Leukoencephalopathy with Calcifications and Cysts—The First

brain sciences

Case Report Leukoencephalopathy with Calciﬁcations and Cysts—The First Polish Patient with Labrune Syndrome

Magdalena Machnikowska-Sokołowska 1 , Jacek Pilch 2 , Justyna Paprocka 2,* , Małgorzata Rydzanicz 3 , Agnieszka Pollak 3, Joanna Kosi ´nska 3, Piotr Gasperowicz 3 , Katarzyna Gruszczy ´nska 1, Ewa Emich-Widera 2 and Rafał Płoski 3

1 Department of Diagnostic Imaging, Radiology and Nuclear Medicine, Faculty of Medical Science in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; [email protected] (M.M.-S.); [email protected] (K.G.) 2 Department of Pediatric Neurology, Faculty of Medical Science in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; [email protected] (J.P.); [email protected] (E.E.-W.) 3 Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland; [email protected] (M.R.); [email protected] (A.P.); [email protected] (J.K.); [email protected] (P.G.); [email protected] (R.P.) * Correspondence: [email protected]

Received: 13 October 2020; Accepted: 16 November 2020; Published: 18 November 2020

Abstract: Leukoencephalopathy with calcifications and cysts (LCC) is a triad of neuroradiological symptoms characteristic of Labrune syndrome, which was first described in 1996. For 20 years, the diagnosis was only based on clinical, neuroradiological and histopathological findings. Differential diagnosis included a wide spectrum of diseases. Finally, in 2016, genetic mutation in the SNORD118 gene was confirmed to cause Labrune syndrome. The authors describe a case of a teenage girl with progressive headaches, without developmental delay, presenting with calcifications and white matter abnormality in neuroimaging. Follow-up studies showed the progression of leukoencephalopathy and cyst formation. The first symptoms and initial imaging results posed diagnostic challenges. The final diagnosis was established based on genetic results. The authors discuss the possible therapy of LCC with Bevacizumab.

Keywords: Labrune syndrome; SNORD118 gene; magnetic resonance imaging

1. Introduction Progressive leukoencephalopathy with calcifications and cysts (LCC) is a very rare disease with autosomal recessive inheritance, which was first reported by Labrune in 1996 [1]. Since then, only individual cases have been reported. The underlying pathology is a diffuse cerebral microangiopathy with the development of micro- and macrocysts, tumor-like vascular hyperplasia, calcifications, glial proliferation, demyelination, necrosis, iron deposition and hemorrhage. In 2016, it was confirmed that mutations in the SNORD118 gene were associated with Labrune syndrome. The gene encodes a small nuclear RNA, which is necessary for ribosomal mRNA processing [2]. The challenge in establishing the diagnosis of Labrune syndrome is due to the rare occurrence of the disease, inconsistent clinico-radiological findings and the necessity for follow-up neuroimaging due to the progression of imaging changes on MRI.

