Childs Nerv Syst DOI 10.1007/s00381-015-2642-5
CASE-BASED UPDATE
Beckwith–Wiedemann syndrome and Chiari I malformation—a case-based review of central nervous system involvement in hemihypertrophy syndromes Suhas Udayakumaran & Chiazor U. Onyia
Received: 9 January 2015 / Accepted: 3 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Background Beckwith–Wiedemann syndrome (BWS) is an unusual complex of abnormalities that includes mainly omphalocele, macroglossia, gigantism, visceromegaly, and neonatal hypoglycemia. Type I Chiari malformation, on the other hand, is defined as ectopia of the cerebellar tonsils below the plane of the foramen magnum. Only one case of association of BWS with Chiari I malformation has been previously reported in the literature. Discussion Several conditions involving congenital hemihypertrophy have been previously reported in association with Type I Chiari malformation. The pathophysiological mechanism for most of these associations is thought to be quite complex and still remains unclear. However, the presence of tonsillar herniation in BWS has been explained by Tubbs and Oakes in the only one existing case report of BWS with Type I Chiari malformation in the literature, to be due to associated hemihypertrophy of the skull base. We additionally suggest that cerebellar hypertrophy may also contribute to the tonsillar herniation and fourth ventricular outlet obstruction. Illustrative case We now report our recent experience on this association following a review of the literature on association of other hemihypertrophy syndromes with the central nervous system anomalies.
No portion of this work has been presented elsewhere. S. Udayakumaran (*) Division of Pediatric Neurosurgery, Department of Neurosurgery, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala 682 041, India e-mail: [email protected] C. U. Onyia Neurosurgery Division, Department of Surgery, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria
Conclusion We believe that a common pathogenesis of Type I Chiari malformation occurs in conditions of hemihypertrophy including BWS, probably secondary to dysmorphology involving the posterior cranial fossa, and is not just an associated finding. Keywords Chiari I . Beckwith–Wiedemann syndrome . Hemihypertrophy
Introduction Association of Beckwith–Wiedemann syndrome (BWS) with Type I Chiari malformation is extremely rare [14, 24]. Only one case has been reported in the English literature to the best of our knowledge [14, 24].We report a case of a child diagnosed with BWS associated with Type I Chiari malformation. We also review other congenital hypertrophy syndromes and their association with the central nervous system anomalies and in particular Chiari malformation.
Background BWS is a rare syndrome characterized by the presence of macroglossia, macrosomia, and defects of the anterior abdominal wall such as omphalocele [10, 15–17]. It is also referred to as exomphalos-macroglossia-gigantism syndrome [10]. BWS was described independently by two investigators— first in 1963 by the American pathologist Dr. John Bruce Beckwith who identified macroglossia, omphalocele, cytomegaly of the fetal adrenal cortex, renal medullary dysplasia, and visceromegaly in three postmortem cases and then in 1964 by a German pediatrician Dr. Hans-Rudolf
Childs Nerv Syst
Wiedemann in a report of three cases of siblings who had similar clinical characteristics, with the addition of diaphragmatic defects and hypoglycemia [2, 7, 16, 30].
Epidemiology It has an incidence of 1 in 13,700 live births [10, 15] and is postulated to have a genetic basis. The mechanism by which it occurs is complex and unclear [15, 16]. It is sporadic in approximately 85 % of cases, inherited in 15 % of cases, and is due to chromosomal abnormalities in 1 % of cases [15, 16].
