Ultrasound Obstet Gynecol 2014; 44: 588–594 Published online 12 October 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.13337
Temporal lobe dysplasia: a characteristic sonographic finding in thanatophoric dysplasia D. C. WANG*, P. SHANNON†, A. TOI‡, D. CHITAYAT§¶, U. MOHAN**, E. BARKOVA††, S. KEATING†, G. TOMLINSON‡‡ and P. GLANC§§ *Faculty of Medicine, University of Toronto, Toronto, ON, Canada; †Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada; ‡Department of Medical Imaging, Mount Sinai Hospital, Toronto, ON, Canada; §Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada; ¶Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, ON, Canada; **Department of Obstetrics and Gynecology, University of Calgary, Calgary, AB, Canada; ††Department of Medical Imaging, South Shore Regional Hospital, Bridgewater, NS, Canada; ‡‡Institute of Health Policy, Management & Evaluation, University of Toronto, Toronto, ON, Canada; §§Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
K E Y W O R D S: abnormal gyration; prenatal ultrasound; skeletal dysplasia; temporal lobe dysplasia; thanatophoric dysplasia
ABSTRACT Objective To determine the incidence of temporal lobe dysplasia (TLD) detected on prenatal ultrasound in thanatophoric dysplasia (TD) over an 11-year period in a tertiary referral center. Methods An 11-year retrospective review of perinatal autopsies from 2002 to 2013 was performed to identify cases of TD. The ultrasound images and corresponding reports of all TD cases were examined for the presence of TLD. The same set of images subsequently underwent a retrospective review by a perinatal radiologist with knowledge of the features of TLD to determine whether they could be identified. Results Thirty-one cases of TD underwent perinatal autopsy, and prenatal ultrasound imaging was available for review in 24 (77%). Mean gestational age at diagnosis of TD was 21.3 (range, 18–36) weeks. TLD was identified and reported in 6/24 (25%) cases; all six cases occurred after 2007. Retrospective interpretation of the ultrasound images identified features of TLD in 10 additional cases. In total, 16/24 (67%) cases displayed sonographic evidence of TLD. Temporal trends showed that TLD features were present in 50% (5/10) of all TD cases between 2002 and 2006 and in 79% (11/14) of those detected between 2007 and 2013. Conclusions At present, the detection rate of TLD by ultrasound is low but may be increased by modified brain images that enhance visualization of the temporal lobes. Prenatal identification of TLD may help in the prenatal diagnosis of TD and thus provide more accurate prenatal
counseling and guide molecular investigations to confirm the specific diagnosis of TD. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION Thanatophoric dysplasia (TD) is a relatively common lethal skeletal dysplasia, with a prevalence of 0.21 to 0.80 per 10 000 births1 – 3 . It is an autosomal dominant condition and part of a group of skeletal disorders associated with mutations in the Fibroblast Growth Factor Receptor 3 gene (FGFR3)4,5 . TD is characterized by severe micromelia and lung hypoplasia and can be divided into two subtypes6,7 . TD type 1 (TD-1) features bowed/bent femurs associated with metaphyseal flaring, resulting in a characteristic ‘telephone receiver’ appearance8,9 . TD type 2 (TD-2) is characterized by straight femurs and a ‘cloverleaf’’ skull, although this feature may also appear in TD-18,10 . In addition to the skeletal findings, the temporal lobes in TD show characteristic findings of temporal lobe dysplasia (TLD) including prominent sulcations and radially directed gyrations11 – 13 . These findings in cases with lethal short-limb skeletal dysplasia are considered to be virtually pathognomonic and can be identified on gross pathology inspection as early as the first trimester14 . Although this specific feature is well known in the pathology literature, an awareness of the sonographic appearance of TLD on prenatal ultrasound is limited as compared with the better known musculoskeletal features. Recent publications and clinical practice guidelines have failed to discuss TLD as a potential diagnostic marker for TD15 – 17 . Given that
Correspondence to: Dr P. Glanc, Department of Medical Imaging, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, ON, Canada, M4N 3 M5 (e-mail: [email protected]) Accepted: 11 February 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Temporal lobe dysplasia in thanatophoric dysplasia the current prenatal diagnostic accuracy of TD ranges from 40% to 87.5%18,19 , detection of TLD on prenatal ultrasound could provide added specificity in patient counseling and guide molecular investigations. Recently, small case series have demonstrated that TLD can be directly visualized on prenatal ultrasound and magnetic resonance imaging20 – 24 . Blaas et al.25 were the first to demonstrate the feasibility of prospective sonographic identification of TLD, in six cases with TD. We report our experience in the prenatal detection of TLD over an 11-year period. We also analyze the trends in rates of detection over this time period and review techniques for achieving optimal visualization of the features of TLD.
METHODS To identify cases of TD, a retrospective review of perinatal autopsies from January 2002 to May 2013 was conducted at Mount Sinai Hospital in Toronto, Ontario, Canada, a tertiary referral center for high-risk obstetrics. The perinatal autopsy cohort included all neonatal deaths, stillbirths, and elective terminations of pregnancy. Inclusion criteria were all perinatal autopsies with a final diagnosis of TD based on a combination of clinical, radiological, pathological and molecular analysis. We excluded cases of TD seen at Mount Sinai Hospital only for pregnancy termination without correlative prenatal ultrasound imaging. Detailed autopsy, including histopathology, X-rays and molecular analysis, was performed in the majority of cases. All cases that underwent complete autopsy had fetal brain evaluation performed by a fetal neuropathologist. In a small number of cases the autopsy was limited to external evaluation, as per parental wishes. Anterior, posterior and lateral radiographs, using a Faxitron Cabinet X-ray system (Faxitron Bioptics, Tucson, AZ, USA), were obtained in all cases. The radiographs were interpreted by a single perinatal radiologist with more than 30 years’ experience in perinatal imaging. External consultation with experts (International Skeletal Dysplasia Registry) was obtained at the discretion of the radiologist. Prenatal ultrasound scans were performed at one of two obstetrical ultrasound clinics at Mount Sinai Hospital. Interpretation was performed by dedicated obstetrical imagers, maternal fetal medicine specialists or radiologists. Research ethics board approval was obtained. In our analysis, TLD is defined as the presence of abnormal prominent gyration and sulcation of the temporal lobes. Each set of prenatal ultrasound images and corresponding reports were reviewed to determine if TLD was noted at the time of the initial study. A second review (‘retrospective interpretation’) was then performed by an expert perinatal radiologist with knowledge of the diagnosis. The results were cross-referenced with the initial interpretation to determine if TLD could be detected in cases for which images specifically looking for this feature were not obtained. The diagnosis of TLD was stratified by year of diagnosis to determine trends in detection over time.
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Demographic, pathologic, radiologic and genetic data and results were entered into a standardized and anonymized web-based reporting system.
RESULTS TD was identified in 31 of 2501 (1%) perinatal autopsies. Neuropathological analysis was performed on 23 (74%) cases of TD, and TLD was observed in all 23 cases. No other cases with TLD were detected on pathology. Of the 31 TD cases, 24 (77%) had prenatal ultrasound imaging and initial interpretation available for review. The average gestational age at sonographic diagnosis of TD was 21.3 (range, 18–36) weeks. The average gestational age at autopsy was 24.7 (range, 20–40) weeks. Twenty cases were terminated electively, three cases were born at term and in one case the pregnancy outcome was not specified. The average maternal age was 31.9 (range, 21–42) years. There were no cases of recurrence. There were 15 males and nine females and all had normal karyotype. All 24 cases had either complete (n = 19) or limited (n = 5) external autopsy. In all 19 cases with complete autopsy, TD was confirmed on neuropathology. The remaining five cases were confirmed to have TD by molecular analysis of the FGFR3 gene. Based on a combination of clinical, radiological, pathological and molecular analysis the cases of TD were sub-classified as TD-1 (n = 20) and TD-2 (n = 4). The initial ultrasound exam found TLD in six (25%) cases, all of which were TD-1. Other central nervous system abnormalities identified in this cohort included mild ventriculomegaly (n = 3) and an individual case of agenesis of the corpus callosum. Cranial vault malformations, including frontal bossing, macrocranium and brachycephaly, were detected in 17 (71%) cases. The retrospective interpretation of the prenatal ultrasound images detected 10 additional cases with TLD. In total, 16/24 (67%) cases (14 TD-1, two TD-2) in our cohort displayed sonographic evidence of TLD. The temporal trend of TLD detection over the study period demonstrated that all six cases for which TLD was reported in the initial interpretation occurred after 2007 (Table 1). In the retrospective interpretation, features of TLD could be seen in five cases before 2007 and an additional five after 2007. Of the total of 24 cases of TLD, 10 were diagnosed between 2002 and 2006 and 14 were diagnosed between 2007 and 2013. In total, following the retrospective interpretation, TLD could be seen in 50% (5/10) of all TD cases from 2002–2006 and 79% (11/14) of TD cases from 2007–2013.
DISCUSSION Temporal lobe abnormalities have been well recognized as a defining pathological feature of TD, occurring in virtually 100% of cases by 18 weeks’ gestation, and earlier in some cases11 – 14,26 . This is a form of medial temporal lobe dysplasia resulting in a striking appearance of multiple deep transverse temporal sulci (Figure 1)14 , which is in contrast to the normal developing temporal
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590 Table 1 Sonographic detection of temporal lobe dysplasia before and after 2007 2002–2006 (n = 10) Time of interpretation Original Retrospective
2007–2013 (n = 14)
2002–2013 (n = 24)
Yes
No
Yes
No
Yes
No
0 5
10 5
6 11
8 3
6 16
18 8
Figure 1 (a) Low transaxial ultrasound image at the temporal lobe level in a 20-week fetus affected with thanatophoric dysplasia, showing abnormal temporal lobe sulcation. The imaging plane includes midbrain (MB) and orbits (O) and arrows point to multiple deep transverse sulci at the inferomedial aspect of the temporal lobes. (b) Autopsy neuropathology image at 23 weeks showing abnormal radially oriented sulci (arrows) on inferior surface of temporal lobe.
Figure 2 Coronal ultrasound image that includes the cerebellum (CB) in a 22-week fetus affected with thanatophoric dysplasia, showing abnormal deep sulcation typical of temporal lobe dysplasia (arrows).
lobe, which does not demonstrate sulcation before 20 weeks’ gestation27 . We report an 11-year retrospective review of 31 consecutive cases of TD, confirmed via perinatal autopsy. Corresponding prenatal ultrasound imaging was available in 24 cases. The primary aim was to determine the incidence of TLD detection on prenatal ultrasound during this study period. In our cohort, TLD was reported initially in only 6/24 (25%) prenatal ultrasound scans, despite being seen in all cases on gross pathological analysis. In comparison, cranial vault malformations, a typical and well recognized, but non-specific, feature of TD8,14 , were reported in 17/24 (71%) prenatal scans.
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
We speculate that several factors contributed to the relatively low detection rate of TLD on prenatal ultrasound. The primary factor was a lack of awareness of the feature, which was not described in the ultrasound literature until 200721 . In corroboration with the literature, all six cases for which features of TLD were reported on the initial ultrasound scan occurred after 2007. However, this represents only 43% (6/14) of all TD cases from 2007 to 2013. An additional factor is that views that optimally display TLD are not included in the standard views taken during the prenatal scan17 . During the retrospective interpretation, features of TLD could be identified in 10 additional cases that inadvertently included views of the temporal lobes (Table 1). The remaining eight cases in which TLD was not seen did not include images of the temporal lobes for interpretation. Since TLD affects parts of the brain that are outside the standard views17 , it is not surprising that the feature would not have been recorded on standard ultrasonographic assessment. Additionally, we speculate that the low incidence of prospective identification in these cases may be due to overshadowing of TLD by the overwhelming additional abnormalities seen in the remaining fetal skeletal structures. In our experience, we have found that TLD can always be identified if specifically sought using non-standard views directed at the lower part of the temporal lobe. The routine axial transthalamic biparietal diameter (BPD) planes are taken cephalad to the inferior and medial surfaces of the temporal and occipital lobes, the region in which abnormal sulcation is most apparent25 . To image the medial surface of the temporal lobe, we find that two imaging planes are most useful. The first is a low axial
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Figure 3 (a,b,c) Multiplanar three-dimensional reconstructed ultrasound images of the head at 20 weeks’ gestation in a fetus with thanatophoric dysplasia, showing where abnormal temporal lobe sulcation is most conspicuous. White lines indicate planes of section on the other views. Abnormal sulcation is most conspicuous on coronal view (b, arrows); it is less obvious on axial view taken at approximately biparietal diameter level (a) and is not visible on mid-sagittal view that includes the falx but is too medial to include the hemispheres (c). (d) Lateral view of brain of same case at 23 weeks, showing enlargement of temporal lobe with deep abnormal sulcation (arrows) on inferior aspect of lobe. (e) Coronal mid-thalamic section of same case, showing deep folds in inferior temporal lobes with prominent expansion of inferior temporal cortex and expansion of temporal horns of lateral ventricles (arrows).
plane below the level of the BPD plane, which roughly includes the orbits and brainstem/midbrain (Figure 1). This plane requires only minimal adjustment downward from the routine transthalamic BPD plane. The second imaging plane is a coronal plane that also includes the cerebellum or midbrain (Figure 2). We have also found three-dimensional imaging with multiplanar reconstructions helpful in achieving the specific views (Figures 3–5). Visualization of TLD can also be achieved via a parasagittal view analyzing the medial periventricular cortex17,25 . Miller et al.23 have described sulcation in the posterior temporal lobe in TD detected via the transcerebellar coronal plane, which might provide an alternative approach to diagnosis. Interestingly, we found that using these modified imaging planes, the abnormal deep medial temporal
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
sulcation can be identified as early as 16 weeks’ gestation (Figure 5). In another case on retrospective review, we felt that abnormal sulcation may have been present even at 12 weeks in a case that was later shown to have TD (Figure 6). The latter two proven cases were not included in our study population as their pathology was performed at an outside institution; however, they represent the earliest cases reported in the literature, and support the use of these additional imaging planes20 – 23,25 . The previous earliest gestational age at which TLD was detected was 19 weeks, reported by Blaas et al.25 . In contrast, the normally developing brain demonstrates virtually no sulcation in this region until the mid-second trimester (Figure 4). To our knowledge, this is the largest cohort of TD to be systematically analyzed for sonographic TLD detection.
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Figure 4 (a,b,c) Multiplanar three-dimensional reconstructed ultrasound images of the head of a normal fetus at 19 weeks’ gestation. (a) Low axial planar view showing absence of abnormal sulci at level that includes orbits (O) and midbrain (MB). (b) Coronal planar view, showing early shallow development of the calcarine sulcus (arrow) as a single shallow indentation in the medial hemisphere, which is quite different from the multiple deep sulci visible in affected brains. Lines on (a) and (c) indicate orthogonal section planes. Axial view (d) and coronal section (e) of normal 19-week brain on neuropathology: there is no sign of temporal lobe enlargement or presence of abnormal fissures on inferior temporal lobes.
We add to the growing evidence that TLD can be detected routinely on prenatal ultrasound20 – 23 . Sonographic detection of TLD can be utilized to enhance diagnostic accuracy in the evaluation of lethal skeletal dysplasias. Although ultrasound evaluation of prenatal lethality of skeletal dysplasia is highly accurate, the accuracy of prenatal TD diagnosis ranges from 40% to 87.5%18,19 . Identification of TLD in fetuses with skeletal dysplasia can help guide specific molecular investigations (i.e. FGFR3 mutation analysis) for definitive diagnosis. The presence of TLD would help distinguish TD from other skeletal dysplasias such as short-rib polydactyly without polydactyly, Ellis–van Creveld syndrome and Jeune dysplasia28 – 30 . Although considered virtually pathognomonic for TD, features of TLD have been reported recently in hypochondroplasia as well as in a single case of achondrogenesis type II31 – 33 . However, hypochondroplasia is a clinically
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
milder variant of the FGFR3-related disorders in which skeletal features are often not evident until infancy6 . Achondrogenesis type II is a lethal skeletal dysplasia but can be distinguished clinically from TD owing to a lack of normal mineralization on prenatal ultrasound34 . Thus, the fact that TLD may be present in these conditions should not affect its utility as a TD-specific sign on prenatal ultrasound. Limitations of our study predominantly involve its retrospective design. Thus, we could not control for the changes in ultrasound technology or changes in knowledge of the diagnosis of TD during this time. Additionally, given the retrospective study design, we were unable to evaluate the sensitivity of TLD detection within this cohort. In conclusion, TLD is a defining pathological feature of TD that is currently under-recognized on prenatal
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Figure 5 Multiplanar three-dimensional reconstructed ultrasound images of the head at 16.1 weeks’ gestation in a fetus with thanatophoric dysplasia. Note that prominent abnormal temporal sulcation is already evident on coronal plane (b) (arrows).
Figure 6 (a) Low axial ultrasound image of head of a 12 + 5-week fetus affected with thanatophoric dysplasia with biparietal diameter of 22 mm appropriate for this gestational age. Note subtle increased number of echogenic sulci on medial surface of temporal lobe (arrows); there should be no sulcation visible at this gestational age. (b) Same fetus at 19 weeks showing abnormal sulcation of medial temporal lobe (arrows). (c,d) Abnormal sulci are shown diagrammatically in same images as (a) and (b), with white lines overlying sulci.
ultrasound. Visualization of TLD can be enhanced by increasing awareness of the feature and by modifications to current prenatal imaging protocols to focus on the inferior medial temporal lobes. The routine
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
search for TLD in suspected cases of lethal skeletal dysplasia would enhance the diagnostic accuracy of TD and help guide prenatal genetic testing and counseling.
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Wang et al. 18. Schramm T, Gloning K, Minderer S, Daumer-Haas C, ¨ Hortnagel K, Nerlich A, Tutschek B. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol 2009; 34: 160–170. 19. Krakow D, Alanay Y, Rimoin LP, Lin V, Wilcox WR, Lachman RS, Rimoin DL. Evaluation of prenatal-onset osteochondrodysplasias by ultrasonography: a retrospective and prospective analysis. Am J Med Genet A 2008; 146A: 1917–1924. 20. Fogliarini C, Chaumoitre K, Chapon F, Fernandez C, L´evrier O, Figarella-Branger D, Girard N. Assessment of cortical maturation with prenatal MRI: part II: abnormalities of cortical maturation. Eur Radiol 2005; 15: 1781–1789. 21. Malinger G, Kidron D, Schreiber L, Ben-Sira L, Hoffmann C, Lev D, Lerman-Sagie T. Prenatal diagnosis of malformations of cortical development by dedicated neurosonography. Ultrasound Obstet Gynecol 2007; 29: 178–191. 22. Fink AM, Hingston T, Sampson A, Ng J, Palma-Dias R. Malformation of the fetal brain in thanatophoric dysplasia: US and MRI findings. Pediatr Radiol 2010; 40 (Suppl 1): S134–S137. 23. Miller E, Blaser S, Shannon P, Widjaja E. Brain and bone abnormalities of thanatophoric dwarfism. AJR Am J Roentgenol 2009; 192: 48–51. 24. Widjaja E, Geibprasert S, Mahmoodabadi SZ, Brown N, Shannon P. Corroboration of normal and abnormal fetal cerebral lamination on postmortem MR imaging with postmortem examination. Am J Neuroradiol 2010; 31: 1987–1993. 25. Blaas HG, Vogt C, Eik-Nes SH. Abnormal gyration of the temporal lobe and megalencephaly are typical features of thanatophoric dysplasia and can be visualized prenatally by ultrasound. Ultrasound Obstet Gynecol 2012; 40: 230–234. 26. Knisely AS, Ambler MW. Temporal-lobe abnormalities in thanatophoric dysplasia. Pediatr Neurosci 1988; 14: 169–176. 27. Toi A, Lister W, Fong K. How early are fetal cerebral sulci visible at prenatal ultrasound and what is the normal pattern of early fetal sulcal development? Ultrasound Obstet Gynecol 2004; 24: 706–715. 28. Dugoff L, Thieme G, Hobbins JC. First trimester prenatal diagnosis of chondroectodermal dysplasia (Ellis–van Creveld syndrome) with ultrasound. Ultrasound Obstet Gynecol 2001; 17: 86–88. 29. Elc¸ioglu NH, Hall CM. Diagnostic dilemmas in the short rib–polydactyly syndrome group. Am J Med Genet 2002; 111: 392–400. 30. den Hollander NS, Robben SG, Hoogeboom AJ, Niermeijer MF, Wladimiroff JW. Early prenatal sonographic diagnosis and follow-up of Jeune syndrome. Ultrasound Obstet Gynecol 2001; 18: 378–383. ¨ 31. Linnankivi T, Makitie O, Valanne L, Toiviainen-Salo S. Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet A 2012; 158A: 3119–3125. 32. Philpott CM, Widjaja E, Raybaud C, Branson HM, Kannu P, Blaser S. Temporal and occipital lobe features in children with hypochondroplasia/FGFR3 gene mutation. Pediatr Radiol 2013; 43: 1190–1195. 33. Wainwright H, Beighton P. Achondrogenesis type II with cutaneous hamartomata. Clin Dysmorphol 2008; 17: 207–209. 34. Schild R, Hunt G, Moore J, Davies H, Horwell D. Antenatal sonographic diagnosis of thanatophoric dysplasia: a report of three cases and a review of the literature with special emphasis on the differential diagnosis. Ultrasound Obstet Gynecol 1996; 8: 62–67.
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Temporal lobe dysplasia: a characteristic sonographic finding in thanatophoric dysplasia D. C. WANG*, P. SHANNON†, A. TOI‡, D. CHITAYAT§¶, U. MOHAN**, E. BARKOVA††, S. KEATING†, G. TOMLINSON‡‡ and P. GLANC§§ *Faculty of Medicine, University of Toronto, Toronto, ON, Canada; †Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada; ‡Department of Medical Imaging, Mount Sinai Hospital, Toronto, ON, Canada; §Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada; ¶Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, ON, Canada; **Department of Obstetrics and Gynecology, University of Calgary, Calgary, AB, Canada; ††Department of Medical Imaging, South Shore Regional Hospital, Bridgewater, NS, Canada; ‡‡Institute of Health Policy, Management & Evaluation, University of Toronto, Toronto, ON, Canada; §§Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
K E Y W O R D S: abnormal gyration; prenatal ultrasound; skeletal dysplasia; temporal lobe dysplasia; thanatophoric dysplasia
ABSTRACT Objective To determine the incidence of temporal lobe dysplasia (TLD) detected on prenatal ultrasound in thanatophoric dysplasia (TD) over an 11-year period in a tertiary referral center. Methods An 11-year retrospective review of perinatal autopsies from 2002 to 2013 was performed to identify cases of TD. The ultrasound images and corresponding reports of all TD cases were examined for the presence of TLD. The same set of images subsequently underwent a retrospective review by a perinatal radiologist with knowledge of the features of TLD to determine whether they could be identified. Results Thirty-one cases of TD underwent perinatal autopsy, and prenatal ultrasound imaging was available for review in 24 (77%). Mean gestational age at diagnosis of TD was 21.3 (range, 18–36) weeks. TLD was identified and reported in 6/24 (25%) cases; all six cases occurred after 2007. Retrospective interpretation of the ultrasound images identified features of TLD in 10 additional cases. In total, 16/24 (67%) cases displayed sonographic evidence of TLD. Temporal trends showed that TLD features were present in 50% (5/10) of all TD cases between 2002 and 2006 and in 79% (11/14) of those detected between 2007 and 2013. Conclusions At present, the detection rate of TLD by ultrasound is low but may be increased by modified brain images that enhance visualization of the temporal lobes. Prenatal identification of TLD may help in the prenatal diagnosis of TD and thus provide more accurate prenatal
counseling and guide molecular investigations to confirm the specific diagnosis of TD. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION Thanatophoric dysplasia (TD) is a relatively common lethal skeletal dysplasia, with a prevalence of 0.21 to 0.80 per 10 000 births1 – 3 . It is an autosomal dominant condition and part of a group of skeletal disorders associated with mutations in the Fibroblast Growth Factor Receptor 3 gene (FGFR3)4,5 . TD is characterized by severe micromelia and lung hypoplasia and can be divided into two subtypes6,7 . TD type 1 (TD-1) features bowed/bent femurs associated with metaphyseal flaring, resulting in a characteristic ‘telephone receiver’ appearance8,9 . TD type 2 (TD-2) is characterized by straight femurs and a ‘cloverleaf’’ skull, although this feature may also appear in TD-18,10 . In addition to the skeletal findings, the temporal lobes in TD show characteristic findings of temporal lobe dysplasia (TLD) including prominent sulcations and radially directed gyrations11 – 13 . These findings in cases with lethal short-limb skeletal dysplasia are considered to be virtually pathognomonic and can be identified on gross pathology inspection as early as the first trimester14 . Although this specific feature is well known in the pathology literature, an awareness of the sonographic appearance of TLD on prenatal ultrasound is limited as compared with the better known musculoskeletal features. Recent publications and clinical practice guidelines have failed to discuss TLD as a potential diagnostic marker for TD15 – 17 . Given that
Correspondence to: Dr P. Glanc, Department of Medical Imaging, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, ON, Canada, M4N 3 M5 (e-mail: [email protected]) Accepted: 11 February 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Temporal lobe dysplasia in thanatophoric dysplasia the current prenatal diagnostic accuracy of TD ranges from 40% to 87.5%18,19 , detection of TLD on prenatal ultrasound could provide added specificity in patient counseling and guide molecular investigations. Recently, small case series have demonstrated that TLD can be directly visualized on prenatal ultrasound and magnetic resonance imaging20 – 24 . Blaas et al.25 were the first to demonstrate the feasibility of prospective sonographic identification of TLD, in six cases with TD. We report our experience in the prenatal detection of TLD over an 11-year period. We also analyze the trends in rates of detection over this time period and review techniques for achieving optimal visualization of the features of TLD.
METHODS To identify cases of TD, a retrospective review of perinatal autopsies from January 2002 to May 2013 was conducted at Mount Sinai Hospital in Toronto, Ontario, Canada, a tertiary referral center for high-risk obstetrics. The perinatal autopsy cohort included all neonatal deaths, stillbirths, and elective terminations of pregnancy. Inclusion criteria were all perinatal autopsies with a final diagnosis of TD based on a combination of clinical, radiological, pathological and molecular analysis. We excluded cases of TD seen at Mount Sinai Hospital only for pregnancy termination without correlative prenatal ultrasound imaging. Detailed autopsy, including histopathology, X-rays and molecular analysis, was performed in the majority of cases. All cases that underwent complete autopsy had fetal brain evaluation performed by a fetal neuropathologist. In a small number of cases the autopsy was limited to external evaluation, as per parental wishes. Anterior, posterior and lateral radiographs, using a Faxitron Cabinet X-ray system (Faxitron Bioptics, Tucson, AZ, USA), were obtained in all cases. The radiographs were interpreted by a single perinatal radiologist with more than 30 years’ experience in perinatal imaging. External consultation with experts (International Skeletal Dysplasia Registry) was obtained at the discretion of the radiologist. Prenatal ultrasound scans were performed at one of two obstetrical ultrasound clinics at Mount Sinai Hospital. Interpretation was performed by dedicated obstetrical imagers, maternal fetal medicine specialists or radiologists. Research ethics board approval was obtained. In our analysis, TLD is defined as the presence of abnormal prominent gyration and sulcation of the temporal lobes. Each set of prenatal ultrasound images and corresponding reports were reviewed to determine if TLD was noted at the time of the initial study. A second review (‘retrospective interpretation’) was then performed by an expert perinatal radiologist with knowledge of the diagnosis. The results were cross-referenced with the initial interpretation to determine if TLD could be detected in cases for which images specifically looking for this feature were not obtained. The diagnosis of TLD was stratified by year of diagnosis to determine trends in detection over time.
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Demographic, pathologic, radiologic and genetic data and results were entered into a standardized and anonymized web-based reporting system.
RESULTS TD was identified in 31 of 2501 (1%) perinatal autopsies. Neuropathological analysis was performed on 23 (74%) cases of TD, and TLD was observed in all 23 cases. No other cases with TLD were detected on pathology. Of the 31 TD cases, 24 (77%) had prenatal ultrasound imaging and initial interpretation available for review. The average gestational age at sonographic diagnosis of TD was 21.3 (range, 18–36) weeks. The average gestational age at autopsy was 24.7 (range, 20–40) weeks. Twenty cases were terminated electively, three cases were born at term and in one case the pregnancy outcome was not specified. The average maternal age was 31.9 (range, 21–42) years. There were no cases of recurrence. There were 15 males and nine females and all had normal karyotype. All 24 cases had either complete (n = 19) or limited (n = 5) external autopsy. In all 19 cases with complete autopsy, TD was confirmed on neuropathology. The remaining five cases were confirmed to have TD by molecular analysis of the FGFR3 gene. Based on a combination of clinical, radiological, pathological and molecular analysis the cases of TD were sub-classified as TD-1 (n = 20) and TD-2 (n = 4). The initial ultrasound exam found TLD in six (25%) cases, all of which were TD-1. Other central nervous system abnormalities identified in this cohort included mild ventriculomegaly (n = 3) and an individual case of agenesis of the corpus callosum. Cranial vault malformations, including frontal bossing, macrocranium and brachycephaly, were detected in 17 (71%) cases. The retrospective interpretation of the prenatal ultrasound images detected 10 additional cases with TLD. In total, 16/24 (67%) cases (14 TD-1, two TD-2) in our cohort displayed sonographic evidence of TLD. The temporal trend of TLD detection over the study period demonstrated that all six cases for which TLD was reported in the initial interpretation occurred after 2007 (Table 1). In the retrospective interpretation, features of TLD could be seen in five cases before 2007 and an additional five after 2007. Of the total of 24 cases of TLD, 10 were diagnosed between 2002 and 2006 and 14 were diagnosed between 2007 and 2013. In total, following the retrospective interpretation, TLD could be seen in 50% (5/10) of all TD cases from 2002–2006 and 79% (11/14) of TD cases from 2007–2013.
DISCUSSION Temporal lobe abnormalities have been well recognized as a defining pathological feature of TD, occurring in virtually 100% of cases by 18 weeks’ gestation, and earlier in some cases11 – 14,26 . This is a form of medial temporal lobe dysplasia resulting in a striking appearance of multiple deep transverse temporal sulci (Figure 1)14 , which is in contrast to the normal developing temporal
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590 Table 1 Sonographic detection of temporal lobe dysplasia before and after 2007 2002–2006 (n = 10) Time of interpretation Original Retrospective
2007–2013 (n = 14)
2002–2013 (n = 24)
Yes
No
Yes
No
Yes
No
0 5
10 5
6 11
8 3
6 16
18 8
Figure 1 (a) Low transaxial ultrasound image at the temporal lobe level in a 20-week fetus affected with thanatophoric dysplasia, showing abnormal temporal lobe sulcation. The imaging plane includes midbrain (MB) and orbits (O) and arrows point to multiple deep transverse sulci at the inferomedial aspect of the temporal lobes. (b) Autopsy neuropathology image at 23 weeks showing abnormal radially oriented sulci (arrows) on inferior surface of temporal lobe.
Figure 2 Coronal ultrasound image that includes the cerebellum (CB) in a 22-week fetus affected with thanatophoric dysplasia, showing abnormal deep sulcation typical of temporal lobe dysplasia (arrows).
lobe, which does not demonstrate sulcation before 20 weeks’ gestation27 . We report an 11-year retrospective review of 31 consecutive cases of TD, confirmed via perinatal autopsy. Corresponding prenatal ultrasound imaging was available in 24 cases. The primary aim was to determine the incidence of TLD detection on prenatal ultrasound during this study period. In our cohort, TLD was reported initially in only 6/24 (25%) prenatal ultrasound scans, despite being seen in all cases on gross pathological analysis. In comparison, cranial vault malformations, a typical and well recognized, but non-specific, feature of TD8,14 , were reported in 17/24 (71%) prenatal scans.
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We speculate that several factors contributed to the relatively low detection rate of TLD on prenatal ultrasound. The primary factor was a lack of awareness of the feature, which was not described in the ultrasound literature until 200721 . In corroboration with the literature, all six cases for which features of TLD were reported on the initial ultrasound scan occurred after 2007. However, this represents only 43% (6/14) of all TD cases from 2007 to 2013. An additional factor is that views that optimally display TLD are not included in the standard views taken during the prenatal scan17 . During the retrospective interpretation, features of TLD could be identified in 10 additional cases that inadvertently included views of the temporal lobes (Table 1). The remaining eight cases in which TLD was not seen did not include images of the temporal lobes for interpretation. Since TLD affects parts of the brain that are outside the standard views17 , it is not surprising that the feature would not have been recorded on standard ultrasonographic assessment. Additionally, we speculate that the low incidence of prospective identification in these cases may be due to overshadowing of TLD by the overwhelming additional abnormalities seen in the remaining fetal skeletal structures. In our experience, we have found that TLD can always be identified if specifically sought using non-standard views directed at the lower part of the temporal lobe. The routine axial transthalamic biparietal diameter (BPD) planes are taken cephalad to the inferior and medial surfaces of the temporal and occipital lobes, the region in which abnormal sulcation is most apparent25 . To image the medial surface of the temporal lobe, we find that two imaging planes are most useful. The first is a low axial
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Figure 3 (a,b,c) Multiplanar three-dimensional reconstructed ultrasound images of the head at 20 weeks’ gestation in a fetus with thanatophoric dysplasia, showing where abnormal temporal lobe sulcation is most conspicuous. White lines indicate planes of section on the other views. Abnormal sulcation is most conspicuous on coronal view (b, arrows); it is less obvious on axial view taken at approximately biparietal diameter level (a) and is not visible on mid-sagittal view that includes the falx but is too medial to include the hemispheres (c). (d) Lateral view of brain of same case at 23 weeks, showing enlargement of temporal lobe with deep abnormal sulcation (arrows) on inferior aspect of lobe. (e) Coronal mid-thalamic section of same case, showing deep folds in inferior temporal lobes with prominent expansion of inferior temporal cortex and expansion of temporal horns of lateral ventricles (arrows).
