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Item Extrahepatic anomalies in infants with biliary atresia: results of a large prospective North American multicenter study(Wiley, 2013-11) Schwarz, Kathleen B.; Haber, Barbara H.; Rosenthal, Philip; Mack, Cara L; Moore, Jeffrey; Bove, Kevin E.; Bezerra, Jorge A.; Karpen, Saul J.; Kerkar, Nanda; Shneider, Benjamin L.; Turmelle, Yumirle P.; Whitington, Peter F.; Molleston, Jean P.; Murray, Karen F.; Ng, Vicky L.; Romero, René; Wang, Kasper S.; Sokol, Ronald J.; Magee, John C.; Pediatrics, School of MedicineBackground and aims The etiology of biliary atresia (BA) is unknown. Given that patterns of anomalies might provide etiopathogenetic clues, we utilized data from the North American Childhood Liver Disease Research and Education Network to analyze patterns of anomalies in infants with BA. Methods Two hundred eighty-nine infants who were enrolled into the prospective database prior to surgery at any of 15 centers participating were evaluated. Results Group 1 was non-syndromic, isolated BA (without major malformations) (n = 242, 84 %), Group 2 was BA and at least one malformation considered major as defined by the National Birth Defects Prevention Study but without laterality defects (n = 17, 6%). Group 3 was syndromic, with laterality defects (n = 30, 10%). In the population as a whole, anomalies (either major or minor) were most prevalent in the cardiovascular (16%) and gastrointestinal (14%) systems. Group 3 patients accounted for the majority of subjects with cardiac, gastrointestinal and splenic anomalies. Group 2 subjects also frequently displayed cardiovascular (71%) and gastrointestinal (24 %) anomalies; interestingly this group had genitourinary anomalies more frequently (47%) compared to Group 3 subjects (10%). Conclusions This study identified a group of BA (Group 2) that differed from the classical syndromic and non-syndromic groups and that was defined by multiple malformations without laterality defects. Careful phenotyping of the patterns of anomalies may be critical to the interpretation of both genetic and environmental risk factors associated with BA, allowing new insight into pathogenesis and/or outcome.Item Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency(Wolters Kluwer, 2021-08) van Wessel, Daan B.E.; Thompson, Richard J.; Gonzales, Emmanuel; Jankowska, Irena; Shneider, Benjamin L.; Sokal, Etienne; Grammatikopoulos, Tassos; Kadaristiana, Agustina; Jacquemin, Emmanuel; Spraul, Anne; Lipiński, Patryk; Czubkowski, Piotr; Rock, Nathalie; Shagrani, Mohammad; Broering, Dieter; Algoufi, Talal; Mazhar, Nejat; Nicastro, Emanuele; Kelly, Deirdre; Nebbia, Gabriella; Arnell, Henrik; Fischler, Björn; Hulscher, Jan B.F.; Serranti, Daniele; Arikan, Cigdem; Debray, Dominique; Lacaille, Florence; Goncalves, Cristina; Hierro, Loreto; Muñoz Bartolo, Gema; Mozer-Glassberg, Yael; Azaz, Amer; Brecelj, Jernej; Dezsőfi, Antal; Calvo, Pier Luigi; Krebs-Schmitt, Dorothee; Hartleif, Steffen; van der Woerd, Wendy L.; Wang, Jian-She; Li, Li-ting; Durmaz, Özlem; Kerkar, Nanda; Hørby Jørgensen, Marianne; Fischer, Ryan; Jimenez-Rivera, Carolina; Alam, Seema; Cananzi, Mara; Laverdure, Noémie; Targa Ferreira, Cristina; Ordonez, Felipe; Wang, Heng; Sency, Valerie; Kim, Kyung Mo; Chen, Huey-Ling; Carvalho, Elisa; Fabre, Alexandre; Bernabeu, Jesus Quintero; Alonso, Estella M.; Sokol, Ronald J.; Suchy, Frederick J.; Loomes, Kathleen M.; McKiernan, Patrick J.; Rosenthal, Philip; Turmelle, Yumirle; Rao, Girish S.; Horslen, Simon; Kamath, Binita M.; Rogalidou, Maria; Karnsakul, Wikrom W.; Hansen, Bettina; Verkade, Henkjan J.; Pediatrics, School of MedicineBackground and aims: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. Approach and results: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] μmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 μmol/L (P = 0.05) tended to be associated with improved NLS. Conclusions: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.Item Impact of long-term