Pediatr Radiol (2012) 42:932–940 DOI 10.1007/s00247-012-2384-4

ORIGINAL ARTICLE

Aicardi-Goutières syndrome with emphasis on sonographic features in infancy L. Rossler & C. Ludwig-Seibold & Ch Thiels & J. Schaper

Received: 5 September 2011 / Revised: 2 February 2012 / Accepted: 12 February 2012 / Published online: 26 May 2012 # Springer-Verlag 2012

Abstract Background Aicardi-Goutières syndrome (AGS) is a severe familial, mostly autosomal recessive encephalopathy, first described in 1984. The clinical picture and genetic abnormalities are heterogeneous. US findings in AGS have thus far not been systematically described. Objective The purpose of this study was to analyse sonographic features in AGS and to compare them to CT/MRI. Materials and methods Four male infants with AGS, two brothers, underwent imaging between the ages of 4 weeks and 6 months. Results Sonographically isolated mineralization of lenticulostriate vessels, dilatation of the lateral ventricles, subependymal cysts, and diffuse and focal hyperechogenicity of the periventricular white matter and basal ganglia, respectively, were the L. Rossler (*) : C. Thiels Klinik für Kinder- und Jugendmedizin der Ruhr-Universität Bochum, Alexandrinenstr. 5, 44791 Bochum, Germany e-mail: [email protected] C. Thiels e-mail: [email protected] C. Ludwig-Seibold Klinik für Kinder- und Jugendmedizin, Oberschwabenklinik GmbH, Nikolausstr. 10, 88212 Ravensburg, Germany e-mail: [email protected] J. Schaper (*) Institut für Diagnostische und Interventionelle Radiologie, Kinderradiologie, Medizinische Einrichtungen der Heinrich-Heine-Universität, Moorenstr. 5, 40225 Düsseldorf, Germany e-mail: [email protected]

abnormal findings, that may be present even before the development of major neurological symptoms. Conclusion Early cranial US is able to visualize the whole spectrum of cerebral anomalies in AGS: calcifying microangiopathy, white matter disease and unusual subependymal cysts. The imaging pattern is similar to that of congenital viral infection of the central nervous system, which may mislead the genetic counseling. Keywords Aicardi-Goutières syndrome . Cerebral ultrasound . Subependymal cyst . Basal ganglia calcification

Introduction Aicardi-Goutières syndrome (AGS) is an autosomal recessive encephalopathy with phenotypical and genetic heterogeneity [1]. Clinical onset is during the first year of life. Presenting symptoms of AGS include postnatal microcephaly, spasticity, abnormal eye movements, developmental delay and muscle hypotonia. Diagnostic criteria are calcifications in the periventricular region and basal ganglia, diffuse leucodystrophy, chronic cerebrospinal fluid (CSF) lymphocytosis and elevated interferon-alpha (IFN-alpha) in blood and CSF in the absence of infection [1–3]. Associated chill-blain type lesions of fingers, toes or earlobes suggest an autoimmune lupus-like mechanism [1]. The five known causative genes encode a DNA exonuclease (TREX1), the ribonuclease H2 enzyme complex (RNASE H2A, B and C) and the SAMHD1 protein (AGS type 1–5 respectively). Mutations in these genes are identified in more than 90 % of individuals with characteristic clinical and radiological findings of AGS [4]. Prenatal diagnosis, based on US, MRI and/or foetal blood analysis, has been reported in families with a previous child affected by the disease [5, 6].

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A few previous reports have described the diagnosis of AGS with US, but these focus exclusively on cerebral calcifications [2, 5]. Overall, other US findings have not been widely described [7–9]. We report four children with AGS in whom US also showed involvement of the thalamostriate vessels and the germinal matrix layers. Comparison is made with CT and MRI.

muscle hypotonia and retrognathism. The course was rapid to a vegetative outcome with medically treated epilepsy and nocturnal noninvasive home ventilation because of sleep apnoeas. Homozygote mutation in the TREX1 gene was found (c.602T > A) (p.Val201Asp). Additional occurrence of insulin dependant diabetes was noted at the age of 5 years. The child is still alive at the age of 12 years.

