Novel Insights from Clinical Practice Fetal Diagn Ther 2014;36:259–262 DOI: 10.1159/000358594
Received: November 5, 2013 Accepted after revision: December 28, 2013 Published online: May 28, 2014
Early Second-Trimester Molar Tooth Sign Ori Shen d Liat Ben-Sira a Daniel Rosenak b Rachel Michaelson-Cohen c a
Department of Radiology, Tel Aviv Medical Center, Tel Aviv, b Department of Obstetrics and Gynaecology, Hadassah Mt Scopus Medical Center, and Departments of c Genetics and d Obstetrics and Gynaecology, Shaare Zedek Medical Center, Jerusalem, Israel
Established Facts • Molar tooth sign (MTS) is pathognomonic for Joubert syndrome (JS) and related disorders. • MTS is diagnosed on pediatric MRI and has been reported on fetal MRI. • A single report exists on MTS on fetal ultrasound (as early as 20+6 weeks’ gestation).
Novel Insights • MTS can be suspected on fetal ultrasound at as early as 16 weeks’ gestation in patients at risk for JS.
Abstract Molar tooth sign (MTS) is pathognomonic for Joubert syndrome (JS) and related disorders. We report a case in which MTS was suspected in an ‘at risk’ patient at 16 weeks’ gestation by sonography and at 18 weeks by additional ultrasound. It was then confirmed at 20 weeks by MRI. A molecular diagnosis of JS was established after termination of the pregnancy. As genetic testing may not be feasible in JS, the ability to identify MTS sonographically as early as possible is important for affected families. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1015–3837/14/0363–0259$39.50/0 E-Mail [email protected] www.karger.com/fdt
Clinical Case A 22-year-old G2P1 patient, in a consanguineous marriage, presented at 16 weeks’ gestation for an anomaly scan and genetic consultation. Her first child, 3 years of age, had been clinically diagnosed with Joubert syndrome (JS), but molecular testing had not been initiated due to cost considerations. During that pregnancy, a normal 20-week anomaly scan had been reported. The patient had been referred at 39 weeks’ gestation due to the suspicion of a posterior fossa anomaly. A dysplastic and rotated vermis had been revealed, but a more specific diagnosis could not be made due to acoustic shadowing. Fetal MRI had been offered, but it was declined because termination of the pregnancy was not considered by the parents. In the pregnancy that forms the subject of this study, there was the suspicion of molar tooth sign (MTS) on a combined transabdominal scan at 16+3 (fig. 1) weeks’ gestation. The scan revealed a broad connection between the fourth ventricle and the cisterna
Ori Shen Department of Obstetrics and Gynaecology Shaare Zedek Medical Center Jerusalem 91031 (Israel) E-Mail orishen @ netvision.net.il
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.216.78.40 - 4/24/2015 2:13:21 PM
Key Words Fetal ultrasound · Molar tooth sign · Joubert syndrome
1
2 Fig. 1. Axial ultrasound at 16 weeks. Fig. 2. Axial ultrasound at 18 weeks: suspected MTS.
Fig. 3. Multiplanar image of posterior fossa
at 18 weeks.
260
Fetal Diagn Ther 2014;36:259–262 DOI: 10.1159/000358594
al reconstruction on multiplanar imaging (fig. 3). There were no further abnormalities. In particular, both the kidneys and eyes (fig. 4) had a normal appearance. The transcerebellar diameter was 18 mm. As sonographic diagnosis of MTS at this gestational age has not been previously described, our multidisciplinary team advised further testing. The patient was willing to consider pregnancy termination until no later than 20 weeks’ gestation due to religious con-
Shen /Ben-Sira /Rosenak / Michaelson-Cohen
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.216.78.40 - 4/24/2015 2:13:21 PM
magna, and a cleft extending towards the midbrain. The medial aspect of both cerebellar hemispheres was hyperechoic. Amniocentesis was performed at 17 weeks. On a repeat scan at 18+3 weeks, although a definite diagnosis could not be made, there was strong suspicion of a midbrain anomaly with a midbrain cleft separating the cerebellar peduncles, suggestive of MTS (fig. 2). The vermis was of normal length, but had an abnormal appearance with no visible fissures or fastigium on mid-sagittal 3-dimension-
Fig. 4. Coronal image of the eyes at 16
weeks.
