Short Communication
247
Christianson Syndrome: Spectrum of Neuroimaging Findings Thangamadhan Bosemani1 Ginevra Zanni2 Adam L. Hartman3 Thierry A. G. M. Huisman1 Enrico Bertini2 Andrea Poretti1
Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States 2 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children’s Research Hospital, Rome, Italy 3 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States 4 Schneider’s Children Medical Center of Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Address for correspondence Andrea Poretti, MD, Section of Pediatric Neuroradiology, Division of Pediatric Radiology, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, Charlotte R. Bloomberg Children’s Center, Sheikh Zayed Tower, Room 4174, 1800 Orleans Street, Baltimore, MD 212870842, United States (e-mail: [email protected]).
Neuropediatrics 2014;45:247–251.
Abstract
Keywords
► Christianson syndrome ► neuroimaging ► cerebellar atrophy ► cerebellar cortex hyperintensity
Christianson syndrome (CS) is caused by mutations in SLC9A6 and is characterized by severe intellectual disability, absent speech, microcephaly, ataxia, seizures, and behavioral abnormalities. The clinical phenotypes of CS and Angelman syndrome (AS) are similar. Differentiation between CS and AS is important in terms of genetic counseling. We report on two children with CS and confirmed mutations in SLC9A6 focusing on neuroimaging findings and review the available literature. Cerebellar atrophy (CA) occurs in approximately 60% of the patients with CS and develops after the age of 12 months. Hyperintense signal of the cerebellar cortex (CbC) is less common, and may be diffuse, patchy, or involve only the inferior part of the cerebellum and is best seen on coronal fluid attenuation inversion recovery images. CA and CbChyperintensity are not neuroimaging features of AS. In a child with the phenotype of AS, CA and/or CbC-hyperintensity are rather specific for CS and should prioritize sequencing of SLC9A6.
Introduction Christianson syndrome (CS; OMIM 300243) is a rare, X-linked disease caused by mutations in SLC9A6, located on chromosome Xq26.3.1 CS is characterized by severe intellectual disability, absent speech, postnatal microcephaly, ataxia, epilepsy, ophthalmoplegia, happy demeanor, easily provoked laughter, and autistic features.1–7 The clinical phenotype of CS
received August 11, 2013 accepted after revision September 25, 2013 published online November 27, 2013
mimics Angelman syndrome (AS) and CS was initially called X-linked Angelman-like syndrome.1,7,8 There are only few articles on neuroimaging findings in CS describing different degrees of cerebellar atrophy (CA) and hyperintense signal of the cortex in the inferior part of the cerebellum. We report on new neuroimaging findings in two children with CS and discuss the specific role of neuroimaging in differentiating between AS and CS.
© 2014 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1363091. ISSN 0174-304X.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
1 Section of Pediatric Neuroradiology, Division of Pediatric Radiology,
Rony Cohen4
Christianson Syndrome: Spectrum of Neuroimaging Findings
Case Report Patient 1 This is a 10-year-old male patient of nonconsanguineous, healthy parents of Caucasian origin. After an uneventful pregnancy, he was born at term by normal delivery. At the age of 6 months, concern for global developmental delay was raised. In addition, microcephaly was noted (head circumference < fifth percentile). Brain magnetic resonance imaging (MRI) at the age of 9 months was normal. At the age of 2 years, he had a first generalized seizure. At this age, he was described as a happy, smiling child. The clinical diagnosis of AS was suggested, but it was not confirmed genetically. His seizure semiology started to change with episodes of pupillary dilation and phases in which he appeared to “look through people.” At the age of approximately 4 years, he developed progressive truncal ataxia. During an episode of status epilepticus, a head computed tomography showed enlarged interfolial cerebellar spaces compatible with CA. At this time, the diagnosis of CS was suspected and confirmed by genetic testing that revealed c.526 þ 1G > A mutation in SLC9A6. A brain MRI obtained at the age of 9 years revealed atrophy of the vermis and cerebellar hemispheres (inferior parts more affected), diffuse fluid attenuation inversion recovery (FLAIR) hyperintensity of the cerebellar cortex (CbC) and secondary enlargement of the fourth ventricle (►Fig. 1A–E). The brain stem, basal ganglia, and supratentorial brain structures were within normal limits. During the last follow-up visit at the age of 10 years, he has medically intractable epilepsy, including both focal onset (left
Bosemani et al.
face grimacing) and generalized seizures in the morning approximately 2 to 4 times a week. A modified Atkins diet was started in addition to his antiepileptic drugs (rufinamide, clobazam, and lamotrigine). His most recent clinical examination revealed microcephaly, muscular hypotonia, truncal ataxia, and AS-like facial dysmorphism. His behavior is characterized by frequent smiling, laughing, and hyperactivity with a shortattention span.