Clinical manifestations and diagnosis The diagnosis of BWS requires at least three clinical findings including at least two major findings [7, 10]. The major clinical findings include macroglossia which is present in more than 95 % of the patients, macrosomia or overgrowth which is defined as prenatal and/or postnatal growth greater than the 97th percentile and is present in about 80 % of the patients, abdominal wall defects (such as exomphalos, umbilical hernia, or diastasis recti) present in 65 % of these patients, and organomegaly involving mainly the abdominal organs such as the kidneys, liver, spleen, pancreas, and adrenal glands in 50 % of cases [10]. The minor criteria include hypoglycemia in the neonatal period (seen in about 40 % of patients), renal malformations or abnormalities as medullary dysplasia, ear creases and pits which occurs in 30 %, facial nevus flammeus also in 30 % of patients, hemihypertrophy which is seen in 30–35 % of patients, embryonal tumors (such as Wilms’ tumor, neuroblastoma, adrenal carcinoma, hepatoblastoma, rhabdomyosarcoma), and polyhydramnios [10]. BWS is one of the syndromes known to present with congenital hemihypertrophy [14, 24]. Congenital hypertrophy itself is known to either occur in isolation or in conjunction with these syndromes such as Proteus, Sotos, Klippel–Trenaunay– Weber, Weaver, Marshal–Smith, Costello, and Simpson– Golabi–Behmel syndromes [6, 8, 9, 11, 12, 14, 18, 20, 21, 24, 26, 27, 29, 31] (Table 1). Congenital hypertrophy is classified as simple when only a single extremity is involved, complex when majority of one half of the body is affected, with involvement of either the same side or both sides, and hemifacial when it involves only one side of the face [26]. Occurrence of BWS with Type I Chiari malformation has been reported in only one case report [14, 24]. Type I Chiari malformation, defined as ectopia of the cerebellar tonsils below the plane of the foramen magnum by more than 3 mm [25, 26], has been explained by various postulations viz. the hindbrain dysgenesis and developmental arrest theory, caudal traction theory, small posterior fossa/hindbrain overgrowth theory, hydrocephalus and hydrodynamic theory of Gardner, and
the lack of embryological ventricular distention theory by McLone and Kneeper [5, 14, 23, 26]. Presence of tonsillar herniation in BWS has been explained by Tubbs and Oakes to be due to associated hemihypertrophy of the skullbase [14, 24]. We additionally suggest that cerebellar hypertrophy may also contribute to the tonsillar herniation and fourth ventricular outlet obstruction. Whether the cerebellar hypertrophy is a part of the hemihypertrophy complex or is an independent organomegaly is difficult to clarify. Some other conditions involving congenital hemihypertrophy have also been reported to be associated with Type I Chiari malformation [3, 25, 26]. The pathophysiological mechanism of this association is thought to be complex [3]. Similar coexistence of both Type I Chiari malformation is seen in a condition called Costello syndrome, a rare genetic disorder that affects parts of the body particularly the head and the heart, hence suggesting that there may be a common pathogenesis of Type I Chiari malformation in these other conditions of hemihypertrophy [3, 12, 14, 19, 26]. Tubbs and Oakes together with coworkers concluded that occurrences of both Type I Chiari malformation and congenital hemihypertrophy in the same patient were pathologically related, perhaps by slight dysmorphologies of the posterior cranial fossa, and are not just spurious findings [24, 26]. They also suggested that this is likely to be from the dysembryology of the mesoderm [25, 26]. BWS has also been previously reported to occur with midline congenital intracranial anomalies such as agenesis of corpus callosum, brainstem abnormalities, and nasal encephalocele and has also been associated with glioma involving the intracranial optic nerves, chiasm, and optic tracts [8, 29]. Presence of these abnormalities coexisting with BWS strongly points to a possible link of BWS with midline anomalies [4]. It has been suggested that the gene Shh may have a key role in the development of encephalocele as well as in occurrence of other midline defects observed in children including BWS, myelomeningocele, and cleft palate. Additionally, these midline defects have been observed to arise at about the same gestational age [4]. This is however still a subject to further investigation. The question remains whether Chiari in BWS is secondary to hypertrophy or a midline anomaly complex as suggested by some.
Management and outcomes Hydrocephalus is associated with Chiari I in about 4–18 % (average of 10 %) of cases, in which case a CSF diversion in form of shunt or endoscopic third ventriculostomy should be the initial form of treatment for the patient [14, 23]. In spite of previously suggested methods of estimating the volume of the
Childs Nerv Syst Table 1 Syndromes with hemihypertrophy associated with Type I Chiari Syndrome
Additional cranial findings other than Chiari I
Aetiology as mentioned by the authors
Proteus
Corpus callosal malformations, hemimegalencephaly, subependymal calcified nodules, periventricular cysts, meningioma, craniosynostosis, exostosis of the skull. Normal size of brain but with prominent extracerebral fluid-filled spaces, thinning of the corpus callosum, enlarged ventricles, particularly in the trigone region, a persistent cavum septum pellucidum and cavum vergae. No other intracranial lesions, but mental retardation and seizures are common. Cysts of septum pellucidum, cerebral atrophy, localized hypervascularization and pachygyria.
Lethal somatic gene mutation which gives rise to a mosaic state that allows survival.
Sotos
Klippel–Trenaunay–Weber Weaver
Marshal–Smith
Costello Simpson–Golabi–Behmel
Hypoplasia of corpus callosum, pachygyria, polymicrogyria, ventriculomegaly, small cerebellum. No other brain structural abnormalities documented. Agenesis of corpus callosum, hydrocephalus, and aplasia of cerebellar vermis.
