Cyclic vomiting and digestive symptoms in White–Sutton syndrome: a participatory study

Cyclic vomiting and digestive symptoms in White–Sutton syndrome: a participatory study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cyclic vomiting and digestive symptoms in White–Sutton syndrome: a participatory study Coline Cormier, Augustin Lefevre, Raphaële Maudinas, Maxime Gonnot, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7065996/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background White–Sutton syndrome is a neurodevelopmental condition with a high prevalence of gastrointestinal disorders (89%), including cyclic vomiting (21–37.5%). Our objective was to better characterize repeated vomiting, cyclic vomiting syndrome in particular, and other digestive symptoms by conducting a participatory study. Methods French White–Sutton Association members received a questionnaire to identify and describe repeated vomiting, constipation, feeding difficulties and gastroesophageal reflux. Families or physicians were contacted in the event of missing or unclear answers. Results 34 patients out of 46 participated in our study, of whom 59% presented with digestive symptoms. 35% (12/34) reported repeated vomiting and 9% (3/34) met Rome IV criteria for cyclic vomiting syndrome, with a significant quality of life impact. 35% (12/34) reported constipation (18% – 6/34 meeting Rome IV criteria for functional constipation), 29% (10/34) feeding difficulties and 29% (10/34) symptoms of gastroesophageal reflux disease. In 70% of cases, patients presented with more than one gastrointestinal disorder. Conclusions Our participatory study is the first focusing on gastrointestinal disorders. It allowed us to obtain very precise information about the digestive phenotype and its consequences for patients. Further studies are required to evaluate if a genotype–phenotype correlation exists. POGZ neurodevelopmental disorders gastrointestinal disorders cyclic vomiting syndrome white-sutton syndrome Figures Figure 1 Figure 2 Background White–Sutton syndrome (WHSUS) (OMIM 616364) is a rare neurodevelopmental disorder (NDD) caused by a heterozygous variant affecting the POGZ gene. POGZ is involved in mitosis and expressed in the brain from the fetal period to adulthood ( 1 ). WHSUS is characterized by a broad spectrum of cognitive dysfunctions, global developmental delays, hypotonia and autism spectrum disorders (ASDs). Gastrointestinal disorders (GIDs) are among the other frequently reported symptoms in WHSUS ( 2 ) with a prevalence from 59% ( 3 ) to 89% ( 4 ). This digestive comorbidity is increasingly described among patients with NDDs, particularly ASDs, with a prevalence ranging from 4.4–96.8% and a median of 46.8% ( 5 ). The most common digestive symptoms encountered are chronic functional constipation and abdominal pain associated or not with diarrhea. Other digestive symptoms include gastroesophageal reflux disease (GERD) and abdominal bloating ( 6 ). The repeated vomiting (RV) prevalence ranges from 4.2–11.4% ( 7 ). In WHSUS, GIDs include feeding difficulties (FD) (52–61%), functional constipation (30–47%) ( 2 , 4 ), GERD and RV, sometimes falling within the nosological framework of cyclic vomiting syndrome (CVS) (21–42%) ( 2 , 8 ). CVS is not generally described within the ASD/NDD population but 25% of patients with CVS have neurological comorbidities ( 9 ). It is characterized by acute, stereotyped and recurrent episodes of intense nausea accompanied by incoercible vomiting, lasting from a few hours to a few days. Prevalence in the general pediatric population is estimated at 1.9% ( 10 ). It is a diagnosis of exclusion with many differential diagnoses, including migraine spectrum disorders, GIDs such as chronic intestine obstruction or GERD ( 11 ). To our knowledge, no study has focused solely on the digestive symptoms presented by WHSUS patients, and more specifically on recurrent vomiting. The objective of this study was to describe gastrointestinal symptomatology in patients with WHSUS, and CVS in particular due to its uncommonness among ASD patients. Methods Ethics In accordance with French legislation, this research qualifies as a project not involving human subjects (RNIPH). The study was registered with the Health Data Hub under registration number 17992342 and was conducted following the guidelines of the CNIL (French Data Protection Authority) MR-004 framework, thus not requiring any specific Ethics committee decision. Furthermore, the study was carried out in accordance with the French Data Protection Act No. 78 − 17 of January 6, 1978, as amended, and to the European General Data Protection Regulation (GDPR) effective since May 25, 2018. This study is in compliance with the Helsinki declaration. Informed consent to participate was obtained from patients or their parents/legal guardians for any patient under the age of 16 years. Patient recruitment and data collection This study took place between April 2024 and September 2024. A dedicated clinical questionnaire was sent by the Association White–Sutton France (AWSF) to its members, 66 parents of 46 children with WHSUS and causal POGZ variants). This charity is highly representative of the French White-Sutton patients since 55 patients are currently included in the Banque Nationale de Données Maladies Rares (BNDMR) ( 12 ). Its members are also particularly interested in participatory medicine and the vast majority of its members contribute to GenIDA, an international participatory database designed to increase knowledge related to genetic forms of NDDs ( 13 ). Questionnaire design We designed a questionnaire to screen for GIDs. It was divided into five sections. The first section addressed general questions including the children’s main medical and surgical histories, age at diagnosis, symptoms leading to the search for a genetic origin and the POGZ variant responsible for the syndrome. We asked the parents if their child had any GIDs and, if so, which ones. We then asked if they have ever consulted a physician for GIDs and which GID was the most impairing for their child. If the child did not have any GIDs, the questionnaire was ended. The second section sought repeated vomiting or nausea and then signs of CVS using Rome IV criteria ( 14 , 15 ), as well as details of age at onset, duration of symptoms, their impact on quality of life (using a scale ranging from 0 – no impact to 5 – major impact), their evolution over time, complementary examinations, treatments implemented and their efficacy. Migraine and abdominal migraine, which are differential diagnoses of CVS, were looked for using the ICHD-3 ( 16 ). We also asked if they have ever consulted a physician for vomiting. The third section focused on constipation. The diagnosis was confirmed using Rome IV criteria ( 14 , 15 ). In cases of constipation, parents had to state if a treatment was prescribed and how effective it was. The fourth section focused on FD. If their child experienced FD, parents had to detail what kind, if enteral feeding was required, the age at onset and the duration. The fifth section focused on GERD. In the event of signs, extra-digestive symptoms were sought ( 17 ). We also asked whether any paraclinical examinations had been carried out, the results and the treatments used. Open-ended questions were asked at the ends of the second section and the questionnaire for parents to provide clarifications or add comments if necessary. A detailed questionnaire is available on request. After an initial review of the questionnaire responses, families and/or referring practitioners were contacted by email and/or telephone in the event of repeated vomiting that might fall within the nosological framework of cyclic vomiting. The same procedure was followed for incomplete responses to avoid missing data. Results 33 parents answered the questionnaire for 34 patients, two being siblings (72% of members of the AWSF). 2 children were not monitored in France, meaning our cohort represents 58% (32/55) of French White–Sutton patients according to the BNDMR survey ( 12 ). The main medical and surgical histories are summarized in Supplemental 1. The median age at diagnosis was 9.5 years and 12 years at the time of last follow-up. The sex ratio was 1:1. The disease was diagnosed because of an ASD or another NDD in all patients. 59% (20/34) suffered from GIDs. The digestive phenotypes and molecular data are summarized in Table 1. Among them, 45% (9/20) had consulted a specialist at least once for these conditions. 35% (12/34) suffered from RV. 10 patients were declared by their parents as suffering from CVS. To verify the CVS criteria, we contacted parents or physicians (with the parents’ written consent) for all patients. Finally, three (8,8%) suffered from CVS according to Rome IV criteria (3/34). According to the ICHD-3, two had migraines and one suffered from abdominal migraines associated with vomiting. Two had vomiting associated with gastritis or constipation, one described signs of GERD, two had nausea associated or not with epigastralgia (without CVS or abdominal migraine criteria), and the last suffered from treatment-induced nausea. 