Brain Sci. 2020, 10, 869; doi:10.3390/brainsci10110869 www.mdpi.com/journal/brainsci Brain Sci. 2020, 10, 869 2 of 7 Brain Sci. 2020, 10, x FOR PEER REVIEW 2 of 7 Brain Sci. 2020, 10, x FOR PEER REVIEW 2 of 7 2. Case Report 2. Case Report The authors report on aa normallynormally developingdeveloping 10-year-old girl who complainedcomplained of chronic headachesThe authors and frequent report upper on a respiratorynormally developing tract infections 10-year-old without girlany additionalwho complained clinical ofsymptoms. symptoms. chronic Theheadaches family historyhistoryand frequent waswas negative.negative. upper respiratory Pregnancy tract and infections the delivery without period any were additional unremarkable.unremarkable. clinical symptoms. The 3-year follow-upThe family started history with was the negative. head CT Pregnancy (at a different diff anderent the hospital) delivery due period to recurrent were unremarkable. and severe Theheadaches. 3-year Non-specific,Non-specific,follow-up started bilateral, with symmetrical,the head CT multifocal(at a different calcifications calcifications hospital) due in deep to recurrent brain brain structures structures and severe were were headaches. reported. reported. (Figure(FigureNon-specific,1 1).). AfterAfter bilateral, sixsix months,months, symmetrical, anan MRI MRI multifocal of of the the brain brai calcificationsn was was performed. performed. in deep Susceptibility-weighted Susceptibility-weighted brain structures were reported. imagingimaging (SWI)(SWI)(Figure artifactsartifacts 1). After correspondingcorresponding six months, to anto the MRIthe calcifications calcificationsof the brain on wason CT CTperformed. and and probably probably Susceptibility-weighted small small areas areas of hemorrhage of hemorrhage imaging with thewith(SWI) areas the artifacts ofareas periventricular ofcorresponding periventricular white to matterthewhite calcifications leukodystrophymatter leukodystrophy on CT wereand found.probably were Additionally,found. small Additionally,areas chronicof hemorrhage sinusitischronic wassinusitiswith diagnosed. the was areas diagnosed. of The periventricular following The following were white suspected: werematter suspec ischemic-hypoxicleukodystrophyted: ischemic-hypoxic were changes; found. post-infectiouschanges; Additionally, post-infectious changes;chronic orchanges;sinusitis Aicardi-Gouti wasor Aicardi-Goutières diagnosed.ères syndrome. The following syndrome. Pediatric were and Pediatric suspec neurologicalted: and ischemic-hypoxic neurological examination revealedexamination changes; no post-infectious abnormalities. revealed no Broadabnormalities.changes; neurological or Aicardi-Goutières Broad assessment neurological includedsyndrome. assessment the Pediatric analysis included ofand the the analysisneurological cerebrospinal of the examination cerebrospinal fluid, which revealed wasfluid, normal. which no EEGwasabnormalities. recordingnormal. EEG Broad showed recording neurological epileptiform showed assessment abnormalities, epileptiform included prominentabnorm the analysisalities, over of prominent thethe temporalcerebrospinal over regions, the fluid, temporal without which was normal. EEG recording showed epileptiform abnormalities, prominent over the temporal seizures.regions, without Disorders seizures. of calcium Disorders and phosphate of calcium metabolism and phosphate and other metabolism endocrine and abnormalities other endocrine were regions, without seizures. Disorders of calcium and phosphate metabolism and other endocrine excluded.abnormalities Most were inborn excluded. errors ofMost metabolism inborn errors werealso of metabolism ruled out during were biochemicalalso ruled assessment.out during abnormalities were excluded. Most inborn errors of metabolism were also ruled out during Afterbiochemical the diagnosis assessment. and treatment After the ofdiagnosis pollen allergy, and trea headachestment of pollen resolved. allergy, The headaches authors obtained resolved. signed The biochemical assessment. After the diagnosis and treatment of pollen allergy, headaches resolved. The informedauthors obtained consent signed of the patient’sinformed parents consent for of thethe publication.patient’s parents for the publication. authors obtained signed informed consent of the patient’s parents for the publication.

FigureFigure 1. 1. Head Head CT,CT, axialaxialaxial plane,plane,plane, (((aaa))) softsoftsoft tissuetissue window;window; (((bb))) bonebonebone window:window:window: bilate bilateral,bilateral,ral, symmetrical symmetricalsymmetrical and and multifocalmultifocal calciﬁcationcalcification calcification ininin deepdeepdeep structuresstructuresstructures (basal(basal ganglia)ganglia) andand dentatedentate nucleinuclei (not (not shown). shown).

TheThe second second brainbrain MRI,MRI, whichwhich waswas performed seve sevenn months later,later, showed showed progression progression of of white white mattermatter hyperintensityhyperintensity andand thethe occurrenceoccurrence of a smallsmall cystcyst inin thethe leftleft thalamusthalamus (Figure (Figure 22). ).2). The The girl’s girl’s psychomotorpsychomotor development development waswas stillstill normal.normal. Considering the progression progression of of radiological radiological changes changes in in thethe brain,brain, brain, thethe the girlgirlgirl waswaswas qualiﬁedqualifiedqualified forforfor geneticgeneticgenetic testingtesting usingusing wholewhole exome exome sequencing sequencingsequencing (WES) (WES)(WES) with withwith the thethe suspicionsuspicion of of an an extremely extremely rarerarerare ororor unknownunknownunknown inborninborn errorerror ofof metabolism.metabolism.metabolism.