Patient 2 This is a 6-year-old male patient of nonconsanguineous healthy parents of Jewish origin. The pregnancy was normal and he was born at term by forceps-assisted delivery. His motor milestones were delayed and he started walking unsteadily at the age of 3 years. He has no expressive language development and his behavior was classified into the autistic spectrum. Since the age of 2 years, he has medically intractable epileptic seizures. At the last follow-up at the age of 6 years, his clinical examination revealed microcephaly (approximately 5 cm below the fifth percentile), AS-like facial dysmorphism, severe muscular hypotonia, and truncal ataxia. The diagnosis of CS was confirmed by genetic testing that revealed a mutation in SLC9A6. MRI of the brain at the age of 4 and 6 years showed atrophy of the vermis and cerebellar hemispheres (inferior parts more affected), patchy FLAIR hyperintense signal of the CbC and enlargement of the fourth ventricle and supravermian cistern (►Fig. 1F–J). The brain stem, basal ganglia, and supratentorial brain structures were within normal limits.
Fig. 1 Magnetic resonance imaging of the brain in two patients with Christianson syndrome. Patient 1 at the age of 9 years: (A) midsagittal T1weighted image shows atrophy of the cerebellar vermis with secondary enlargement of the fourth ventricle; (B) axial and (C) coronal T2-weighted images demonstrate cerebellar atrophy (CA) with widening of the interfoliar spaces involving mostly the inferior part of the cerebellum; (D) coronal and (E) axial fluid attenuation inversion recovery (FLAIR) images reveal CA with diffuse hyperintensity of the cerebellar cortex (CbC) (arrows). Patient 2 at the age of 6 years: (F) midsagittal T2-weighted image shows atrophy of the vermis with secondary enlargement of the fourth ventricle and supravermian cistern; (G) axial T2-weighted and (H) coronal T1-inversion recovery images demonstrate CA with widening of the interfoliar spaces involving mostly the inferior part of the cerebellum; and (I, J) axial FLAIR images demonstrate CA and patchy foci of hyperintensity in the CbC (arrow). Neuropediatrics
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248
F4/P4
1
7
4/6
0.8/10
49
5
1/8/14/21
1.4
3
1.3
14
7
20
24
10
37
20
3
9
4/7
Age at MRI (y)
10/17
Yes
Yes
No
No
Yes
No
Yes
Yes
Yes
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Presence
Cerebellar atrophy
—
—
— Inferior > superior Inferior > superior
Vermis > hemispheres Vermis > hemispheres
—
—
—
Inferior > superior
Vermis > hemispheres
—
Inferior > superior
only vermis
—
Inferior > superior Inferior > superior
Vermis > hemispheres Vermis > hemispheres
NA
No
NA
Vermis > hemispheres
NA
Yes, only inferior
—
—
No
No
Brain atrophy
No
No
Lipoma between inferior colliculi
No
T2 hyperintense signal periventricular white matter
No
Hippocampal atrophy and T2 hyperintense signal
Brain stem atrophy
NA
NA
NA
NA
NA
NA
NA
Other
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
4/8
Yes, patchy
Yes, diffuse
No
NA
No
NA
No
Yes, only inferior
NA
NA
NA
—
—
NA
NA
NA
NA
NA
NA
Cerebellar cortex hyperintensity
NA
NA
—
— NA
NA
Superior $ inferior
NA
Vermis $ hemispheres
Abbreviations: F, family; MRI, magnetic resonance imaging; NA, not available; P, patient. a Same patient.
Total (N ¼ 17)
2
1
5
This article
1
4
III.9
1
3
1
2
3
This article
F1/IV-6
3
9
F1/IV-1
F1/IV-4
3
V.4
F4/P3
1
2
F4/P2
1
a
F1/P3
F4/P1
F1/P2
1
1a
F1/P1
1
1
Patient
Reference
Table 1 Neuroimaging findings in 17 patients with Christianson syndrome
Christianson Syndrome: Spectrum of Neuroimaging Findings
Neuropediatrics
Bosemani et al.