a
siderations. Fetal MRI at 20+1 weeks (fig. 5) showed a typical MTS with an interpeduncular cleft and elongated superior cerebellar peduncles visible in the axial plane. In addition, an enlarged fourth ventricle with an abnormal fastigium, elevation of the roof of the fourth ventricle and a thin midbrain were depicted. The vermis appeared dysmorphic. Based on the combined imaging findings, the pregnancy was terminated at 20+5 weeks’ gestational age. Autopsy was declined. One day after the termination, the patient’s first child was found to have a homozygous nonsense mutation c.5788A>T [K1930X] in the CEP290 gene. Subsequently, it was found that the aborted fetus was homozygous for the mutation and that both parents were carriers. The patient has enrolled in a preimplantation genetic diagnosis program, to prevent JS in future offspring.
Discussion
JS, an autosomal recessive disease, initially described in 1969 [1], has a broad spectrum of clinical and imaging manifestations. It typically presents in early infancy with hypotonia, developmental delay, jerky irregular rapid eye movements and an abnormal pattern of breathing, notably episodic hyperpnea alternating with apnea. AnomaEarly Second-Trimester MTS
b
c
lies associated with JS which are potentially detectable by prenatal ultrasound [2–5] include cerebellar vermian and midbrain defects, enlarged cisterna magna, agenesis of the corpus callosum, occipital encephalocele, ventriculomegaly, flat sulcation, increased nuchal translucency, retinal colobomata, polydactyly and renal cysts. The prognosis is generally poor, with many of those affected dying in the first year of life and the remainder being neurologically impaired, usually severely so. The pathognomonic finding in cases with JS was described on pediatric axial-plane MRI and was coined ‘molar tooth sign’ by Maria et al. [6] due to the specific shape, reminiscent of the shape of a molar tooth. This anomaly represents hypoplasia of the vermis, elongated and thickened superior cerebellar peduncles, a deep interpeduncular fossa and a split midbrain tectum. The only case of JS based on sonographic MTS was reported by Pugash et al. [2]. They reported on 2 cases, the earliest at 20+6 weeks’ gestation. The earliest report of MTS on fetal MRI was at 17–18 weeks [3]. Other studies have reported on nonspecific posterior fossa abnormalities detected on prenatal sonography. These included a Fetal Diagn Ther 2014;36:259–262 DOI: 10.1159/000358594
261
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.216.78.40 - 4/24/2015 2:13:21 PM
Fig. 5. MRI at 20 weeks. a Axial view. b Coronal view. c Mid-sagittal view.
‘keyhole’ communication between the fourth ventricle and the cisterna magna at 20 weeks [4], the absence of the cerebellar vermis at 22 weeks [5] associated with a smooth cortex and ventriculomegaly. Due to the family history, we suspected JS based on MTS. This is the second case reported and it provides the earliest depiction of the MTS on sonography.
References
When a mutation is found by molecular diagnosis, preimplantation genetic diagnosis or prenatal invasive testing are offered to the family. However, in many cases, a specific mutation is not identified, and prenatal diagnosis of this severe disease may rely exclusively on imaging. Adding early prenatal sonography to the diagnostic tool kit for JS enhances management and counseling with regard to decisions for cases at risk.