FigureFigure 2. 2.2. Second SecondSecond brain brainbrain MRI; MRI;MRI; one oneone year yearyear later, later, axial axial plane: plane: (a) T2; ((aa ()b) )T2;T2; Flair ((bb T2;)) FlairFlair (c) T1; T2;T2; ( d ((c)c) T1) T1;T1;+ CE (d(d) sequences,) T1T1 ++ CE CE correspondingsequences,sequences, correspondingcorresponding calciﬁcation artifacts,calcificationcalcification small leftartifact thalamics, small cyst left andleft whitethalamicthalamic matter cystcyst hyperintensity. andand whitewhite mattermatter hyperintensity.hyperintensity.

OnOn thethe thirdthird follow-upfollow-up MRI,MRI, whichwhich was performed oneone yearyear later,later, cystscysts grewgrew upup toto 22 cm, cm, showingshowing the the mass mass effect effect onon thethe leftleft laterallateral ventricle and white mattermatter hyperintensityhyperintensity with with the the sparing sparing Brain Sci. 2020, 10, 869 3 of 7

BrainOn Sci. the 2020 third, 10, x follow-upFOR PEER REVIEW MRI, which was performed one year later, cysts grew up to 2 cm, showing3 of 7 the mass effect on the left lateral ventricle and white matter hyperintensity with the sparing of the of the subcortical U-fibers (Figure 3). The suspicion of progressive leukoencephalopathy with subcorticalcalcifications U-fibers and cysts (Figure (LCC)3). Thewas suspicion raised. At of that progressive time, pediatric leukoencephalopathy and neurological withexamination calcifications was andnormal. cysts (LCC) was raised. At that time, pediatric and neurological examination was normal.

FigureFigure 3. 3.Third Third brainbrain MRIMRI two years years after after th thee first first imaging, imaging, axial axial plane: plane: (a) T2; (a) ( T2;b) Flair (b) FlairT2; (c T2;) T1; (c ()d T1;) (d)DWI; DWI; (e ()e T1) T1 + +CE;CE; (f ()f SWI) SWI (used (used for for the the assessment assessment of of blood blood metabolites metabolites and and calcifications) calcifications) sequences; sequences; whitewhite matter matter hyperintensity hyperintensity progression, progression, cyst cyst enlargement enlargement with with the mass the emassffect andeffect calcification and calcification artifacts. artifacts. 3. Genetic Analysis 3. Genetic Analysis DNA from the proband and her parents was extracted from peripheral blood using the standard protocol.DNA Library from the preparation proband and for her WES parents was performed was extracted using from the peripheral DNA sample blood ofusing the the proband standard with theprotocol. SureSelectXT Library Human preparation kit Allfor ExonWES was v7 (Agilent,performed Agilent using the Technologies, DNA sample Santa of the Clara, proband CA, with USA) andthe paired-end SureSelectXT sequence Human kit (2 All100 Exon bp) v7 on (Agilent, HiSeq Agilent 1500 (Illumina, Technologies, San Diego,Santa Clara, CA, CA, USA) USA) to obtain and × 64,810,369paired-end reads sequence (89.4% (2 of × target 100 bp) bases on HiSeq were covered1500 (Illumina, at a minimum San Diego, of 20 CA,, whereas USA) to 95.2% obtain had 64,810,369 coverage × ofreads min. (89.4% 10 ). of The target obtained bases were raw covered data were at a processed minimum withof 20×, the whereas pipeline 95.2% previously had coverage described of min. [3 ]. × WES10×). data The were obtained inspected raw withdata anwere Integrative processed Genomics with the Viewer pipeline (IGV). previously Two heterozygous described [3]. variants WES data in the SNORD118were inspectedgene were with prioritized an Integrative for further Genomics verification Viewer (NR_033294.1:n.19C (IGV). Two heterozygous> G and variants NR_033294.1:n.* in the 5CSNORD118> G). Both disease-causinggene were prioritized variants werefor validatedfurther ve inrification the proband, (NR_033294.1:n.19C and studied in his> parentsG and by NR_033294.1:n.* 5C > G). Both disease-causing variants were validated in the proband, and studied amplicon deep sequencing (ADS) (Figure4). in his parents by amplicon deep sequencing (ADS) (Figure 4).

