Childs Nerv Syst DOI 10.1007/s00381-014-2377-8
CASE REPORT
Comparison of ultrasound and magnetic resonance imaging in the prenatal diagnosis of Apert syndrome: report of a case A. Giancotti & V. D’Ambrosio & A. De Filippis & C. Aliberti & G. Pasquali & S. Bernardo & L. Manganaro & PECRAM Study Group
Received: 27 January 2014 / Accepted: 28 January 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background The birth prevalence of Apert syndrome is estimated at 1:64,500 and accounts for about 4.5 % of all craniosynostosis with a male/female ratio equal to 1:1. It is associated to allelic mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Majority cases are sporadic. Prenatal ultrasound diagnosis is based on the detection of abnormal cranial shape, midfacial hypoplasia and bilateral syndactyly of hands and feet, hypertelorism, and exorbitism. Other abnormalities includes central nervous system anomalies, congenital heart diseases, cleft palate, and urogenital diseases. Case report A 37-year-old Caucasian woman, gravida 2, para 1, was referred to our center of Prenatal Diagnosis for routine ultrasound at 21 weeks of gestation. We detected irregular head shape, dolicocephaly, prominent forehead, bilateral mild ventriculomegaly, suspicion of partial agenesis of the corpus callosum, hypertelorism, and midfacial hypoplasia, with a depressed nasal bridge and syndactyly, prompting a suspicion for Apert syndrome. Magnetic resonance excluded agenesis of corpus callosum and confirmed bilateral mild ventriculomegaly. A follow-up ultrasound, performed at 23 weeks, confirmed the anomalies showed in the previous scan. An amniocentesis was performed. The results showed a normal male karyotype, while PECRAM Study Group members: Polimeni A., Pizzuti A., Cascone P., Silvestri A., Roggini M., Tarani L., Papoff P., Castori M., and Lenzi J. from “Sapienza” University. A. Giancotti (*) : V. D’Ambrosio : A. De Filippis : C. Aliberti : G. Pasquali Department of Obstetrics, Gynecology and Urologic Sciences, Umberto I Hospital, “Sapienza” University, Viale del Policlinico 155, 00161 Rome, Italy e-mail: [email protected] S. Bernardo : L. Manganaro Department of Radiological Oncological and Anatomopathological Sciences, Umberto I Hospital, “Sapienza” University, Viale Regina Elena 324, 00161 Rome, Italy
the molecular genetic test confirmed a mutation in FGFR2 gene. Fetus macroscopic analysis showed compatible features. Conclusions Our case underlines the complementary role of ultrasound and magnetic resonance imaging in the early prenatal diagnosis of Apert syndrome. Keywords Apert syndrome . Prenatal diagnosis . Fetal ultrasound . Magnetic resonance
Introduction Apert syndrome (AS) or acrocephalosyndactyly type I is a rare congenital disorder characterized by the triad of coronal craniosynostosis, midfacial hypoplasia, and symmetric syndactyly of the hands and feet [1]. Ventriculomegaly (VM), alteration in corpus callosum, and other central nervous system (CNS) abnormalities are usually present in this condition and may be responsible for mental retardation present in half of affected individuals [2]. Other signs include cleft palate, congenital heart diseases, and urogenital abnormalities [3]. The birth prevalence is estimated at 1/64,500 and accounts for about 4.5 % of all cases of craniosynostosis [2, 4] with a male/female ratio equal to 1:1 [5]. The majority of AS cases are sporadic as the result of de novo mutations [6]. Rarely, the syndrome is transmitted in autosomal dominant manner [5]. Some rare cases of recurrence in the offspring of healthy couples can be explained by germinal mosaicism [7]. A small number of chromosomal abnormalities have been reported in AS; however, the majority of the patients has a normal karyotype [6]. Advanced paternal age seems to be a risk factor for the occurrence of this syndrome [5]. We report a case of prenatal diagnosis of AS in the second trimester of pregnancy confirmed by molecular genetic test, comparing the results of ultrasound (US) and magnetic resonance imaging (MRI).