58% (7/12) had never consulted a specialist physician including one with CVS. Two declared that they had never consulted for vomiting. The impact of RV on quality of life was assessed to be an average 4.25/5 and CVS 5/5. The two patients who had never consulted a physician put the impact on quality of life at 5/5. The mean age of symptom onset for RV was 6.7 years and 3.7 years for CVS. RV’s evolution showed improvement in 67% (6/9, now aged 8, 12, 16, 17, 24, 38 years) of cases, stability in 22% (2/9, now aged 9 and 25 years) and worsening in 11% (1/9, now aged 11 years). Concerning the management of the three patients presenting with CVS, all had been hospitalized on several occasions for episodes of vomiting, requiring parenteral hydration. CVS was not diagnosed during patient 2’s symptomatic period. He was hospitalized on a regular basis for uncontrollable vomiting over a period of four years, with vomiting every month from the ages of two to six, and required parenteral hydration followed by progressive refeeding. Patient 3 presented with a serious case of WHSUS, combining severe intellectual development disorder, absence of speech and a predominant digestive phenotype. He has a medical history of incomplete common mesentery and stomach volvulus. Since the age of four years and six months, he repeatedly presented with episodes of vomiting requiring recurring hospitalizations. His symptoms were long attributed to his severe constipation before CVS was diagnosed. He has been treated for CVS since the age of nine years and six months and received transient parenteral nutrition. He had background therapy with Levocarnitine and crisis treatment with Hydroxyzine, Niflumic Acid, PPI and Ondansetron. Cyproheptadine was tried as a background treatment but was not well tolerated. After a transient improvement, his symptoms have worsened since the age of eleven years and ten months, requiring transient parenteral nutrition. Patient 5 presented with vomiting every four months for fifteen years, from the ages of five to twenty, and had background therapy with Flunarizine and crisis treatment with Ibuprofen, Paracetamol and Ondansetron. The evolution of CVS among our patients is represented in Supplemental 2. 35% (12/34) suffered from constipation. 50% (6/12) met Rome IV criteria for functional constipation. Of these, four were treated with polyethylene glycol (PEG), one followed dietary rules and one had no treatment. Of the remaining six patients who did not meet Rome IV criteria, four were treated with PE (two requiring occasional enemas), one with a combination of osmotic laxative and lubricant, and one had no treatment. 29% of patients reported FD (10/34). Parents described chewing problems in 70% of cases (7/10), swallowing difficulties in 60% (6/10), gastroesophageal reflux responsible for the difficulties in 60% (6/10), hypersensitivity of the oral region in 30% (3/10) and allergy to cow milk proteins in one patient (10%). In all cases, several symptoms were associated. Two patients (5.9%, 2/34) required enteral nutrition: patient 3 because of FD during the neonatal period for a duration of eight months. He then required enteral nutrition later, from the age of nine years, and now parenteral nutrition. Patient 10 was fed by nasogastric tube for several months from the age of sixteen months. 29% (10/34) showed signs of GERD. Four described extra-digestive symptoms. 40% (4/10) reported sleeping difficulties linked to GERD. Five patients underwent complementary examinations. One had pH and esogastroduodenal transit monitoring confirming the diagnosis and discovering hiatal hernia. He benefited from a gastric fundoplication. Three patients underwent esogastroduodenal fibroscopy confirming the diagnosis, with one suffering from Barrett’s esophagus. One patient underwent pH monitoring without showing signs of acid reflux but was treated with PPIs. In total, six patients were treated with PPIs. 30% of patients (6/20) had only one GID, 25% (5/20) had two, 25% (5/20) had three and 20% (4/20) had four. The different combinations of GIDs are shown in Fig. 1 . RV was associated with other GIDs in 89% of cases (8/9). It was the most important GID in 62.5% (5/8) of cases. CVS was associated with other GIDs in 67% of cases (2/3) and, was the most important GID in 100% of cases (2/2). Among patients with RV, 56% (5/9) suffered from constipation, and among patients with CVS, 67% (2/3) suffered from constipation. The following additional digestive symptoms were reported by parents: one inguinal hernia, one rectal prolapse (associated with constipation), one intestinal malrotation, and one Hirschsprung’s disease requiring surgery. The total 34 patients carried 30 different variants, occurring de novo for 32 patients. The c.1180_1181del variant recurred in three patients and the c.1524-3C > G one was shared by siblings and inherited from the affected father. Variants identified were frameshift (43% – 13/30), nonsense (33% – 10/30), missense (17% – 5/30), splice-site (10% – 3/30), small in-frame deletion (3% – 1/30) and larger deletions encompassing the whole gene (6% – 2/30). 