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249
Christianson Syndrome: Spectrum of Neuroimaging Findings
Discussion CS is a rare disorder mimicking AS. AS is more common than CS and is characterized by severe developmental delay with absent or minimal speech, ataxia, easily provoked laughter, epilepsy, and microcephaly.9 So far, these are all features of CS and CS was initially called X-linked AS-like disease. Neuroimaging findings differ between CS and AS and this may help to differentiate these syndromes. Differentiation between CS and AS is important in terms of diagnosis and genetic counseling. CS has an X-linked inheritance, while there are four major genetic mechanisms which are now known to cause AS.9 The recurrence risk is generally low (< 1%), but there are few exceptions with a much higher recurrence risk.9 To our knowledge, 47 patients with CS have been reported to date.1–7,10 Neuroimaging findings have been reported only in 15 of them (10 children and 5 adults), making it now a total of 17 patients including our 2 children (►Table 1). CA is the most common neuroimaging finding and is present in 10 of 17 patients (59%, including 4/5 adult patients).1–3,5 In 6 of 10 patients, atrophy affected predominantly the inferior parts of the vermis and cerebellar hemispheres.3 In 6 of 10 patients, the cerebellar vermis appeared to be more atrophic compared with the hemispheres,2,3 while in 2 other patients vermis and hemispheres appeared to be equally atrophic.3 CA is defined as having an initially normal cerebellum in a normal size posterior fossa which displays enlarged fissures in comparison to the foliae, secondary to irreversible loss of tissue on follow-up.11 The progressive loss of cerebellar tissue and matching enlargement of interfoliar cerebellar spaces has been shown in CS by serial brain MRI in two patients. Mignot et al reported on neuroimaging findings in a patient with CS at the age of 1, 8, 14, and 21 years. On the first MRI, the cerebellum appeared normal. On the second MRI, interfoliar spaces were enlarged and CA was progressive on the followup MRI studies. Patient 1 in this article had a normal brain MRI at the age of 9 months; however, the cerebellum was markedly atrophic at the age of 9 years. On the basis of the data shown here, CA appears to have its onset in the second year of life. The absence of CA on a brain MRI at less than the age of 12 months does not exclude CS and follow-up studies may be indicated. Of course, the data are limited and further longitudinal MRI studies in young children with CS are needed to confirm this observation. In CS, neuropathological studies have shown that CA is caused by neuronal loss in Purkinje cells within the CbC, whereas the dentate nuclei are spared.2,10 An extensive and progressive loss of Purkinje cells and gliosis of the CbC were observed in the cerebellum of Slc9a6 mutant mice.12 Gliosis of the CbC was also revealed in CS patients by histology.10 On MRI, gliosis is characterized by a T2/FLAIR hyperintensity. T2 and FLAIR hyperintensity of the CbC is the second most common neuroimaging finding in CS and has been reported in 4 of 8 patients (50%; in nine patients no information about CbC signal was available, possibly because of lack of awareness because FLAIR images have been acquired in some of these patients).3 In all four patients, hyperintensity of the CbC was associated with CA. CbC-hyperintensity is evaluated Neuropediatrics
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Bosemani et al.
