Sturge-Weber Syndrome in a Multinational Paediatric Cohort: A Systematic Analysis of Different Types

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Different types are reflected in the Roach classification. Most previous studies have focussed on classic SWS Type I, but Type III cases, lacking facial birthmark, were mostly described in case reports. We systematically compare cases with and without facial birthmark, with a focus on epilepsy variables, cerebral involvement, use of aspirin, and overall outcome. Methods Using a cross-sectional observational study conducted through a well-established child neurologists’ network, we recruited paediatric patients with clinically diagnosed SWS from Germany, Switzerland, and Austria. The patients’ guardians and attending child neurologists filled in detailed questionnaires. All patients were classified according to the Roach classification by both attending child neurologists and the study team. Results Out of 111 paediatric SWS patients identified, 47 participated (43.2%). 35 cases (74.5%) fulfilled the criteria for classic SWS (Roach Type I); six cases (12.8%) showed no skin involvement (Roach Type III), the remaining six cases had overlap/atypical phacomatoses with capillary-venous malformation. Cases without facial birthmark were older at diagnosis (p = 0.005), and none showed ophthalmologic involvement. Age at first seizure did not differ significantly after adjustment for multiple comparisons. No significant differences were observed in seizure frequency, seizures types, number of used antiseizure medication (ASM), epilepsy surgery, cerebral involvement including atrophy and calcifications, SWS neuroscores or use of supportive therapies. Multivariable logistic regression showed seizure frequency was independent of SWS type and epilepsy surgery, but positively associated with the number of ASM required for seizure control (p = 0.0056). Half of operated patients were seizure-free at inclusion. Conclusions In our multinational cohort, Type I and Type III cases showed comparable epilepsy features, SWS neuroscores, number of required ASM and supportive therapy requirements. Type III patients were older at diagnosis and showed no ophthalmologic involvement, indicating a milder phenotype. Irrespective of SWS type, patients with uncontrolled epilepsy were 3.8-times more likely to require additional ASM. Despite uncontrolled epilepsy, only few patients underwent surgical evaluation or intervention. Larger cohorts are needed to evaluate surgical outcomes across SWS subtypes. Sturge-Weber Syndrome phacomatosis observational study Roach classification facial portwine birthmark Introduction Sturge-Weber Syndrome (SWS) belongs to a heterogenous group of rare neurocutaneous diseases characterized by concurrent skin and brain manifestations. Clinical symptoms in SWS vary widely between affected individuals, a diversity reflected in the Roach classification( 1 ): Type I SWS, the “classic” type of SWS, shows “facial and leptomeningeal angiomas, may have glaucoma( 1 )” – today, the angioma is classified as a capillary-venous malformation. Type II SWS is defined by “facial angioma without evidence of intracranial disease; may have glaucoma( 1 )”. In contrast, Type III lacks any skin and eye involvement and is characterized by “isolated leptomeningeal-brain angioma [and] usually, no glaucoma( 1 )”. While numerous case reports depict the clinical presentations and imaging studies in patients diagnosed as SWS Roach Type III / SWS- “without facial nevus” (e.g.( 2 – 4 )), systematic clinical data on different types of SWS are scarce. In most published SWS cohorts, the proportion of SWS cases with isolated brain involvement has been stable over the past years, ranging around 4–14 %( 5 – 8 ), irrespective f nationality/ethnicity. An internet-based, self-recruited U.S. cohort comprised a relatively low proportion of 7.7 % patients without faial portwine birthmark (FPB, total n = 628); likely through sampling bias with selection of more severely affected patients( 9 ). Previous clinical studies have investigated skin involvement in SWS thoroughly( 10 – 12 ). They have identified different facial localisations( 10 , 11 ) and greater size of FPB( 12 ) as associated with “high-risk” of SWS: The high-risk sites are the “forehead region”( 10 ), and distinct upper facial embryonic patterns, e.g. “hemifacial, upper quarter and cheek involvement” as described in detail elsewhere( 11 ). Powell et al.( 13 ) systematically compared patients with and without facial portwine birthmark (FPB) in a large (n = 140) retrospective national U.K. cohort. They hypothesized similar outcomes in both SWS types due to the common somatic mutation. However, FPB-negative cases in this study showed less extensive angioma, better language and cognitive outcomes, and absence of glaucoma( 13 ). The rates of status epilepticus and seizure clusters were comparable between the two groups despite significantly earlier status epilepticus onset in FPB positive cases. The finding was attributed to the shared, disease-causing GNAQ mutations( 14 – 16 ). Since Shirley et al.( 14 ) first identified the forementioned mutation on Chr. 9q21 in 23 out of 26 patients as the molecular cause of SWS in 2013, further research has identified additional mutations involved in other cellular pathways( 17 – 19 ), contributing to a deeper understanding of pathophysiology in SWS. Yet, the biology of the FPB negative cases remains to be fully understood. In brain specimens obtained during epilepsy surgery, digital droplet PCR detected the same GNAQ R183Q mutation with low mutation frequency in 4/4 FPB negative-SWS patients – which are often referred to as “forme fruste” of the condition( 16 ). In summary, current state of knowledge on the role of different clinical subtypes of SWS, i.e. with and without FPB, is scarce. This study builds on prior findings from a multinational cohort of paediatric SWS patients( 20 ) to expand current understanding of these two main subtypes of SWS and to support patient/parent counselling. We hypothesize that similar types of symptoms in FPB-negative and FPB-positive cases may occur, but with an overall milder phenotype in the FPB-negative subcohort. This study retrospectively compares different types of SWS in our previously described multinational cohort of 47 paediatric SWS patients( 20 ) with regard to epidemiologic features, epilepsy variables, neurocognitive function as assessed by previously described SWS neuroscores( 21 ) and with regard to antiseizure medication (ASM) and epilepsy surgery data. Materials and methods We conducted a multinational, cross-sectional study in Germany, Switzerland, and Austria to recruit paediatric SWS patients. For the study, we used an established network of child neurologists (“ESNEK,” i.e. in German “Erhebung Seltener Neurologischer Erkrankungen im Kindesalter”; engl. “Registry of Rare Neurological Disorders in Childhood”)( 22 ). We have given detailed descriptions of the study method and procedures in our previous studies( 20 , 22 ). We registered the study in the German Clinical Trials Registry (ID: DRKS 00013551, UTN U1111-1206-9923). The study protocol was approved by the responsible Institutional Review Board in Saarbrücken, University of Saarland, Germany (ID 209/17, October 2017). Altogether, 49 child neurologists notified us of 111 SWS patients in their attendance. Via the German SWS support group or by personal contacts between patients, 10 patients self-recruited. Their diagnoses were verified by our study team. Altogether, 47 patients were included in our study. The patients’ legal guardians gave informed consent in 44 cases. Three cases were sent anonymously by their attending child neurologists. This study included all patients aged < 18 years at the time of study inclusion with clinically diagnosed SWS who currently live in Germany, Switzerland, or Austria. Following internationally recognized SWS criteria by Roach et al.( 1 ), we enrolled patients with SWS types I-III. Additionally, we included atypical cases of SWS, i.e., overlap with other phacomatoses or presence of systemic angiomatosis. Patients were enrolled between January 2018 and December 2018; a few cases reported late until June 2019. For all cases, we verified the collected data through the attending child neurologists. We used two modified versions of our previously described questionnaires( 20 , 23 ) to build up a comprehensive database. One questionnaire each was adapted for caregivers, and one for child neurologists. The caregiver’s questionnaire comprised questions on patients’ demographics, family history, birth and prenatal history, ethnicity, current symptoms, including organ involvement, hearing, feeding, language skills, neurocognitive development, and use of health services. The child neurologists’ questionnaire included questions on SWS-specific organ involvement – under consideration of recent findings( 12 ) – family history, birth and prenatal history, current symptoms including components of SWS clinical severity scores( 21 ), further organ involvement, diagnostic procedures incl. genetics, therapies and therapeutic success, including the use of ASM and epilepsy surgery. Clinical severity scores( 21 ) comprise the severity of visual field defect, hemiparesis, seizure frequency and cognitive function, were calculated from the child neurologists’ questionnaires. As paper questionnaires allowed users to skip questions, we formally handled some missing data as normal values in the section on SWS clinical severity scores, if this section was otherwise complete and the given values medically plausible. We used a previously( 24 ) demonstrated cut-off value to distinguish between intellectually impaired patients (score ≥ 4) and non-impaired patients (score < 4; sensitivity 75 %, specificity 65 %). For some questionnaire items, we acknowledge missing data as follows: epileptic seizures during lifetime (n = 1), paresis (n = 3), need of visual aid (n = 5), laterality of FPB (n = 3), data on neuroscore incomplete and thus not included (n = 12). Data on cerebral atrophy in cerebral MRI not explicitly documented (n = 5), on EEG diagnostics (n = 1), and some questionnaires lacked a formal diagnosis of developmental status/delay (n = 6). Statistical methods Data analysis was exploratory. Systematic comparisons were conducted between Roach Type I and Type III patients. We used RStudio (2024.9.0.375’), R version 4.4.1 (2024-06-14 ucrt) for data analysis( 25 ). For normally distributed numerical covariates, we each indicated mean and standard deviation. If the assumptions were not fulfilled, we used median/interquartile ranges. For categorical variables, absolute and relative frequencies are given. We used Exact Fisher’s test or Chi Square test – depending on expected cell frequencies – to evaluate the independence of categorical variables. As a multivariable analysis, logistic regression evaluated the association between seizure frequency as a dependent (dichotomized) variable, and SWS type, epilepsy surgery and the number of ASM as predictor variables. We chose the following two groups for dichotomization of seizure frequency, i.e. group 1 (= controlled