administration of maralixibat on children with cholestasis secondary to Alagille syndrome(Wolters Kluwer, 2022) Shneider, Benjamin L.; Spino, Catherine A.; Kamath, Binita M.; Magee, John C.; Ignacio, Rosalinda V.; Huang, Suiyuan; Horslen, Simon P.; Molleston, Jean P.; Miethke, Alexander G.; Kohli, Rohit; Leung, Daniel H.; Jensen, M. Kyle; Loomes, Kathleen M.; Karpen, Saul J.; Mack, Cara; Rosenthal, Philip; Squires, Robert H.; Baker, Alastair; Rajwal, Sanjay; Kelly, Deirdre; Sokol, Ronald J.; Thompson, Richard J.; Pediatrics, School of MedicineThere is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine two similar randomized placebo-controlled trials with subsequent extension phases investigating the impact of maralixibat in children with severe cholestasis secondary to Alagille Syndrome (n = 57). The primary outcomes were measures of pruritus (ItchRO[Obs]) and clinician scratch scale (CSS), both increasing in severity from 0 to 4) and quality of life (QoL) (Parent PedsQL and Multidimensional Fatigue Scale module [MFS] scaled 0-100 with increased QoL) at week 48 of the extension phase relative to the baseline of the placebo-controlled trials (week 13). Secondary assessments included other clinical and biochemical parameters assessed in participants at week 72 or end of treatment (after week 48). At week 48, statistically and clinically significant least square mean (95% CI) improvements in pruritus and QoL were observed (ItchRO[Obs] -1.59 [-1.81, -1.36], CSS -1.36 [-1.67, -1.05], PedsQL +10.17 [4.48, 15.86], and multidimension fatigue [MFS] +13.97 [7.85, 20.08]). At week 48, serum bile acids, platelet count, and cholesterol decreased, whereas alanine aminotransferase (ALT) increased and total bilirubin (TB) and albumin were stable. Changes were durable at week 72 and end of treatment. There were no deaths; 2 participants underwent liver transplantation. Study drug was discontinued in 9 participants after treatment-emergent adverse events, 6 of which were events of increased ALT or TB. Conclusion: Maralixibat administration was associated with marked improvement in pruritus and QoL. Interpretation of these findings is complicated by the complex natural history of severe cholestasis in Alagille syndrome.Item Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial(Elsevier, 2018-11) Alonso, Estella M.; Ye, Wen; Hawthorne, Kieran; Venkat, Veena; Loomes, Kathleen M.; Mack, Cara L.; Hertel, Paula M.; Karpen, Saul J.; Kerkar, Nanda; Molleston, Jean P.; Murray, Karen F.; Romero, Rene; Rosenthal, Philip; Schwarz, Kathleen B.; Shneider, Benjamin L.; Suchy, Frederick J.; Turmelle, Yumirle P.; Wang, Kasper S.; Sherker, Averell H.; Sokol, Ronald J.; Bezerra, Jorge A.; Magee, John C.; Pediatrics, School of MedicineOBJECTIVE: To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants. STUDY DESIGN: A total of 140 infants were enrolled in START, with 70 randomized to each treatment arm: steroid and placebo. Length, weight, and head circumference were obtained at baseline and follow-up visits to 24 months of age. RESULTS: Patients treated with steroids had significantly lower length and head circumference z scores during the first 3 months post-hepatoportoenterostomy (HPE), and significantly lower weight until 12 months. Growth trajectories in the steroid and placebo arms differed significantly for length (P < .0001), weight (P = .009), and head circumference (P < .0001) with the largest impact noted for those with successful HPE. Growth trajectory for head circumference was significantly lower in patients treated with steroids irrespective of HPE status, but recovered during the second 6 months of life. CONCLUSIONS: Steroid therapy following HPE in patients with biliary atresia is associated with impaired length, weight, and head circumference growth trajectories for at least 6 months post-HPE, especially impacting infants with successful bile drainage.Item Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study(Elsevier, 2018-05) Ng, Vicky L.; Sorensen, Lisa G.; Alonso, Estella M.; Fredericks, Emily M.; Ye, Wen; Moore, Jeff; Karpen, Saul J.; Shneider, Benjamin L.