better on FLAIR compared with T2-weighted images, where the hyperintense signal of the cerebrospinal fluid in the prominent interfolial spaces may mask the adjacent cortex signal changes.11 In two CS-patients reported by Schroer et al, hyperintense signal was seen only in the inferior part of the cerebellum.3 In our two patients, T2-/FLAIR-CbC-hyperintensity was diffuse in one and patchy (affecting mostly the inferior part of the cerebellum) in the other child, respectively. Diffuse and patchy hyperintensity of the CbC was not previously reported in CS. In AS, MRI is usually normal or may show mild cerebral atrophy, delayed myelination, decreased white matter volume, or focal white matter signal change.9 CA and T2-/FLAIRCbC-hyperintensity are not neuroimaging findings of AS. The differential diagnosis of clinical features of AS is wide and includes not only CS, but it also includes other disorders such as Mowat–Wilson syndrome, Pitt–Hopkins syndrome, Rett syndrome, MECP2 duplication, Prader–Willi syndrome, MBD5 mutation, Phelan–McDermid syndrome, adenylosuccinate lyase deficiency, and MTHFR deficiency.13 CA is not a feature of all these disorders, but adenylosuccinate lyase deficiency. In adenylosuccinate lyase deficiency, CA is a rare, late neuroimaging findings superimposed to cerebellar hypoplasia.14,15 T2-/FLAIR-CbC-hyperintensity, however, has not been reported in adenylosuccinate lyase deficiency. Therefore, in a child with clinical features of AS, CA, and/or T2-/FLAIR-CbChyperintensity are rather specific for CS and should initiate the sequencing of SLC9A6. CA with CbC-hyperintensity is however not pathognomonic for CS, and has been reported in few other disorders including infantile neuroaxonal dystrophy (OMIM 256600), Marinesco– Sjögren syndrome (OMIM 248800), phosphomannomutase 2 deficiency (OMIM 212065), and mitochondrial disorders, particularly complex I and Coenzyme Q10 deficiency.16 History, clinical findings, and additional neuroimaging features usually differentiate these disorders from CS. In Slc9a6 mutant mice, cell loss was limited to the cerebellum.12 This observation matches the absence of cerebral atrophy on brain MRI studies of all, but one (the oldest one) CSpatient.10 Neuropathology in this patient revealed global cerebral atrophy with neuronal loss and gliosis predominantly involving CbC, substantia nigra, putamen, and globus pallidus, whereas cerebral cortex and hippocampus were only mildly involved. On neuroimaging, substantia nigra, putamen, and globus pallidus appeared normal in all patients. In a 7-year-old child, hippocampi were atrophic and showed hyperintense signal on T2-weighted images. It is unclear whether hippocampal MRI changes are primarily related to CS or a nonspecific finding secondary to frequent, prolonged seizures. In summary, we present two children with CS who have CA and a new type of CbC-hyperintensity. CA is a common but not consistent neuroimaging finding in CS. In a child with AS-like phenotype, CA and/or CbC-hyperintensity are rather specific for CS and should prioritize sequencing of SLC9A6.
Acknowledgment We thank the patients and their families for their cooperation.
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Christianson Syndrome: Spectrum of Neuroimaging Findings
9 Williams CA, Driscoll DJ, Dagli AI. Clinical and genetic aspects of
Angelman syndrome. Genet Med 2010;12(7):385–395
1 Gilfillan GD, Selmer KK, Roxrud I, et al. SLC9A6 mutations cause X-
2
3 4
5
6
7
8
linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am J Hum Genet 2008;82(4):1003–1010 Christianson AL, Stevenson RE, van der Meyden CH, et al. X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindred is localised to Xq24-q27. J Med Genet 1999;36(10):759–766 Schroer RJ, Holden KR, Tarpey PS, et al. Natural history of Christianson syndrome. Am J Med Genet A 2010;152A(11):2775–2783 Tzschach A, Ullmann R, Ahmed A, et al. Christianson syndrome in a patient with an interstitial Xq26.3 deletion. Am J Med Genet A 2011;155A(11):2771–2774 Mignot C, Héron D, Bursztyn J, et al. Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Brain Dev 2013;35(2):172–176 Riess A, Rossier E, Krüger R, et al. Novel SLC9A6 mutations in two families with Christianson syndrome. Clin Genet 2013;83(6): 596–597 Takahashi Y, Hosoki K, Matsushita M, et al. A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome. Am J Med Genet B Neuropsychiatr Genet 2011;156B(7):799–807 Fichou Y, Bahi-Buisson N, Nectoux J, et al. Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome. Eur J Hum Genet 2009;17(11):1378–1380
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10 Garbern JY, Neumann M, Trojanowski JQ, et al. A mutation affect-
11
12
13
14
15
16
ing the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain 2010;133(Pt 5):1391–1402 Poretti A, Wolf NI, Boltshauser E. Differential diagnosis of cerebellar atrophy in childhood. Eur J Paediatr Neurol 2008;12(3): 155–167 Strømme P, Dobrenis K, Sillitoe RV, et al. X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction. Brain 2011;134(Pt 11): 3369–3383 Dagli AI, Williams CA. Angelman syndrome. In: Pagon RA, Adam MP, Bird TD, et al, eds. GeneReviews. Seattle, WA: University of Washington; 2011 Edery P, Chabrier S, Ceballos-Picot I, Marie S, Vincent MF, Tardieu M. Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: a report on three patients. Am J Med Genet A 2003;120A(2):185–190 Jurecka A, Zikanova M, Jurkiewicz E, Tylki-Szymańska A. Attenuated adenylosuccinate lyase deficiency: a report of one case and a review of the literature. Neuropediatrics 2013 (epub ahead of print). doi:10.1055/s-0033-1337335 Poretti A, Boltshauser E. Table 20. Cerebellar cortex hyperintensity. In: Boltshauser E, Schmahmann JD, eds. Cerebellar Disorders in Children. London, United Kingdom: Mac Keith Press; 2012:415
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References
Bosemani et al.