43% (13/30) of variants were predicted to escape nonsense-mediated RNA decay (NMD). Among the 20/34 patients presenting with GIDs, 7/20 (35%) of nonsense variants, 6/20 (30%) frameshift variants, 2/20 (10%) missense variants, 2/20 (10%) splice-site, 2/20 (10%) larger deletions encompassing the whole gene and 1/20 (5%) small-in frame deletions. 9/20 variants were predicted to escape NMD. The different variants and their respective digestive presentations are shown in Fig. 2 .a. Discussion To our knowledge, this is the first study to focus solely on GIDs in patients suffering from WHSUS. Few studies are based on the parent’s perspective while there is good correlation with the specialist on GID ( 18 ). We obtained a very satisfying response rate from members of the AWSF, allowing us to describe more than half of French patients known to the BNDMR. We carried out a literature review on PubMed by selecting all known articles with information on GIDs presented by WHSUS patients (19 articles), accounting for a total of 103 patients ( 3 , 4 , 8 , 19 – 34 ). The information about the presence and/or subtype of GID was available for 84 patients and we found a prevalence of 65% (55/84), as can be seen in Table 2, close to the prevalence in our study. If we focus on vomiting, we report for the first time on other causes of vomiting than CVS ( 4 , 21 , 29 ). Our 8.8% (3/34) prevalence of CVS approaches the 14.8% we found in the literature review (12/81), confirming its higher prevalence compared to the general population ( 10 ) or patients with ASD ( 5 ). The median age of CVS onset coincided with that of the general population ( 35 ) as did the 66% positive evolution ( 10 ). The management of CVS in our patients appeared to partially follow current pediatric recommendations ( 10 , 36 ). Diagnosing CVS is difficult because of a periodicity sometimes difficult to identify, the absence of confirmatory testing and its status as an exclusion diagnosis. It relies entirely on diagnosis criteria, for which three main sets are available ( 14 – 16 , 36 ). We chose to use Rome IV, which is tailored to the pediatric population and widely used in the literature, as in Batzir et al . ( 4 ). We were not able to find how CVS was diagnosed in other studies ( 8 , 29 , 33 ). Diagnosing CVS seems to be even more challenging among WHSUS patients. First because of the association of several GIDs. Indeed, diagnosing CVS is complex when a patient presents with several digestive symptoms, some of which may cause vomiting, such as constipation ( 37 ). Furthermore, patients with ASD can have limited verbal ability and/or abnormal sensory perception, making it difficult for them to localize or describe the sources of their discomfort ( 38 ). However, pain is an important symptom of GIDs, helping to guide or rule out diagnoses, including the differential diagnosis of CVS, such as gastritis, abdominal migraine, etc. ( 10 , 11 ). These difficulties also apply to the etiological diagnosis of repeated vomiting. Therefore, it was surprising to find that more than half of patients presenting with RV had never consulted a specialist physician. Furthermore, parents described the strong impact of RV and even stronger impact of CVS on their child’s quality of life. When several GIDs were associated, the majority of parents described RV and CVS as the most important GID. This shows the prominent place that RV and CVS have in patients’ lives. Our 18% prevalence of constipation according to Rome IV criteria approaches the one reported in the literature ( 2 , 4 ) and remains higher than that of the general European population ( 39 ) and is closer to the one among ASD patients ( 5 ). 