Childs Nerv Syst
Case report A 37-year-old Caucasian woman, gravida 2, para 1, was referred to our center of Prenatal Diagnosis for routine second trimester ultrasound at 21 weeks of gestation (WG). The partner was 40 years old and there was no consanguinity. The woman’s past obstetrical, medical, and family history was unremarkable. The anomaly scan showed irregular head shape, dolicocephaly (occipital frontal diameter, 74 mm; >95° centile), prominent forehead, flat occiput, bilateral mild VM (right ventricle 10 mm, left ventricle 11 mm), visualization of the anterior part of the corpus callosum with a suspicion of partial agenesis of corpus callosum (p-ACC), hypertelorism, and midfacial hypoplasia, with a depressed nasal bridge (Fig. 1). Furthermore, malformations of the upper and lower extremities were detected consistent with syndactyly (Fig. 2). Those sonographic findings gave the suspect for AS. A fetal MRI was suggested and performed after 2 days. It excluded agenesis of corpus callosum (ACC) (Fig. 3), confirmed bilateral mild VM, but no other anomalies were highlighted (Fig. 4). A follow-up US examination was performed at 23 WG and confirmed the abnormalities of the fetal cranium visualized in the precedent scan. Bilateral mild VM was visualized (right ventricle 9 mm, left ventricle 11 mm) and both hands appeared in adduction position; malformations of the upper and lower extremities were still detected by twodimensional/three-dimensional (2D/3D) scan (Fig. 5). Feet US images showed a bilateral abnormal position associated to atypical organization of the phalanges with syndactyly. Furthermore, a polyhydramnios was found (Amniotic Fluid Index 24.5 cm). A genetic counseling was carried out and prenatal diagnosis test was offered to the couple. An amniocentesis was performed. Conventional chromosomal analysis revealed a normal male karyotype (46, XY), but the molecular genetic test confirmed a mutation in fibroblast growth factor receptor 2 (FGFR2) gene. In testing for different craniofacial
Fig. 1 Sonogram showing a fetal profile with prominent forehead, mifdacial hypoplasia, and depressed nasal bridge at 21 weeks of gestation
Fig. 2 Sonogram showing anomaly of the hand with syndactily
syndromes, the patient DNA was further evaluated for FGFR type 1 (exon V), 2 (exon III A/C), and 3 (exon VII) mutations. A heterozygous for the FGFR2 mutation c.758C> G (p.Pro253Arg) was found in the fetus. The parents decided to terminate their pregnancy. Fetus macroscopic analysis showed features compatible with the syndrome: bilateral syndactyly of the hands (“spoon hands”) and feet, midface hypoplasia, and prominent forehead. The couple declined a postmortem autopsy.
Discussion AS is one of the four craniosynostosis syndromes associated with allelic mutations in the FGFR2 gene [8]; the defect was localized in chromosome 10 (10q25–10q26). Two MISSENSE mutations of the FGFR2 gene, Ser252Trp (S252W) and Pro253Arg (P253R), in the linker region between the second and third extracellular immunoglobulin-like domains of the receptor, account for over 98 % of cases [9]. Park et al. [10] identified the frequency to be 71 and 26 % for p.S252W and p.P253R mutations, respectively. The p.P253R mutation has been proposed to be associated with severe syndactyly, whereas the p.S252W may be related to more severe craniofacial malformations [11]. Prenatal sonographic diagnosis of AS is based on detection of the triad of abnormal cranial shape, midfacial hypoplasia, and bilateral syndactyly of hands and feet. Ocular hypertelorism and exorbitism are also important associated features that could alert the sonologists in the suspicion of craniosynostosis syndromes. Other encountered visceral abnormalities include CNS anomalies, congenital heart disease, cleft palate, and urogenital disease. CNS anomalies include VM (48.5 %), hydrocephalus (9 %), gyral abnormalities, and others (21 %; agenesis or hypogenesis of the corpus callosum or posterior fossa anomalies) [12]. ACC and VM were first described in AS by de Leon et al. [13] and have been frequently founded in Apert patients since documented [14–17]. For this reason it has been proposed that prenatal identification of ACC or borderline VM should also lead to
Childs Nerv Syst
Fig. 3 MRI visualization of corpus callosum 21 weeks of gestation Fig. 5 3D sonogram showing abnormality of the hand
consideration of AS [18]. The abnormal cranial shape and orbital hypertelorism so typical of AS may be absent or very subtle in the second trimester of pregnancy, becoming obvious only in the third trimester [17, 19, 20]. MRI may play an important role in the prenatal diagnosis of AS; in fact, it is considered the gold standard to assess CNS anomalies after 19 WG. In our case MRI, performed at 21 weeks + 3 days, excluded the p-ACC and confirmed the mild VM. It is the first case of prenatal diagnosis of AS where the MRI was practiced so early in gestation. Bregeum et al. [21] described an AS case where a severe dysgenesis of the corpus callosum was discovered by a MRI performed after 28 WG. Weber et al. [22] reported an AS case in which a MRI performed at 32 WG diagnosed borderline VM. In another case, an ACC was excluded by a MRI done at 26 WG [23]. Our case confirms the main role of MRI as diagnostic imaging techniques for
Fig. 4 MRI Ventriculomegaly 21 weeks of gestation
intracranial structure study, as it can confirm or exclude the presence of CNS anomalies with a greater accuracy than US and in an early gestational period [24]. Nevertheless, the early gestational period, in which the MRI was performed, was a limitation for this diagnostic technique. Indeed, cranial anomalies, such as hyperthelorism, prominent forehead, turricephaly, and depressed nasal bridge founded by the US at 21 weeks, could not be revealed. In a case [23], a MRI confirmed the presence of cranial anomalies (hypertelorism, brachicephaly, verticalization of the clivus, flattened angle of the cranial base) but was performed at 26 WG. Consequently, it emerges the US superiority concerning the study of cranial anomalies in early gestational period. In fact, thanks to the improved resolution of sonographic scan, several cases of AS, including our case, have been detected in early second trimester [12, 25–29]. Furthermore, it deserves to be noticed that in our case, slight anomalies of fetal profile, such as a mild midfacial hypoplasia and a slight prominent forehead were visualized at MRI retrospectively but were not detected at the time of the examination. These findings underline that fetal maxillofacial and profile anomalies are still based on subjective impressions and that there is a lack in literature of a real standardization to check these defects. This case emphasizes the need for a methodical analysis of the fetal profile and maxillofacial anomalies in order to get standard parameters for earlier and easier feasible diagnosis. The two techniques are substantially in agreement in defining the degree of VM [30]. For what concerns hand anomalies, in literature, there is a case of abnormal hands revealed, retrospectively, at a MRI performed at 32 WG but not detected at the time of the examination. This can be considered an occasional survey, as MRI is not indicated for the study of fetal muscle-skeletal structures. Given the limited evidence in the literature and the
Childs Nerv Syst
difficulty in performing the examination, it is currently not possible to include musculoskeletal structures and in particular, the developing limbs and osteo-cartilaginous components of the vertebral column among the anatomical areas studied with fetal MRI [31]. On the other side, 2D and 3D US has showed an important role in the diagnosis of hands anomalies. Some authors suggested that in suspected cases of craniosynostosis, complementary use of 3D scans could be essential for prenatal diagnosis and may be useful to demonstrate abnormalities of the hands, feet, and face [26, 32, 33]. In the light of above, we can assess that in our case the suspicion of the AS was carried out early in pregnancy thanks to US and MRI findings. We suggest the complementary role of these two diagnostic techniques for the diagnosis of this genetic syndrome in early pregnancy (since 19–20 WG).
References 1. Apert M (1906) De l’acrocéphalosyndactylie. Bull Mém Soc Med Hop Paris 23:1310–1313 2. Cohen MM Jr, Kreiborg S (1992) New indirect method for estimating the birth prevalence of the Apert syndrome. Int J Oral Maxillofac Surg 21:107–109 3. Cohen MM Jr, Kreiborg S (1993) Visceral anomalies in the Apert syndrome. Am J Med Genet 45:758–760 4. Cohen MM Jr, Kreiborg S, Lammer EJ, Cordero JF, Mastroiacovo P, Erickson JD, Roeper P, Martínez-Frías ML (1992) Birth prevalence study of the Apert syndrome. Am J Med Genet 42:655–659 5. Tolarova MM, Harris JA, Ordway DE, Vargervik K (1997) Birth prevalence, mutation rate, sex ratio, parents’ age, and ethnicity in Apert syndrome. Am J Med Genet 72:394–398 6. Kaplan L (1991) Clinical assessment and multispeciality management of Apert syndrome. Clin Plast Surg 18:217–225 7. Allanson JE (1986) Germinal mosaicism in Apert syndrome. Clin Genet 29:429–433 8. Wilkie AO, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, Hayward RD, David DJ, Pulleyn LJ, Rutland P, Malcolm S, Winter RM, Reardon W (1995) Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9:165–172 9. Wilkie AOM (1997) Craniosynostosis: genes and mechanisms. Hum Mol Genet 6:1647–1656 10. Park WJ, Theda C, Maestri NE, Meyers GA, Fryburg JS, Dufresne C, Cohen MM Jr, Jabs EW (1995) Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet 57:321–328 11. Von Gernet S, Golla A, Ehrenfels Y, Schuffenhauer S, Fairley JD (2000) Genotype-phenotype analysis in Apert syndrome suggests opposite effects of the two recurrent mutations on syndactyly and outcome of craniofacial surgery. Clin Genet 57:137–139 12. Ferreira JC, Carter SM, Bernstein PS, Jabs EW, Glickstein JS, Marion RW, Baergen RN, Gross SJ (1999) Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome following suspicious ultrasound findings. Ultrasound Obstet Gynecol 14:426–430 13. De Leon GA, De Leon G, Grover WD, Zaeri N, Alburger PD (1987) Agenesis of the corpus callosum and limbic malformation in Apert syndrome (type acrocephalosyndactyly). Arch Neurol 44:979–982 14. Cohen MM, Kreiborg S (1990) The central nervous system in the Apert syndrome. Am J Med Genet 35:36–45
15. Renier D, Arnaud E, Cinalli G, Sebag G, Zerah M, Marchac D (1996) Prognosis for mental function in Apert’s syndrome. Neurosurgery 85: 66–72 16. Yacubian-Fernandes A, Palhares A, Giglio A, Gabarra RC, Zanini S, Portela L, Plese JP (2004) Apert syndrome: analysis of associated brain malformations and conformational changes determined by surgical treatment. J Neuroradiol 31:116–122 17. Quintero-Rivera F, Robson CD, Reiss RE, Levine D, Benson CB, Mulliken JB, Kimonis VE (2006) Intracranial anomalies detected by imaging studies in 30 patients with Apert syndrome. Am J Med Genet 140:1337–1338 18. Quintero-Rivera F, Robson CD, Reiss RE, Levine D, Benson C, Mulliken JB, Kimonis VE (2006) Apert syndrome: what prenatal radiographic findings should prompt its consideration? Prenat Diagn 26:966–972 19. Pooh RK, Nakagawa Y, Pooh KH, Nakagawa Y, Nagamachi N (1999) Fetal craniofacial structure and intracranial morphology in a case of Apert syndrome. Ultrasound Obstet Gynecol 13:274–280 20. Respondek-Liberska M, Smigiel R, Zielinski A, Sasiadek MM (2010) Progressive development of sonographic features in prenatal diagnosis of Apert syndrome—case report and literature review. Ginekol Pol 81(12):935–939 21. Au PK, Kwok YK, Leung KY, Tang LY, Tang MH, Lau ET (2011) Detection of the S252W mutation in fibroblast growth factor receptor 2 (FGFR2) in fetal DNA from maternal plasma in a pregnancy affected by Apert syndrome. Prenat Diagn 31(2):218–220 22. Breugem CC, Fitzpatrick DF, Verchere C (2008) Monozygotic twins with Apert syndrome. Cleft Palate Craniofac J 45:101–104 23. Weber B, Schwabegger AH, Vodopiutz J, Janecke AR, Forstner R, Steiner H (2010) Prenatal diagnosis of Apert syndrome with cloverleaf skull deformity using ultrasound, fetal magnetic resonance imaging and genetic analysis. Fetal Diagn Ther 27:51–56 24. Boog G, Le Vaillant C, Winer N, David A, Quere MP, Nomballais MF (1999) Contribution of tridimensional sonography and magnetic resonance imaging to prenatal diagnosis of Apert syndrome at midtrimester fetal. Diagn Ther 14:20–23 25. Blaicher W, Prayer D, Bernaschek G (2003) Magnetic resonance imaging and ultrasound in the assessment of the fetal central nervous system. J Perinat Med 31(6):459–468 26. Skidmore DL, Pai AP, Toi A, Steele L, Chitayat D (2003) Prenatal diagnosis of Apert syndrome: report of two cases. Prenat Diagn 23(12):1009–1013 27. Lam H, Lo TK, Lau E, Chin R, Tang L (2006) The use of 2- and 3dimensional sonographic scans in the evaluation of cranial sutures: prenatal diagnosis of Apert syndrome. J Ultrasound Med 25(11): 1481–1484 28. David AL, Turnbull C, Scott R, Freeman J, Bilardo CM, van Maarle M, Chitty LS (2007) Diagnosis of Apert syndrome in the secondtrimester using 2D and 3D ultrasound. Prenat Diagn 27(7):629–632 29. Athanasiadis AP, Zafrakas M, Polychronou P, Florentin-Arar L, Papasozomenou P, Norbury G, Bontis JN (2008) Apert syndrome: the current role of prenatal ultrasound and genetic analysis in diagnosis and counselling. Fetal Diagn Ther 24(4):495–498 30. Manganaro L, Savelli S, Francioso A, Di Maurizio M, Coratella F, Vilella G, Noia G, Giancotti A, Tomei A, Fierro F, Ballesio L (2009) Role of fetal MRI in the diagnosis of cerebral ventriculomegaly assessed by ultrasonography. Radiol Med 114(7):1013–1023 31. Triulzi F, Manganaro L, Volpe P (2011) Fetal magnetic resonance imaging: indications, study, protocols and safety. Radiol Med 116(3): 337–350 32. Esser T, Rogalla P, Bamberg C, Kalache KD (2005) Application of the three-dimensional maximum mode in prenatal diagnosis of Apert syndrome. Am J Obstet Gynecol 193(5):1743–1745 33. Faro C, Chaoui R, Wegrzyn P, Levaillant JM, Benoit B, Nicolaides KH (2006) Metopic sutures in fetuses with Apert syndrome from 22– 27 weeks’ gestation. Ultrasound Obstet Gynecol 27:28–33
CASE REPORT
Comparison of ultrasound and magnetic resonance imaging in the prenatal diagnosis of Apert syndrome: report of a case A. Giancotti & V. D’Ambrosio & A. De Filippis & C. Aliberti & G. Pasquali & S. Bernardo & L. Manganaro & PECRAM Study Group
Received: 27 January 2014 / Accepted: 28 January 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background The birth prevalence of Apert syndrome is estimated at 1:64,500 and accounts for about 4.5 % of all craniosynostosis with a male/female ratio equal to 1:1. It is associated to allelic mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Majority cases are sporadic. Prenatal ultrasound diagnosis is based on the detection of abnormal cranial shape, midfacial hypoplasia and bilateral syndactyly of hands and feet, hypertelorism, and exorbitism. Other abnormalities includes central nervous system anomalies, congenital heart diseases, cleft palate, and urogenital diseases. Case report A 37-year-old Caucasian woman, gravida 2, para 1, was referred to our center of Prenatal Diagnosis for routine ultrasound at 21 weeks of gestation. We detected irregular head shape, dolicocephaly, prominent forehead, bilateral mild ventriculomegaly, suspicion of partial agenesis of the corpus callosum, hypertelorism, and midfacial hypoplasia, with a depressed nasal bridge and syndactyly, prompting a suspicion for Apert syndrome. Magnetic resonance excluded agenesis of corpus callosum and confirmed bilateral mild ventriculomegaly. A follow-up ultrasound, performed at 23 weeks, confirmed the anomalies showed in the previous scan. An amniocentesis was performed. The results showed a normal male karyotype, while PECRAM Study Group members: Polimeni A., Pizzuti A., Cascone P., Silvestri A., Roggini M., Tarani L., Papoff P., Castori M., and Lenzi J. from “Sapienza” University. A. Giancotti (*) : V. D’Ambrosio : A. De Filippis : C. Aliberti : G. Pasquali Department of Obstetrics, Gynecology and Urologic Sciences, Umberto I Hospital, “Sapienza” University, Viale del Policlinico 155, 00161 Rome, Italy e-mail: [email protected] S. Bernardo : L. Manganaro Department of Radiological Oncological and Anatomopathological Sciences, Umberto I Hospital, “Sapienza” University, Viale Regina Elena 324, 00161 Rome, Italy
the molecular genetic test confirmed a mutation in FGFR2 gene. Fetus macroscopic analysis showed compatible features. Conclusions Our case underlines the complementary role of ultrasound and magnetic resonance imaging in the early prenatal diagnosis of Apert syndrome. Keywords Apert syndrome . Prenatal diagnosis . Fetal ultrasound . Magnetic resonance
Introduction Apert syndrome (AS) or acrocephalosyndactyly type I is a rare congenital disorder characterized by the triad of coronal craniosynostosis, midfacial hypoplasia, and symmetric syndactyly of the hands and feet [1]. Ventriculomegaly (VM), alteration in corpus callosum, and other central nervous system (CNS) abnormalities are usually present in this condition and may be responsible for mental retardation present in half of affected individuals [2]. Other signs include cleft palate, congenital heart diseases, and urogenital abnormalities [3]. The birth prevalence is estimated at 1/64,500 and accounts for about 4.5 % of all cases of craniosynostosis [2, 4] with a male/female ratio equal to 1:1 [5]. The majority of AS cases are sporadic as the result of de novo mutations [6]. Rarely, the syndrome is transmitted in autosomal dominant manner [5]. Some rare cases of recurrence in the offspring of healthy couples can be explained by germinal mosaicism [7]. A small number of chromosomal abnormalities have been reported in AS; however, the majority of the patients has a normal karyotype [6]. Advanced paternal age seems to be a risk factor for the occurrence of this syndrome [5]. We report a case of prenatal diagnosis of AS in the second trimester of pregnancy confirmed by molecular genetic test, comparing the results of ultrasound (US) and magnetic resonance imaging (MRI).
Childs Nerv Syst
Case report A 37-year-old Caucasian woman, gravida 2, para 1, was referred to our center of Prenatal Diagnosis for routine second trimester ultrasound at 21 weeks of gestation (WG). The partner was 40 years old and there was no consanguinity. The woman’s past obstetrical, medical, and family history was unremarkable. The anomaly scan showed irregular head shape, dolicocephaly (occipital frontal diameter, 74 mm; >95° centile), prominent forehead, flat occiput, bilateral mild VM (right ventricle 10 mm, left ventricle 11 mm), visualization of the anterior part of the corpus callosum with a suspicion of partial agenesis of corpus callosum (p-ACC), hypertelorism, and midfacial hypoplasia, with a depressed nasal bridge (Fig. 1). Furthermore, malformations of the upper and lower extremities were detected consistent with syndactyly (Fig. 2). Those sonographic findings gave the suspect for AS. A fetal MRI was suggested and performed after 2 days. It excluded agenesis of corpus callosum (ACC) (Fig. 3), confirmed bilateral mild VM, but no other anomalies were highlighted (Fig. 4). A follow-up US examination was performed at 23 WG and confirmed the abnormalities of the fetal cranium visualized in the precedent scan. Bilateral mild VM was visualized (right ventricle 9 mm, left ventricle 11 mm) and both hands appeared in adduction position; malformations of the upper and lower extremities were still detected by twodimensional/three-dimensional (2D/3D) scan (Fig. 5). Feet US images showed a bilateral abnormal position associated to atypical organization of the phalanges with syndactyly. Furthermore, a polyhydramnios was found (Amniotic Fluid Index 24.5 cm). A genetic counseling was carried out and prenatal diagnosis test was offered to the couple. An amniocentesis was performed. Conventional chromosomal analysis revealed a normal male karyotype (46, XY), but the molecular genetic test confirmed a mutation in fibroblast growth factor receptor 2 (FGFR2) gene. In testing for different craniofacial
Fig. 1 Sonogram showing a fetal profile with prominent forehead, mifdacial hypoplasia, and depressed nasal bridge at 21 weeks of gestation
Fig. 2 Sonogram showing anomaly of the hand with syndactily
syndromes, the patient DNA was further evaluated for FGFR type 1 (exon V), 2 (exon III A/C), and 3 (exon VII) mutations. A heterozygous for the FGFR2 mutation c.758C> G (p.Pro253Arg) was found in the fetus. The parents decided to terminate their pregnancy. Fetus macroscopic analysis showed features compatible with the syndrome: bilateral syndactyly of the hands (“spoon hands”) and feet, midface hypoplasia, and prominent forehead. The couple declined a postmortem autopsy.
Discussion AS is one of the four craniosynostosis syndromes associated with allelic mutations in the FGFR2 gene [8]; the defect was localized in chromosome 10 (10q25–10q26). Two MISSENSE mutations of the FGFR2 gene, Ser252Trp (S252W) and Pro253Arg (P253R), in the linker region between the second and third extracellular immunoglobulin-like domains of the receptor, account for over 98 % of cases [9]. Park et al. [10] identified the frequency to be 71 and 26 % for p.S252W and p.P253R mutations, respectively. The p.P253R mutation has been proposed to be associated with severe syndactyly, whereas the p.S252W may be related to more severe craniofacial malformations [11]. Prenatal sonographic diagnosis of AS is based on detection of the triad of abnormal cranial shape, midfacial hypoplasia, and bilateral syndactyly of hands and feet. Ocular hypertelorism and exorbitism are also important associated features that could alert the sonologists in the suspicion of craniosynostosis syndromes. Other encountered visceral abnormalities include CNS anomalies, congenital heart disease, cleft palate, and urogenital disease. CNS anomalies include VM (48.5 %), hydrocephalus (9 %), gyral abnormalities, and others (21 %; agenesis or hypogenesis of the corpus callosum or posterior fossa anomalies) [12]. ACC and VM were first described in AS by de Leon et al. [13] and have been frequently founded in Apert patients since documented [14–17]. For this reason it has been proposed that prenatal identification of ACC or borderline VM should also lead to
Childs Nerv Syst
Fig. 3 MRI visualization of corpus callosum 21 weeks of gestation Fig. 5 3D sonogram showing abnormality of the hand
consideration of AS [18]. The abnormal cranial shape and orbital hypertelorism so typical of AS may be absent or very subtle in the second trimester of pregnancy, becoming obvious only in the third trimester [17, 19, 20]. MRI may play an important role in the prenatal diagnosis of AS; in fact, it is considered the gold standard to assess CNS anomalies after 19 WG. In our case MRI, performed at 21 weeks + 3 days, excluded the p-ACC and confirmed the mild VM. It is the first case of prenatal diagnosis of AS where the MRI was practiced so early in gestation. Bregeum et al. [21] described an AS case where a severe dysgenesis of the corpus callosum was discovered by a MRI performed after 28 WG. Weber et al. [22] reported an AS case in which a MRI performed at 32 WG diagnosed borderline VM. In another case, an ACC was excluded by a MRI done at 26 WG [23]. Our case confirms the main role of MRI as diagnostic imaging techniques for
Fig. 4 MRI Ventriculomegaly 21 weeks of gestation
intracranial structure study, as it can confirm or exclude the presence of CNS anomalies with a greater accuracy than US and in an early gestational period [24]. Nevertheless, the early gestational period, in which the MRI was performed, was a limitation for this diagnostic technique. Indeed, cranial anomalies, such as hyperthelorism, prominent forehead, turricephaly, and depressed nasal bridge founded by the US at 21 weeks, could not be revealed. In a case [23], a MRI confirmed the presence of cranial anomalies (hypertelorism, brachicephaly, verticalization of the clivus, flattened angle of the cranial base) but was performed at 26 WG. Consequently, it emerges the US superiority concerning the study of cranial anomalies in early gestational period. In fact, thanks to the improved resolution of sonographic scan, several cases of AS, including our case, have been detected in early second trimester [12, 25–29]. Furthermore, it deserves to be noticed that in our case, slight anomalies of fetal profile, such as a mild midfacial hypoplasia and a slight prominent forehead were visualized at MRI retrospectively but were not detected at the time of the examination. These findings underline that fetal maxillofacial and profile anomalies are still based on subjective impressions and that there is a lack in literature of a real standardization to check these defects. This case emphasizes the need for a methodical analysis of the fetal profile and maxillofacial anomalies in order to get standard parameters for earlier and easier feasible diagnosis. The two techniques are substantially in agreement in defining the degree of VM [30]. For what concerns hand anomalies, in literature, there is a case of abnormal hands revealed, retrospectively, at a MRI performed at 32 WG but not detected at the time of the examination. This can be considered an occasional survey, as MRI is not indicated for the study of fetal muscle-skeletal structures. Given the limited evidence in the literature and the
Childs Nerv Syst
difficulty in performing the examination, it is currently not possible to include musculoskeletal structures and in particular, the developing limbs and osteo-cartilaginous components of the vertebral column among the anatomical areas studied with fetal MRI [31]. On the other side, 2D and 3D US has showed an important role in the diagnosis of hands anomalies. Some authors suggested that in suspected cases of craniosynostosis, complementary use of 3D scans could be essential for prenatal diagnosis and may be useful to demonstrate abnormalities of the hands, feet, and face [26, 32, 33]. In the light of above, we can assess that in our case the suspicion of the AS was carried out early in pregnancy thanks to US and MRI findings. We suggest the complementary role of these two diagnostic techniques for the diagnosis of this genetic syndrome in early pregnancy (since 19–20 WG).
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