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247
Christianson Syndrome: Spectrum of Neuroimaging Findings Thangamadhan Bosemani1 Ginevra Zanni2 Adam L. Hartman3 Thierry A. G. M. Huisman1 Enrico Bertini2 Andrea Poretti1
Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States 2 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children’s Research Hospital, Rome, Italy 3 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States 4 Schneider’s Children Medical Center of Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Address for correspondence Andrea Poretti, MD, Section of Pediatric Neuroradiology, Division of Pediatric Radiology, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, Charlotte R. Bloomberg Children’s Center, Sheikh Zayed Tower, Room 4174, 1800 Orleans Street, Baltimore, MD 212870842, United States (e-mail: [email protected]).
Neuropediatrics 2014;45:247–251.
Abstract
Keywords
► Christianson syndrome ► neuroimaging ► cerebellar atrophy ► cerebellar cortex hyperintensity
Christianson syndrome (CS) is caused by mutations in SLC9A6 and is characterized by severe intellectual disability, absent speech, microcephaly, ataxia, seizures, and behavioral abnormalities. The clinical phenotypes of CS and Angelman syndrome (AS) are similar. Differentiation between CS and AS is important in terms of genetic counseling. We report on two children with CS and confirmed mutations in SLC9A6 focusing on neuroimaging findings and review the available literature. Cerebellar atrophy (CA) occurs in approximately 60% of the patients with CS and develops after the age of 12 months. Hyperintense signal of the cerebellar cortex (CbC) is less common, and may be diffuse, patchy, or involve only the inferior part of the cerebellum and is best seen on coronal fluid attenuation inversion recovery images. CA and CbChyperintensity are not neuroimaging features of AS. In a child with the phenotype of AS, CA and/or CbC-hyperintensity are rather specific for CS and should prioritize sequencing of SLC9A6.
Introduction Christianson syndrome (CS; OMIM 300243) is a rare, X-linked disease caused by mutations in SLC9A6, located on chromosome Xq26.3.1 CS is characterized by severe intellectual disability, absent speech, postnatal microcephaly, ataxia, epilepsy, ophthalmoplegia, happy demeanor, easily provoked laughter, and autistic features.1–7 The clinical phenotype of CS
received August 11, 2013 accepted after revision September 25, 2013 published online November 27, 2013
mimics Angelman syndrome (AS) and CS was initially called X-linked Angelman-like syndrome.1,7,8 There are only few articles on neuroimaging findings in CS describing different degrees of cerebellar atrophy (CA) and hyperintense signal of the cortex in the inferior part of the cerebellum. We report on new neuroimaging findings in two children with CS and discuss the specific role of neuroimaging in differentiating between AS and CS.
© 2014 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1363091. ISSN 0174-304X.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
1 Section of Pediatric Neuroradiology, Division of Pediatric Radiology,
Rony Cohen4
Christianson Syndrome: Spectrum of Neuroimaging Findings
Case Report Patient 1 This is a 10-year-old male patient of nonconsanguineous, healthy parents of Caucasian origin. After an uneventful pregnancy, he was born at term by normal delivery. At the age of 6 months, concern for global developmental delay was raised. In addition, microcephaly was noted (head circumference < fifth percentile). Brain magnetic resonance imaging (MRI) at the age of 9 months was normal. At the age of 2 years, he had a first generalized seizure. At this age, he was described as a happy, smiling child. The clinical diagnosis of AS was suggested, but it was not confirmed genetically. His seizure semiology started to change with episodes of pupillary dilation and phases in which he appeared to “look through people.” At the age of approximately 4 years, he developed progressive truncal ataxia. During an episode of status epilepticus, a head computed tomography showed enlarged interfolial cerebellar spaces compatible with CA. At this time, the diagnosis of CS was suspected and confirmed by genetic testing that revealed c.526 þ 1G > A mutation in SLC9A6. A brain MRI obtained at the age of 9 years revealed atrophy of the vermis and cerebellar hemispheres (inferior parts more affected), diffuse fluid attenuation inversion recovery (FLAIR) hyperintensity of the cerebellar cortex (CbC) and secondary enlargement of the fourth ventricle (►Fig. 1A–E). The brain stem, basal ganglia, and supratentorial brain structures were within normal limits. During the last follow-up visit at the age of 10 years, he has medically intractable epilepsy, including both focal onset (left
Bosemani et al.