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Loomes, Kathleen M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper; Arnon, Ronen; Schwarz, Kathleen B.; Turmelle, Yumirle P.; Haber, Barbara H.; Sherker, Averell H.; Magee, John C.; Sokol, Ronald J.; Pediatrics, School of MedicineOBJECTIVES: To assess neurodevelopmental outcomes among participants with biliary atresia with their native liver at ages 12 months (group 1) and 24 months (group 2), and to evaluate variables predictive of neurodevelopmental impairment. STUDY DESIGN: Participants enrolled in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with either the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition. Scores (normative mean = 100 ± 15) were categorized as ≥100, 85-99, and <85 for χ2 analysis. Risk for neurodevelopmental impairment (defined as ≥1 score of <85 on the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition, scales) was analyzed using logistic regression. RESULTS: There were 148 children who completed 217 Bayley Scales of Infant and Toddler Development, 3rd edition, examinations (group 1, n = 132; group 2, n = 85). Neurodevelopmental score distributions significantly shifted downward compared with test norms at 1 and 2 years of age. Multivariate analysis identified ascites (OR, 3.17; P = .01) and low length z-scores at time of testing (OR, 0.70; P < .04) as risk factors for physical/motor impairment; low weight z-score (OR, 0.57; P = .001) and ascites (OR, 2.89; P = .01) for mental/cognitive/language impairment at 1 year of age. An unsuccessful hepatoportoenterostomy was predictive of both physical/motor (OR, 4.88; P < .02) and mental/cognitive/language impairment (OR, 4.76; P = .02) at 2 years of age. CONCLUSION: Participants with biliary atresia surviving with native livers after hepatoportoenterostomy are at increased risk for neurodevelopmental delays at 12 and 24 months of age. Those with unsuccessful hepatoportoenterostomy are >4 times more likely to have neurodevelopmental impairment compared with those with successful hepatoportoenterostomy. Growth delays and/or complications indicating advanced liver disease should alert clinicians to the risk for neurodevelopmental delays, and expedite appropriate interventions.Item Presentation and Outcomes of Infants With Idiopathic Cholestasis: A Multicenter Prospective Study(Wolters Kluwer, 2021-10-01) Hertel, Paula M.; Hawthorne, Kieran; Kim, Sehee; Finegold, Milton J.; Shneider, Benjamin L.; Squires, James E.; Gupta, Nitika A.; Bull, Laura N.; Murray, Karen F.; Kerkar, Nanda; Ng, Vicky L.; Molleston, Jean P.; Bezerra, Jorge A.; Loomes, Kathleen M.; Taylor, Sarah A.; Schwarz, Kathleen B.; Turmelle, Yumirle P.; Rosenthal, Philip; Magee, John C.; Sokol, Ronald J.; Pediatrics, School of MedicineObjectives: The aim of the study was to determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multicenter cohort of infants. Methods: We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) "PROBE" protocol with a final diagnosis of IC; they were followed up to 30 months of age. Results: Male sex (66/94; 70%), preterm birth (22/90 with data; 24% born at < 37 weeks' gestational age), and low birth weight (25/89; 28% born at <2500 g) were frequent, with no significant differences between outcomes. Clinical outcomes included death (n = 1), liver transplant (n = 1), biochemical resolution (total bilirubin [TB] ≤1 mg/dL and ALT < 35 U/L; n = 51), partial resolution (TB > 1 mg/dL and/or ALT > 35 U/L; n = 7), and exited healthy (resolved disease per study site report but without documented biochemical resolution; n = 34). Biochemical resolution occurred at median of 9 months of age. GGT was <100 U/L at baseline in 34 of 83 participants (41%). Conclusions: Frequency of IC and of death or liver transplant was less common in this cohort than in previously published cohorts, likely because of recent discovery