Beckwith–Wiedemann syndrome Dandy–Walker malformation, agenesis of corpus callosum, and brainstem abnormalities. It has also been associated with glioma involving the intracranial optic nerves, chiasm, and optic tracts. Nasal encephalocele.
posterior fossa in the literature, the lack of comparisons to normal does not allow strict conclusions [1, 22, 28]. However, patients with classical symptoms of Type I Chiari such as posterior headaches and an MR showing foramen magnum crowding or abnormalities in CSF flow often benefit from foramen magnum decompression or decompressive craniotomy, with or without duroplasty [13]. Conservative management is safe in the asymptomatic cases [13].
Illustrative case A 1 1/2-year-old male child presented to the pediatric outpatient department with a 6-month history of breath holding, vacant stare, and bluish discoloration lasting for less than a minute. He had no other significant complaint. His initial Fig. 1 Clinical picture showing. a Picture of the presence of an omphalocele in the patient. b Demonstrating facial asymmetry in the same patient. c Asymmetry in sizes of both lower limbs in the patient
Either mutations in or deletion of NSD1 gene. A sporadic condition but rarely genetic transmission as a dominant trait has been observed including male-to-male transmission. None. Either occurs sporadically or is inherited by autosomal dominance. NSD1 mutations as in Sotos but in addition arises from mutations in zeste homolog 2 (EZH2) gene. Typically occurs sporadically. An inverted duplication of Chromosome 2q. All documented cases are sporadic. Unknown. An X-linked recessive syndrome. Due to either mutations in the gene encoding glypican (GPC3) on Xq26 or duplication of the GPC4 gene in Type I form. Involves Xp22 in the more severe Type II form. Alteration in expression of IGF2 and H19 on telomeric region, and CDKN1C, KCNQ1, and KCNQIOT1 genes of the centromeric region of chromosome 11p15.5.
evaluation for seizure disorder with an electroencephalography was normal. On general examination, he had asymmetry of size of one side of the body compared to the other side (Fig. 1). He also had macrocephaly with fundoscopy showing papilledema. Past medical history included clinical examination findings at birth of an abdominal mass which was confirmed by ultrasound scan to be bilateral adrenal gland hematoma with multiloculated cystic appearance of the right adrenal gland and left renal multiple calyceal cysts. There was no significant family history. On examination, the child was conscious and alert, normal vital signs, and with an occipitofrontal head circumference of 50 cm (95th percentile for same age and sex) with fundus showing papilledema. He had increased muscle bulk of the right upper and lower limb compared to the left. Central nervous system examination was normal. He also had an
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Fig. 2 Pre-op MRI scan. a Sagittal T2-weighted and MRI brain showing tonsillar herniation through the foramen magnum in the sagittal section. Notice the wide open aqueduct with fourth ventricular obstruction and
descended tonsils. b Axial T2-weighted MRI showing ventriculomegaly. c Sagittal section of computerized tomography to depict the crowded posterior fossa
omphalocele (Fig. 1) with bilateral undescended testes. A clinical diagnosis of Beckwith–Wiedemann syndrome (BWS) was made. His magnetic resonance imaging (MRI) of the brain showed dilatation of both lateral ventricles and the third ventricle but with normal-sized fourth ventricle. There was also tonsillar herniation of 11.2 mm length below the foramen magnum on the MRI with no evidence of cervical syrinx (Fig. 2). Endocrinology screening showed a normal serum cortisol and plasma glucose levels, eliminating hypoglycemia which is one of the characteristics of BWS. He underwent endoscopic third ventriculostomy for his obstructive hydrocephalus prior to considering foramen magnum decompression. There was significant improvement of his symptoms with reduced frequency and duration of the episodes. He has been on follow-up since then. On the follow-up MRI scan, the tonsil descent remained the same but with resolution of clinical signs and radiological improvement of ventriculomegaly at 1-year follow-up (Fig. 3). At 1year follow-up, he does not have any significant complaints.