face grimacing) and generalized seizures in the morning approximately 2 to 4 times a week. A modified Atkins diet was started in addition to his antiepileptic drugs (rufinamide, clobazam, and lamotrigine). His most recent clinical examination revealed microcephaly, muscular hypotonia, truncal ataxia, and AS-like facial dysmorphism. His behavior is characterized by frequent smiling, laughing, and hyperactivity with a shortattention span.
Patient 2 This is a 6-year-old male patient of nonconsanguineous healthy parents of Jewish origin. The pregnancy was normal and he was born at term by forceps-assisted delivery. His motor milestones were delayed and he started walking unsteadily at the age of 3 years. He has no expressive language development and his behavior was classified into the autistic spectrum. Since the age of 2 years, he has medically intractable epileptic seizures. At the last follow-up at the age of 6 years, his clinical examination revealed microcephaly (approximately 5 cm below the fifth percentile), AS-like facial dysmorphism, severe muscular hypotonia, and truncal ataxia. The diagnosis of CS was confirmed by genetic testing that revealed a mutation in SLC9A6. MRI of the brain at the age of 4 and 6 years showed atrophy of the vermis and cerebellar hemispheres (inferior parts more affected), patchy FLAIR hyperintense signal of the CbC and enlargement of the fourth ventricle and supravermian cistern (►Fig. 1F–J). The brain stem, basal ganglia, and supratentorial brain structures were within normal limits.
Fig. 1 Magnetic resonance imaging of the brain in two patients with Christianson syndrome. Patient 1 at the age of 9 years: (A) midsagittal T1weighted image shows atrophy of the cerebellar vermis with secondary enlargement of the fourth ventricle; (B) axial and (C) coronal T2-weighted images demonstrate cerebellar atrophy (CA) with widening of the interfoliar spaces involving mostly the inferior part of the cerebellum; (D) coronal and (E) axial fluid attenuation inversion recovery (FLAIR) images reveal CA with diffuse hyperintensity of the cerebellar cortex (CbC) (arrows). Patient 2 at the age of 6 years: (F) midsagittal T2-weighted image shows atrophy of the vermis with secondary enlargement of the fourth ventricle and supravermian cistern; (G) axial T2-weighted and (H) coronal T1-inversion recovery images demonstrate CA with widening of the interfoliar spaces involving mostly the inferior part of the cerebellum; and (I, J) axial FLAIR images demonstrate CA and patchy foci of hyperintensity in the CbC (arrow). Neuropediatrics
Vol. 45
No. 4/2014
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
248
F4/P4
1
7
4/6
0.8/10
49
5
1/8/14/21
1.4
3
1.3
14
7
20
24
10
37
20
3
9
4/7
Age at MRI (y)
10/17
Yes
Yes
No
No
Yes
No
Yes
Yes
Yes
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Presence
Cerebellar atrophy
—
—
— Inferior > superior Inferior > superior
Vermis > hemispheres Vermis > hemispheres
—
—
—
Inferior > superior
Vermis > hemispheres
—
Inferior > superior
only vermis
—
Inferior > superior Inferior > superior
Vermis > hemispheres Vermis > hemispheres
NA
No
NA
Vermis > hemispheres
NA
Yes, only inferior
—
—
No
No
Brain atrophy
No
No
Lipoma between inferior colliculi
No
T2 hyperintense signal periventricular white matter
No
Hippocampal atrophy and T2 hyperintense signal
Brain stem atrophy
NA
NA
NA
NA
NA
NA
NA
Other
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
4/8
Yes, patchy
Yes, diffuse
No
NA
No
NA
No
Yes, only inferior
NA
NA
NA
—
—
NA
NA
NA
NA
NA
NA
Cerebellar cortex hyperintensity
NA
NA
—
— NA
NA
Superior $ inferior
NA
Vermis $ hemispheres
Abbreviations: F, family; MRI, magnetic resonance imaging; NA, not available; P, patient. a Same patient.
