesttionl ge () compred to tht in mid-gesttion. No evidence of hydrocephlus ws found during pregnncy despite the presence of mild ventriculomegly. The nterior horns of the lterl ventricles were wider thn norml ut the prietl surchnoid spce ws preserved (Figure 2e). A fusion etween the ilterl nterior horns nd the cvum septum pellucidi ws demonstrted in the coronl plne including the ilterl suproritl mrgin (Figure 2f). In the third trimester, the gyri nd sulci of the cererum ppered norml. The norml fetl profile with frontl ossing nd low nsl ridge ecme more mrked with gesttion (Figure 3 c). Mgnetic resonnce imging (MRI) performed t 34 weeks ws le to demonstrte the whole crniofcil shpe (Figure 3d) ut no dditionl informtion on the intrcrnil structure could e otined. A lck of seprtion of the second to fourth digits on oth hnds, lrge thums nd deformed plnte were detected (Figure 4). There were no dditionl normlities. Fetl growth ws norml nd fetl hert rte monitoring showed rective pttern. The flow ssessment of the umilicl rtery nd the middle cererl rtery showed norml circultion. Polyhydrmnios ws oserved from 30 weeks of gesttion despite fetl swllowing. The prents were counselled y ostetricins nd peditric neurosurgeons during the course of the pregnncy. The femle neworn (Figure 5) ws delivered t 37 weeks y Cesren section nd weighed 3152 g, with n Apgr score of 9 t 1 nd 5 min. In ddition to the norml ppernce of the fce, ilterl symmetricl syndctyly of the second to fourth digits nd prtilly to the fifth digit, lrge thums, deformed plnte nd isolted mild cleft plte were confirmed. The fusion of ilterl coronl sutures ws confirmed y crnil X-ry. Postntl MRI (Figure 6) confirmed the prentl sonogrphic findings of intrcrnil structure nd isolted cleft plte. These chrcteristic clinicl fetures led to the dignosis of Apert syndrome. The y underwent trcheostomy ecuse of stenosis of the upper irwy ssocited with sifcil dysplsi. Three-dimensionl reconstruction of computed tomogrphy (CT) scn (Figure 7) performed t 81 dys showed the detiled ppernce of the fusion of ilterl coronl sutures, sifcil hypoplsi nd wide mid-line clvril defect extending from the glell to the posterior fontnelle. Chromosoml exmintion demonstrted norml femle kryotype. Muttionl nlysis in the firolst growth fctor receptor 2 (FGFR2) from genomic DNA reveled Ser252Trp (C to G trnsversion t position 934), which is specified muttion of Apert syndrome. There hve een no neurologicl deficits for 4 months. The neurosurgicl opertion of crnioplsty nd tretment for syndctyly re now under considertion. DISCUSSION Crniosynostosis is congenitl normlity chrcterized y premture fusion of one or more clvril sutures nd is clssified into vrious syndromes or isolted crniosynostosis ccording to the clinicl fetures. The fusion cn occur in ny sutures, either symmetriclly or symmetriclly, nd the profiles nd skull shpes re different in ech type of crniosynostosis. For instnce, synostosis of the coronl, sgittl nd lmdoid sutures results in crocephly in Crouzon nd Crpenter syndromes nd synostosis of coronl nd sgittl sutures results in rchycephly in Pfeiffer syndrome. In Apert syndrome, rchycephly results from synostosis of the coronl suture. Finger normlities such s polydctyly nd/or syndctyly re common in Crpenter, Apert nd Pfeiffer syndromes. Apert syndrome is chrcterized y crniosynostosis of the coronl suture, ilterl syndctyly of the fingers nd Ultrsound in Ostetrics nd Gynecology 275
c d e f Figure 2 Morphologicl chnge of the rin in trnsvginl views of mid-sgittl (,), olique (c,d) nd coronl (e,f) sections. Although the corpus cllosum ws detected s norml t 20 weeks (), the nterior prominence of the corpus cllosum nd the cvum septum pellucidi were demonstrted t 35 weeks (). The occipitl prt of cererum, lterl ventricles nd surchnoid spce ppered to e deformed y oppression from the posterior direction, from 20 weeks (c). The shpe of the cererum nd ventricles ecme prominent in the nterior region t 35 weeks (d) ut did not remrkly chnge compred to tht in mid-gesttion. No evidence of hydrocephlus ws found during pregnncy, despite the presence of ventriculomegly. The nterior horns of the lterl ventricles were wider thn norml (e, 30 weeks) nd fusion etween the ilterl nterior horns nd the cvum septum pellucidi ws demonstrted in lte pregnncy (f, 35 weeks). The norml ppernce of the cererl gyri nd sulci in lte pregnncy (,d) indictes normlly developed rin toes, the presence of rod distl thum nd ig toes nd mid-fcil hypoplsi. It is consistent with utosoml dominnt inheritnce, lthough most cses rise y muttion. The irth prevlence of Apert syndrome is estimted t 15.5/1 000 000 nd this syndrome ccounts for out 4.5% of ll cses of crniosynostosis 1. The cuse of Apert syndrome hs recently een pinpointed s specific sustitutions involving djcent mino cids (Ser252Trp or Pro253Arg) in the linker etween the second nd third extrcellulr immunogloulin domins of firolst growth fctor receptor 2 (FGFR2) 2,3. The reltionships etween phenotype nd different muttions hve een ssessed 4. Severl reports which descrie the prentl dignosis of crniosynostosis hve een pulished. Crniosynostosis, especilly due to fusions of multiple crnil sutures, shows 276 Ultrsound in Ostetrics nd Gynecology
c d Figure 3 The sonogrphic chnges of the fetl profile t 22 weeks (), 27 weeks () nd 35 weeks of gesttion (c). Frontl ossing nd low nsl ridge grdully progressed with the gesttion. Mgnetic resonnce imging performed t 34 weeks in sgittl section (d) reveled the whole crniofcil shpe, ut no dditionl informtion on the intrcrnil structure ws otined Figure 4 Anorml ppernces of fetl hnds () nd feet (). Bilterl fingers of the second to fourth digits without seprtion were demonstrted (). Bilterl deformed plnte () were lso detected conspicuous crnil ppernce. Recently, Bernstein nd collegues 5 reported the prentl dignosis of Pfeiffer syndrome with chrcteristic sonogrphic ppernce of clover-lef skull. In cses with the presence of one fused suture such s in Apert syndrome, however, ntentl detection is difficult, ecuse the deformity of the skull is not severe. The first cse report of prentl dignosis of Apert syndrome ws pulished in 1982 6 when fetoscopy ws performed t 17 weeks ecuse of mternl Apert syndrome nd reveled cupped fingers. The sonogrphic detection of Apert syndrome ws first reported in 1986 7, nd further cses hve een descried susequently 8 13.Of Ultrsound in Ostetrics nd Gynecology 277
Figure 5 The ppernce of the fce, hnd nd foot of the neworn. Mid-fcil hypoplsi, ilterl syndctyly nd lrge thums re visulized these, six spordic cses were dignosed etween 26 nd 33 weeks of gesttion nd one inherited cse from n ffected mother 9 ws dignosed in the erly second trimester y the presence of mitten hnds nd n irregulrly shped skull. The initil sonogrphic signs of the spordic cses were ventriculomegly, izrre skull ppernce nd polyhydrmnios. Out of eight cses of the prentl detection of Apert syndrome, the pregnncies were terminted in four, intruterine fetl demise occurred in one cse nd neontl deth fter preterm delivery occurred in one cse. There were two cses delivered t term nd one underwent surgery for crniosynostosis fter irth 8. Detils of the intrcrnil structure nd longitudinl morphologicl chnges of the fetl profile, however, hve not een descried. In our cse, the deformity of the crnil one ws not prticulrly severe, nd the BPD ws not influenced despite the fusion of the ilterl coronl sutures. This might hve een ecuse the sgittl nd metopic sutures with clvril defects, which were confirmed y postntl three-dimensionl CT scn, were dilted in compenstory mnner to help the development of the rin. Cohen nd Kreiorg 14 suggested tht the wide mid-line defect from the glell to the posterior fontnelle is seen in the skull of the infnt of less thn 3 months of ge who is ffected y Apert syndrome nd tht the clvril immturity nd the meglencephlic rin chrcteristic of Apert syndrome pper to work in concert to produce the mid-line defect. The fused coronl suture develops first ecuse the ossifiction centers of the frontl nd prietl ones re in intimte contct during erly intruterine life 14. However, there hs een no informtion on how erly is the crucil period of the complete coronl fusion. Of interest is the fct tht the ilterl spces etween the frontl nd prietl ones were detectle t 14 weeks in our cse; this my indicte the coronl suture efore the fusion. This fct nd the grdul progression of the clvril deformity during pregnncy suggested tht fusion of the ilterl coronl sutures my hve grdully progressed fter 14 weeks in our cse. As for neurodevelopmentl prognosis, significnt numer of ptients with Apert syndrome re mentlly retrded, ut mentl retrdtion is not so common in some of the crniosynostosis syndromes such s Pfeiffer nd Antley Bixler syndromes. Coher nd Kreiorg 15 suggested tht mlformtions of the centrl nervous system my e responsile for most cses of mentl retrdtion. In our cse, no dditionl mlformtion of the rin except for mild non-progressive ventriculomegly ws found. Neurosurgicl follow-up nd long-term oservtion will e necessry. CONCLUSION The time course of the different prentl findings my help to understnd the intruterine nturl history of Apert syndrome. However, s it is difficult to prove the fusion of the crnil suture in utero, every piece of informtion otined from sonogrms my e circumstntil evidence of suspected crniosynostosis. Therefore, the prentl dignosis nd counselling of couples in suspected cses re difficult nd should e undertken prudently. 278 Ultrsound in Ostetrics nd Gynecology
c d Figure 6 Postntl mgnetic resonnce imging. The nterior coronl view () shows the isolted cleft plte. The mid-sgittl view () demonstrtes prominent nterior prts of the cererum, the corpus cllosum nd the cvum septum pellucidi. The xil view (c) revels exophthlmus nd hypoplstic ethmoidl sinus. The coronl view (d) shows mildly enlrged nterior horns fused with the cvum septum pellucidi c Figure 7 Three-dimensionl reconstruction of computed tomogrphy scn imges t 81 dys. The fusion of the coronl sutures () nd wide mid-line clvril defect extending from the glell to the posterior fontnelle ( c) re clerly demonstrted. Lmdoid sutures ppered normlly in the prietl view () Ultrsound in Ostetrics nd Gynecology 279
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