Materials and methods

Patient 2

We retrospectively reviewed the clinical charts and the imaging findings (US, CT and MRI) in four infants with a diagnosis of AGS. These infants were seen during a 10-year period at two academic children’s hospitals. Investigations were performed according to good clinical practice and approved by the local institutional review board.

A 3-month-old boy of healthy, unrelated parents presented with abnormal crying especially while feeding and with severe psychomotoric retardation. Physical examination noted a floppy infant with opisthotonus and microcephaly (head circumference, 39 cm; < 3rd percentile). Prolonged salaam convulsions were observed during the hospital stay. On cerebral US, there was mild enlargement of the lateral ventricles, bilateral subependymal cysts and periventricular hyperechogenicities (Fig. 2). CSF showed elevated protein and pleocytosis with lymphocytosis (Table 1). Screening for congenital infection and HIV was negative. When he was 3 months old, MRI showed extensive white matter disease, cerebral atrophy of unknown origins (Fig. 2) and hypoplasia of the corpus callosum. At the age of 2.5 years, the boy was hospitalised because of necrotising vasculitis of the toes of the right foot. Blistering responded well to symptomatic treatment (corticosteroids, acetylsalicylic acid and cotton wool padding). The diagnosis of AGS was made at the age of 4 years, when a sibling with AGS was born (patient 3). Cranial CT then revealed symmetrical calcifications in the basal ganglia and in the nucleus dentatus (Fig. 2). Subsequently, AGS was verified genetically by homozygote mutation in the TREX1-gene (c.341G > A) (p.Arg114His). The patient is now 20 years old and has severe physical and mental retardation, tetraparesis, epilepsy, scoliosis, joint contractures, percutaneous gastrostomy and suprapubic catheter.

Results Patient 1 A 4-week-old boy of healthy, related (first cousins) Turkish parents presented with two large cephalhaematomas, feeding problems and poor weight gain. He was delivered spontaneously at 41 weeks of gestation after an uneventful pregnancy. On physical examination, he had a horizontal nystagmus but no other neurological symptoms. Cranial US showed moderate symmetrical dilatation of the lateral ventricles, a giant subependymal cyst on the right side, and diffuse and focal hyperechogenicity of the periventricular white matter and basal ganglia, respectively (Fig. 1). Periventricular and basal ganglia calcifications were confirmed by CT (Fig. 1). In addition, CT and MRI showed bilateral marked demyelination, mainly in the frontal lobes, and extensive cystic changes in the temporal lobes with fluid attenuation (resembling findings in congenital cytomegalo virus infection; Fig. 1). Lumbar puncture revealed mild CSF lymphocytosis and elevated CSF protein (Table 1). Repeated screening for congenital infections and metabolic diseases was negative. Interferon-alpha levels were raised in CSF and in serum (Table 1). Severe delay of psychomotoric development, particularly muscle hypotonia, became evident soon after the neonatal period. After a few months, microcephaly became apparent and the child developed convulsions. At the age of 14 months, he showed poor spontaneous activity, trunk hypotonia, beginning bilateral spasticity of the legs and roving eye movements. Head circumference had passed from 37.5 cm (25–50th percentile) to 45 cm (below the 3rd percentile), while body weight and length were within normal limits (25–50th percentile). Feeding was difficult and complicated by aspirations. Short apnoeas occurred due to upper airway obstruction caused by

Patient 3 This was the second affected child (sibling of patient 2) of healthy, unrelated parents. When he was 6 days old, cranial US found normal ventricles (Fig. 3). CT showed small ventricles and periventricular calcifications when the boy was 17 days old. Leucodystrophy, periventricular calcifications and cerebral atrophy with secondary ventricular enlargement were wellseen in the follow-up imaging with CT and MRI when he ws 7 months (Fig. 3). The diagnosis of AGS was suspected from the clinical symptoms (feeding difficulty, failure of normal development, nystagmus, microcephaly, trunk hypotonia, spasticity and convulsions) and finally confirmed by proving the same

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Fig. 1 A 4-week-old boy with bilateral cephalhaematomas (patient 1). a Transcranial US: Coronal (left) and parasagittal (right) sections reveal moderate enlargement of the lateral ventricles with an arched intraventricular septum on the right side (short white arrows), diffuse hyperechogenicity of the periventricular white matter (arrowheads) and focal echodensities in the basal ganglia (long white arrows) strongly suggestive of a subependymal cyst, demyelination and calcifications, respectively. b Axial non-enhanced cranial CT through the basal ganglia (left) and directly above the third ventricle (right) at the age of 3 months shows enlargement of the ventricles, hypodensity of the frontal white matter,

coarse-grained basal ganglia (putamen and thalamus) and punctate periventricular calcifications. c Non-enhanced brain MRI at the age of 3 months. Axial T1-weighted image (left) shows dilated lateral ventricles, decreased signal intensity of the white matter in the frontal lobes (white asterisk) and a bilateral cystic lesion in the germinal matrix zone. Coronal FLAIR image (right) shows increased signal intensity of the white matter in the frontal lobes, confirms subependymal cysts (white arrows) as well as an extensive cystic abnormality in the anterior part of temporal lobes (black asterisk) with fluid attenuation (similar to findings in congenital CMV infection)

homozygous mutation in TREX1 as the older brother. CSF pleocytosis was shown repeatedly from the second month of life. Elevated IFN-alpha completed the typical findings in CSF when the boy was 2 years old (Table 1).

Despite identical genotype, the clinical evolution was different from that of the older brother and seemed less severe, e.g., oral nutrition was possible without aspiration. The patient is still alive at the age of 16 years.

Table 1 Clinical and laboratory findings in four infants with Aicardi-Goutières syndrome

a b

Brothers

CSF lymphocytosis is defined as > 5 lymphocytes/µl

Characteristics

Patient 1

Patient 2a

Patient 3a

Patient 4

Nationality Sex Parental consanguinity Gene mutation Age at diagnosis

Turkish Male Yes TREX1 3 months

German Male No TREX1 4 years

German Male No TREX1 7 months

German Male No TREX1 7 months

CSF findings, age Cell count per µl / %lymphocytesb Protein (mg/dl) Interferon-alpha (normal < 2 IU/ml)

3 months 38/40

4 months 20/not available

4 months/2 years 52/70 14/80

6 months 34/79

133 50 (200 in serum)

65 Not available

Not available 9 (CSF) at 2 years

Not available Not available

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Fig. 2 A 3-month-old boy with abnormal crying (patient 2). a Transcranial US: Coronal (left) and parasagittal (right) sonograms show mild enlargement of the lateral ventricles, focal periventricular hyperechogenicity and bilateral cysts in the germinal matrix zone (white arrows). b Nonenhanced axial MRI (T2, T1 proton density) reveals diffusely abnormal signal intensity of the white matter including the internal capsules, and brain atrophy seen as interhemispheric and ventricular widening. c Nonenhanced axial CT at the age of 5 years demonstrates interhemispheric frontal focal widening and cerebral calcifications in symmetrical patterns within the basal ganglia and the dentate nucleus

Fig. 3 Patient 3, the brother of patient 2. a Normal ventricles on transcranial US at 6 days of age. b Nonenhanced CT (17 days old): normal ventricles, periventricular punctiform calcifications (arrow). c Follow -up imaging at 7 months of age: ventricular widening and interhemispheric

frontal focal widening; abnormal white matter signal on MRI (leftmost two images); punctiform calcifications (periventricular, nucleus dentatus) are clearly seen only on CT (rightmost three images)

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Fig. 4 A 6-month-old boy with developmental delay (patient 4). a Transcranial US. Coronal (left) and parasagittal (right) sonograms show appearances similar to those of congenital infection with echogenic streaks in the basal ganglia (lenticulostriate vasculopathy; arrows) and mildly enlarged ventricles. MRI T2, T1 (b) and CT (c) show delayed myelinisation and/or loss of white matter and internal capsule, widening of the pericerebral spaces and calcifying angiopathy (on CT)

Patient 4 A 6-month-old boy presented with developmental delay. The dominant clinical symptoms were feeding difficulties, hypotonia, microcephaly, nystagmus and seizures. There was marked lymphocytosis in CSF (Table 1). The congenital infection-like appearance of lenticulostriate mineralisation was clearly seen on cranial US, which also showed mild ventricular enlargement (Fig. 4). MRI demonstrated myelinisation delay, mildly enlarged lateral and third ventricles, as well as a widening of the frontal and temporal subarachnoid spaces. Cerebral calcifications were only well-depicted on CT. Genetic analysis revealed a mutation in the TREX1 gene. Like patients 1–3, the boy is of stunted growth and short weight, wheelchair-bound and severely handicapped with tetraspasticity. He is alive at the age of 14 years.

Discussion AGS, first described in 1984, is a rare familial encephalopathy with onset of clinical symptoms in early infancy [1]. In our series, autosomal recessive inheritance was strongly suggested in patient 1, who was born to consanguineous parents, and in patients 2 and 3, who were siblings. Early symptoms are poor feeding, jitteriness, irregular eye

movements, psychomotor developmental delay and/or regression. The clinical picture is completed by progressive microcephaly, bilateral spasticity and, frequently (53 % of patients), seizures [2]. Further criteria for the diagnosis of AGS are typical neuroimaging findings with calcifications in the basal ganglia and periventricular regions, brain atrophy and diffuse leucodystrophy. Chronic, often mild, CSF lymphocytosis, and elevated interferon-alpha in blood and CSF represent obligatory laboratory findings after the exclusion of congenital (TORCH) infection [3]. Extraneurological signs like thrombocytopaenia, hepatosplenomegaly, elevated liver enzymes, and unexplained episodes of fever are inconsistent and may misleadingly indicate infection. Chilblain lesions of the extremities, first described by Tolmie [4] as a major extraneurological feature of AGS, are common (40 %) [2, 4, 5]. In patient 2, these were interpreted as necrotising vasculitis of unknown aetiology. Phenotypical overlap between AGS and systemic lupus erythematosus has been documented [6, 7]. A common pathophysiology between systemic lupus eythematosus and AGS is suggested by high interferon-alpha levels in both entities [8–10]. Differential diagnoses include metabolic disorders, other familial encephalopathies with leucodystrophy and calcifications (e.g. Cockayne syndrome with cerebellar atrophy) and congenital infections of the central nervous system (e.g. CMV encephalopathy with involvement of the cerebral cortex).

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Apart from inflammatory or autoimmune mechanisms, Aicardi and Goutières predicted a genetic origin of the disorder [1]. Significant linkage of AGS mutations to chromosome 3p21 in some patients was first described by Crow et al. [11]. There were mutations in TREX1 [12], a gene encoding a DNA exonuclease. Their findings indicate that AGS is an autosomal recessive inherited disease with locus heterogeneity [11, 13]. Rarely, TREX1-related AGS (AGS 1) is the result of a de novo dominant mutation. AGS is both genetically and phenotypically heterogeneous, with a spectrum of severity ranging from life-threatening perinatal illness to mild lateinfancy onset [2]. By 2010, recessive mutations had been identified in five genes, of which four are nuclease genes. These five genes are incriminated in approximately 90 % of the families with AGS [14]. Besides the DNA exonuclease TREX1 (found in all patients of our series), all three subunits (A,B,C) of the ribonuclease H2 enzyme complex (AGS 2–4) are involved [15]. Lack of exonuclease and ribonuclease activity leads to intracellular storage of replication intermediates mimicking viral infection and thus results in an inappropriate immune answer with production of IFN-alpha [12, 15]. Thus, elevation of IFN-alpha in AGS is likely to be due to dysregulation of production and is not a response to a real infection. This mechanism would explain the typical neuropathological findings of cerebral microangiopathy [16], and extraneurological symptoms like thrombocytopaenia, hepatosplenomegaly and recurrent fever. IFN-alpha is already secreted in fetal life and postnatally over several years in the CSF and blood. Synthesis of IFN-alpha precedes CNS damage [17]. Recently, a mutation in the SAMHD1 gene was proved to extend the known clinical spectrum of AGS by intracranial large-vessel disease with stenoses (stroke) and aneurysms [18], most likely in the context of a vasculitis caused by selfactivation of innate immunity by cell intrinsic components [19, 20]. In this new clarified context, AGS may be assimilated to autosomal recessive genetic disorders ongoing with early onset encephalopathy and manifesting with intracranial calcification as a diagnostic feature. Many reports of these disorders have been published since 1983 [21, 22], describing synonymous entities known as congenital infection-like syndrome [23], pseudo-TORCH syndrome [21, 24, 25] and microcephaly-intracranial calcification syndrome (MICS) [26, 27]. If these phenotypes and AGS may be a different presentation of the same disease in many cases [11, 28, 29], in other cases they seem to be a separate condition differing from “classical AGS” by a specific pattern of intracranial calcification (cortical, band-like), by the additional presence of gyration anomalies, by the congenital and not postnatal microcephaly, by a normal CSF white cell count or by the additional presence of dysmorphic facial features.

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In future, with the AGS loci mapped almost entirely and the corresponding genes sequenced, it will be possible to answer the question of allelism in such cases. The clinical presentation of AGS is variable [30–32]. A neonatal onset with a severe and rapidly progressive clinical course [2, 12] leading to a vegetative outcome and often to death before adulthood is typically associated with TREX1 mutations. A subacute encephalopathy after a symptom-free period of many months (up to 16 months) and with a selflimited disease progression is generally related to RNASEH2 B mutations [33, 34]. Symptomatic disease may even first appear in adulthood [20]. Identification of dominant TREX1 gene mutations in SLE and in familial chilblain-type lupus suggest that AGS and SLE are closely related [35–37]. In 2010, Ramantani et al. [38] showed an abnormally high prevalence of clinical and laboratory auto-immunity markers of SLE in 20 patients with molecularly confirmed AGS. The fundamental role of impaired nucleic acid metabolism in the induction of neurological inflammation and systemic autoimmunity is now undisputed [39–41]. To our knowledge, this is a unique detailed report on the extended spectrum of sonographic features in the early course of postnatal AGS. Anomalies on cranial US may be visible at a time when the child is asymptomatic (patient 1) and bilateral intracranial calcifications may even be seen on antenatal US [42, 43]. Calcifications are best seen on CT (Table 2). Sonographic visualisation depends on locations and on the moment of examination. In the basal ganglia, calcifications can easily be detected as rock-like echodensities or as mineralised vasculopathy (crow’s foot-like). When they are located in the fossa posterior (nucleus dentatus) or in the immediate vicinity of a ventricular wall, demonstration of punctate calcifications is impossible. Calcifications may appear later, after the neonatal period (patient 3), depending on the onset of the disease [1, 3, 33, 44]. MRI is less suited for showing cerebral calcifications, even on susceptibility-prone T2*-weighted images [45]. US demonstrated cerebral calcifications in two of the children in our series, whereas it was demonstrated on CT in all four children. Subependymal cysts have previously not been described in AGS. These are typically found in congenital central nervous system infections with neurotropic viruses and in metabolic disease, e.g. Zellweger syndrome. Disorders of energy metabolism, e.g. mitochondrial diseases, may cause US findings similar to those seen in AGS: intracerebral calcifications, white matter damage, ventriculomegaly and subependymal cysts [46–48]. The possible involvement of mitochondria in the pathogenesis of AGS may be suggested by high levels of brain lactate [49]. Bilateral multiple subependymal pseudocysts or choroid plexus cysts have a probability of being associated in 22 % of cases to a congenital infection or

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Table 2 Sonographic findings compared to CT and MRI in four infants with Aicardi-Goutières syndrome Findings

Patient 1

Patient 2

Patient 3

Patient 4

Neuroradiological investigation Age at examination

US/CT/MRI 4 w/3 mo/3 mo

US/CT/MRI 3 mo/5y/3mo

US/CT/MRI 6d/17d/1mo 7mo/7mo

US/CT/MRI 6mo/7mo/6mo

+ US/CT/MRI

+ US/CT/MRI + CT/MRI

- US/CT/MRI + CT /MRI (7 mo) + CT /MRI (7 mo)

+ US/CT/MRI

Brain atrophy -Ventriculomegaly -Interhemispheric focal widening -Pericerebral spaces widening Calcifications -Basal ganglia/Lenticulostriate vessels -Periventricular -Cerebellum (Nucleus dentatus) Subependymal cysts (bilateral) Leucodystrophy -Abnormal white matter signal -Cystic changes in temporal lobes