Total (N ¼ 17)
2
1
5
This article
1
4
III.9
1
3
1
2
3
This article
F1/IV-6
3
9
F1/IV-1
F1/IV-4
3
V.4
F4/P3
1
2
F4/P2
1
a
F1/P3
F4/P1
F1/P2
1
1a
F1/P1
1
1
Patient
Reference
Table 1 Neuroimaging findings in 17 patients with Christianson syndrome
Christianson Syndrome: Spectrum of Neuroimaging Findings
Neuropediatrics
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Christianson Syndrome: Spectrum of Neuroimaging Findings
Discussion CS is a rare disorder mimicking AS. AS is more common than CS and is characterized by severe developmental delay with absent or minimal speech, ataxia, easily provoked laughter, epilepsy, and microcephaly.9 So far, these are all features of CS and CS was initially called X-linked AS-like disease. Neuroimaging findings differ between CS and AS and this may help to differentiate these syndromes. Differentiation between CS and AS is important in terms of diagnosis and genetic counseling. CS has an X-linked inheritance, while there are four major genetic mechanisms which are now known to cause AS.9 The recurrence risk is generally low (< 1%), but there are few exceptions with a much higher recurrence risk.9 To our knowledge, 47 patients with CS have been reported to date.1–7,10 Neuroimaging findings have been reported only in 15 of them (10 children and 5 adults), making it now a total of 17 patients including our 2 children (►Table 1). CA is the most common neuroimaging finding and is present in 10 of 17 patients (59%, including 4/5 adult patients).1–3,5 In 6 of 10 patients, atrophy affected predominantly the inferior parts of the vermis and cerebellar hemispheres.3 In 6 of 10 patients, the cerebellar vermis appeared to be more atrophic compared with the hemispheres,2,3 while in 2 other patients vermis and hemispheres appeared to be equally atrophic.3 CA is defined as having an initially normal cerebellum in a normal size posterior fossa which displays enlarged fissures in comparison to the foliae, secondary to irreversible loss of tissue on follow-up.11 The progressive loss of cerebellar tissue and matching enlargement of interfoliar cerebellar spaces has been shown in CS by serial brain MRI in two patients. Mignot et al reported on neuroimaging findings in a patient with CS at the age of 1, 8, 14, and 21 years. On the first MRI, the cerebellum appeared normal. On the second MRI, interfoliar spaces were enlarged and CA was progressive on the followup MRI studies. Patient 1 in this article had a normal brain MRI at the age of 9 months; however, the cerebellum was markedly atrophic at the age of 9 years. On the basis of the data shown here, CA appears to have its onset in the second year of life. The absence of CA on a brain MRI at less than the age of 12 months does not exclude CS and follow-up studies may be indicated. Of course, the data are limited and further longitudinal MRI studies in young children with CS are needed to confirm this observation. In CS, neuropathological studies have shown that CA is caused by neuronal loss in Purkinje cells within the CbC, whereas the dentate nuclei are spared.2,10 An extensive and progressive loss of Purkinje cells and gliosis of the CbC were observed in the cerebellum of Slc9a6 mutant mice.12 Gliosis of the CbC was also revealed in CS patients by histology.10 On MRI, gliosis is characterized by a T2/FLAIR hyperintensity. T2 and FLAIR hyperintensity of the CbC is the second most common neuroimaging finding in CS and has been reported in 4 of 8 patients (50%; in nine patients no information about CbC signal was available, possibly because of lack of awareness because FLAIR images have been acquired in some of these patients).3 In all four patients, hyperintensity of the CbC was associated with CA. CbC-hyperintensity is evaluated Neuropediatrics