This patient had macroglossia and omphalocele which form part of the major criteria and also had hemihypertrophy, which is a minor criterion for the diagnosis of BWS. He additionally had multiloculated cystic appearance of the right gland along with multiple left renal calyceal cysts which add to the diagnosis of BWS, hence confirming the phenotype of BWS. Unfortunately, his genetic confirmation with chromosomal studies could not be undertaken for financial reasons. Since our patient presented with hydrocephalus secondary to the fourth ventricular obstruction due to the Chiari malformation, we began with management of the hydrocephalus (Fig. 2). The presentation of hydrocephalus was probably secondary to the fourth ventricular outlet obstruction and in turn would have added to the pathology of tonsillar herniation. On the follow-up MRI scan, the tonsil descent remained the same despite the resolution of clinical signs and radiological improvement of the ventriculomegaly at 1-year follow-up (Fig. 3). In view of clinical and radiological improvement of hydrocephalus, persistent tonsillar descent points to his diagnosis being Chiari primarily. At 1-year follow-up, he did not
Fig. 3 Post-op MRI scan. Sagittal T2-weighted cuts in a Turbo spin-echo (TSE) sequence and b three-dimensional (3D) constructive interference in steady-state (CISS) sequence respectively at 3 months post-op demonstrating the presence of flow voids (long line arrow) along with reduced caliber of the aqueduct (short block arrow). Notice the
persistence of tonsillar herniation through the foramen magnum but with significant decrease of the ventriculomegaly. c Axial cut of T2weighted of the same MRI scan also showing reduction of the ventriculomegaly
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have any significant complaints, but we agree that he requires a longer follow-up in view of Btight^ posterior fossa and a possibility of newer development secondary to the Chiari malformation in growing years. The fact that the fourth ventricle was not dilated suggests a relatively tight posterior fossa secondary to the hypertrophied cerebellum or skull base.
Conclusion We report a rare association of Chiari with BWS and with a rare presentation of reflex apneic spells. Chiari in BWS may be a manifestation of the hemihypertrophic phenotype and is a rare CNS involvement. We believe that a common pathogenesis of Type I Chiari malformation occurs in conditions of hemihypertrophy including BWS, probably secondary to dysmorphology involving the posterior cranial fossa, and is not just an associated finding. Conflict of interest The authors declare that they have no competing interests.
References 1. Alperin N, Bagci A, Monette D, Green BA (2012). Automated measurement of posterior cranial fossa volume and relationship with linear pcf landmarks in Chiari malformations I. Congress of Neurological Surgeons. 2012 Annual Meeting 2. Beckwith JB (1963) Extreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of the kidneys and pancreas, and Leydig cell hyperplasia—another syndrome? Presented at the Annual Meeting of Western Society for Pediatric Research, Los Angeles 3. Benjamin MD, Santiago J, Hebert JC, Thirion S, Ranaivojaona S, Alvarez C et al (2011) Hemihypertrophy and scoliosis revealing a Chiari 1 malformation with syringomyelia. Arch Pediatr 8(11):1210– 1215 4. Broekman MLD, Hoving EW, Kho KH, Speleman L, Han KS, Hanlo PW (2008) Hanlo. Nasal encephalocele in a child with Beckwith– Wiedemann syndrome. J Neurosurg Pediatr 1:485–487 5. Dias MS, Partington MD (2011) Normal and abnormal embryology of the brain. In: Winn HR (ed) Youmans Neurological Surgery, 6th edn. Elsevier Saunders, Philadelphia, pp 1895–1896 6. Dietrich RB, Glidden DE, Roth GM, Martin RA, Demo DS (1998) The Proteus syndrome: CNS manifestations. AJNR Am J Neuroradiol 19:987–990 7. Elliott M, Maher ER (1994) Beckwith-Wiedemann syndrome. J Med Genet 31:560–564 8. Gardiner K, Chitayat D, Choufani S, Shuman C, Blaser S, Terespolsky D et al (2012) Brain abnormalities in patients with Beckwith-Wiedemann syndrome. Am J Med Genet 158A:1388– 1394 9. Gibson WT, Hood RL, Zhan SH, Bulman DE, Fejes AP, Moore R et al (2012) Mutations in EZH2 Cause Weaver syndrome. Am J Hum Genet 90:110–118 10. Gicquel C, Rossignol S, Le Bouc Y (2005) Beckwith-Wiedemann syndrome. Orphanet Encycl