+ US/CT + US/CT

+ CT

+ CT/MRI + US/CT

+ US/MRI

+ CT + US

+ CT(7 mo) + CT(7 mo) -

-

+ US/CT/MRI

+ MRI

+ MRI

+ MRI

+ MRI

w weeks, y years, mo months, d days, + positive finding seen, - not an observed finding at the time of examination

chromosomal anomaly [50]. Subependymal cysts and ventricular enlargement are not a consistent finding in early US of AGS as shown in patients 1 and 2, who showed the same severe clinical phenotype and the same gene affected (TREX1), albeit with different mutations. Arciform intraventricular septation likely results from subependymal germinolysis and is most likely a sign of ongoing inflammatory response when considering the echogenic content of the cystic lesion and the ventricular enlargement. US is highly accurate for showing subependymal cysts when they are present. Corresponding to cerebral atrophy and/or white matter disease, the lateral ventricles are enlarged or become enlarged with time. Ventriculomegaly was the most common and constant finding detected by any of the available imaging techniques. Subarachnoid widening was only seen in patient 4 but not on US. Interhemispheric focal widening was seen in two of the four patients and only on MRI or CT. In AGS, the pattern of leucodystrophy suggests arrest of myelination rather than demyelination. Therefore, early myelinated structures, like the brain stem, optic radiations and cerebellum, tend to be spared. In contrast, white matter appears swollen with cystic degeneration in the temporal and/or frontal lobes [51] identical to the changes described by Uggetti et al. [44] and recently by Henneke et al. [52]. The first author reviewed the neuroradiological investigations of 36 patients selected from the IAGSA (International Aicardi-Goutières Syndrome Association) database. The second supports the role of RNA metabolism in brain development by an inborn cystic leukoencephalopathy resembling congenital cytomegalovirus brain infection and related to RNASE T2 deficiency; until now, this RNASE is not yet

known as being involved in the genesis of AGS. Cystic abnormalities in the white matter are not ubiquitous in AGS, but they represent a characteristic MRI finding when present [45]. In our series, the pattern and extent of white matter anomalies were best seen on CT or MRI and were described in all patients on MRI. Patient 1 had extensive cystic abnormality in the temporal lobes (Fig. 1). Leucodystrophy is not accurately diagnosed with US, but streaky hyperechogenicity in the white matter may represent a lack of myelin, a finding in patient 1 (Fig. 1). We did not see cystic abnormalities in the temporal lobes on US. Early findings on cerebral US illustrate that prenatal diagnosis is possible, particularly when there is a family history of AGS, as demonstrated by Le Garrec [42]. In the context of subependymal cysts and foetal intracranial calcification, AGS has to be considered among other differential diagnoses [53]. Accuracy of prenatal diagnosis is improved by measuring interferon-alpha in foetal blood [17]. Molecular genetics is now available and may also be offered to parents with known disease-causing mutations. The radiological natural history of the disease is welldocumented in the retrospective work by Uggetti [44]. Neuroimaging findings remain stable over time in about 70 % of patients, corresponding with the clinical natural history of AGS, namely, that further progression is unlikely after two years.

Conclusion In summary, we have presented four boys with AGS and with a variable spectrum of anomalies on early cerebral US (Table 2).

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Conspicuous US findings were detected in three of these, whilst in one, US was performed before imaging findings became apparent (1 week old). Ventriculomegaly was the most common finding and the finding that had the closest correspondence with CT and MRI. White matter abnormalities were not reliably detected by US. Subependymal cysts, not previously described sonographically in AGS, were seen in two of the patients. Calcifications are easily detected on US when located in the basal ganglia, otherwise they are not, and they are not reliably seen on MRI, which is why additional CT is important at initial investigation. The initial sonographic pattern in AGS is variable, also with identical genotypes. While mortality is correlated with genotype [36], a variable severity of the neurological outcome among siblings is known [30, 31]. The spectrum and variability of clinical, neuroimaging and laboratory findings in AGS seem much broader than initially thought, possible explaining why this rare disease is likely to be underdiagnosed.

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