and diagnosis of genetic etiologies of severe/persistent cholestasis that previously were labeled as idiopathic. Preterm birth and other factors associated with increased vulnerability in neonates are relatively frequent and may contribute to IC. Overall outcome in IC is excellent. Low/normal GGT was common, possibly indicating a role for variants in genes associated with low-GGT cholestasis-this warrants further study.Item Risk of variceal hemorrhage and pretransplant mortality in children with biliary atresia(Wiley, 2022) Bass, Lee M.; Ye, Wen; Hawthorne, Kieran; Leung, Daniel H.; Murray, Karen F.; Molleston, Jean P.; Romero, Rene; Karpen, Saul; Rosenthal, Philip; Loomes, Kathleen M.; Wang, Kasper S.; Squires, Robert H.; Miethke, Alexander; Ng, Vicky L.; Horslen, Simon; Jensen, M. Kyle; Sokol, Ronald J.; Magee, John C.; Shneider, Benjamin L.; ChiLDReN; Pediatrics, School of MedicineBackground and aims: The natural history of gastroesophageal variceal hemorrhage (VH) in biliary atresia (BA) is not well characterized. We analyzed risk factors, incidence, and outcomes of VH in a longitudinal multicenter study. Approach and results: Participants enrolled in either an incident (Prospective Database of Infants with Cholestasis [PROBE]) or prevalent (Biliary Atresia Study of Infants and Children [BASIC]) cohort of BA were included. Variceal hemorrhage (VH) was defined based on gastrointestinal bleeding in the presence of varices accompanied by endoscopic or nontransplant surgical intervention. Cumulative incidence of VH and transplant-free survival was compared based on features of portal hypertension (e.g., splenomegaly, thrombocytopenia) and clinical parameters at baseline in each cohort (PROBE: 1.5 to 4.5 months after hepatoportoenterostomy [HPE]; BASIC: at enrollment > 3 years of age). Analyses were conducted on 869 children with BA enrolled between June 2004 and December 2020 (521 in PROBE [262 (51%) with a functioning HPE] and 348 in BASIC). The overall incidence of first observed VH at 5 years was 9.4% (95% CI: 7.0-12.4) in PROBE and 8.0% (5.2-11.5) in BASIC. Features of portal hypertension, platelet count, total bilirubin, aspartate aminotransferase (AST), albumin, and AST-to-platelet ratio index at baseline were associated with an increased risk of subsequent VH in both cohorts. Transplant-free survival at 5 years was 45.1% (40.5-49.6) in PROBE and 79.2% (74.1-83.4) in BASIC. Two (2.5%) of 80 participants who had VH died, whereas 10 (12.5%) underwent transplant within 6 weeks of VH. Conclusions: The low risk of VH and associated mortality in children with BA needs to be considered in decisions related to screening for varices and primary prophylaxis of VH.Item Serum bile acids as a prognostic biomarker in biliary atresia following Kasai portoenterostomy(Wolters Kluwer, 2023) Harpavat, Sanjiv; Hawthorne, Kieran; Setchell, Kenneth D. R.; Narvaez Rivas, Monica; Henn, Lisa; Beil, Charlotte A.; Karpen, Saul J.; Ng, Vicky L.; Alonso, Estella M.; Bezerra, Jorge A.; Guthery, Stephen L.; Horslen, Simon; Loomes, Kathy M.; McKiernan, Patrick; Magee, John C.; Merion, Robert M.; Molleston, Jean P.; Rosenthal, Philip; Thompson, Richard J.; Wang, Kasper S.; Sokol, Ronald J.; Shneider, Benjamin L.; Childhood Liver Disease Research Network (ChiLDReN); Pediatrics, School of MedicineBackground and aims: In biliary atresia, serum bilirubin is commonly used to predict outcomes after Kasai portoenterostomy (KP). Infants with persistently high levels invariably need liver transplant, but those achieving normalized levels have a less certain disease course. We hypothesized that serum bile acid levels could help predict outcomes in the latter group. Approach and results: Participants with biliary atresia from the Childhood Liver Disease Research Network were included if they had normalized bilirubin levels 6 months after KP and stored serum samples from the 6-month post-KP clinic visit ( n = 137). Bile acids were measured from the stored serum samples and used to