11. Gorlin RJ (1984) Proteus syndrome. J Clin Dysmorphol 2:8–9 12. Kawame H, Matsui M, Kurosawa K, Matsuo M, Masuno M, Ohashi H et al (2003) Further delineation of the behavioral and neurologic features in Costello syndrome. Am J Med Genet 118A:8–14 13. Keh YS, Abernethy L, Pettorini B (2013) Association between Noonan syndrome and Chiari I malformation: a case-based update. Childs Nerv Syst 29:749–752 14. Loukas M, Shayota BJ, Oelhafen K, Miller JH, Chern JJ, Tubbs RS et al (2011) Associated disorders of Chiari Type I malformations. A review. Neurosurg Focus 31(3):e3 15. Macías-Gómez NM, Leal-Ugarte E, Gutiérrez-Angulo M, Domínguez-Quezada G, Rivera H, Barros-Núñez P (2012) 46, XX ovotesticular disorder in a Mexican patient with Beckwith– Wiedemann syndrome: a case report. J Med Case Rep 6:301 16. Matamala GN, Toro MAF, Ugarte EV, Mendoza ML (2008) Beckwith-Wiedemann Syndrome: presentation of a case report. Med Oral Patol Oral Cir Bucal 13(10):e640–e643 17. Meizner I, Carmi R, Katz M, Insler V (1989) In-utero prenatal diagnosis of Beckwith-Wiedemann syndrome: a case report. Eur J Obstet Gynecol Reprod Biol 32(3):259–264 18. Melo DG, Acosta AX, de Almeida Salles MA, Pina-Neto JM, de Catro JD V, Santos AC (2002) Sotos syndrome (cerebral gigantism): analysis of 8 cases. Arq Neuropsiquiatr 60(2-A):234–238 19. Pettorini BL, Oesman C, Magdum S (2010) New presenting symptoms of Chiari I malformation: report of two cases. Childs Nerv Syst 26(3):399–402 20. Shaw AC, van Balkom IDC, Bauer M, Cole TRP, Delrue MA, van Haeringen A et al (2010) Phenotype and natural history in Marshall– Smith syndrome. Am J Med Genet 152A:2714–2726 21. Shawky RM, Abd-Elkhalek HS, Gad S (2014) Interfamilial variability in Simpson–Golabi–Behmel syndrome with bilateral posterior ear lobule creases. Egyptian J Med Hum Genet 15:87–90 22. Tubbs RS, Elton S, Grabb P, Dockery SE, Bartolucci AA, Oakes WJ (2001) Analysis of the posterior fossa in children with the Chiari 0 malformation. Neurosurgery 48(5):1050–1055 23. Tubbs RS, Hankinson TC, Wellons JC III (2012) Chiari malformations and syringohydromyelia. In: Ellenbogen RG, Abdulrauf SI, Sekhar LN (eds) Principles of neurosurgery, 3rd edn. Elsevier Saunders, Philadelphia, pp 157–168 24. Tubbs RS, Oakes WJ (2005) Beckwith-Wiedemann syndrome in a child with Chiari I malformation. J Neurosurg Pediatr 103(2):172– 174 25. Tubbs RS, Smyth MD, Wellons JC, Blount JP, Oakes WJ (2003) Cutaneous manifestations and the Chiari I malformation. Pediatr Neurol 29(3):250–252 26. Tubbs RS, Smyth MD, Wellons JC, Oakes WJ (2003) Hemihypertrophy and the Chiari I malformation. Pediatr Neurosurg 38(5):258–261 27. Viljoen DL (1998) Klippel-Trenaunay-Weber syndrome (angiomacroglossia-gigantism syndrome). J Med Genet 25:250–252 28. Vurdem UE, Acer N, Ertekin T, Savranlar A, Inci MF (2012) Analysis of the volumes of the posterior cranial fossa, cerebellum, and herniated tonsils using the stereological methods in patients with chiari type imalformation. Sci World J. doi:10.1100/2012/616934 29. Weinstein JM, Backonja M, Houston LW, Gilbert EE, Finlay JL, Duff TA et al (1986) Optic glioma associated with Beckwith-Wiedemann syndrome. Pediatr Neurol 2(5):308–310 30. Wiedemann HR (1964) Familial malformation complex with umbilical hernia and macroglossia—a Bnew syndrome?^. J Genet Hum 13: 232–233 31. Young EL, Wishnow R, Nigro MA (2006) Expanding the clinical picture of Simpson-Golabi-Behmel syndrome. Pediatr Neurol 34(2): 139–142
CASE-BASED UPDATE
Beckwith–Wiedemann syndrome and Chiari I malformation—a case-based review of central nervous system involvement in hemihypertrophy syndromes Suhas Udayakumaran & Chiazor U. Onyia
Received: 9 January 2015 / Accepted: 3 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Background Beckwith–Wiedemann syndrome (BWS) is an unusual complex of abnormalities that includes mainly omphalocele, macroglossia, gigantism, visceromegaly, and neonatal hypoglycemia. Type I Chiari malformation, on the other hand, is defined as ectopia of the cerebellar tonsils below the plane of the foramen magnum. Only one case of association of BWS with Chiari I malformation has been previously reported in the literature. Discussion Several conditions involving congenital hemihypertrophy have been previously reported in association with Type I Chiari malformation. The pathophysiological mechanism for most of these associations is thought to be quite complex and still remains unclear. However, the presence of tonsillar herniation in BWS has been explained by Tubbs and Oakes in the only one existing case report of BWS with Type I Chiari malformation in the literature, to be due to associated hemihypertrophy of the skull base. We additionally suggest that cerebellar hypertrophy may also contribute to the tonsillar herniation and fourth ventricular outlet obstruction. Illustrative case We now report our recent experience on this association following a review of the literature on association of other hemihypertrophy syndromes with the central nervous system anomalies.