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better on FLAIR compared with T2-weighted images, where the hyperintense signal of the cerebrospinal fluid in the prominent interfolial spaces may mask the adjacent cortex signal changes.11 In two CS-patients reported by Schroer et al, hyperintense signal was seen only in the inferior part of the cerebellum.3 In our two patients, T2-/FLAIR-CbC-hyperintensity was diffuse in one and patchy (affecting mostly the inferior part of the cerebellum) in the other child, respectively. Diffuse and patchy hyperintensity of the CbC was not previously reported in CS. In AS, MRI is usually normal or may show mild cerebral atrophy, delayed myelination, decreased white matter volume, or focal white matter signal change.9 CA and T2-/FLAIRCbC-hyperintensity are not neuroimaging findings of AS. The differential diagnosis of clinical features of AS is wide and includes not only CS, but it also includes other disorders such as Mowat–Wilson syndrome, Pitt–Hopkins syndrome, Rett syndrome, MECP2 duplication, Prader–Willi syndrome, MBD5 mutation, Phelan–McDermid syndrome, adenylosuccinate lyase deficiency, and MTHFR deficiency.13 CA is not a feature of all these disorders, but adenylosuccinate lyase deficiency. In adenylosuccinate lyase deficiency, CA is a rare, late neuroimaging findings superimposed to cerebellar hypoplasia.14,15 T2-/FLAIR-CbC-hyperintensity, however, has not been reported in adenylosuccinate lyase deficiency. Therefore, in a child with clinical features of AS, CA, and/or T2-/FLAIR-CbChyperintensity are rather specific for CS and should initiate the sequencing of SLC9A6. CA with CbC-hyperintensity is however not pathognomonic for CS, and has been reported in few other disorders including infantile neuroaxonal dystrophy (OMIM 256600), Marinesco– Sjögren syndrome (OMIM 248800), phosphomannomutase 2 deficiency (OMIM 212065), and mitochondrial disorders, particularly complex I and Coenzyme Q10 deficiency.16 History, clinical findings, and additional neuroimaging features usually differentiate these disorders from CS. In Slc9a6 mutant mice, cell loss was limited to the cerebellum.12 This observation matches the absence of cerebral atrophy on brain MRI studies of all, but one (the oldest one) CSpatient.10 Neuropathology in this patient revealed global cerebral atrophy with neuronal loss and gliosis predominantly involving CbC, substantia nigra, putamen, and globus pallidus, whereas cerebral cortex and hippocampus were only mildly involved. On neuroimaging, substantia nigra, putamen, and globus pallidus appeared normal in all patients. In a 7-year-old child, hippocampi were atrophic and showed hyperintense signal on T2-weighted images. It is unclear whether hippocampal MRI changes are primarily related to CS or a nonspecific finding secondary to frequent, prolonged seizures. In summary, we present two children with CS who have CA and a new type of CbC-hyperintensity. CA is a common but not consistent neuroimaging finding in CS. In a child with AS-like phenotype, CA and/or CbC-hyperintensity are rather specific for CS and should prioritize sequencing of SLC9A6.
Acknowledgment We thank the patients and their families for their cooperation.
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9 Williams CA, Driscoll DJ, Dagli AI. Clinical and genetic aspects of
Angelman syndrome. Genet Med 2010;12(7):385–395
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ing the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain 2010;133(Pt 5):1391–1402 Poretti A, Wolf NI, Boltshauser E. Differential diagnosis of cerebellar atrophy in childhood. Eur J Paediatr Neurol 2008;12(3): 155–167 Strømme P, Dobrenis K, Sillitoe RV, et al. X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction. Brain 2011;134(Pt 11): 3369–3383 Dagli AI, Williams CA. Angelman syndrome. In: Pagon RA, Adam MP, Bird TD, et al, eds. GeneReviews. Seattle, WA: University of Washington; 2011 Edery P, Chabrier S, Ceballos-Picot I, Marie S, Vincent MF, Tardieu M. Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: a report on three patients. Am J Med Genet A 2003;120A(2):185–190 Jurecka A, Zikanova M, Jurkiewicz E, Tylki-Szymańska A. Attenuated adenylosuccinate lyase deficiency: a report of one case and a review of the literature. Neuropediatrics 2013 (epub ahead of print). doi:10.1055/s-0033-1337335 Poretti A, Boltshauser E. Table 20. Cerebellar cortex hyperintensity. In: Boltshauser E, Schmahmann JD, eds. Cerebellar Disorders in Children. London, United Kingdom: Mac Keith Press; 2012:415
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References
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