divide participants into ≤40 μmol/L ( n = 43) or >40 μmol/L ( n = 94) groups. At 2 years of age, the ≤40 μmol/L compared with >40 μmol/L group had significantly lower total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bile acids, and spleen size, as well as significantly higher albumin and platelet counts. Furthermore, during 734 person-years of follow-up, those in the ≤40 μmol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension. The ≤40 μmol/L group had a 10-year cumulative incidence of liver transplant/death of 8.5% (95% CI: 1.1%-26.1%), compared with 42.9% (95% CI: 28.6%-56.4%) for the >40 μmol/L group ( p = 0.001). Conclusions: Serum bile acid levels may be a useful prognostic biomarker for infants achieving normalized bilirubin levels after KP.Item Total Serum Bilirubin within 3 Months of Hepatoportoenterostomy Predicts Short-Term Outcomes in Biliary Atresia(Elsevier, 2016-03) Shneider, Benjamin L.; Magee, John C.; Karpen, Saul J.; Rand, Elizabeth B.; Narkewicz, Michael R.; Bass, Lee M.; Schwarz, Kathleen; Whitington, Peter F.; Bezerra, Jorge A.; Kerkar, Nanda; Haber, Barbara; Rosenthal, Philip; Turmelle, Yumirle P.; Molleston, Jean P.; Murray, Karen F.; Nguyen, Vicky L.; Wang, Kasper S.; Romero, Rene; Squires, Robert H.; Arnon, Ronen; Sherker, Averell H.; Moore, Jeffrey; Ye, Wen; Sokol, Ronald J.; Department of Pediatrics, IU School of MedicineOBJECTIVES: To prospectively assess the value of serum total bilirubin (TB) within 3 months of hepatoportoenterostomy (HPE) in infants with biliary atresia as a biomarker predictive of clinical sequelae of liver disease in the first 2 years of life. STUDY DESIGN: Infants with biliary atresia undergoing HPE between June 2004 and January 2011 were enrolled in a prospective, multicenter study. Complications were monitored until 2 years of age or the earliest of liver transplantation (LT), death, or study withdrawal. TB below 2 mg/dL (34.2 μM) at any time in the first 3 months (TB <2.0, all others TB ≥ 2) after HPE was examined as a biomarker, using Kaplan-Meier survival and logistic regression. RESULTS: Fifty percent (68/137) of infants had TB < 2.0 in the first 3 months after HPE. Transplant-free survival at 2 years was significantly higher in the TB < 2.0 group vs TB ≥ 2 (86% vs 20%, P < .0001). Infants with TB ≥ 2 had diminished weight gain (P < .0001), greater probability of developing ascites (OR 6.4, 95% CI 2.9-14.1, P < .0001), hypoalbuminemia (OR 7.6, 95% CI 3.2-17.7, P < .0001), coagulopathy (OR 10.8, 95% CI 3.1-38.2, P = .0002), LT (OR 12.4, 95% CI 5.3-28.7, P < .0001), or LT or death (OR 16.8, 95% CI 7.2-39.2, P < .0001). CONCLUSIONS: Infants whose TB does not fall below 2.0 mg/dL within 3 months of HPE were at high risk for early disease progression, suggesting they should be considered for LT in a timely fashion. Interventions increasing the likelihood of achieving TB <2.0 mg/dL within 3 months of HPE may enhance early outcomes.Item Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases-Examination of cholestatic liver disease in Alagille syndrome(Wolters Kluwer, 2022) Shneider, Benjamin L.; Kamath, Binita M.; Magee, John C.; Goodrich, Nathan P.; Loomes, Kathleen M.; Ye, Wen; Spino, Cathie; Alonso, Estella M.; Molleston, Jean P.; Bezerra, Jorge A.; Wang, Kasper S.; Karpen, Saul J.; Horslen, Simon P.; Guthery, Stephen L.; Rosenthal, Philip; Squires, Robert H.; Sokol, Ronald J.; Childhood Liver Disease Research Network (ChiLDReN); Pediatrics, School of MedicineThe conduct of long-term conventional randomized clinical trials in rare diseases is very difficult, making evidenced-based drug development problematic. As a result, real-world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2-year prospective follow-up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (-1.43 [0.28] -1.99, -0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (-65.2 [16.2] -98.3, -32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real-world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies.