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Bilateral Periventricular Nodular Heterotopia with Amniotic Band Syndrome
Bilateral Periventricular Nodular Heterotopia with Amniotic Band Syndrome
Ruggieri M, Spalice A, Polizzi A, Roggini M, Iannetti P. Bilateral periventricular nodular heterotopia with amniotic band syndrome. Pediatr Neurol 2007;36: 407-410.
Introduction
The amniotic (constriction) band syndrome is characterized by distal ring constrictions, intrauterine amputations, and acrosyndactyly. External constriction by amniotic bands is the generally accepted mechanism: early amniotic rupture leads to formation of mesodermal fibrous strands that constrict, entangle, and amputate distal portions of limbs. Etiology is heterogeneous. Anecdotal cases involving central nervous system abnormalities (e.g., acrania, anencephaly, polymicrogyria, congenital bilateral perisylvian syndrome, neuronal heterotopia, septo-optic dysplasia, and spinal cord tethering) have been reported. We describe a 9-yearold girl with typical features of constriction band syndrome localized to the lower limbs who had also profound mental retardation and drug-resistant epilepsy associated with bilateral periventricular nodular heterotopia (a brain malformation of neuronal migration and proliferation caused by mutations in the X-linked filamin 1 gene [FLN1] on chromosome Xq28). The karyotype was normal, as was mutational screening for FLN1. The occurrence of bilateral periventricular nodular heterotopia in the context of amniotic band syndrome is novel (chance occurrence of both: 0.000004%). © 2007 by Elsevier Inc. All rights reserved.
Congenital constriction band syndrome (OMIM 217100; OMIM: Online Mendelian Inheritance in Man database; available at http://www.ncbi.nlm.nih.gov) is a disruption disorder causing disfigurement and disability that can vary widely, from digital ring constrictions to major craniofacial and visceral defects [1]. External constriction by amniotic bands is the most generally accepted mechanism, although debate persists. Early amniotic rupture leads to the formation of mesodermal fibrous strands that constrict, entangle, and amputate distal portions of limbs. Bilateral periventricular nodular heterotopia is a brain malformation of neuronal migration, and perhaps proliferation, in which heterotopic nodular masses of gray matter line the walls of the lateral ventricles protruding into the lumen [2,3]. Most affected individuals are females of normal intelligence who have epilepsy, but sporadic cases of mentally handicapped children with bilateral periventricular nodular heterotopia have been recorded [2]. Mutations in the X-linked filamin 1 (FLN1) gene (located on Xq28) have been recently demonstrated to cause bilateral periventricular nodular heterotopia in males as well as females (periventricular nodular heterotopia 1 gene PVNH1; OMIM 300049) [2-4]. Additional forms associated with chromosome 5p anomalies (PVNH3; OMIM 608098) and a form with Ehlers-Danlos features (PVNH4; OMIM 300537) have been identified [2,4]. Anecdotal cases of brain abnormalities (e.g., acrania, anencephaly, polymicrogyria, congenital bilateral perisylvian syndrome, neuronal heterotopia, spinal cord tethering, and septo-optic dysplasia) have been reported in the context of amniotic band syndrome [5-15]. We report the case of a 9-year-old girl with the typical features of constriction band syndrome who in addition had profound mental retardation and drug-resistant epilepsy associated with bilateral periventricular nodular heterotopia.
From the *Institute of Neurological Science, National Research Council, Catania, Italy; †Department of Pediatrics, University of Catania, Catania, Italy; ‡Second Chair of Pediatrics, Division of Pediatric Neurology, Department of Pediatrics, University “La Sapienza,” Rome, Italy; and §Pediatric Radiology Unit, Department of Pediatrics, University “La Sapienza,” Rome, Italy.
Communications should be addressed to: Dr. Ruggieri; Institute of Neurological Science (ISN); National Research Council (CNR); Viale R. Margherita, 6; 95125 Catania, Italy. E-mail: [email protected] Received August 7, 2006; accepted February 5, 2007.
Martino Ruggieri, MD, PhD*†, Alberto Spalice, MD, PhD‡, Agata Polizzi, MD, PhD†, Mario Roggini, MD§, and Paola Iannetti, MD‡
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.02.006 ● 0887-8994/07/$—see front matter
Ruggieri et al: BPNH and Amniotic Bands 407
Case Report This 9-year-old girl was first referred at age 5 years because of drug-resistant epilepsy (onset age, 3 years). She was the product of a 38-week gestation, delivered by caesarean section because of chronic abruptio placentae and fetal distress. At gestational week 28, prenatal ultrasonographic examination revealed partial and near-total amputation of the digits of both feet in association with intrauterine bands. Family history was unrevealing; parents were unrelated. Birthweight was 3150 g (50th percentile), length was 50 cm (50th percentile), and occipitofrontal circumference was 33 cm (25th percentile). Apgar scores were 7 at 1 minute and 9 at 10 minutes. Ring constriction and partial and near-total amputation of the digits in both feet were observed at birth. At that age, a skeletal survey revealed near-total missing of proximal and distal phalanxes of all digits in the feet, with hypoplastic metatarsal and no other bone anomaly. The patient had no cleft lip and no palate or visceral anomalies. Early developmental milestones were delayed: head control was attained at age 6 months, sitting unaided at 10 months, standing unaided at 16 months, and walking unaided at age 24 months. She had also difficulties in speaking, and was able to understand simple commands by the age of 30 months. She could not speak in phrases of several words until age 3 years. At that age, 3 years, she started to have several episodes of simple partial seizures per day, consisting of clonic movements of the right hand and fingers accompanied by brief episodes of right hand constriction. An electroencephalogram displayed multifocal spikes and polyspike-andwave discharges. Cranial magnetic resonance imaging revealed an isointense tissue with gray matter lining the bilateral ventricular walls, compatible with nodular heterotopia. The corpus callosum was well
preserved, as was the rest of brain anatomy. She was diagnosed as having simple partial epilepsy and was started on valproic acid treatment, but with poor seizure control. When partial complex seizures and absences ensued, carbamazepine and lamotrigine were added, with fair seizure control. The karyotype was normal (46,XX). Upon admission to the University “La Sapienza” Department of Pediatrics in Rome at age 5 years, the child’s weight and length were at the 50th percentile and head circumference was at the 25th percentile. Both the great toes appeared to be amputated, and the remaining digits were partially or nearly entirely amputated with distal ring constrictions. There were no birthmarks or vascular or other skin malformations, except for a skin appendage of the dermal sinus type in the lower lumbar area. The face was normal, and there were no other dysmorphic features. The general examination was otherwise unrevealing. Neurological examination showed a profoundly mentally retarded child with poor vocalization, difficulties in comprehension, normal deep tendon reflexes, no pathologic reflexes, and normal cranial nerve examination. The gag reflex was absent. Vocalizations were sparse and difficult to comprehend. Muscle tone was mildly decreased, as was muscular strength. Radiographs of the lower limbs confirmed previous findings (Fig. 1). A repeated magnetic resonance imaging scan of the brain (Fig. 2) revealed bilateral periventricular nodular heterotopia. She underwent surgical removal of the remnants of the digits in both feet. Mutational screening for the FLN1 gene was performed, using the following protocol. DNA from the patient was extracted from peripheral blood leukocytes using a DNA isolation kit (DNAZol; Molecular Research Center, Cincinnati, OH) and from hair root using a blood DNA spin extraction kit (Genomed, Bad Oeynhasen, Germany), with minor protocol modifications [2,16]. FLN1 coding regions and exon-intron boundaries, including approximately 50 base pairs upstream and down-
Figure 1. Radiograph of the third distal segment of the legs and the feet (lateral close-up view) at age 5 years showing total and near-total absence of the phalanxes in both feet, with abnormal metatarsals and remnants of the digits and the metatarsal bones.
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Figure 2. Axial (A) and coronal (B) T1-weighted (TR/TE ⫽ 400/40 ms) brain images obtained at age 5 years, showing isointense tissue with gray matter lining bilaterally the ventricular walls (arrows) compatible with nodular heterotopia. Note the preserved architecture of the rest of the cerebral structures, including the cerebral cortex and the subcortical white matter: the corpus callosum (A) and the cerebellum (B). stream of the exons were amplified by polymerase chain reaction. FLN1 primers were as described previously by Zenker et al. [16]. Heteroduplex analysis was performed using an automated denaturing high-performance liquid chromatography instrument (WAVE System; Transgenomic, La Jolla, CA). Sample preparation for this liquid chromatography analysis was performed by denaturing and reannealing for unpurified polymerase chain reaction products. The temperature conditions required for the successful resolution of heteroduplexes were obtained using Navigator software (Transgenomic). No altered peaks were identified in the FLN1 gene. At her most recent follow-up monitoring, at age 9 years, the girl appeared to be severely mentally retarded; fair seizure control had been achieved with valproic acid and topiramate treatment.
Discussion The unique aspect of this child is that, aside from neurological abnormalities and associated brain malformation of the bilateral periventricular nodular heterotopia type [2,3,16], she showed congenital deformations of the feet suggestive of amniotic band syndrome [1]. The essential triad for congenital constriction band syndrome is distal ring constrictions, intrauterine amputations, and acrosyndactyly [1,16]. Our patient demonstrated features of limb deformity typical for congenital band syndrome. Notably, the degree of severity was high, in that not only the phalanxes were missing in both feet but also part of the metatarsals (Fig. 1). In a patient manifesting bilateral periventricular nodular heterotopia in combination with frontometaphyseal dysplasia (OMIM 304120), a
skeletal dysplasia of the otopalatodigital spectrum, Zenker et al. [16] identified a de novo 7315C-A transversion in exon 45 of the FLN1A gene, resulting in two aberrant transcripts. Otopalatodigital abnormalities in the present case were excluded on clinical and imaging grounds. External constriction by amniotic bands is the most generally accepted mechanism for congenital constriction band syndrome [1,15]. Early amniotic rupture leads to the formation of mesodermal fibrous strands that constrict, entangle, and amputate distal portions of limbs. The etiology is heterogeneous, including infection, poor nutrition, smoking, and genital or transvaginal bleeding. A chronic abruptio placentae is thought to be one cause for transvaginal bleeding, leading to increased uterine irritability and intrauterine pressure, associated with premature constrictions and placental separation [1,15]. These mechanisms of chronic uterine damage compromise fetal circulation and may lead to amniotic band syndrome but also to (partial or generalized) fetal vascular disturbances affecting organs or systems and causing a single or multiple anomalies. In particular, a vascular pathogenesis has been suggested for the accompanying brain abnormality in previous cases of amniotic band syndrome associated with central nervous system abnormalities [14,15]. For example chronic abruptio placentae was related to both polymicrogyria and septo-optic dysplasia [14,15] and congenital constriction band syndrome
Ruggieri et al: BPNH and Amniotic Bands 409
in previous reports. The sporadic occurrence of polymicrogyria [13] and septo-optic dysplasia [15] and its association with decreased maternal age, vascular teratogens, and neuropathology findings suggestive of vascular insults in both instances [15] could also support this hypothesis. The parallel between the role of FLN1 protein in vascular development or maldevelopment (the FLN1 gene function is essential in normal embryonic development of blood vessels) [2,3,15] and the vascular pathogenesis of the amniotic disruptive sequence could explain this unusual combination of in utero vascular insult and central nervous system disruption. The negative findings from mutational screening of FLN1 gene in the present case could support the latter hypothesis and explain why a (usually) genetic brain malformation occurred in the context of a teratogenic event. An alternative to the vascular hypothesis could be an immunologic attack mediated by maternal antibodies acting during a critical period of fetal development. The amniotic band syndrome has been frequently recorded in association with fetuses affected by multiple deformities including multiple joint contractures (the so-called arthrogryposis multiplex congenital) [17,18]. The mouse model of arthrogryposis multiplex congenital demonstrated the role of maternal antibodies to fetal antigens in causing fetal deformities in cases of arthrogryposis multiplex congenital associated with immune-mediated maternal diseases [18]. Offspring born to myasthenic mothers (but also to mothers with other immune-mediated diseases) have been affected by neonatal myasthenia gravis complicated by arthrogryposis multiplex congenital, dysmorphic facies, lung hypoplasia, abnormal genitalia and various central nervous system malformations associated or not to psychomotor retardation: fetal akinesia deformation sequence was inferred as the factor responsible for these complex phenotypes [17,18]. In the present case (as in the others with amniotic band syndrome and associated organ or system malformations), we could not exclude a direct role of specific maternal antibodies directed both to placental components and to fetal antigens, including brain antigens. This hypothetical pathogenic mechanism (i.e., immune attack against brain antigens) could perhaps explain the patient’s profound mental retardation, a feature not characteristic of bilateral periventricular nodular heterotopia. Even though cranial magnetic resonance imaging in our case did not reveal associated cortical dysgeneses to explain this clinical alteration, microscopic neuronal alterations could be present, as occurred in the mouse model of arthrogryposis multiplex congenital [17,18]. In conclusion, to our knowledge this report represents the first case of bilateral periventricular nodular heterotopia in the context of amniotic band syndrome. We hypothesize that the combination of these two malformation disorders was not coincidental: the calculated chance
410
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occurrence of both conditions based on epidemiological data is 0.000004% [1,2]. Instead, fetal circulatory disturbance related to chronic abruptio placentae might account for the combination.
This work was done at the Department of Pediatrics, University “La Sapienza,” Rome, Italy. The authors wish to thank Mr. N. Bonanno (Catania) for his skillful photomicrographic assistance.
References [1] Taybi H. Amniotic band syndrome. In: Taybi H, Lachman RS, editors. Radiology of syndromes, metabolic disorders, and skeletal dysplasias, 4th ed. St. Louis: Mosby, 1996:651-3. [2] Parrini E, Ramazzotti A, Dobyns WB, Mei D, Moro F, Veggiotti P, et al. Periventricular heterotopia: phenotypic heterogeneity and correlation with filamin A mutations. Brain 2006;129:1892-906. [3] Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. A developmental and genetic classification for malformations of cortical development. Neurology 2005;65:1873-8. [4] Robertson SP, Twigg SR, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D, et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. OPD-Spectrum Disorders Clinical Collaborative Group. Nat Genet 2003; 33:487-91. [5] Hughes RM, Benzie RJ, Thompson CL. Amniotic band syndrome causing fetal head deformity. Prenatal Diagn 1984;4:447-50. [6] Urich H, Herrick MK. The amniotic band syndrome as a cause of anencephaly: report of a case. Acta Neuropathol (Berl) 1985;67:190-4. [7] Chen H, Gonzalez E. Amniotic band sequence and its neurocutaneous manifestations. Am J Med Genet 1987;28:661-73. [8] Peer D, Moroder W, Delucca A. Prenatal diagnosis of the pentalogy of Cantrell combined with exencephaly and amniotic band syndrome [In German]. Ultraschall Med 1993;14:94-5. [9] Cusi V, Antich J, Vela A, Vila J. Neural tube defect and amniotic band syndrome. Genet Couns 1993;4:203-5. [10] Prabhu VC, Tomita T. Spinal cord tethering associated with amniotic band syndrome. Pediatr Neurosurg 1999;31:177-82. [11] Budorick NE, Pretorius DH, McGahan JP, Grafe MR, James HE, Slivka J. Cephalocele detection in utero: sonographic and clinical features. Ultrasound Obstet Gynecol 1995;5:77-85. [12] Chandran S, Lim MK, Yu VY. Fetal acalvaria with amniotic band syndrome. Arch Dis Child Fetal Neonatal Ed 2000;82:F11-3. [13] Yamanouchi H, Ota T, Imataka G, Hagiwara Y, Nakagawa E, Eguchi M. Congenital bilateral perisylvian syndrome associated with congenital constriction band syndrome. J Child Neurol 2002;17:448-50. [14] Cincore V, Ninios AP, Pavlik J, Hsu CD. Prenatal diagnosis of acrania associated with amniotic band syndrome. Obstet Gynecol 2003; 102:1176-8. [15] Stevens CA, Dobyns WB. Septo-optic dysplasia and amniotic bands: further evidence for a vascular pathogenesis. Am J Med Genet 2004;125A:12-6. [16] Zenker M, Rauch A, Winterpacht A, Tagariello A, Kraus C, Rupprecht T, et al. A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts. Am J Hum Genet 2004;74:731-7. [17] Jacobsen L, Polizzi A, Moriss-Key G, Vincent A. Plasma from human mothers of fetuses with severe arthrogryposis multiplex congenital causes deformities in mice. J Clin Invest 1999;103:1031-8. [18] Polizzi A, Huson SM, Vincent A. Teratogens update: maternal myasthenia gravis as a cause of congenital arthrogryposis. Teratology 2000;62:332-41.
Ruggieri M, Spalice A, Polizzi A, Roggini M, Iannetti P. Bilateral periventricular nodular heterotopia with amniotic band syndrome. Pediatr Neurol 2007;36: 407-410.
Introduction
The amniotic (constriction) band syndrome is characterized by distal ring constrictions, intrauterine amputations, and acrosyndactyly. External constriction by amniotic bands is the generally accepted mechanism: early amniotic rupture leads to formation of mesodermal fibrous strands that constrict, entangle, and amputate distal portions of limbs. Etiology is heterogeneous. Anecdotal cases involving central nervous system abnormalities (e.g., acrania, anencephaly, polymicrogyria, congenital bilateral perisylvian syndrome, neuronal heterotopia, septo-optic dysplasia, and spinal cord tethering) have been reported. We describe a 9-yearold girl with typical features of constriction band syndrome localized to the lower limbs who had also profound mental retardation and drug-resistant epilepsy associated with bilateral periventricular nodular heterotopia (a brain malformation of neuronal migration and proliferation caused by mutations in the X-linked filamin 1 gene [FLN1] on chromosome Xq28). The karyotype was normal, as was mutational screening for FLN1. The occurrence of bilateral periventricular nodular heterotopia in the context of amniotic band syndrome is novel (chance occurrence of both: 0.000004%). © 2007 by Elsevier Inc. All rights reserved.
Congenital constriction band syndrome (OMIM 217100; OMIM: Online Mendelian Inheritance in Man database; available at http://www.ncbi.nlm.nih.gov) is a disruption disorder causing disfigurement and disability that can vary widely, from digital ring constrictions to major craniofacial and visceral defects [1]. External constriction by amniotic bands is the most generally accepted mechanism, although debate persists. Early amniotic rupture leads to the formation of mesodermal fibrous strands that constrict, entangle, and amputate distal portions of limbs. Bilateral periventricular nodular heterotopia is a brain malformation of neuronal migration, and perhaps proliferation, in which heterotopic nodular masses of gray matter line the walls of the lateral ventricles protruding into the lumen [2,3]. Most affected individuals are females of normal intelligence who have epilepsy, but sporadic cases of mentally handicapped children with bilateral periventricular nodular heterotopia have been recorded [2]. Mutations in the X-linked filamin 1 (FLN1) gene (located on Xq28) have been recently demonstrated to cause bilateral periventricular nodular heterotopia in males as well as females (periventricular nodular heterotopia 1 gene PVNH1; OMIM 300049) [2-4]. Additional forms associated with chromosome 5p anomalies (PVNH3; OMIM 608098) and a form with Ehlers-Danlos features (PVNH4; OMIM 300537) have been identified [2,4]. Anecdotal cases of brain abnormalities (e.g., acrania, anencephaly, polymicrogyria, congenital bilateral perisylvian syndrome, neuronal heterotopia, spinal cord tethering, and septo-optic dysplasia) have been reported in the context of amniotic band syndrome [5-15]. We report the case of a 9-year-old girl with the typical features of constriction band syndrome who in addition had profound mental retardation and drug-resistant epilepsy associated with bilateral periventricular nodular heterotopia.
From the *Institute of Neurological Science, National Research Council, Catania, Italy; †Department of Pediatrics, University of Catania, Catania, Italy; ‡Second Chair of Pediatrics, Division of Pediatric Neurology, Department of Pediatrics, University “La Sapienza,” Rome, Italy; and §Pediatric Radiology Unit, Department of Pediatrics, University “La Sapienza,” Rome, Italy.
Communications should be addressed to: Dr. Ruggieri; Institute of Neurological Science (ISN); National Research Council (CNR); Viale R. Margherita, 6; 95125 Catania, Italy. E-mail: [email protected] Received August 7, 2006; accepted February 5, 2007.
Martino Ruggieri, MD, PhD*†, Alberto Spalice, MD, PhD‡, Agata Polizzi, MD, PhD†, Mario Roggini, MD§, and Paola Iannetti, MD‡
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.02.006 ● 0887-8994/07/$—see front matter
Ruggieri et al: BPNH and Amniotic Bands 407
Case Report This 9-year-old girl was first referred at age 5 years because of drug-resistant epilepsy (onset age, 3 years). She was the product of a 38-week gestation, delivered by caesarean section because of chronic abruptio placentae and fetal distress. At gestational week 28, prenatal ultrasonographic examination revealed partial and near-total amputation of the digits of both feet in association with intrauterine bands. Family history was unrevealing; parents were unrelated. Birthweight was 3150 g (50th percentile), length was 50 cm (50th percentile), and occipitofrontal circumference was 33 cm (25th percentile). Apgar scores were 7 at 1 minute and 9 at 10 minutes. Ring constriction and partial and near-total amputation of the digits in both feet were observed at birth. At that age, a skeletal survey revealed near-total missing of proximal and distal phalanxes of all digits in the feet, with hypoplastic metatarsal and no other bone anomaly. The patient had no cleft lip and no palate or visceral anomalies. Early developmental milestones were delayed: head control was attained at age 6 months, sitting unaided at 10 months, standing unaided at 16 months, and walking unaided at age 24 months. She had also difficulties in speaking, and was able to understand simple commands by the age of 30 months. She could not speak in phrases of several words until age 3 years. At that age, 3 years, she started to have several episodes of simple partial seizures per day, consisting of clonic movements of the right hand and fingers accompanied by brief episodes of right hand constriction. An electroencephalogram displayed multifocal spikes and polyspike-andwave discharges. Cranial magnetic resonance imaging revealed an isointense tissue with gray matter lining the bilateral ventricular walls, compatible with nodular heterotopia. The corpus callosum was well
preserved, as was the rest of brain anatomy. She was diagnosed as having simple partial epilepsy and was started on valproic acid treatment, but with poor seizure control. When partial complex seizures and absences ensued, carbamazepine and lamotrigine were added, with fair seizure control. The karyotype was normal (46,XX). Upon admission to the University “La Sapienza” Department of Pediatrics in Rome at age 5 years, the child’s weight and length were at the 50th percentile and head circumference was at the 25th percentile. Both the great toes appeared to be amputated, and the remaining digits were partially or nearly entirely amputated with distal ring constrictions. There were no birthmarks or vascular or other skin malformations, except for a skin appendage of the dermal sinus type in the lower lumbar area. The face was normal, and there were no other dysmorphic features. The general examination was otherwise unrevealing. Neurological examination showed a profoundly mentally retarded child with poor vocalization, difficulties in comprehension, normal deep tendon reflexes, no pathologic reflexes, and normal cranial nerve examination. The gag reflex was absent. Vocalizations were sparse and difficult to comprehend. Muscle tone was mildly decreased, as was muscular strength. Radiographs of the lower limbs confirmed previous findings (Fig. 1). A repeated magnetic resonance imaging scan of the brain (Fig. 2) revealed bilateral periventricular nodular heterotopia. She underwent surgical removal of the remnants of the digits in both feet. Mutational screening for the FLN1 gene was performed, using the following protocol. DNA from the patient was extracted from peripheral blood leukocytes using a DNA isolation kit (DNAZol; Molecular Research Center, Cincinnati, OH) and from hair root using a blood DNA spin extraction kit (Genomed, Bad Oeynhasen, Germany), with minor protocol modifications [2,16]. FLN1 coding regions and exon-intron boundaries, including approximately 50 base pairs upstream and down-
Figure 1. Radiograph of the third distal segment of the legs and the feet (lateral close-up view) at age 5 years showing total and near-total absence of the phalanxes in both feet, with abnormal metatarsals and remnants of the digits and the metatarsal bones.
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Figure 2. Axial (A) and coronal (B) T1-weighted (TR/TE ⫽ 400/40 ms) brain images obtained at age 5 years, showing isointense tissue with gray matter lining bilaterally the ventricular walls (arrows) compatible with nodular heterotopia. Note the preserved architecture of the rest of the cerebral structures, including the cerebral cortex and the subcortical white matter: the corpus callosum (A) and the cerebellum (B). stream of the exons were amplified by polymerase chain reaction. FLN1 primers were as described previously by Zenker et al. [16]. Heteroduplex analysis was performed using an automated denaturing high-performance liquid chromatography instrument (WAVE System; Transgenomic, La Jolla, CA). Sample preparation for this liquid chromatography analysis was performed by denaturing and reannealing for unpurified polymerase chain reaction products. The temperature conditions required for the successful resolution of heteroduplexes were obtained using Navigator software (Transgenomic). No altered peaks were identified in the FLN1 gene. At her most recent follow-up monitoring, at age 9 years, the girl appeared to be severely mentally retarded; fair seizure control had been achieved with valproic acid and topiramate treatment.
Discussion The unique aspect of this child is that, aside from neurological abnormalities and associated brain malformation of the bilateral periventricular nodular heterotopia type [2,3,16], she showed congenital deformations of the feet suggestive of amniotic band syndrome [1]. The essential triad for congenital constriction band syndrome is distal ring constrictions, intrauterine amputations, and acrosyndactyly [1,16]. Our patient demonstrated features of limb deformity typical for congenital band syndrome. Notably, the degree of severity was high, in that not only the phalanxes were missing in both feet but also part of the metatarsals (Fig. 1). In a patient manifesting bilateral periventricular nodular heterotopia in combination with frontometaphyseal dysplasia (OMIM 304120), a
skeletal dysplasia of the otopalatodigital spectrum, Zenker et al. [16] identified a de novo 7315C-A transversion in exon 45 of the FLN1A gene, resulting in two aberrant transcripts. Otopalatodigital abnormalities in the present case were excluded on clinical and imaging grounds. External constriction by amniotic bands is the most generally accepted mechanism for congenital constriction band syndrome [1,15]. Early amniotic rupture leads to the formation of mesodermal fibrous strands that constrict, entangle, and amputate distal portions of limbs. The etiology is heterogeneous, including infection, poor nutrition, smoking, and genital or transvaginal bleeding. A chronic abruptio placentae is thought to be one cause for transvaginal bleeding, leading to increased uterine irritability and intrauterine pressure, associated with premature constrictions and placental separation [1,15]. These mechanisms of chronic uterine damage compromise fetal circulation and may lead to amniotic band syndrome but also to (partial or generalized) fetal vascular disturbances affecting organs or systems and causing a single or multiple anomalies. In particular, a vascular pathogenesis has been suggested for the accompanying brain abnormality in previous cases of amniotic band syndrome associated with central nervous system abnormalities [14,15]. For example chronic abruptio placentae was related to both polymicrogyria and septo-optic dysplasia [14,15] and congenital constriction band syndrome
Ruggieri et al: BPNH and Amniotic Bands 409
in previous reports. The sporadic occurrence of polymicrogyria [13] and septo-optic dysplasia [15] and its association with decreased maternal age, vascular teratogens, and neuropathology findings suggestive of vascular insults in both instances [15] could also support this hypothesis. The parallel between the role of FLN1 protein in vascular development or maldevelopment (the FLN1 gene function is essential in normal embryonic development of blood vessels) [2,3,15] and the vascular pathogenesis of the amniotic disruptive sequence could explain this unusual combination of in utero vascular insult and central nervous system disruption. The negative findings from mutational screening of FLN1 gene in the present case could support the latter hypothesis and explain why a (usually) genetic brain malformation occurred in the context of a teratogenic event. An alternative to the vascular hypothesis could be an immunologic attack mediated by maternal antibodies acting during a critical period of fetal development. The amniotic band syndrome has been frequently recorded in association with fetuses affected by multiple deformities including multiple joint contractures (the so-called arthrogryposis multiplex congenital) [17,18]. The mouse model of arthrogryposis multiplex congenital demonstrated the role of maternal antibodies to fetal antigens in causing fetal deformities in cases of arthrogryposis multiplex congenital associated with immune-mediated maternal diseases [18]. Offspring born to myasthenic mothers (but also to mothers with other immune-mediated diseases) have been affected by neonatal myasthenia gravis complicated by arthrogryposis multiplex congenital, dysmorphic facies, lung hypoplasia, abnormal genitalia and various central nervous system malformations associated or not to psychomotor retardation: fetal akinesia deformation sequence was inferred as the factor responsible for these complex phenotypes [17,18]. In the present case (as in the others with amniotic band syndrome and associated organ or system malformations), we could not exclude a direct role of specific maternal antibodies directed both to placental components and to fetal antigens, including brain antigens. This hypothetical pathogenic mechanism (i.e., immune attack against brain antigens) could perhaps explain the patient’s profound mental retardation, a feature not characteristic of bilateral periventricular nodular heterotopia. Even though cranial magnetic resonance imaging in our case did not reveal associated cortical dysgeneses to explain this clinical alteration, microscopic neuronal alterations could be present, as occurred in the mouse model of arthrogryposis multiplex congenital [17,18]. In conclusion, to our knowledge this report represents the first case of bilateral periventricular nodular heterotopia in the context of amniotic band syndrome. We hypothesize that the combination of these two malformation disorders was not coincidental: the calculated chance
410
PEDIATRIC NEUROLOGY
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occurrence of both conditions based on epidemiological data is 0.000004% [1,2]. Instead, fetal circulatory disturbance related to chronic abruptio placentae might account for the combination.
This work was done at the Department of Pediatrics, University “La Sapienza,” Rome, Italy. The authors wish to thank Mr. N. Bonanno (Catania) for his skillful photomicrographic assistance.
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