epilepsy/seizures): patient never had seizures OR one/more seizures but now seizure-free; group 2 (= uncontrolled epilepsy/seizures): breakthrough seizures, monthly seizures, OR weekly seizures or more. Analysis of Generalized Variance Inflation factors showed no relevant multicollinearity of the model. The threshold for statistical significance was set at p < 0.05. To adjust for multiple testing, we performed Benjamini Hochberg procedure with a false discovery rate of 0.2 (as in a previous study on SWS ( 13 )). Due to the very small number of operated patients, we conducted a retrospective statistical power calculation for the detection of a significant difference in seizure frequency between surgical and non-surgical patients. The calculation was approximative, based on a Welch’s t-test for unequal variances with the following parameters: the observed effect size Cohen’s d = 0.12, the observed unequal sample sizes of n1 = 4 and n2 = 42, and a significance level of alpha = 0.05. It showed that, under the conservative assumptions of Welch’s t-test, retrospective power for this question was insufficient in this cohort, i.e. only 55.3%. Results Overview of the study cohort Among 111 reported non-related paediatric patients with clinically diagnosed SWS, 47 patients fulfilled the inclusion criteria, consented to participate in our survey and completed our questionnaires (response rate 43.2%). Twenty-five patients were male and 22 female (ratio m/f = 1.13). The median age was 4.0 years (IQR 1.0-8.5 years), with an age range of 115 days to 17 years. Of these, 35 patients had both a facial birthmark (angioma) and cerebral capillary-venous malformation, and were classified as Roach Type I. Six patients fulfilled criteria for Type III, and 6 were categorized as overlap/atypical phacomatoses. We systematically compared Roach Type I (FPB positive) and Type III (FPB negative) cases; the patients with overlap/ atypical phacomatoses are presented separately (see Table 2 ). Epilepsy Seizures were reported in 91.5% of the cohort (43/47). Among Type III patients, 33% were seizure-free at study inclusion following one or more prior seizures (2/6), while another 33% experienced breakthrough seizures (2/6, 2 missing data points). Among Type I patients, 48.6% were seizure-free following one or more prior seizures (17/35), and 2.9% experienced breakthrough seizures (1/35). No Type III patients reported monthly or weekly seizures, while 14,3% (5/35) of Type I patients had monthly seizures, and 14,3% (5/35) had weekly seizures. Type I patients were younger at first seizure (median age 6 months) compared to Type III patients (median age 13 months), though the difference was not significant after adjustment (p = 0.026). Regarding seizure types, most Type III patients reported only generalized seizures (83.3%, 5/6), rarely both generalized and focal seizures. Type I patients more frequently reported focal seizures compared to Type III patients (14.3% vs 0%). However, this difference did not reach statistical significance (p = 0.692). Further details are presented in Table 2. Cerebral involvement, SWS neuroscores, and cognitive impairment Cerebral atrophy was prevalent across the cohort, irrespective of SWS Type (74.5% of the whole cohort). Brain atrophy was documented in all atypical cases (100%, 6/6). Calcifications occurred more frequently in Type I (45.7%) than in Type III (16.7%). Migraine was only reported in Type I cases (20%). Median SWS neuroscore was lower in Type III patients (3.0, IQR 2.8–3.8) than in Type I (median 6.0, IQR 4.0–9.0) and atypical cases (median 7.5, IQR 4.5–9.3). Cognitive impairment was present in 76.6% of the cohort, while Type III patients showed a higher rate of normal cognitive function (66.7%) compared to Type I patients (17.1%). Differences in overall cognitive impairment were not statistically significant (p = 0.158). Ophthalmologic involvement Congenital glaucoma was reported in 30% of the cohort (14/47), but none of the Type III patients was affected. Glaucoma developed later in an additional 19% of cases (9/47). Therapy included combined surgery and drugs in 25.5% and drugs only in 14.9%. Approximately one-third of the cohort had visual field deficits, with no significant differences between Type I and Type III patients. Antiseizure medication (ASM), aspirin use and epilepsy surgery The median number of ASM used across the cohort was 2.0 (IQR 1.0–2.0), with no significant difference between SWS types (p = 0.924). Aspirin was administered equally across subtypes. Four patients underwent epilepsy surgery: two had focal cortical resections, and another two hemispheric procedures. Surgery was performed both in three Type I cases and in one Type III case. Details on the patients who underwent epilepsy surgery are given below. Post-hoc subcohort analysis: Cases with epilepsy surgery All four cases which received epilepsy surgery were female. 75% of operated patients were SWS Type I (n = 3), and 25% were Type III (n = 1). Age ranged from 4 years to 17 years, with a median age of 13.5 years. All patients displayed cerebral capillary malformation, cerebral atrophy, and half had cerebral calcifications (n = 2). Two patients suffered from stroke-like episodes with significant sequelae, and severity of paresis ranged from grade 3–4 1 . SWS neuroscores among surgical patients ranged from 5–11. Half of operated patients also suffered from congenital glaucoma. The number of ASM used post-surgery ranged from 0–3, and none of the patients received additional aspirin. After surgery, at least half of this subcohort were seizure-free at study inclusion (n = 2), one reported “weekly seizures” (NA = 1 for this item, in a normally developed Type III patient without paresis). The median number of required ASM in operated patients was 1.5 (versus 2.0 in the nonsurgical subcohort). Multivariable model of seizure frequency as a function of SWS type Our multivariable model included SWS type, current number of ASM, and epilepsy surgery as predictors of seizure frequency. Binary logistic regression showed a significant, positive association between seizure frequency and the number of administered ASM (p = 0.0056), with a regression coefficient of 1.33 (i.e. OR 3.77, 95% CI 1.64; 11.22). SWS type and epilepsy surgery each were not associated with seizure frequency. Discussion/ conclusions This study represents the first multinational cohort to systematically investigate differences between SWS types Type I (classic form) and III (no skin involvement). We provide detailed clinical data on epilepsy including ASM, aspirin use, and epilepsy surgery, cerebral and ophthalmologic involvement, and neurocognitive outcomes. Key epidemiologic data of our cohort The cohort comprised 47 paediatric SWS cases, including 87.2% Type I (FPB positive) and 12.8% Type III (FPB negative) cases. These proportions are in line with the U.K. cohort by Powell et al. (85.7% FPB positive cases)( 13 ) and U.S. cohorts( 5 , 7 , 8 ). We have described other key demographic and epidemiologic data of our cohort in our previous publication( 20 ). Epilepsy in different SWS types The median age at first seizure in our cohort (6.5 months) is consistent with previous studies 2 ( 8 , 13 ). In concordance with these findings, Smegal et al.( 5 ) reported a seizure onset ≤ 12 months in 73.1 % of patiets – in one of the to date largest cohorts. Most SWS cohorts did not investigate epilepsy in different SWS types( 5 , 7 ). Type III patients in our cohort showed numerically later seizure onset (median 13 months) than Type I. Likewise, in the UK cohort by Powell et al( 13 ) (9 months) median age at onset of status epilepticus was significantly later in FPB negative patients, but the number of episodes with status epilepticus was comparable. Day et. al( 8 ) also found a later seizure onset in FPB negative patients (17 months) vs patients with unilateral FPB (10 months) or bilateral FPB (5 months). Early seizure onset is strongly associated with poorer neurocognitive outcomes( 8 , 13 , 26 , 27 ). Hence, delayed seizure onset is Type III may contribute to better intellectual outcomes. Regarding seizure type s Type III patients reported generalized seizures or both focal and generalized seizures. Previous studies and case reports, however, often indicate a predominance of focal onset seizures in FPB negative patients( 28 ) and in SWS in general( 6 , 27 , 29 , 30 ). In some studies, the types of seizures are not explicitly stated( 5 ). The UK cohort by Powell et al.( 13 ) specified that first seizure semiology was focal motor in 16 out of 20 FPB negative cases (80 %), as compared to 58 % FB negative cases. Diferences in seizure types in our cohort may reflect a selection bias toward more severely affected patients. We did not assess the frequency of seizure clusters, but this is another common type of seizures in SWS( 27 ) that probably occurs slightly more frequent in classic SWS( 13 ). Seizure frequency , analysed as a binary variable (controlled vs. uncontrolled seizures) was independent of SWS type in our multivariable analysis. As expected, our model showed that the odds for an additional ASM were more than threefold higher in uncontrolled versus controlled seizures (odds ratio = 3.7). In the Powell cohort, the number of seizures also did not differ between FPB positive and FPB negative patients( 13 ). Neurocognitive outcomes in different SWS types SWS is an often progressive( 31 ) neurovascular disorder which puts neurocognitive development of affected patients at risk. In our study, two thirds of patients showed various degrees of intellectual impairment (64 %),and among these, severe impairment was frequent (43 %).However, two thirds of our Type III patients showed normal cognitive function (66.7 %),and none of Type III patients showed severely or moderately impaired cognitive function. The findings are in line with Powell et al. (n = 140)( 13 ): 25 % of FP-positive cases were not impaired (in our own cohort: 17.1 % of Tye I cases not impaired), and 50 % of FP-negative cases were not impaired (in our own cohort: 66.7 % of Tye III not impaired). Intellectual status was not addressed in some of the other cohorts( 5 ). However, one of the so far largest published SWS cohorts by Day et al.( 8 ) with 277 paediatric (85.6 %) and adult articipants – recruited from 7 U.S. sites – reported a far smaller proportion of patients with “intellectual disability” (14.8 %), and 41.9 with a “leaning disorder” – despite a relatively high proportion of patients with bilateral FPB (35.7 %) and a simiar proportion of Type III patients. Even so, the authors estimated their results to be “likely skewed toward the more severely involved subjects” due to patient recruitment from tertiary centres. The higher rate of impaired patients in our and the above-cited studies is likely due to the large sample size in the Day cohort( 8 ). Additionally, our patients´ younger age, possibly points towards a more severe involvement and thus, a selection of more severely affected cases in our study (see below) might contribute. Finally, worse seizure control has been described in Caucasian patients( 7 ), and the proportion of Caucasians was moderately higher in our study (91 %) than in the Day ohort (84%) ( 8 ). Analysis of 11 published cases with SWS Type III reported on as single case reports or as small series shows that their intellectual status was mostly within normal limits( 2 – 4 , 32 – 35 ); only very few cases depicted intellectual impairment( 36 ) or progressive deterioration( 37 ). This may be explained by the fact that, on average – as shown by Powell et al( 13 ) – Type III patients show significantly reduced brain involvement as compared to classic Type I patients, i.e. fewer lobes with angioma, and the angioma is always unilateral. On a molecular basis, an intact intellectual function and less extensive angioma are compatible with the smaller mutant allele frequencies of the causative GNAQ gene mutation found in SWS Type III cases (0.42% − 7.1%)( 16 ) as compared to the allele mutation frequency described in classic Type I cases (1 % − 18.1 %)( 14 ) - presumably, de to a lter occurrence of the shared somatic mutation. Diagnosis in SWS Type III In our cohort, all Type III cases were diagnosed within the first two years of life. However, late manifestations( 4 , 32 , 35 ) and/or delayed diagnoses( 3 , 32 , 35 , 36 ) are commonly reported, with intervals of up to 26 years between first symptoms and final diagnosis( 32 ): One patient showed first symptoms at the age of 6 years (with status migrainosus; initially suspected for encephalitis( 3 )), and was diagnosed with SWS Type III three years later. Another patient became symptomatic at the age of 10 years with headaches and visual aura and was finally diagnosed with SWS Type III at the age of 36 years( 32 ). Finally, a 62-year old man was diagnosed with SWS Type III after a first generalized seizure and typical MRI findings; his first manifestation three years before had been misclassified as a culture-negative “focal leptomeningitis”( 38 ). To conclude, diagnosis in SWS Type III can be particularly challenging and requires regular training of medical staff on SWS clinical signs and imaging features. Aspirin therapy and epilepsy surgery in different SWS types In our cohort, aspirin use was equally common in both SWS types, in line with the U.K. cohort by Powell et al( 13 ), reflecting similar occurrence of stroke-like episodes. Epilepsy surgery was performed in SWS patients of both types. Both surgical patients which remained seizure-free after surgery (i.e. 50% of the operated patients) were Type I SWS patients (no information available on outcomes of the operated Type III patient), and one had received hemispherotomy, the other a cortical resection. Hemispherectomies were the most frequently used surgical technique in the Powell cohort( 13 ). A recently published study by Ramantani et al. including 36 patients with SWS found no difference in outcomes with regard to surgical technique in paediatric hemispherotomy( 39 ). As compared to postsurgical paediatric cases of other etiology, SWS cases were more likely to walk independently and speak short sentences or age-appropriately, but they were rarely able to grasp voluntarily with their hemiplegic hand ( 40 ). Potential sources of bias Our study used a non-mandatory neuropaediatric network for recruitment, which may have led to incomplete SWS case registration. Yet, estimation of completeness is difficult as no obligatory reporting system exists in the German-speaking countries. Notably, we cannot rule out an increased inclusion of more severely affected SWS patients for this cohort as severely affected patients tend to seek medical attention in tertiary centres and university hospitals more often than mildly affected patients( 41 ) – where rare disease networks such as ESNEK are more well-known. A differential recruiting completeness- depending on the disease severity – could result in selection bias. Vice versa, less severely affected patients– may have been missed by the reporting system. Potential selection bias would also explain why no patients with SWS Type II (no neurologic involvement) were reported in this cohort. Using capture-recapture methods, the experience from other German paediatric rare-disease networks such as ESPED (transl.: German Paediatric Surveillance Unit) showed that overall completeness of registration ranged between 37 and 44% for Kawasaki Disease( 42 ). Such methods are not available for this study, as no other independent estimates for SWS prevalence are available for the German-speaking countries. For future research, an analysis of hospital records could potentially provide a remedy here. As Type III patients display no externally visible signs of the condition, this type is especially prone to detection bias . Undiagnosed patients with Type III SWS, e.g. cases misclassified as migraine( 3 , 32 ) or as meningitis( 38 ) (s.a.), escape every reporting system, resulting in underestimation of SWS Type III prevalence. Additionally, we cannot rule out underreporting of mildly affected phenotypes which may lead to overestimation of disease severity in SWS Type III cases. Strengths and limitations of our study Our multinational cohort gives insight into detailed clinical profiles not only in classic SWS Type I, but also in SWS Type III, which has so far been mostly described in case reports. We included data on SWS neuroscores, use of aspirin, ASM and epilepsy surgery. As main limitations, we acknowledge that incompleteness of registration through a non-obligatory, though well-established neuropaediatric network may lead to potential bias. Given the rarity of SWS, the small sample size of Type III patients may increase the probability of chance findings and it may decrease the power for the detection of significant findings. The achieved sample size restricted our possibilities for multivariable modelling. Yet, our exploratory analyses serve as a valuable basis for new directions in future research. Conclusions Our findings suggest that SWS Type III represents a milder phenotype compared to classic Type I, with later diagnosis, better neurocognitive outcomes, and similar epilepsy characteristics. Increased awareness and training on the clinical and imaging characteristics of SWS are necessary for timely diagnosis and intervention. Further research, particularly in larger cohorts, is necessary to evaluate surgical outcomes and optimize management strategies across SWS subtypes. Abbreviations ASM: antiseizure medication; CI: confidence interval; ESNEK (German “ E rhebung S eltener N eurologischer E rkrankungen im K indesalter”; English translation “Survey of Rare Neurological Disorders in Childhood”); FPB: facial portwine birthmark; SWS: Sturge-Weber Syndrome Declarations Ethics approval and consent to participate The study protocol was approved by the responsible Institutional Review Board in Saarbrücken, University of Saarland, Germany (ID 209/17, October 2017). Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analysed during the current study are not publicly available because of potentially identifiable, confidential patient data, but are available from the corresponding author on reasonable request. Competing interests Interim results of this study were presented at a Meeting of the German National Sturge-Weber Foundation (IG, “Interessengemeinschaft” SWS) in Herbstein/Germany in 2019. The main study findings were presented at the German National Conference on Paediatrics as a poster in 2020. All authors declare that they have no competing financial interests. Funding SD received a personal career development fellowship by University Regensburg („KUNO Fellowship“), which supported this research. This study received financial support for mailing cost and office supplies by Children’s University Hospital Saarland, Dept. of Neuropaediatrics. SD was reimbursed for travel cost by the German National Sturge-Weber Foundation. All funding had no role in the conceptualization, design, data collection, analysis, decision to publish, or in the content of the manuscript. Authors’ contributions: Study idea: SD. Study design: SD, SM. Data acquisition: HK, AB, GCK, GR, BW, MP, RT, KB, SS. Coordination of child neurologists’ network for data acquisition: SS, KB. Organizational study support: SW. Statistical analysis: SD. Drafting of manuscript: SD. Critical revision of the manuscript: all authors. Study supervision: SM. Acknowledgements We would like to thank all participating SWS patients and their families as well as all contributing neuropaediatric colleagues from the ESNEK network for their support of this study. References Roach ES. Neurocutaneous syndromes. Pediatr Clin North Am 1992; 39(4):591–620. Aydin A, Cakmakçi H, Kovanlikaya A, Dirik E. Sturge-Weber syndrome without facial nevus. Pediatr Neurol 2000; 22(5):400–2. 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Physical and Family History Variables Associated With Neurological and Cognitive Development in Sturge-Weber Syndrome. Pediatr Neurol 2019; 96:30–6. Cho S, Maharathi B, Ball KL, Loeb JA, Pevsner J. Sturge-Weber Syndrome Patient Registry: Delayed Diagnosis and Poor Seizure Control. J Pediatr 2019; 215:158-163.e6. Waelchli R, Aylett SE, Robinson K, Chong WK, Martinez AE, Kinsler VA. New vascular classification of port-wine stains: improving prediction of Sturge-Weber risk. Br J Dermatol 2014; 171(4):861–7. Dutkiewicz A-S, Ezzedine K, Mazereeuw-Hautier J, Lacour J-P, Barbarot S, Vabres P et al. A prospective study of risk for Sturge-Weber syndrome in children with upper facial port-wine stain. J Am Acad Dermatol 2015; 72(3):473–80. Dymerska M, Kirkorian AY, Offermann EA, Lin DD, Comi AM, Cohen BA. Size of Facial Port-Wine Birthmark May Predict Neurologic Outcome in Sturge-Weber Syndrome. J Pediatr 2017; 188:205-209.e1. Powell S, Fosi T, Sloneem J, Hawkins C, Richardson H, Aylett S. 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Identification of a Mosaic Activating Mutation in GNA11 in Atypical Sturge-Weber Syndrome. J Invest Dermatol 2021; 141(3):685–8. Polubothu S, Al-Olabi L, Del Carmen Boente M, Chacko A, Eleftheriou G, Glover M et al. GNA11 Mutation as a Cause of Sturge-Weber Syndrome: Expansion of the Phenotypic Spectrum of Gα/11 Mosaicism and the Associated Clinical Diagnoses. J Invest Dermatol 2020; 140(5):1110–3. Disse S, Küpper H, Bock A, Korenke, Georg-Christoph, Ramantani, Georgia, Weidner B, Preisel M et al. The Natural History of Pediatric Sturge-Weber Syndrome: A Population-based, Multinational Observational Study Manuscript currently under Review. Kelley TM, Hatfield LA, Lin DDM, Comi AM. Quantitative analysis of cerebral cortical atrophy and correlation with clinical severity in unilateral Sturge-Weber syndrome. J Child Neurol 2005; 20(11):867–70. Brockmann K. Erhebung Seltener Neurologischer Erkrankungen im Kindesalter. Neuropediatrics 2014; 45(S 01). Disse SC, Toelle SP, Schroeder S, Theiler M, Weibel L, Broser P et al. Epidemiology, Clinical Features, and Use of Early Supportive Measures in PHACE Syndrome: A European Multinational Observational Study. Neuroepidemiology 2020; 54(5):383–91. Kavanaugh B, Sreenivasan A, Bachur C, Papazoglou A, Comi A, Zabel TA. Intellectual and adaptive functioning in Sturge-Weber Syndrome. Child Neuropsychol 2016; 22(6):635–48. RStudio.: R: A language and environment for statistical computing. Version 1.2.1335 ed2017. Vienna, Austria.: R Foundation for Statistical Computing. Available from: URL: https://www.R-project.org. Bosnyák E, Behen ME, Guy WC, Asano E, Chugani HT, Juhász C. Predictors of Cognitive Functions in Children With Sturge-Weber Syndrome: A Longitudinal Study. Pediatr Neurol 2016; 61:38–45. Luat AF, Juhász C, Loeb JA, Chugani HT, Falchek SJ, Jain B et al. Neurological Complications of Sturge-Weber Syndrome: Current Status and Unmet Needs. Pediatr Neurol 2019; 98:31–8. Gazeteci Tekin H, Gökben S, Yılmaz S, Tekgül H, Serdaroğlu G. Sturge-Weber Syndrome Type III. jpr 2018; 5(2):103–5. Maraña Pérez AI, Ruiz-Falcó Rojas ML, Puertas Martín V, Domínguez Carral J, Carreras Sáez I, Duat Rodríguez A et al. Analysis of Sturge–Weber syndrome: A retrospective study of multiple associated variables. Neurología (English Edition) 2017; 32(6):363–70. Zhang Y, Niu J, Wang J, Cai A, Wang Y, Wei G et al. Neurological function and drug-refractory epilepsy in Sturge-Weber syndrome children: a retrospective analysis. Eur J Pediatr 2024; 183(4):1881–90. Kossoff EH, Bachur CD, Quain AM, Ewen JB, Comi AM. EEG evolution in Sturge-Weber syndrome. Epilepsy Res 2014; 108(4):816–9. Huang HY, Lin K-H, Chen J-C, Hsu Y-T. Type III Sturge-Weber syndrome with migraine-like attacks associated with prolonged visual aura. Headache 2013; 53(5):845–9. Crosley CJ, Binet EF. Sturge-Weber Syndrome: presentation as a focal seizure disorder without nevus flammeus. Clin Pediatr (Phila) 1978; 17(8):606–9. Jagtap SA, Srinivas G, Radhakrishnan A, Harsha KJ. A clinician's dilemma: Sturge-Weber syndrome 'without facial nevus'!! Ann Indian Acad Neurol 2013; 16(1):118–20. Kim W, Kim J-S, An J-Y, Lee S-J, Chung S-R, Kim Y-I et al. Sturge‐Weber syndrome, without a facial port‐wine stain, with epilepsy onset in the fifth decade. Epileptic Disorders 2008; 10(1):76–7. Sen Y, Dilber E, Odemis E, Ahmetoglu A, Aynaci FM. Sturge-Weber syndrome in a 14-year-old girl without facial naevus. Eur J Pediatr 2002; 161(9):505–6. Taly AB, Nagaraja D, Das S, Shankar SK, Pratibha NG. Sturge-Weber-Dimitri disease without facial nevus. Neurology 1987; 37(6):1063–4. Muralidharan V, Failla G, Travali M, Cavallaro TL, Politi MA. Isolated leptomeningeal angiomatosis in the sixth decade of life, an adulthood variant of Sturge Weber Syndrome (Type III): role of advanced Magnetic Resonance Imaging and Digital Subtraction Angiography in diagnosis. BMC Neurol 2020; 20(1):366. Ramantani G, Bulteau C, Cserpan D, Otte WM, Dorfmüller G, Cross JH et al. Not surgical technique, but etiology, contralateral MRI, prior surgery, and side of surgery determine seizure outcome after pediatric hemispherotomy. Epilepsia 2023; 64(5):1214–24. Ramantani G, Cserpan D, Tisdall M, Otte WM, Dorfmüller G, Cross JH et al. Determinants of Functional Outcome after Pediatric Hemispherotomy. Ann Neurol 2024; 95(2):377–87. Kanafani ZA, Kanj SS, Cabell CH, Cecchi E, Oliveira Ramos A de, Lejko-Zupanc T et al. Revisiting the effect of referral bias on the clinical spectrum of infective endocarditis in adults. Eur J Clin Microbiol Infect Dis 2010; 29(10):1203–10. Jakob A, Whelan J, Kordecki M, Berner R, Stiller B, Arnold R et al. Kawasaki Disease in Germany: A Prospective, Population-based Study Adjusted for Underreporting. Pediatr Infect Dis J 2016; 35(2):129–34. Footnotes Paresis grade 3: gross and fine motricity significantly affected, grade 4: gross and fine motricity severely affected, independent gait severely compromised or not possible Powell et al: seizure onset at 7 months(13), Day et al. 5 months/10 months for bilateral/unilateral PWS(5). Tables Tables are available in the Supplementary Files section. Supplementary Files Tables.docx Cite Share Download PDF Status: Published Journal Publication published 02 Jul, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Reviewers invited by journal 05 Feb, 2025 Editor assigned by journal 26 Jan, 2025 First submitted to journal 23 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Gottingen","correspondingAuthor":false,"prefix":"","firstName":"Knut","middleName":"","lastName":"Brockmann","suffix":""},{"id":411471690,"identity":"472b2522-902c-4301-bd93-b7ada4cb0104","order_by":11,"name":"Simone Schröder","email":"","orcid":"","institution":"University Medical Center Göttingen: Universitatsmedizin Gottingen","correspondingAuthor":false,"prefix":"","firstName":"Simone","middleName":"","lastName":"Schröder","suffix":""},{"id":411471691,"identity":"129e7b84-51ea-49a3-b6f2-39df0fe4e6b1","order_by":12,"name":"Sascha Meyer","email":"","orcid":"","institution":"Franz-Lust Klinik für Kinder und Jugendliche Karlsruhe","correspondingAuthor":false,"prefix":"","firstName":"Sascha","middleName":"","lastName":"Meyer","suffix":""}],"badges":[],"createdAt":"2025-01-23 17:52:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5890276/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5890276/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-025-03769-2","type":"published","date":"2025-07-02T15:57:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86179121,"identity":"0bef8518-797e-4da1-9099-c2138d9dd9b6","added_by":"auto","created_at":"2025-07-07 16:15:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":811541,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5890276/v1/4e354ebb-08b1-4899-9d87-97123de88e4a.pdf"},{"id":75701593,"identity":"d02aff8e-3cf4-4ee6-abd5-1be87e894e39","added_by":"auto","created_at":"2025-02-07 09:27:03","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29745,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5890276/v1/5c68c88cc2810682a01e0281.docx"}],"financialInterests":"","formattedTitle":"Sturge-Weber Syndrome in a Multinational Paediatric Cohort: A Systematic Analysis of Different Types","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSturge-Weber Syndrome (SWS) belongs to a heterogenous group of rare neurocutaneous diseases characterized by concurrent skin and brain manifestations. Clinical symptoms in SWS vary widely between affected individuals, a diversity reflected in the Roach classification(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e): Type I SWS, the \u0026ldquo;classic\u0026rdquo; type of SWS, shows \u0026ldquo;facial and leptomeningeal angiomas, may have glaucoma(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u0026rdquo; \u0026ndash; today, the angioma is classified as a capillary-venous malformation. Type II SWS is defined by \u0026ldquo;facial angioma without evidence of intracranial disease; may have glaucoma(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u0026rdquo;. In contrast, Type III lacks any skin and eye involvement and is characterized by \u0026ldquo;isolated leptomeningeal-brain angioma [and] usually, no glaucoma(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u0026rdquo;. While numerous case reports depict the clinical presentations and imaging studies in patients diagnosed as SWS Roach Type III / SWS- \u0026ldquo;without facial nevus\u0026rdquo; (e.g.(\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)), systematic clinical data on different types of SWS are scarce. In most published SWS cohorts, the proportion of SWS cases with isolated brain involvement has been stable over the past years, ranging around 4\u0026ndash;14 %(\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), irrespective f nationality/ethnicity. An internet-based, self-recruited U.S. cohort comprised a relatively low proportion of 7.7 % patients without faial portwine birthmark (FPB, total n\u0026thinsp;=\u0026thinsp;628); likely through sampling bias with selection of more severely affected patients(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious clinical studies have investigated skin involvement in SWS thoroughly(\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). They have identified different facial localisations(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) and greater size of FPB(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) as associated with \u0026ldquo;high-risk\u0026rdquo; of SWS: The high-risk sites are the \u0026ldquo;forehead region\u0026rdquo;(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), and distinct upper facial embryonic patterns, e.g. \u0026ldquo;hemifacial, upper quarter and cheek involvement\u0026rdquo; as described in detail elsewhere(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePowell et al.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) systematically compared patients with and without facial portwine birthmark (FPB) in a large (n\u0026thinsp;=\u0026thinsp;140) retrospective national U.K. cohort. They hypothesized similar outcomes in both SWS types due to the common somatic mutation. However, FPB-negative cases in this study showed less extensive angioma, better language and cognitive outcomes, and absence of glaucoma(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The rates of status epilepticus and seizure clusters were comparable between the two groups despite significantly earlier status epilepticus onset in FPB positive cases. The finding was attributed to the shared, disease-causing GNAQ mutations(\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Since Shirley et al.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) first identified the forementioned mutation on Chr. 9q21 in 23 out of 26 patients as the molecular cause of SWS in 2013, further research has identified additional mutations involved in other cellular pathways(\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), contributing to a deeper understanding of pathophysiology in SWS. Yet, the biology of the FPB negative cases remains to be fully understood. In brain specimens obtained during epilepsy surgery, digital droplet PCR detected the same GNAQ R183Q mutation with low mutation frequency in 4/4 FPB negative-SWS patients \u0026ndash; which are often referred to as \u0026ldquo;forme fruste\u0026rdquo; of the condition(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In summary, current state of knowledge on the role of different clinical subtypes of SWS, i.e. with and without FPB, is scarce. This study builds on prior findings from a multinational cohort of paediatric SWS patients(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) to expand current understanding of these two main subtypes of SWS and to support patient/parent counselling. We hypothesize that similar types of symptoms in FPB-negative and FPB-positive cases may occur, but with an overall milder phenotype in the FPB-negative subcohort. This study retrospectively compares different types of SWS in our previously described multinational cohort of 47 paediatric SWS patients(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) with regard to epidemiologic features, epilepsy variables, neurocognitive function as assessed by previously described SWS neuroscores(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) and with regard to antiseizure medication (ASM) and epilepsy surgery data.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eWe conducted a multinational, cross-sectional study in Germany, Switzerland, and Austria to recruit paediatric SWS patients. For the study, we used an established network of child neurologists (\u0026ldquo;ESNEK,\u0026rdquo; i.e. in German \u0026ldquo;Erhebung Seltener Neurologischer Erkrankungen im Kindesalter\u0026rdquo;; engl. \u0026ldquo;Registry of Rare Neurological Disorders in Childhood\u0026rdquo;)(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). We have given detailed descriptions of the study method and procedures in our previous studies(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). We registered the study in the German Clinical Trials Registry (ID: DRKS 00013551, UTN U1111-1206-9923). The study protocol was approved by the responsible Institutional Review Board in Saarbr\u0026uuml;cken, University of Saarland, Germany (ID 209/17, October 2017). Altogether, 49 child neurologists notified us of 111 SWS patients in their attendance. Via the German SWS support group or by personal contacts between patients, 10 patients self-recruited. Their diagnoses were verified by our study team. Altogether, 47 patients were included in our study. The patients\u0026rsquo; legal guardians gave informed consent in 44 cases. Three cases were sent anonymously by their attending child neurologists.\u003c/p\u003e \u003cp\u003eThis study included all patients aged\u0026thinsp;\u0026lt;\u0026thinsp;18 years at the time of study inclusion with clinically diagnosed SWS who currently live in Germany, Switzerland, or Austria. Following internationally recognized SWS criteria by Roach et al.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), we enrolled patients with SWS types I-III. Additionally, we included atypical cases of SWS, i.e., overlap with other phacomatoses or presence of systemic angiomatosis. Patients were enrolled between January 2018 and December 2018; a few cases reported late until June 2019. For all cases, we verified the collected data through the attending child neurologists.\u003c/p\u003e \u003cp\u003eWe used two modified versions of our previously described questionnaires(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) to build up a comprehensive database. One questionnaire each was adapted for caregivers, and one for child neurologists. The caregiver\u0026rsquo;s questionnaire comprised questions on patients\u0026rsquo; demographics, family history, birth and prenatal history, ethnicity, current symptoms, including organ involvement, hearing, feeding, language skills, neurocognitive development, and use of health services. The child neurologists\u0026rsquo; questionnaire included questions on SWS-specific organ involvement \u0026ndash; under consideration of recent findings(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) \u0026ndash; family history, birth and prenatal history, current symptoms including components of SWS clinical severity scores(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), further organ involvement, diagnostic procedures incl. genetics, therapies and therapeutic success, including the use of ASM and epilepsy surgery. Clinical severity scores(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) comprise the severity of visual field defect, hemiparesis, seizure frequency and cognitive function, were calculated from the child neurologists\u0026rsquo; questionnaires. As paper questionnaires allowed users to skip questions, we formally handled some missing data as normal values in the section on SWS clinical severity scores, if this section was otherwise complete and the given values medically plausible. We used a previously(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) demonstrated cut-off value to distinguish between intellectually impaired patients (score\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;4) and non-impaired patients (score\u0026thinsp;\u0026lt;\u0026thinsp;4; sensitivity 75 %, specificity 65 %).\u003c/p\u003e \u003cp\u003eFor some questionnaire items, we acknowledge missing data as follows: epileptic seizures during lifetime (n\u0026thinsp;=\u0026thinsp;1), paresis (n\u0026thinsp;=\u0026thinsp;3), need of visual aid (n\u0026thinsp;=\u0026thinsp;5), laterality of FPB (n\u0026thinsp;=\u0026thinsp;3), data on neuroscore incomplete and thus not included (n\u0026thinsp;=\u0026thinsp;12). Data on cerebral atrophy in cerebral MRI not explicitly documented (n\u0026thinsp;=\u0026thinsp;5), on EEG diagnostics (n\u0026thinsp;=\u0026thinsp;1), and some questionnaires lacked a formal diagnosis of developmental status/delay (n\u0026thinsp;=\u0026thinsp;6).\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical methods\u003c/b\u003e \u003c/p\u003e \u003cp\u003eData analysis was exploratory. Systematic comparisons were conducted between Roach Type I and Type III patients. We used RStudio (2024.9.0.375\u0026rsquo;), R version 4.4.1 (2024-06-14 ucrt) for data analysis(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). For normally distributed numerical covariates, we each indicated mean and standard deviation. If the assumptions were not fulfilled, we used median/interquartile ranges. For categorical variables, absolute and relative frequencies are given. We used Exact Fisher\u0026rsquo;s test or Chi Square test \u0026ndash; depending on expected cell frequencies \u0026ndash; to evaluate the independence of categorical variables.\u003c/p\u003e \u003cp\u003eAs a multivariable analysis, logistic regression evaluated the association between seizure frequency as a dependent (dichotomized) variable, and SWS type, epilepsy surgery and the number of ASM as predictor variables. We chose the following two groups for dichotomization of seizure frequency, i.e. group 1\u003c/p\u003e \u003cp\u003e(=\u0026thinsp;controlled epilepsy/seizures): patient never had seizures OR one/more seizures but now seizure-free; group 2 (=\u0026thinsp;uncontrolled epilepsy/seizures): breakthrough seizures, monthly seizures, OR weekly seizures or more. Analysis of Generalized Variance Inflation factors showed no relevant multicollinearity of the model.\u003c/p\u003e \u003cp\u003eThe threshold for statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. To adjust for multiple testing, we performed Benjamini Hochberg procedure with a false discovery rate of 0.2 (as in a previous study on SWS (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)).\u003c/p\u003e \u003cp\u003eDue to the very small number of operated patients, we conducted a retrospective statistical power calculation for the detection of a significant difference in seizure frequency between surgical and non-surgical patients. The calculation was approximative, based on a Welch\u0026rsquo;s t-test for unequal variances with the following parameters: the observed effect size Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;0.12, the observed unequal sample sizes of n1\u0026thinsp;=\u0026thinsp;4 and n2\u0026thinsp;=\u0026thinsp;42, and a significance level of alpha\u0026thinsp;=\u0026thinsp;0.05. It showed that, under the conservative assumptions of Welch\u0026rsquo;s t-test, retrospective power for this question was insufficient in this cohort, i.e. only 55.3%.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003eOverview of the study cohort\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAmong 111 reported non-related paediatric patients with clinically diagnosed SWS, 47 patients fulfilled the inclusion criteria, consented to participate in our survey and completed our questionnaires (response rate 43.2%). Twenty-five patients were male and 22 female (ratio m/f\u0026thinsp;=\u0026thinsp;1.13). The median age was 4.0 years (IQR 1.0-8.5 years), with an age range of 115 days to 17 years. Of these, 35 patients had both a facial birthmark (angioma) and cerebral capillary-venous malformation, and were classified as Roach Type I. Six patients fulfilled criteria for Type III, and 6 were categorized as overlap/atypical phacomatoses. We systematically compared Roach Type I (FPB positive) and Type III (FPB negative) cases; the patients with overlap/ atypical phacomatoses are presented separately (see \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eEpilepsy\u003c/b\u003e \u003c/p\u003e \u003cp\u003eSeizures were reported in 91.5% of the cohort (43/47). Among Type III patients, 33% were seizure-free at study inclusion following one or more prior seizures (2/6), while another 33% experienced breakthrough seizures (2/6, 2 missing data points). Among Type I patients, 48.6% were seizure-free following one or more prior seizures (17/35), and 2.9% experienced breakthrough seizures (1/35). No Type III patients reported monthly or weekly seizures, while 14,3% (5/35) of Type I patients had monthly seizures, and 14,3% (5/35) had weekly seizures.\u003c/p\u003e \u003cp\u003eType I patients were younger at first seizure (median age 6 months) compared to Type III patients (median age 13 months), though the difference was not significant after adjustment (p\u0026thinsp;=\u0026thinsp;0.026).\u003c/p\u003e \u003cp\u003eRegarding seizure types, most Type III patients reported only generalized seizures (83.3%, 5/6), rarely both generalized and focal seizures. Type I patients more frequently reported focal seizures compared to Type III patients (14.3% vs 0%). However, this difference did not reach statistical significance (p\u0026thinsp;=\u0026thinsp;0.692). Further details are presented in \u003cb\u003eTable\u0026nbsp;2.\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eCerebral involvement, SWS neuroscores, and cognitive impairment\u003c/b\u003e \u003c/p\u003e \u003cp\u003eCerebral atrophy was prevalent across the cohort, irrespective of SWS Type (74.5% of the whole cohort). Brain atrophy was documented in all atypical cases (100%, 6/6). Calcifications occurred more frequently in Type I (45.7%) than in Type III (16.7%). Migraine was only reported in Type I cases (20%).\u003c/p\u003e \u003cp\u003eMedian SWS neuroscore was lower in Type III patients (3.0, IQR 2.8\u0026ndash;3.8) than in Type I (median 6.0, IQR 4.0\u0026ndash;9.0) and atypical cases (median 7.5, IQR 4.5\u0026ndash;9.3).\u003c/p\u003e \u003cp\u003eCognitive impairment was present in 76.6% of the cohort, while Type III patients showed a higher rate of normal cognitive function (66.7%) compared to Type I patients (17.1%). Differences in overall cognitive impairment were not statistically significant (p\u0026thinsp;=\u0026thinsp;0.158).\u003c/p\u003e \u003cp\u003e \u003cb\u003eOphthalmologic involvement\u003c/b\u003e \u003c/p\u003e \u003cp\u003eCongenital glaucoma was reported in 30% of the cohort (14/47), but none of the Type III patients was affected. Glaucoma developed later in an additional 19% of cases (9/47). Therapy included combined surgery and drugs in 25.5% and drugs only in 14.9%. Approximately one-third of the cohort had visual field deficits, with no significant differences between Type I and Type III patients.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAntiseizure medication (ASM), aspirin use and epilepsy surgery\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe median number of ASM used across the cohort was 2.0 (IQR 1.0\u0026ndash;2.0), with no significant difference between SWS types (p\u0026thinsp;=\u0026thinsp;0.924). Aspirin was administered equally across subtypes.\u003c/p\u003e \u003cp\u003eFour patients underwent epilepsy surgery: two had focal cortical resections, and another two hemispheric procedures. Surgery was performed both in three Type I cases and in one Type III case. Details on the patients who underwent epilepsy surgery are given below.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePost-hoc subcohort analysis: Cases with epilepsy surgery\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAll four cases which received epilepsy surgery were female. 75% of operated patients were SWS Type I (n\u0026thinsp;=\u0026thinsp;3), and 25% were Type III (n\u0026thinsp;=\u0026thinsp;1). Age ranged from 4 years to 17 years, with a median age of 13.5 years. All patients displayed cerebral capillary malformation, cerebral atrophy, and half had cerebral calcifications (n\u0026thinsp;=\u0026thinsp;2). Two patients suffered from stroke-like episodes with significant sequelae, and severity of paresis ranged from grade 3\u0026ndash;4\u003csup\u003e1\u003c/sup\u003e. SWS neuroscores among surgical patients ranged from 5\u0026ndash;11. Half of operated patients also suffered from congenital glaucoma. The number of ASM used post-surgery ranged from 0\u0026ndash;3, and none of the patients received additional aspirin. After surgery, at least half of this subcohort were seizure-free at study inclusion (n\u0026thinsp;=\u0026thinsp;2), one reported \u0026ldquo;weekly seizures\u0026rdquo; (NA\u0026thinsp;=\u0026thinsp;1 for this item, in a normally developed Type III patient without paresis). The median number of required ASM in operated patients was 1.5 (versus 2.0 in the nonsurgical subcohort).\u003c/p\u003e \u003cp\u003e \u003cb\u003eMultivariable model of seizure frequency as a function of SWS type\u003c/b\u003e \u003c/p\u003e \u003cp\u003eOur multivariable model included SWS type, current number of ASM, and epilepsy surgery as predictors of seizure frequency. Binary logistic regression showed a significant, positive association between seizure frequency and the number of administered ASM (p\u0026thinsp;=\u0026thinsp;0.0056), with a regression coefficient of 1.33 (i.e. OR 3.77, 95% CI 1.64; 11.22). SWS type and epilepsy surgery each were not associated with seizure frequency.\u003c/p\u003e"},{"header":"Discussion/ conclusions","content":"\u003cp\u003eThis study represents the first multinational cohort to systematically investigate differences between SWS types Type I (classic form) and III (no skin involvement). We provide detailed clinical data on epilepsy including ASM, aspirin use, and epilepsy surgery, cerebral and ophthalmologic involvement, and neurocognitive outcomes.\u003c/p\u003e \u003cp\u003e \u003cb\u003eKey epidemiologic data of our cohort\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe cohort comprised 47 paediatric SWS cases, including 87.2% Type I (FPB positive) and 12.8% Type III (FPB negative) cases. These proportions are in line with the U.K. cohort by Powell et al. (85.7% FPB positive cases)(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) and U.S. cohorts(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). We have described other key demographic and epidemiologic data of our cohort in our previous publication(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eEpilepsy in different SWS types\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eThe median age at first seizure\u003c/span\u003e in our cohort (6.5 months) is consistent with previous studies\u003csup\u003e2\u003c/sup\u003e(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In concordance with these findings, Smegal et al.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) reported a seizure onset\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;12 months in 73.1 % of patiets \u0026ndash; in one of the to date largest cohorts. Most SWS cohorts did not investigate epilepsy in different SWS types(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Type III patients in our cohort showed numerically later seizure onset (median 13 months) than Type I. Likewise, in the UK cohort by Powell et al(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) (9 months) median age at onset of status epilepticus was significantly later in FPB negative patients, but the number of episodes with status epilepticus was comparable. Day et. al(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) also found a later seizure onset in FPB negative patients (17 months) vs patients with unilateral FPB (10 months) or bilateral FPB (5 months). Early seizure onset is strongly associated with poorer neurocognitive outcomes(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Hence, delayed seizure onset is Type III may contribute to better intellectual outcomes.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eRegarding seizure type\u003c/span\u003es Type III patients reported generalized seizures or both focal and generalized seizures. Previous studies and case reports, however, often indicate a predominance of focal onset seizures in FPB negative patients(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) and in SWS in general(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). In some studies, the types of seizures are not explicitly stated(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The UK cohort by Powell et al.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) specified that \u003cem\u003efirst seizure semiology\u003c/em\u003e was focal motor in 16 out of 20 FPB negative cases (80 %), as compared to 58 % FB negative cases. Diferences in seizure types in our cohort may reflect a selection bias toward more severely affected patients. We did not assess the frequency of seizure clusters, but this is another common type of seizures in SWS(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) that probably occurs slightly more frequent in classic SWS(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSeizure frequency\u003c/span\u003e, analysed as a binary variable (controlled vs. uncontrolled seizures) was independent of SWS type in our multivariable analysis. As expected, our model showed that the odds for an additional ASM were more than threefold higher in uncontrolled versus controlled seizures (odds ratio\u0026thinsp;=\u0026thinsp;3.7). In the Powell cohort, the number of seizures also did not differ between FPB positive and FPB negative patients(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eNeurocognitive outcomes in different SWS types\u003c/b\u003e \u003c/p\u003e \u003cp\u003eSWS is an often progressive(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) neurovascular disorder which puts neurocognitive development of affected patients at risk. In our study, two thirds of patients showed various degrees of intellectual impairment (64 %),and among these, severe impairment was frequent (43 %).However, two thirds of our Type III patients showed normal cognitive function (66.7 %),and none of Type III patients showed severely or moderately impaired cognitive function. The findings are in line with Powell et al. (n\u0026thinsp;=\u0026thinsp;140)(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e): 25 % of FP-positive cases were not impaired (in our own cohort: 17.1 % of Tye I cases not impaired), and 50 % of FP-negative cases were not impaired (in our own cohort: 66.7 % of Tye III not impaired). Intellectual status was not addressed in some of the other cohorts(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, one of the so far largest published SWS cohorts by Day et al.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) with 277 paediatric (85.6 %) and adult articipants \u0026ndash; recruited from 7 U.S. sites \u0026ndash; reported a far smaller proportion of patients with \u0026ldquo;intellectual disability\u0026rdquo; (14.8 %), and 41.9 with a \u0026ldquo;leaning disorder\u0026rdquo; \u0026ndash; despite a relatively high proportion of patients with bilateral FPB (35.7 %) and a simiar proportion of Type III patients. Even so, the authors estimated their results to be \u0026ldquo;likely skewed toward the more severely involved subjects\u0026rdquo; due to patient recruitment from tertiary centres. The higher rate of impaired patients in our and the above-cited studies is likely due to the large sample size in the Day cohort(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Additionally, our patients\u0026acute; younger age, possibly points towards a more severe involvement and thus, a selection of more severely affected cases in our study (see below) might contribute. Finally, worse seizure control has been described in Caucasian patients(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), and the proportion of Caucasians was moderately higher in our study (91 %) than in the Day ohort (84%) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnalysis of 11 published cases with SWS Type III reported on as single case reports or as small series shows that their intellectual status was mostly within normal limits(\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR33 CR34\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e); only very few cases depicted intellectual impairment(\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) or progressive deterioration(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). This may be explained by the fact that, on average \u0026ndash; as shown by Powell et al(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) \u0026ndash; Type III patients show significantly reduced brain involvement as compared to classic Type I patients, i.e. fewer lobes with angioma, and the angioma is always unilateral. On a molecular basis, an intact intellectual function and less extensive angioma are compatible with the smaller mutant allele frequencies of the causative GNAQ gene mutation found in SWS Type III cases (0.42% \u0026minus;\u0026thinsp;7.1%)(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) as compared to the allele mutation frequency described in classic Type I cases (1 % \u0026minus;\u0026thinsp;18.1 %)(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) - presumably, de to a lter occurrence of the shared somatic mutation.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDiagnosis in SWS Type III\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn our cohort, all Type III cases were diagnosed within the first two years of life. However, late manifestations(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) and/or delayed diagnoses(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) are commonly reported, with intervals of up to 26 years between first symptoms and final diagnosis(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e): One patient showed first symptoms at the age of 6 years (with status migrainosus; initially suspected for encephalitis(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)), and was diagnosed with SWS Type III three years later. Another patient became symptomatic at the age of 10 years with headaches and visual aura and was finally diagnosed with SWS Type III at the age of 36 years(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Finally, a 62-year old man was diagnosed with SWS Type III after a first generalized seizure and typical MRI findings; his first manifestation three years before had been misclassified as a culture-negative \u0026ldquo;focal leptomeningitis\u0026rdquo;(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). To conclude, diagnosis in SWS Type III can be particularly challenging and requires regular training of medical staff on SWS clinical signs and imaging features.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAspirin therapy and epilepsy surgery in different SWS types\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn our cohort, aspirin use was equally common in both SWS types, in line with the U.K. cohort by Powell et al(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), reflecting similar occurrence of stroke-like episodes.\u003c/p\u003e \u003cp\u003eEpilepsy surgery was performed in SWS patients of both types. Both surgical patients which remained seizure-free after surgery (i.e. 50% of the operated patients) were Type I SWS patients (no information available on outcomes of the operated Type III patient), and one had received hemispherotomy, the other a cortical resection. Hemispherectomies were the most frequently used surgical technique in the Powell cohort(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). A recently published study by Ramantani et al. including 36 patients with SWS found no difference in outcomes with regard to surgical technique in paediatric hemispherotomy(\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). As compared to postsurgical paediatric cases of other etiology, SWS cases were more likely to walk independently and speak short sentences or age-appropriately, but they were rarely able to grasp voluntarily with their hemiplegic hand (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003ePotential sources of bias\u003c/b\u003e \u003c/p\u003e \u003cp\u003eOur study used a non-mandatory neuropaediatric network for recruitment, which may have led to incomplete SWS case registration. Yet, estimation of completeness is difficult as no obligatory reporting system exists in the German-speaking countries. Notably, we cannot rule out an increased inclusion of more severely affected SWS patients for this cohort as severely affected patients tend to seek medical attention in tertiary centres and university hospitals more often than mildly affected patients(\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) \u0026ndash; where rare disease networks such as ESNEK are more well-known. A differential recruiting completeness- depending on the disease severity \u0026ndash; could result in \u003cem\u003eselection bias.\u003c/em\u003e Vice versa, less severely affected patients\u0026ndash; may have been missed by the reporting system. Potential \u003cem\u003eselection bias\u003c/em\u003e would also explain why no patients with SWS Type II (no neurologic involvement) were reported in this cohort.\u003c/p\u003e \u003cp\u003eUsing capture-recapture methods, the experience from other German paediatric rare-disease networks such as ESPED (transl.: German Paediatric Surveillance Unit) showed that overall completeness of registration ranged between 37 and 44% for Kawasaki Disease(\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Such methods are not available for this study, as no other independent estimates for SWS prevalence are available for the German-speaking countries. For future research, an analysis of hospital records could potentially provide a remedy here.\u003c/p\u003e \u003cp\u003eAs Type III patients display no externally visible signs of the condition, this type is especially prone to \u003cem\u003edetection bias\u003c/em\u003e. Undiagnosed patients with Type III SWS, e.g. cases misclassified as migraine(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) or as meningitis(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) (s.a.), escape every reporting system, resulting in underestimation of SWS Type III prevalence. Additionally, we cannot rule out underreporting of mildly affected phenotypes which may lead to overestimation of disease severity in SWS Type III cases.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStrengths and limitations of our study\u003c/b\u003e \u003c/p\u003e \u003cp\u003eOur multinational cohort gives insight into detailed clinical profiles not only in classic SWS Type I, but also in SWS Type III, which has so far been mostly described in case reports. We included data on SWS neuroscores, use of aspirin, ASM and epilepsy surgery. As main limitations, we acknowledge that incompleteness of registration through a non-obligatory, though well-established neuropaediatric network may lead to potential bias. Given the rarity of SWS, the small sample size of Type III patients may increase the probability of chance findings and it may decrease the power for the detection of significant findings. The achieved sample size restricted our possibilities for multivariable modelling. Yet, our exploratory analyses serve as a valuable basis for new directions in future research.\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusions\u003c/b\u003e \u003c/p\u003e \u003cp\u003eOur findings suggest that SWS Type III represents a milder phenotype compared to classic Type I, with later diagnosis, better neurocognitive outcomes, and similar epilepsy characteristics. Increased awareness and training on the clinical and imaging characteristics of SWS are necessary for timely diagnosis and intervention. Further research, particularly in larger cohorts, is necessary to evaluate surgical outcomes and optimize management strategies across SWS subtypes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eASM: antiseizure medication; CI: confidence interval; ESNEK (German \u0026ldquo;\u003cu\u003eE\u003c/u\u003erhebung \u003cu\u003eS\u003c/u\u003eeltener \u003cu\u003eN\u003c/u\u003eeurologischer \u003cu\u003eE\u003c/u\u003erkrankungen im \u003cu\u003eK\u003c/u\u003eindesalter\u0026rdquo;; English translation \u0026ldquo;Survey of Rare Neurological Disorders in Childhood\u0026rdquo;); FPB: facial portwine birthmark; SWS: Sturge-Weber Syndrome\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the responsible Institutional Review Board in Saarbrücken, University of Saarland, Germany (ID 209/17, October 2017).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available because of potentially identifiable, confidential patient data, but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInterim results of this study were presented at a Meeting of the German National Sturge-Weber Foundation (IG, “Interessengemeinschaft” SWS) in Herbstein/Germany in 2019. The main study findings were presented at the German National Conference on Paediatrics as a poster in 2020. All authors declare that they have no competing financial interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSD received a personal career development fellowship by University Regensburg („KUNO Fellowship“), which supported this research. This study received financial support for mailing cost and office supplies by Children’s University Hospital Saarland, Dept. of Neuropaediatrics. SD was reimbursed for travel cost by the German National Sturge-Weber Foundation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll funding had no role in the conceptualization, design, data collection, analysis, decision to publish, or in the content of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy idea: SD. Study design: SD, SM. Data acquisition: HK, AB, GCK, GR, BW, MP, RT, KB, SS. Coordination of child neurologists’ network for data acquisition: SS, KB. Organizational study support: SW. Statistical analysis: SD. Drafting of manuscript: SD. Critical revision of the manuscript: all authors. Study supervision: SM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all participating SWS patients and their families as well as all contributing neuropaediatric colleagues from the ESNEK network for their support of this study.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRoach ES. Neurocutaneous syndromes. Pediatr Clin North Am 1992; 39(4):591\u0026ndash;620.\u003c/li\u003e\n\u003cli\u003eAydin A, Cakmak\u0026ccedil;i H, Kovanlikaya A, Dirik E. Sturge-Weber syndrome without facial nevus. Pediatr Neurol 2000; 22(5):400\u0026ndash;2.\u003c/li\u003e\n\u003cli\u003eJordan PR, Iqbal M, Prasad M. Sturge-Weber syndrome type 3 manifesting as \u0026apos;Status migrainosus\u0026apos;. BMJ Case Rep 2016; 2016.\u003c/li\u003e\n\u003cli\u003eFerrari L, Coppi E, Caso F, Santangelo R, Politi LS, Martinelli V et al. Sturge-Weber syndrome with an unusual onset in the sixth decade: a case report. Neurol Sci 2012; 33(4):949\u0026ndash;50.\u003c/li\u003e\n\u003cli\u003eSmegal LF, Sebold AJ, Hammill AM, Juh\u0026aacute;sz C, Lo WD, Miles DK et al. Multicenter Research Data of Epilepsy Management in Patients With Sturge-Weber Syndrome. Pediatr Neurol 2021; 119:3\u0026ndash;10.\u003c/li\u003e\n\u003cli\u003eJagtap S, Srinivas G, Harsha KJ, Radhakrishnan N, Radhakrishnan A. Sturge-Weber syndrome: clinical spectrum, disease course, and outcome of 30 patients. J Child Neurol 2013; 28(6):725\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003eKaplan EH, Kossoff EH, Bachur CD, Gholston M, Hahn J, Widlus M et al. Anticonvulsant Efficacy in Sturge-Weber Syndrome. Pediatr Neurol 2016; 58:31\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eDay AM, McCulloch CE, Hammill AM, Juh\u0026aacute;sz C, Lo WD, Pinto AL et al. Physical and Family History Variables Associated With Neurological and Cognitive Development in Sturge-Weber Syndrome. Pediatr Neurol 2019; 96:30\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eCho S, Maharathi B, Ball KL, Loeb JA, Pevsner J. Sturge-Weber Syndrome Patient Registry: Delayed Diagnosis and Poor Seizure Control. J Pediatr 2019; 215:158-163.e6.\u003c/li\u003e\n\u003cli\u003eWaelchli R, Aylett SE, Robinson K, Chong WK, Martinez AE, Kinsler VA. New vascular classification of port-wine stains: improving prediction of Sturge-Weber risk. Br J Dermatol 2014; 171(4):861\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eDutkiewicz A-S, Ezzedine K, Mazereeuw-Hautier J, Lacour J-P, Barbarot S, Vabres P et al. A prospective study of risk for Sturge-Weber syndrome in children with upper facial port-wine stain. J Am Acad Dermatol 2015; 72(3):473\u0026ndash;80.\u003c/li\u003e\n\u003cli\u003eDymerska M, Kirkorian AY, Offermann EA, Lin DD, Comi AM, Cohen BA. Size of Facial Port-Wine Birthmark May Predict Neurologic Outcome in Sturge-Weber Syndrome. J Pediatr 2017; 188:205-209.e1.\u003c/li\u003e\n\u003cli\u003ePowell S, Fosi T, Sloneem J, Hawkins C, Richardson H, Aylett S. Neurological presentations and cognitive outcome in Sturge-Weber syndrome. Eur J Paediatr Neurol 2021; 34:21\u0026ndash;32.\u003c/li\u003e\n\u003cli\u003eShirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 2013; 368(21):1971\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eSundaram SK, Michelhaugh SK, Klinger NV, Kupsky WJ, Sood S, Chugani HT et al. GNAQ Mutation in the Venous Vascular Malformation and Underlying Brain Tissue in Sturge-Weber Syndrome. Neuropediatrics 2017; 48(5):385\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eHildebrand MS, Harvey AS, Malone S, Damiano JA, Do H, Ye Z et al. Somatic GNAQ mutation in the forme fruste of Sturge-Weber syndrome. Neurol Genet 2018; 4(3):e236.\u003c/li\u003e\n\u003cli\u003eFj\u0026aelig;r R, Marciniak K, Sundnes O, Hjorthaug H, Sheng Y, Hammarstr\u0026ouml;m C et al. A novel somatic mutation in GNB2 provides new insights to the pathogenesis of Sturge-Weber syndrome. Hum Mol Genet 2021; 30(21):1919\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003eThorpe J, Frelin LP, McCann M, Pardo CA, Cohen BA, Comi AM et al. Identification of a Mosaic Activating Mutation in GNA11 in Atypical Sturge-Weber Syndrome. J Invest Dermatol 2021; 141(3):685\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003ePolubothu S, Al-Olabi L, Del Carmen Boente M, Chacko A, Eleftheriou G, Glover M et al. GNA11 Mutation as a Cause of Sturge-Weber Syndrome: Expansion of the Phenotypic Spectrum of G\u0026alpha;/11 Mosaicism and the Associated Clinical Diagnoses. J Invest Dermatol 2020; 140(5):1110\u0026ndash;3.\u003c/li\u003e\n\u003cli\u003eDisse S, K\u0026uuml;pper H, Bock A, Korenke, Georg-Christoph, Ramantani, Georgia, Weidner B, Preisel M et al. The Natural History of Pediatric Sturge-Weber Syndrome: A Population-based, Multinational Observational Study Manuscript currently under Review.\u003c/li\u003e\n\u003cli\u003eKelley TM, Hatfield LA, Lin DDM, Comi AM. Quantitative analysis of cerebral cortical atrophy and correlation with clinical severity in unilateral Sturge-Weber syndrome. J Child Neurol 2005; 20(11):867\u0026ndash;70.\u003c/li\u003e\n\u003cli\u003eBrockmann K. Erhebung Seltener Neurologischer Erkrankungen im Kindesalter. Neuropediatrics 2014; 45(S 01).\u003c/li\u003e\n\u003cli\u003eDisse SC, Toelle SP, Schroeder S, Theiler M, Weibel L, Broser P et al. Epidemiology, Clinical Features, and Use of Early Supportive Measures in PHACE Syndrome: A European Multinational Observational Study. Neuroepidemiology 2020; 54(5):383\u0026ndash;91.\u003c/li\u003e\n\u003cli\u003eKavanaugh B, Sreenivasan A, Bachur C, Papazoglou A, Comi A, Zabel TA. Intellectual and adaptive functioning in Sturge-Weber Syndrome. Child Neuropsychol 2016; 22(6):635\u0026ndash;48.\u003c/li\u003e\n\u003cli\u003eRStudio.: R: A language and environment for statistical computing. Version 1.2.1335 ed2017. Vienna, Austria.: R Foundation for Statistical Computing. Available from: URL: https://www.R-project.org.\u003c/li\u003e\n\u003cli\u003eBosny\u0026aacute;k E, Behen ME, Guy WC, Asano E, Chugani HT, Juh\u0026aacute;sz C. Predictors of Cognitive Functions in Children With Sturge-Weber Syndrome: A Longitudinal Study. Pediatr Neurol 2016; 61:38\u0026ndash;45.\u003c/li\u003e\n\u003cli\u003eLuat AF, Juh\u0026aacute;sz C, Loeb JA, Chugani HT, Falchek SJ, Jain B et al. Neurological Complications of Sturge-Weber Syndrome: Current Status and Unmet Needs. Pediatr Neurol 2019; 98:31\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eGazeteci Tekin H, G\u0026ouml;kben S, Yılmaz S, Tekg\u0026uuml;l H, Serdaroğlu G. Sturge-Weber Syndrome Type III. jpr 2018; 5(2):103\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eMara\u0026ntilde;a P\u0026eacute;rez AI, Ruiz-Falc\u0026oacute; Rojas ML, Puertas Mart\u0026iacute;n V, Dom\u0026iacute;nguez Carral J, Carreras S\u0026aacute;ez I, Duat Rodr\u0026iacute;guez A et al. Analysis of Sturge\u0026ndash;Weber syndrome: A retrospective study of multiple associated variables. Neurolog\u0026iacute;a (English Edition) 2017; 32(6):363\u0026ndash;70.\u003c/li\u003e\n\u003cli\u003eZhang Y, Niu J, Wang J, Cai A, Wang Y, Wei G et al. Neurological function and drug-refractory epilepsy in Sturge-Weber syndrome children: a retrospective analysis. Eur J Pediatr 2024; 183(4):1881\u0026ndash;90.\u003c/li\u003e\n\u003cli\u003eKossoff EH, Bachur CD, Quain AM, Ewen JB, Comi AM. EEG evolution in Sturge-Weber syndrome. Epilepsy Res 2014; 108(4):816\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eHuang HY, Lin K-H, Chen J-C, Hsu Y-T. Type III Sturge-Weber syndrome with migraine-like attacks associated with prolonged visual aura. Headache 2013; 53(5):845\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eCrosley CJ, Binet EF. Sturge-Weber Syndrome: presentation as a focal seizure disorder without nevus flammeus. Clin Pediatr (Phila) 1978; 17(8):606\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eJagtap SA, Srinivas G, Radhakrishnan A, Harsha KJ. A clinician\u0026apos;s dilemma: Sturge-Weber syndrome \u0026apos;without facial nevus\u0026apos;!! Ann Indian Acad Neurol 2013; 16(1):118\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eKim W, Kim J-S, An J-Y, Lee S-J, Chung S-R, Kim Y-I et al. Sturge‐Weber syndrome, without a facial port‐wine stain, with epilepsy onset in the fifth decade. Epileptic Disorders 2008; 10(1):76\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eSen Y, Dilber E, Odemis E, Ahmetoglu A, Aynaci FM. Sturge-Weber syndrome in a 14-year-old girl without facial naevus. Eur J Pediatr 2002; 161(9):505\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eTaly AB, Nagaraja D, Das S, Shankar SK, Pratibha NG. Sturge-Weber-Dimitri disease without facial nevus. Neurology 1987; 37(6):1063\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eMuralidharan V, Failla G, Travali M, Cavallaro TL, Politi MA. Isolated leptomeningeal angiomatosis in the sixth decade of life, an adulthood variant of Sturge Weber Syndrome (Type III): role of advanced Magnetic Resonance Imaging and Digital Subtraction Angiography in diagnosis. BMC Neurol 2020; 20(1):366.\u003c/li\u003e\n\u003cli\u003eRamantani G, Bulteau C, Cserpan D, Otte WM, Dorfm\u0026uuml;ller G, Cross JH et al. Not surgical technique, but etiology, contralateral MRI, prior surgery, and side of surgery determine seizure outcome after pediatric hemispherotomy. Epilepsia 2023; 64(5):1214\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eRamantani G, Cserpan D, Tisdall M, Otte WM, Dorfm\u0026uuml;ller G, Cross JH et al. Determinants of Functional Outcome after Pediatric Hemispherotomy. Ann Neurol 2024; 95(2):377\u0026ndash;87.\u003c/li\u003e\n\u003cli\u003eKanafani ZA, Kanj SS, Cabell CH, Cecchi E, Oliveira Ramos A de, Lejko-Zupanc T et al. Revisiting the effect of referral bias on the clinical spectrum of infective endocarditis in adults. Eur J Clin Microbiol Infect Dis 2010; 29(10):1203\u0026ndash;10.\u003c/li\u003e\n\u003cli\u003eJakob A, Whelan J, Kordecki M, Berner R, Stiller B, Arnold R et al. Kawasaki Disease in Germany: A Prospective, Population-based Study Adjusted for Underreporting. Pediatr Infect Dis J 2016; 35(2):129\u0026ndash;34.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Footnotes","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e Paresis grade 3: gross and fine motricity significantly affected, grade 4: gross and fine motricity severely affected, independent gait severely compromised or not possible\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e Powell et al: seizure onset at 7 months(13), Day et al. 5 months/10 months for bilateral/unilateral PWS(5).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Sturge-Weber Syndrome, phacomatosis, observational study, Roach classification, facial portwine birthmark","lastPublishedDoi":"10.21203/rs.3.rs-5890276/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5890276/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSturge-Weber Syndrome (SWS) is a rare neurocutaneous disease, characterized by cerebral capillary-venous malformation, glaucoma, and facial vascular birthmark. Different types are reflected in the Roach classification. Most previous studies have focussed on classic SWS Type I, but Type III cases, lacking facial birthmark, were mostly described in case reports. We systematically compare cases with and without facial birthmark, with a focus on epilepsy variables, cerebral involvement, use of aspirin, and overall outcome.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eUsing a cross-sectional observational study conducted through a well-established child neurologists\u0026rsquo; network, we recruited paediatric patients with clinically diagnosed SWS from Germany, Switzerland, and Austria. The patients\u0026rsquo; guardians and attending child neurologists filled in detailed questionnaires. All patients were classified according to the Roach classification by both attending child neurologists and the study team.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOut of 111 paediatric SWS patients identified, 47 participated (43.2%). 35 cases (74.5%) fulfilled the criteria for classic SWS (Roach Type I); six cases (12.8%) showed no skin involvement (Roach Type III), the remaining six cases had overlap/atypical phacomatoses with capillary-venous malformation. Cases without facial birthmark were older at diagnosis (p\u0026thinsp;=\u0026thinsp;0.005), and none showed ophthalmologic involvement. Age at first seizure did not differ significantly after adjustment for multiple comparisons. No significant differences were observed in seizure frequency, seizures types, number of used antiseizure medication (ASM), epilepsy surgery, cerebral involvement including atrophy and calcifications, SWS neuroscores or use of supportive therapies. Multivariable logistic regression showed seizure frequency was independent of SWS type and epilepsy surgery, but positively associated with the number of ASM required for seizure control (p\u0026thinsp;=\u0026thinsp;0.0056). Half of operated patients were seizure-free at inclusion.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn our multinational cohort, Type I and Type III cases showed comparable epilepsy features, SWS neuroscores, number of required ASM and supportive therapy requirements. Type III patients were older at diagnosis and showed no ophthalmologic involvement, indicating a milder phenotype. Irrespective of SWS type, patients with uncontrolled epilepsy were 3.8-times more likely to require additional ASM. Despite uncontrolled epilepsy, only few patients underwent surgical evaluation or intervention. Larger cohorts are needed to evaluate surgical outcomes across SWS subtypes.\u003c/p\u003e","manuscriptTitle":"Sturge-Weber Syndrome in a Multinational Paediatric Cohort: A Systematic Analysis of Different Types","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-07 09:18:59","doi":"10.21203/rs.3.rs-5890276/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2025-02-05T09:42:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-26T23:22:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2025-01-24T04:40:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1563afe6-75ca-4836-86ea-e22e495decec","owner":[],"postedDate":"February 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-07T16:04:06+00:00","versionOfRecord":{"articleIdentity":"rs-5890276","link":"https://doi.org/10.1186/s13023-025-03769-2","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2025-07-02 15:57:51","publishedOnDateReadable":"July 2nd, 2025"},"versionCreatedAt":"2025-02-07 09:18:59","video":"","vorDoi":"10.1186/s13023-025-03769-2","vorDoiUrl":"https://doi.org/10.1186/s13023-025-03769-2","workflowStages":[]},"version":"v1","identity":"rs-5890276","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5890276","identity":"rs-5890276","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}