1 Joubert M, Eisenring J, Robb JP, Andermann F: Familial agenesis of the cerebellar vermis. Neurology 1969;19:813–825. 2 Pugash D, Oh T, Godwin K, Robinson AJ, Byrne A, Van Allen MI, Osiovich H: Sonographic ‘molar tooth’ sign in the diagnosis of Joubert syndrome. Ultrasound Obstet Gynecol 2011;38:598–602. 3 Saleem SN, Zaki MS, Soliman NA, Momtaz M: Prenatal magnetic resonance imaging diagnosis of molar tooth sign at 17 to 18 weeks of gestation in two fetuses at risk for Joubert syndrome and related cerebellar disorders. Neuropediatrics 2011;42:35–38. 4 Doherty D, Glass IA, Siebert JR, Strouse PJ, Parisi MA, Shaw DW, Chance PF, Barr M Jr,
Nyberg D: Prenatal diagnosis in pregnancies at risk for Joubert syndrome by ultrasound and MRI. Prenat Diagn 2005;25:442–447. 5 Fluss J, Blaser S, Chitayat D, Akoury H, Glanc P, Skidmore M, Raybaud C: Molar tooth sign in fetal brain magnetic resonance imaging leading to the prenatal diagnosis of Joubert syndrome and related disorders. J Child Neurol 2006;21:320–324. 6 Maria BL, Hoang KB, Tusa RJ, Mancuso AA, Hamed LM, Quisling RG, Hove MT, Fennell EB, Booth-Jones M, Ringdahl DM, Yachnis AT, Creel G, Frerking B: Joubert syndrome revisited: key ocular motor signs with magnetic resonance imaging correlation. J Child Neurol 1997;12:423–430.
Erratum
262
Fetal Diagn Ther 2014;36:259–262 DOI: 10.1159/000358594
Shen /Ben-Sira /Rosenak / Michaelson-Cohen
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.216.78.40 - 4/24/2015 2:13:21 PM
In the article by Gratacós E and Nicolaides K, entitled ‘Clinical perspective of cell-free DNA testing for fetal aneuploidies’ [Fetal Diagn Ther 2014;35:151–155, DOI: 10.1159/ 000362940], in the section Implications of a Low-Risk Result, the 1,000 in the first sentence should be replaced with 100 (‘The negative likelihood when cfDNA testing gives a low-risk result is about 100, 31 and 13 for trisomies 21, 18 and 13, respectively [5].’) and the 500,000 in the last sentence should be replaced with 50,000 (‘For example, if prior screening by the combined test had shown that the risk for trisomy 21 was 1 in 500 and cfDNA testing gives a low-risk result, the chance that the fetus is affected is 1 in 50,000; ...’) and not as erroneously stated in a previous Erratum with 5,000 [Fetal Diagn Ther 2014;36:68].
Received: November 5, 2013 Accepted after revision: December 28, 2013 Published online: May 28, 2014
Early Second-Trimester Molar Tooth Sign Ori Shen d Liat Ben-Sira a Daniel Rosenak b Rachel Michaelson-Cohen c a
Department of Radiology, Tel Aviv Medical Center, Tel Aviv, b Department of Obstetrics and Gynaecology, Hadassah Mt Scopus Medical Center, and Departments of c Genetics and d Obstetrics and Gynaecology, Shaare Zedek Medical Center, Jerusalem, Israel
Established Facts • Molar tooth sign (MTS) is pathognomonic for Joubert syndrome (JS) and related disorders. • MTS is diagnosed on pediatric MRI and has been reported on fetal MRI. • A single report exists on MTS on fetal ultrasound (as early as 20+6 weeks’ gestation).
Novel Insights • MTS can be suspected on fetal ultrasound at as early as 16 weeks’ gestation in patients at risk for JS.
Abstract Molar tooth sign (MTS) is pathognomonic for Joubert syndrome (JS) and related disorders. We report a case in which MTS was suspected in an ‘at risk’ patient at 16 weeks’ gestation by sonography and at 18 weeks by additional ultrasound. It was then confirmed at 20 weeks by MRI. A molecular diagnosis of JS was established after termination of the pregnancy. As genetic testing may not be feasible in JS, the ability to identify MTS sonographically as early as possible is important for affected families. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1015–3837/14/0363–0259$39.50/0 E-Mail [email protected] www.karger.com/fdt
Clinical Case A 22-year-old G2P1 patient, in a consanguineous marriage, presented at 16 weeks’ gestation for an anomaly scan and genetic consultation. Her first child, 3 years of age, had been clinically diagnosed with Joubert syndrome (JS), but molecular testing had not been initiated due to cost considerations. During that pregnancy, a normal 20-week anomaly scan had been reported. The patient had been referred at 39 weeks’ gestation due to the suspicion of a posterior fossa anomaly. A dysplastic and rotated vermis had been revealed, but a more specific diagnosis could not be made due to acoustic shadowing. Fetal MRI had been offered, but it was declined because termination of the pregnancy was not considered by the parents. In the pregnancy that forms the subject of this study, there was the suspicion of molar tooth sign (MTS) on a combined transabdominal scan at 16+3 (fig. 1) weeks’ gestation. The scan revealed a broad connection between the fourth ventricle and the cisterna
Ori Shen Department of Obstetrics and Gynaecology Shaare Zedek Medical Center Jerusalem 91031 (Israel) E-Mail orishen @ netvision.net.il
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.216.78.40 - 4/24/2015 2:13:21 PM
Key Words Fetal ultrasound · Molar tooth sign · Joubert syndrome
1
2 Fig. 1. Axial ultrasound at 16 weeks. Fig. 2. Axial ultrasound at 18 weeks: suspected MTS.
Fig. 3. Multiplanar image of posterior fossa
at 18 weeks.
260
Fetal Diagn Ther 2014;36:259–262 DOI: 10.1159/000358594
al reconstruction on multiplanar imaging (fig. 3). There were no further abnormalities. In particular, both the kidneys and eyes (fig. 4) had a normal appearance. The transcerebellar diameter was 18 mm. As sonographic diagnosis of MTS at this gestational age has not been previously described, our multidisciplinary team advised further testing. The patient was willing to consider pregnancy termination until no later than 20 weeks’ gestation due to religious con-
Shen /Ben-Sira /Rosenak / Michaelson-Cohen
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.216.78.40 - 4/24/2015 2:13:21 PM
magna, and a cleft extending towards the midbrain. The medial aspect of both cerebellar hemispheres was hyperechoic. Amniocentesis was performed at 17 weeks. On a repeat scan at 18+3 weeks, although a definite diagnosis could not be made, there was strong suspicion of a midbrain anomaly with a midbrain cleft separating the cerebellar peduncles, suggestive of MTS (fig. 2). The vermis was of normal length, but had an abnormal appearance with no visible fissures or fastigium on mid-sagittal 3-dimension-
Fig. 4. Coronal image of the eyes at 16
weeks.
a
siderations. Fetal MRI at 20+1 weeks (fig. 5) showed a typical MTS with an interpeduncular cleft and elongated superior cerebellar peduncles visible in the axial plane. In addition, an enlarged fourth ventricle with an abnormal fastigium, elevation of the roof of the fourth ventricle and a thin midbrain were depicted. The vermis appeared dysmorphic. Based on the combined imaging findings, the pregnancy was terminated at 20+5 weeks’ gestational age. Autopsy was declined. One day after the termination, the patient’s first child was found to have a homozygous nonsense mutation c.5788A>T [K1930X] in the CEP290 gene. Subsequently, it was found that the aborted fetus was homozygous for the mutation and that both parents were carriers. The patient has enrolled in a preimplantation genetic diagnosis program, to prevent JS in future offspring.
Discussion
JS, an autosomal recessive disease, initially described in 1969 [1], has a broad spectrum of clinical and imaging manifestations. It typically presents in early infancy with hypotonia, developmental delay, jerky irregular rapid eye movements and an abnormal pattern of breathing, notably episodic hyperpnea alternating with apnea. AnomaEarly Second-Trimester MTS
b
c
lies associated with JS which are potentially detectable by prenatal ultrasound [2–5] include cerebellar vermian and midbrain defects, enlarged cisterna magna, agenesis of the corpus callosum, occipital encephalocele, ventriculomegaly, flat sulcation, increased nuchal translucency, retinal colobomata, polydactyly and renal cysts. The prognosis is generally poor, with many of those affected dying in the first year of life and the remainder being neurologically impaired, usually severely so. The pathognomonic finding in cases with JS was described on pediatric axial-plane MRI and was coined ‘molar tooth sign’ by Maria et al. [6] due to the specific shape, reminiscent of the shape of a molar tooth. This anomaly represents hypoplasia of the vermis, elongated and thickened superior cerebellar peduncles, a deep interpeduncular fossa and a split midbrain tectum. The only case of JS based on sonographic MTS was reported by Pugash et al. [2]. They reported on 2 cases, the earliest at 20+6 weeks’ gestation. The earliest report of MTS on fetal MRI was at 17–18 weeks [3]. Other studies have reported on nonspecific posterior fossa abnormalities detected on prenatal sonography. These included a Fetal Diagn Ther 2014;36:259–262 DOI: 10.1159/000358594
261
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.216.78.40 - 4/24/2015 2:13:21 PM
Fig. 5. MRI at 20 weeks. a Axial view. b Coronal view. c Mid-sagittal view.
‘keyhole’ communication between the fourth ventricle and the cisterna magna at 20 weeks [4], the absence of the cerebellar vermis at 22 weeks [5] associated with a smooth cortex and ventriculomegaly. Due to the family history, we suspected JS based on MTS. This is the second case reported and it provides the earliest depiction of the MTS on sonography.
References
When a mutation is found by molecular diagnosis, preimplantation genetic diagnosis or prenatal invasive testing are offered to the family. However, in many cases, a specific mutation is not identified, and prenatal diagnosis of this severe disease may rely exclusively on imaging. Adding early prenatal sonography to the diagnostic tool kit for JS enhances management and counseling with regard to decisions for cases at risk.
1 Joubert M, Eisenring J, Robb JP, Andermann F: Familial agenesis of the cerebellar vermis. Neurology 1969;19:813–825. 2 Pugash D, Oh T, Godwin K, Robinson AJ, Byrne A, Van Allen MI, Osiovich H: Sonographic ‘molar tooth’ sign in the diagnosis of Joubert syndrome. Ultrasound Obstet Gynecol 2011;38:598–602. 3 Saleem SN, Zaki MS, Soliman NA, Momtaz M: Prenatal magnetic resonance imaging diagnosis of molar tooth sign at 17 to 18 weeks of gestation in two fetuses at risk for Joubert syndrome and related cerebellar disorders. Neuropediatrics 2011;42:35–38. 4 Doherty D, Glass IA, Siebert JR, Strouse PJ, Parisi MA, Shaw DW, Chance PF, Barr M Jr,
Nyberg D: Prenatal diagnosis in pregnancies at risk for Joubert syndrome by ultrasound and MRI. Prenat Diagn 2005;25:442–447. 5 Fluss J, Blaser S, Chitayat D, Akoury H, Glanc P, Skidmore M, Raybaud C: Molar tooth sign in fetal brain magnetic resonance imaging leading to the prenatal diagnosis of Joubert syndrome and related disorders. J Child Neurol 2006;21:320–324. 6 Maria BL, Hoang KB, Tusa RJ, Mancuso AA, Hamed LM, Quisling RG, Hove MT, Fennell EB, Booth-Jones M, Ringdahl DM, Yachnis AT, Creel G, Frerking B: Joubert syndrome revisited: key ocular motor signs with magnetic resonance imaging correlation. J Child Neurol 1997;12:423–430.
Erratum
262
Fetal Diagn Ther 2014;36:259–262 DOI: 10.1159/000358594
Shen /Ben-Sira /Rosenak / Michaelson-Cohen
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.216.78.40 - 4/24/2015 2:13:21 PM
In the article by Gratacós E and Nicolaides K, entitled ‘Clinical perspective of cell-free DNA testing for fetal aneuploidies’ [Fetal Diagn Ther 2014;35:151–155, DOI: 10.1159/ 000362940], in the section Implications of a Low-Risk Result, the 1,000 in the first sentence should be replaced with 100 (‘The negative likelihood when cfDNA testing gives a low-risk result is about 100, 31 and 13 for trisomies 21, 18 and 13, respectively [5].’) and the 500,000 in the last sentence should be replaced with 50,000 (‘For example, if prior screening by the combined test had shown that the risk for trisomy 21 was 1 in 500 and cfDNA testing gives a low-risk result, the chance that the fetus is affected is 1 in 50,000; ...’) and not as erroneously stated in a previous Erratum with 5,000 [Fetal Diagn Ther 2014;36:68].