Figure 4. Pedigree of the studied family (A) and the results of WES and ADS for the variants in the FigureSNORD118 4. Pedigree gene; of(B the)—WES studied results; family (C) (Aresults) and of the amplicon results of deep WES se andquencing ADS forin the proband, variants inher the SNORD118parents (I–proband,gene; (B) WES II–mother, results; I (II–father).C) results ofThe amplicon obtained deep coverage sequencing of the in ADS the proband,for the n.19C her parents > G (I–proband,position in II–mother,the SNORD118 III–father). gene was: The 9508 obtained reads coveragefor the proband of the ADS(II.1); for 8923 the reads n.19C for> theG positionmother (I.2); in the SNORD118and 7578 readsgene for was: the 9508 father reads (I.1). for The the obtained proband cove (II.1);rage 8923 of the reads ADS for for the the mother n.* 5C (I.2);> G position and 7578 in readsthe

forSNORD118 the father gene (I.1). was: The obtained11,529 reads coverage for the of proband the ADS (II.1) for; the7721 n.* reads 5C > forG the position mother in (I.2); the SNORD118 and 8440 genereads was: for 11,529the father reads (I.1). for the proband (II.1); 7721 reads for the mother (I.2); and 8440 reads for the father (I.1). The transmission of the variants was consistent with the autosomal recessive pattern, as revealed by Thefamily transmission assessment. of The the variantspopulation was frequency consistent for with the the variants: autosomal n.19C recessive > G and pattern, n.* 5C as> revealedG was by0.00003492 family assessment. and The0.0006978, population frequencyrespectively, for the variants:in gnomAD n.19C > G and(database, n.* 5C > Gv.3, was https://gnomad.broadinstitute.org/) and 0.000834725 and 0.000554939 in in-house datasets of >3500 WES of Polish individuals. Both variants were previously described, although these were only single

Brain Sci. 2020, 10, 869 4 of 7

0.00003492 and 0.0006978, respectively, in gnomAD (database, v.3, https://gnomad.broadinstitute.org/) and 0.000834725 and 0.000554939 in in-house datasets of >3500 WES of Polish individuals. Both variants wereBrain previously Sci. 2020, 10, x described, FOR PEER REVIEW although these were only single reports [2,4]. They were reported4 of 7 as causative of LCC, although no comprehensive characteristics of patients with n.19C > G variant reports [2,4]. They were reported as causative of LCC, although no comprehensive characteristics of were raised. patients with n.19C > G variant were raised. The suspicion of Labrune syndrome was raised due to cyst progression in the degenerated white The suspicion of Labrune syndrome was raised due to cyst progression in the degenerated white matter and increasing calcifications in the follow-up studies (Figure5). Identified variants in the matter and increasing calcifications in the follow-up studies (Figure 5). Identified variants in the SNORD118SNORD118gene gene in in correlation correlation with with radiological radiological changeschanges confirmedconfirmed this this diagnosis. diagnosis.

FigureFigure 5. 5.Follow-up Follow-up MRI MRI of of the the brain, brain, axialaxial planeplane in the T2 FLAIR FLAIR sequence; sequence; (a ()a First) First MRI—at MRI—at the the age age of 7of years;7 years; (b )(b Second) Second MRI MRI 6 6 months months later;later; ((cc)) ThirdThird MRI 1 1 year year later—prog later—progressionression of of calcifications, calciﬁcations, cystscysts in in the the left left thalamus thalamus with with the the mass mass e effectﬀecton on MRIMRI andand white matter abnormalities. abnormalities.

4. Discussion4. Discussion InIn 1996, 1996, Labrune Labrune et al.et al. described described a newa new disorder disorder in threein three unrelated unrelated children. children. It wasIt was a triad a triad of LCCof as aLCC separate as a separate entity. entity. Diagnosis Diagnosis of LCC of wasLCC basedwas bas oned clinical on clinical and and neuroradiological neuroradiological findings findings with with the histologicalthe histological examination examination in some in some patients patients [1,5]. [1,5]. InIn 2016, 2016, it wasit was confirmed confirmed that that LCC LCC waswas aa novelnovel single-genesingle-gene disorder disorder due due to to germ-line germ-line biallelic biallelic mutationmutation in in the the box box C /C/DD snoRNA snoRNA [ 2[2].]. ThoseThose authorsauthors analyzed the the clinical clinical data data and and the the biological biological samplessamples of of 40 40 patients patients with with LCC LCC over over a a period period ofof 1212 years.years. In In 2016, 2016, Iwama Iwama et et al. al. identified identified eight eight mutations of the same gene in patients from unrelated families [4]. The last information on genetic mutations of the same gene in patients from unrelated families [4]. The last information on genetic background was described by Crow et al. [6]. background was described by Crow et al. [6]. Due to the progressive nature of the disease, follow-up MRI and the clinical observations are of Due to the progressive nature of the disease, follow-up MRI and the clinical observations are of primary importance, as a single examination is not sufficient to establish the diagnosis [7]. primary importance, as a single examination is not sufficient to establish the diagnosis [7]. Discrepancy Discrepancy between the relative well-being of our patient and abnormal imaging findings poses betweendifficulties the relativein diagnosis. well-being Patients of with our LCC patient may and complain abnormal of focal imaging neurological findings deficits, poses progressive difficulties in diagnosis.extrapyramidal, Patients pyramidal with LCC and may cerebellar complain symptoms, of focal neurological headaches deficits,and/or seizures. progressive In most, extrapyramidal, cognitive pyramidaldeficits are and also cerebellar reported. symptoms, We observed headaches a discrepanc and/yor between seizures. clinical In most, and cognitiveradiological deficits data in are our also reported.patient. WeThe observed subject was a discrepancy a normally between developing clinical girl and who radiological sought medical data in attention our patient. for recurrent The subject washeadaches a normally only. developing girl who sought medical attention for recurrent headaches only. DifferentialDifferential diagnosis diagnosis was was difficult, difficult, especiallyespecially with slowly occurring occurring changes changes in in the the follow-up follow-up imagingimaging studies. studies. First, First, calcifications calcifications in thein the basal basal ganglia ganglia on CTon CT prompted prompted further further diagnostic diagnostic testing. testing. Basal gangliaBasal calcificationsganglia calcifications on CT (which on CT were (which found were in ourfound patient in our in thepatient first in neuroimaging) the first neuroimaging)are non-specific, are andnon-specific, may occur inand many may diseases occur asin amany primary diseases or secondary as a primary sign. They or secondary may be idiopathic, sign. They toxic may (carbon be monoxide,idiopathic, lead toxic exposure), (carbon monoxide, infectious lead (TORCH exposure), complex, infectious AIDS), (TORCH metabolic complex, (hypoparathyroidism, AIDS), metabolic pseudohypoparathyroidism,(hypoparathyroidism, pseudohypoparathyroidism Cockayne syndrome I and, Cockayne II, mitochondrial syndrome diseases I and II, (MELAS, mitochondrial MERRF), neuroferritinopathy,diseases (MELAS, MERRF), neurodegeneration neuroferritinopathy, with brain neurodegeneration iron accumulation—NBIA) with brain iron accumulation— and inherited in originNBIA) (chromosomal and inherited abnormalities:in origin (chromosomalSLC20A2 abnormalities: 8p11.21 PDGFRB SLC20A2 5q32 8p11.21 PDGFB PDGFRB 22q13.1 5q32 XPR1 PDGFB 1q25.3 MYORG22q13.1 9p13.3). XPR1 1q25.3 MYORG 9p13.3). In our case, the CT finding of basal ganglia calcifications prompted wide chemical and metabolic testing, which resulted in the exclusion of infectious, toxic or metabolic origin. Fahr disease can reveal bilateral deep nuclei and subcortical calcifications without white matter abnormalities, which were found in our patient. Endocrinopathies (e.g., hypo, hyper-parathyroidism) Brain Sci. 2020, 10, 869 5 of 7

In our case, the CT finding of basal ganglia calcifications prompted wide chemical and metabolic testing, which resulted in the exclusion of infectious, toxic or metabolic origin. Fahr disease can reveal bilateral deep nuclei and subcortical calcifications without white matter abnormalities, which were found in our patient. Endocrinopathies (e.g., hypo, hyper-parathyroidism) were relatively easily excluded by laboratory testing. White matter changes found on the first MRI extended the diagnosis to leukodystrophy with calcifications. However, they were not useful in establishing the diagnosis. When infectious, toxic and hormonal factors were excluded, further metabolic investigation was necessary. Leukoencephalopathy with possible calcifications is known to occur in patients after radio- or chemotherapy, which was not observed in our case. The development of cysts with the progression of leukoencephalopathy on the third follow-up MRI examination added to the differential diagnosis, which concentrated on LCC. In Aicardi-Goutières syndrome, severe symptoms can already be present in infancy. Our patient was seven years old, and brain cysts were not typical of this syndrome. The symptoms of RNASET-2 deficient encephalopathy can also be present in infancy. However, the triad of leukoencephalopathy, calcifications and cysts is often observed. The older age of our patient and the clinical picture with further genetic testing were crucial for the differential diagnosis [8]. In Cockayne syndrome, systemic changes, which were absent in our patient, are associated with neurological symptoms. Brain atrophy, white matter signal abnormality and calcifications are the most prevalent in neuroimaging studies. Late-onset Krabbe disease presents different neurological signs, including ataxia, weakness and spasticity. Cystic changes with calcifications require the exclusion of parasitic (hydatid, cysticercosis and cryptococcosis) changes. No serologic evidence for parasitic infestation was found. Parasitic diseases do not typically present with white matter abnormalities. The Coats plus syndrome resembled Labrune syndrome. In neuroimaging, a triad of symptoms is so similar that before genetic explanation and differentiation between these diseases, they were considered the spectrum of the same pathology [9]. Neurological symptoms and pathologic findings, particularly cerebral microangiopathy [10], posed further problems with differentiation. In these cases, additional retinopathy and sometimes systemic pathology is observed. In 2014, Livingstone et al. suggested a different genetic origin of Coats plus syndrome and LCC, based on negative testing for typical Coats plus, which is related to gene mutation [11]. In the Coats plus syndrome, the genetic origin is different, and the disease presents with the CTC1 gene abnormality [12]. Therefore, genetic testing is crucial for the final diagnosis. Next to clinical findings and neuroimaging studies [13–16], genetics has significantly contributed to the explanation of the etiology of the syndrome. Labrune syndrome is a progressive disorder with onset at different ages, but usually in childhood. Clinical severity is highly variable. In many cases, severe developmental delay, progressive neurological and cognitive decline with premature death are reported. Some patients require neurosurgical intervention due to symptoms of increased intracranial pressure. This clinical variability is most likely related to the location of the cysts, and from a clinical point of view, it fails to distinguish the most characteristic symptoms of LCC. There is also no clear correlation between the type of mutation and clinical symptoms. In our patient only an increase in radiological changes was observed, which so far are not accompanied by any clinical symptoms. To date, there is no causal treatment in the LCC. Most of the clinical symptoms result from cerebral microangiopathy as tumor-like vascular hyperplasia. One possible disease mechanism may be a malfunction in the signaling pathway of vascular endothelial growth factors (VEGF). In 2017, Fay et al. reported first data on treatment with Bevacizumab, a monoclonal antibody anti-VEGF [17]. After one year of therapy for an 18-year-old patient with Bevacizumab and inhibition of VEGA signaling pathway, the authors observed significant improvement in neurological function, and brain MRI demonstrated a marked reduction in cyst volume and white matter lesions. Considering the lack of clinical symptoms and possible causal treatment, we plan to undertake similar Bevacizumab treatment in our patient in the near future. Brain Sci. 2020, 10, 869 6 of 7

5. Conclusions Only follow-up MRI examinations in a normally developing child and a correlation with an in-depth genetic analysis prompted to establish the diagnosis of this rare genetic metabolic syndrome. Cooperation between clinicians, radiologists and geneticists was crucial for establishing the ﬁnal diagnosis, and for personalized therapy.

Author Contributions: M.M.-S., J.P. (Jacek Pilch) and J.P. (Justyna Paprocka) conceived and designed the experiments; M.M.-S., J.P. (Jacek Pilch), J.P. (Justyna Paprocka), M.R., A.P., J.K. and P.G. performed the experiments; M.M.-S., J.P. (Jacek Pilch), J.P. (Justyna Paprocka), M.R., A.P., J.K. and P.G. analyzed the data; M.M.-S., J.P. (Jacek Pilch), J.P. (Justyna Paprocka), M.R., A.P., J.K. and P.G. contributed reagents/materials/analysis tools; M.M.-S., J.P. (Jacek Pilch), J.P. (Justyna Paprocka), M.R., A.P., J.K., P.G., K.G., E.E.-W. and R.P. wrote the paper. All authors have read and agreed to the published version of the manuscript. Funding: The paper was supported by Institutional Grant of the Medical University of Silesia: PCN-1-195/K/9/K. Acknowledgments: The authors would like to thank the parents for their cooperation. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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