plane below the level of the BPD plane, which roughly includes the orbits and brainstem/midbrain (Figure 1). This plane requires only minimal adjustment downward from the routine transthalamic BPD plane. The second imaging plane is a coronal plane that also includes the cerebellum or midbrain (Figure 2). We have also found three-dimensional imaging with multiplanar reconstructions helpful in achieving the specific views (Figures 3–5). Visualization of TLD can also be achieved via a parasagittal view analyzing the medial periventricular cortex17,25 . Miller et al.23 have described sulcation in the posterior temporal lobe in TD detected via the transcerebellar coronal plane, which might provide an alternative approach to diagnosis. Interestingly, we found that using these modified imaging planes, the abnormal deep medial temporal
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sulcation can be identified as early as 16 weeks’ gestation (Figure 5). In another case on retrospective review, we felt that abnormal sulcation may have been present even at 12 weeks in a case that was later shown to have TD (Figure 6). The latter two proven cases were not included in our study population as their pathology was performed at an outside institution; however, they represent the earliest cases reported in the literature, and support the use of these additional imaging planes20 – 23,25 . The previous earliest gestational age at which TLD was detected was 19 weeks, reported by Blaas et al.25 . In contrast, the normally developing brain demonstrates virtually no sulcation in this region until the mid-second trimester (Figure 4). To our knowledge, this is the largest cohort of TD to be systematically analyzed for sonographic TLD detection.
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Figure 4 (a,b,c) Multiplanar three-dimensional reconstructed ultrasound images of the head of a normal fetus at 19 weeks’ gestation. (a) Low axial planar view showing absence of abnormal sulci at level that includes orbits (O) and midbrain (MB). (b) Coronal planar view, showing early shallow development of the calcarine sulcus (arrow) as a single shallow indentation in the medial hemisphere, which is quite different from the multiple deep sulci visible in affected brains. Lines on (a) and (c) indicate orthogonal section planes. Axial view (d) and coronal section (e) of normal 19-week brain on neuropathology: there is no sign of temporal lobe enlargement or presence of abnormal fissures on inferior temporal lobes.
We add to the growing evidence that TLD can be detected routinely on prenatal ultrasound20 – 23 . Sonographic detection of TLD can be utilized to enhance diagnostic accuracy in the evaluation of lethal skeletal dysplasias. Although ultrasound evaluation of prenatal lethality of skeletal dysplasia is highly accurate, the accuracy of prenatal TD diagnosis ranges from 40% to 87.5%18,19 . Identification of TLD in fetuses with skeletal dysplasia can help guide specific molecular investigations (i.e. FGFR3 mutation analysis) for definitive diagnosis. The presence of TLD would help distinguish TD from other skeletal dysplasias such as short-rib polydactyly without polydactyly, Ellis–van Creveld syndrome and Jeune dysplasia28 – 30 . Although considered virtually pathognomonic for TD, features of TLD have been reported recently in hypochondroplasia as well as in a single case of achondrogenesis type II31 – 33 . However, hypochondroplasia is a clinically
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milder variant of the FGFR3-related disorders in which skeletal features are often not evident until infancy6 . Achondrogenesis type II is a lethal skeletal dysplasia but can be distinguished clinically from TD owing to a lack of normal mineralization on prenatal ultrasound34 . Thus, the fact that TLD may be present in these conditions should not affect its utility as a TD-specific sign on prenatal ultrasound. Limitations of our study predominantly involve its retrospective design. Thus, we could not control for the changes in ultrasound technology or changes in knowledge of the diagnosis of TD during this time. Additionally, given the retrospective study design, we were unable to evaluate the sensitivity of TLD detection within this cohort. In conclusion, TLD is a defining pathological feature of TD that is currently under-recognized on prenatal
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Figure 5 Multiplanar three-dimensional reconstructed ultrasound images of the head at 16.1 weeks’ gestation in a fetus with thanatophoric dysplasia. Note that prominent abnormal temporal sulcation is already evident on coronal plane (b) (arrows).
Figure 6 (a) Low axial ultrasound image of head of a 12 + 5-week fetus affected with thanatophoric dysplasia with biparietal diameter of 22 mm appropriate for this gestational age. Note subtle increased number of echogenic sulci on medial surface of temporal lobe (arrows); there should be no sulcation visible at this gestational age. (b) Same fetus at 19 weeks showing abnormal sulcation of medial temporal lobe (arrows). (c,d) Abnormal sulci are shown diagrammatically in same images as (a) and (b), with white lines overlying sulci.
ultrasound. Visualization of TLD can be enhanced by increasing awareness of the feature and by modifications to current prenatal imaging protocols to focus on the inferior medial temporal lobes. The routine
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search for TLD in suspected cases of lethal skeletal dysplasia would enhance the diagnostic accuracy of TD and help guide prenatal genetic testing and counseling.
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