No portion of this work has been presented elsewhere. S. Udayakumaran (*) Division of Pediatric Neurosurgery, Department of Neurosurgery, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala 682 041, India e-mail: [email protected] C. U. Onyia Neurosurgery Division, Department of Surgery, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria
Conclusion We believe that a common pathogenesis of Type I Chiari malformation occurs in conditions of hemihypertrophy including BWS, probably secondary to dysmorphology involving the posterior cranial fossa, and is not just an associated finding. Keywords Chiari I . Beckwith–Wiedemann syndrome . Hemihypertrophy
Introduction Association of Beckwith–Wiedemann syndrome (BWS) with Type I Chiari malformation is extremely rare [14, 24]. Only one case has been reported in the English literature to the best of our knowledge [14, 24].We report a case of a child diagnosed with BWS associated with Type I Chiari malformation. We also review other congenital hypertrophy syndromes and their association with the central nervous system anomalies and in particular Chiari malformation.
Background BWS is a rare syndrome characterized by the presence of macroglossia, macrosomia, and defects of the anterior abdominal wall such as omphalocele [10, 15–17]. It is also referred to as exomphalos-macroglossia-gigantism syndrome [10]. BWS was described independently by two investigators— first in 1963 by the American pathologist Dr. John Bruce Beckwith who identified macroglossia, omphalocele, cytomegaly of the fetal adrenal cortex, renal medullary dysplasia, and visceromegaly in three postmortem cases and then in 1964 by a German pediatrician Dr. Hans-Rudolf
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Wiedemann in a report of three cases of siblings who had similar clinical characteristics, with the addition of diaphragmatic defects and hypoglycemia [2, 7, 16, 30].
Epidemiology It has an incidence of 1 in 13,700 live births [10, 15] and is postulated to have a genetic basis. The mechanism by which it occurs is complex and unclear [15, 16]. It is sporadic in approximately 85 % of cases, inherited in 15 % of cases, and is due to chromosomal abnormalities in 1 % of cases [15, 16].
Clinical manifestations and diagnosis The diagnosis of BWS requires at least three clinical findings including at least two major findings [7, 10]. The major clinical findings include macroglossia which is present in more than 95 % of the patients, macrosomia or overgrowth which is defined as prenatal and/or postnatal growth greater than the 97th percentile and is present in about 80 % of the patients, abdominal wall defects (such as exomphalos, umbilical hernia, or diastasis recti) present in 65 % of these patients, and organomegaly involving mainly the abdominal organs such as the kidneys, liver, spleen, pancreas, and adrenal glands in 50 % of cases [10]. The minor criteria include hypoglycemia in the neonatal period (seen in about 40 % of patients), renal malformations or abnormalities as medullary dysplasia, ear creases and pits which occurs in 30 %, facial nevus flammeus also in 30 % of patients, hemihypertrophy which is seen in 30–35 % of patients, embryonal tumors (such as Wilms’ tumor, neuroblastoma, adrenal carcinoma, hepatoblastoma, rhabdomyosarcoma), and polyhydramnios [10]. BWS is one of the syndromes known to present with congenital hemihypertrophy [14, 24]. Congenital hypertrophy itself is known to either occur in isolation or in conjunction with these syndromes such as Proteus, Sotos, Klippel–Trenaunay– Weber, Weaver, Marshal–Smith, Costello, and Simpson– Golabi–Behmel syndromes [6, 8, 9, 11, 12, 14, 18, 20, 21, 24, 26, 27, 29, 31] (Table 1). Congenital hypertrophy is classified as simple when only a single extremity is involved, complex when majority of one half of the body is affected, with involvement of either the same side or both sides, and hemifacial when it involves only one side of the face [26]. Occurrence of BWS with Type I Chiari malformation has been reported in only one case report [14, 24]. Type I Chiari malformation, defined as ectopia of the cerebellar tonsils below the plane of the foramen magnum by more than 3 mm [25, 26], has been explained by various postulations viz. the hindbrain dysgenesis and developmental arrest theory, caudal traction theory, small posterior fossa/hindbrain overgrowth theory, hydrocephalus and hydrodynamic theory of Gardner, and
the lack of embryological ventricular distention theory by McLone and Kneeper [5, 14, 23, 26]. Presence of tonsillar herniation in BWS has been explained by Tubbs and Oakes to be due to associated hemihypertrophy of the skullbase [14, 24]. We additionally suggest that cerebellar hypertrophy may also contribute to the tonsillar herniation and fourth ventricular outlet obstruction. Whether the cerebellar hypertrophy is a part of the hemihypertrophy complex or is an independent organomegaly is difficult to clarify. Some other conditions involving congenital hemihypertrophy have also been reported to be associated with Type I Chiari malformation [3, 25, 26]. The pathophysiological mechanism of this association is thought to be complex [3]. Similar coexistence of both Type I Chiari malformation is seen in a condition called Costello syndrome, a rare genetic disorder that affects parts of the body particularly the head and the heart, hence suggesting that there may be a common pathogenesis of Type I Chiari malformation in these other conditions of hemihypertrophy [3, 12, 14, 19, 26]. Tubbs and Oakes together with coworkers concluded that occurrences of both Type I Chiari malformation and congenital hemihypertrophy in the same patient were pathologically related, perhaps by slight dysmorphologies of the posterior cranial fossa, and are not just spurious findings [24, 26]. They also suggested that this is likely to be from the dysembryology of the mesoderm [25, 26]. BWS has also been previously reported to occur with midline congenital intracranial anomalies such as agenesis of corpus callosum, brainstem abnormalities, and nasal encephalocele and has also been associated with glioma involving the intracranial optic nerves, chiasm, and optic tracts [8, 29]. Presence of these abnormalities coexisting with BWS strongly points to a possible link of BWS with midline anomalies [4]. It has been suggested that the gene Shh may have a key role in the development of encephalocele as well as in occurrence of other midline defects observed in children including BWS, myelomeningocele, and cleft palate. Additionally, these midline defects have been observed to arise at about the same gestational age [4]. This is however still a subject to further investigation. The question remains whether Chiari in BWS is secondary to hypertrophy or a midline anomaly complex as suggested by some.
Management and outcomes Hydrocephalus is associated with Chiari I in about 4–18 % (average of 10 %) of cases, in which case a CSF diversion in form of shunt or endoscopic third ventriculostomy should be the initial form of treatment for the patient [14, 23]. In spite of previously suggested methods of estimating the volume of the
Childs Nerv Syst Table 1 Syndromes with hemihypertrophy associated with Type I Chiari Syndrome
Additional cranial findings other than Chiari I
Aetiology as mentioned by the authors
Proteus
Corpus callosal malformations, hemimegalencephaly, subependymal calcified nodules, periventricular cysts, meningioma, craniosynostosis, exostosis of the skull. Normal size of brain but with prominent extracerebral fluid-filled spaces, thinning of the corpus callosum, enlarged ventricles, particularly in the trigone region, a persistent cavum septum pellucidum and cavum vergae. No other intracranial lesions, but mental retardation and seizures are common. Cysts of septum pellucidum, cerebral atrophy, localized hypervascularization and pachygyria.
Lethal somatic gene mutation which gives rise to a mosaic state that allows survival.
Sotos
Klippel–Trenaunay–Weber Weaver
Marshal–Smith
Costello Simpson–Golabi–Behmel
Hypoplasia of corpus callosum, pachygyria, polymicrogyria, ventriculomegaly, small cerebellum. No other brain structural abnormalities documented. Agenesis of corpus callosum, hydrocephalus, and aplasia of cerebellar vermis.
Beckwith–Wiedemann syndrome Dandy–Walker malformation, agenesis of corpus callosum, and brainstem abnormalities. It has also been associated with glioma involving the intracranial optic nerves, chiasm, and optic tracts. Nasal encephalocele.
posterior fossa in the literature, the lack of comparisons to normal does not allow strict conclusions [1, 22, 28]. However, patients with classical symptoms of Type I Chiari such as posterior headaches and an MR showing foramen magnum crowding or abnormalities in CSF flow often benefit from foramen magnum decompression or decompressive craniotomy, with or without duroplasty [13]. Conservative management is safe in the asymptomatic cases [13].
Illustrative case A 1 1/2-year-old male child presented to the pediatric outpatient department with a 6-month history of breath holding, vacant stare, and bluish discoloration lasting for less than a minute. He had no other significant complaint. His initial Fig. 1 Clinical picture showing. a Picture of the presence of an omphalocele in the patient. b Demonstrating facial asymmetry in the same patient. c Asymmetry in sizes of both lower limbs in the patient
Either mutations in or deletion of NSD1 gene. A sporadic condition but rarely genetic transmission as a dominant trait has been observed including male-to-male transmission. None. Either occurs sporadically or is inherited by autosomal dominance. NSD1 mutations as in Sotos but in addition arises from mutations in zeste homolog 2 (EZH2) gene. Typically occurs sporadically. An inverted duplication of Chromosome 2q. All documented cases are sporadic. Unknown. An X-linked recessive syndrome. Due to either mutations in the gene encoding glypican (GPC3) on Xq26 or duplication of the GPC4 gene in Type I form. Involves Xp22 in the more severe Type II form. Alteration in expression of IGF2 and H19 on telomeric region, and CDKN1C, KCNQ1, and KCNQIOT1 genes of the centromeric region of chromosome 11p15.5.
evaluation for seizure disorder with an electroencephalography was normal. On general examination, he had asymmetry of size of one side of the body compared to the other side (Fig. 1). He also had macrocephaly with fundoscopy showing papilledema. Past medical history included clinical examination findings at birth of an abdominal mass which was confirmed by ultrasound scan to be bilateral adrenal gland hematoma with multiloculated cystic appearance of the right adrenal gland and left renal multiple calyceal cysts. There was no significant family history. On examination, the child was conscious and alert, normal vital signs, and with an occipitofrontal head circumference of 50 cm (95th percentile for same age and sex) with fundus showing papilledema. He had increased muscle bulk of the right upper and lower limb compared to the left. Central nervous system examination was normal. He also had an
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Fig. 2 Pre-op MRI scan. a Sagittal T2-weighted and MRI brain showing tonsillar herniation through the foramen magnum in the sagittal section. Notice the wide open aqueduct with fourth ventricular obstruction and
descended tonsils. b Axial T2-weighted MRI showing ventriculomegaly. c Sagittal section of computerized tomography to depict the crowded posterior fossa
omphalocele (Fig. 1) with bilateral undescended testes. A clinical diagnosis of Beckwith–Wiedemann syndrome (BWS) was made. His magnetic resonance imaging (MRI) of the brain showed dilatation of both lateral ventricles and the third ventricle but with normal-sized fourth ventricle. There was also tonsillar herniation of 11.2 mm length below the foramen magnum on the MRI with no evidence of cervical syrinx (Fig. 2). Endocrinology screening showed a normal serum cortisol and plasma glucose levels, eliminating hypoglycemia which is one of the characteristics of BWS. He underwent endoscopic third ventriculostomy for his obstructive hydrocephalus prior to considering foramen magnum decompression. There was significant improvement of his symptoms with reduced frequency and duration of the episodes. He has been on follow-up since then. On the follow-up MRI scan, the tonsil descent remained the same but with resolution of clinical signs and radiological improvement of ventriculomegaly at 1-year follow-up (Fig. 3). At 1year follow-up, he does not have any significant complaints.
This patient had macroglossia and omphalocele which form part of the major criteria and also had hemihypertrophy, which is a minor criterion for the diagnosis of BWS. He additionally had multiloculated cystic appearance of the right gland along with multiple left renal calyceal cysts which add to the diagnosis of BWS, hence confirming the phenotype of BWS. Unfortunately, his genetic confirmation with chromosomal studies could not be undertaken for financial reasons. Since our patient presented with hydrocephalus secondary to the fourth ventricular obstruction due to the Chiari malformation, we began with management of the hydrocephalus (Fig. 2). The presentation of hydrocephalus was probably secondary to the fourth ventricular outlet obstruction and in turn would have added to the pathology of tonsillar herniation. On the follow-up MRI scan, the tonsil descent remained the same despite the resolution of clinical signs and radiological improvement of the ventriculomegaly at 1-year follow-up (Fig. 3). In view of clinical and radiological improvement of hydrocephalus, persistent tonsillar descent points to his diagnosis being Chiari primarily. At 1-year follow-up, he did not
Fig. 3 Post-op MRI scan. Sagittal T2-weighted cuts in a Turbo spin-echo (TSE) sequence and b three-dimensional (3D) constructive interference in steady-state (CISS) sequence respectively at 3 months post-op demonstrating the presence of flow voids (long line arrow) along with reduced caliber of the aqueduct (short block arrow). Notice the
persistence of tonsillar herniation through the foramen magnum but with significant decrease of the ventriculomegaly. c Axial cut of T2weighted of the same MRI scan also showing reduction of the ventriculomegaly
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have any significant complaints, but we agree that he requires a longer follow-up in view of Btight^ posterior fossa and a possibility of newer development secondary to the Chiari malformation in growing years. The fact that the fourth ventricle was not dilated suggests a relatively tight posterior fossa secondary to the hypertrophied cerebellum or skull base.
Conclusion We report a rare association of Chiari with BWS and with a rare presentation of reflex apneic spells. Chiari in BWS may be a manifestation of the hemihypertrophic phenotype and is a rare CNS involvement. We believe that a common pathogenesis of Type I Chiari malformation occurs in conditions of hemihypertrophy including BWS, probably secondary to dysmorphology involving the posterior cranial fossa, and is not just an associated finding. Conflict of interest The authors declare that they have no competing interests.
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