83% (5/6) of patients suffering from constipation according to their parents but not meeting Rome IV criteria were treated. This indicates some difficulties in applying those criteria to NDD/ASD patients, which have been reported in previous publications ( 38 , 40 ). Several questionnaires have been developed in the past few years to assess GIDs among the ASD population ( 40 , 41 ) but literature lacks uniformity in that regard and Rome IV are still the most used criteria. Concerning FD, our 29% prevalence was below the 52% reported in the literature ( 2 ). The lack of a clear definition of FD leads us to suppose that parents might not have considered some symptoms as such. FDs can be severe enough to require enteral nutrition and we report here a case of parenteral nutrition lasting several months, which has never been previously discussed to our knowledge. Several studies have already signaled the presence of GERD among WHSUS patients ( 4 , 20 , 23 ) without giving a prevalence. If we only consider patients whose diagnosis was confirmed by complementary examinations or who were treated by PPIs, our prevalence of GERD was 17.6% (6/34). It is higher than among the general pediatric population ( 45 , 46 ) but less than among children suffering from neurological disorders ( 47 ). It is an important feature that can lead to FDs, and an organic etiology should not be neglected as one of our patients had a hiatal hernia and required fundoplication. We report an additional case of malrotation, bringing the total number of cases in the literature to four ( 4 , 21 ) and the prevalence to 3.3%, which is higher than among the general population ( 48 ). We also report a case of Hirschsprung’s disease, which has never been discussed among WHSUS patients. It will be interesting to follow this up to identify whether WHSUS is a predisposing syndrome for Hirschsprung’s disease. Concerning genetic variants, Nagy et al . ( 49 ) showed that missense variants were more often associated with milder phenotypes and truncating variants predicted to escape NMD were associated with more severe phenotypes. We had more missense variants compared to Nagy et al . ( 49 ) and we had less variants predicted to escape NMD than in Batzir et al . ( 4 ). This could explain why they had higher GID prevalences. The variants and digestive phenotypes of patients presenting with GIDs are represented in Fig. 2 .b. We believe that conducting a participatory study gave us a more comprehensive description of patients’ digestive phenotype and its consequences on their daily life. We used validated criteria to confirm a diagnosis suspected by the parents in order to limit bias. Concerning CVS, when the diagnosis was suggested, we crossed data from the questionnaire to medical data available from physicians or given by families, enabling us to obtain more precise information and sometimes to rule out the diagnosis. However, the data available were not uniform and not always exhaustive. The use of a questionnaire we designed, even if based on validated criteria, is also a limitation to our study. Conclusions Ours is the first study focused solely on the GIDs presented by patients with WHSUS. We took a particular interest in CVS, which has been previously described in the literature because of its unusual presentation among patients suffering from ASDs or NDDs. Our study confirms the remarkable prevalence of GIDs, repeated vomiting and CVS in particular. This disease, its major impact on quality of life, plus the delays and difficulties in diagnosis must be addressed to improve the care of affected children and referrals to a gastroenterologist pediatrician need to be more systematic. The reason why so many WHSUS patients experience GIDs is yet to be discovered, and further studies are needed to find if phenotype–genotype correlations exist. Abbreviations ASD autism spectrum disorder AWSF association White-Sutton France BNDMR banque nationale de données maladies rares CVS cyclic vomiting syndrome FD feeding difficulties GERD gastroesophageal reflux disease GID gastrointestinal disorders HP1 heterochromatin binding protein ICHD international classification of headache disorders NASPGHAN North American society for pediatric gastroenterology, hepatology and nutrition NDD neurodevelopmental disorder NMD non-sens mediated decay PEG polyethylene glycol PN parenteral nutrition POGZ pogo transposable element with ZNF domain PPI proton pump inhibitor RV repeated vomiting WHSUS White-Sutton syndrome ZNF zinc finger fonction Declarations Ethics approval and consent to participate In accordance with French legislation, this research qualifies as a project not involving human subjects (RNIPH). The study was registered with the Health Data Hub under registration number 17992342 and was conducted following the guidelines of the CNIL (French Data Protection Authority) MR-004 framework, thus not requiring any specific Ethics committee decision. Furthermore, the study was carried out in accordance with the French Data Protection Act No. 78-17 of January 6, 1978, as amended, and to the European General Data Protection Regulation (GDPR) effective since May 25, 2018.This study is in compliance with the Helsinki declaration. Informed consent to participate was obtained from patients or their parents/legal guardians for any patient under the age of 16 years. Consent for publication Patients/families agreed for publication. Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request. Competing interests Authors do not declare any conflict of interest. Funding No funding was provided for this study. Authors’ contributions CC: conception and design, acquisition of data, analysis and interpretation of data, article drafting AL, RM, MG, PB, JLM, FH: conception and design AG: acquisition of data CR: interpretation of data MM, CTR: acquisition and interpretation of data JA, EG, SO, LP, CC, RC, AV, SJ, MF, EB, JP, AT, ES, CPE, KJG: acquisition of data LF: conception and design, acquisition and interpretation of data All authors read and approved the final manuscript. Acknowledgements The authors thank Laura Grayston for proofreading and editing the manuscript. We are grateful to the patients and their families for their participation in this study. References Nozawa RS, Nagao K, Masuda HT, et al. Human POGZ modulates dissociation of HP1α from mitotic chromosome arms through Aurora B activation. Nat Cell Biol. 2010;12(7):719–27. Assia Batzir N, White J, Sutton VR et al. White-Sutton Syndrome. 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Gastro-oesophageal reflux disease in children with neurological impairment: a retrospective cohort study. BMJ Paediatr Open. 2022;6(1):e001577. Adams SD, Stanton MP. Malrotation and intestinal atresias. Early Hum Dev. 2014;90(12):921–5. Nagy D, Verheyen S, Wigby KM, et al. Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring. Genes. 2022;13(1):154. Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table 1. Digestive phenotypes and molecular data of White–Sutton patients presenting with gastrointestinal disorders All HGVS were annotated on RefSeq transcript NM_015100.4; GrCh38. +, present; -, not present; dark grey box, not concerned; del, deletion; fs, frameshift; PPI, proton-pump inhibitor; CVS, cyclic vomiting syndrome; GERD, gastroesophageal reflux disease; ND, no data; GID, gastrointestinal disorder. Table2.docx Table 2. Review of articles on White–Sutton syndrome containing information on gastrointestinal disorders GID, gastrointestinal disorder; CVS, cyclic vomiting syndrome; GER, gastroesophageal reflux; UKN, unknown; fs, frameshift; del, deletion. Supplemental1.pptx Supplemental 1. Representation of the main categories of patient history in our cohort ENT, ear, nose, throat. Supplemental2.pptx Supplemental 2. Representation of the evolution of cyclic vomiting syndrome over time among our cohort Patient 2 presented with vomiting every month from two to six years old. He was not diagnosed during his symptomatic period. Patient 3 presented with episodes of vomiting since the age of four years and six months. He has been treated for CVS since the age of nine years and six months and received transient parenteral nutrition. After a transient improvement, his symptoms have worsened since the age of eleven years and ten months. Patient 5 presented with vomiting every four months for fifteen years, from five to twenty years old. PN, parenteral nutrition; CVS, cyclic vomiting syndrome. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 18 Aug, 2025 Reviewers invited by journal 08 Aug, 2025 Editor assigned by journal 05 Aug, 2025 Editor invited by journal 18 Jul, 2025 Submission checks completed at journal 17 Jul, 2025 First submitted to journal 17 Jul, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7065996","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":498930962,"identity":"624aec8b-75b2-487c-a278-bc084c379d7e","order_by":0,"name":"Coline 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Sud","correspondingAuthor":false,"prefix":"","firstName":"Laurent","middleName":"","lastName":"Pasquier","suffix":""},{"id":498930977,"identity":"403ebd44-2f13-4e67-aa70-a5ce817b1bff","order_by":11,"name":"Christine Coubes","email":"","orcid":"","institution":"Hôpital Arnaud de Villeneuve, CHRU Montpellier","correspondingAuthor":false,"prefix":"","firstName":"Christine","middleName":"","lastName":"Coubes","suffix":""},{"id":498930978,"identity":"5a7cafc8-1757-473f-9ba7-4a13345a8780","order_by":12,"name":"Roseline Caumes","email":"","orcid":"","institution":"CHU Lille, Clinique de Génétique","correspondingAuthor":false,"prefix":"","firstName":"Roseline","middleName":"","lastName":"Caumes","suffix":""},{"id":498930979,"identity":"4e36a7ed-b02c-4443-b340-89f4ed2ba439","order_by":13,"name":"Aline Vincent","email":"","orcid":"","institution":"University Hospital of Caen","correspondingAuthor":false,"prefix":"","firstName":"Aline","middleName":"","lastName":"Vincent","suffix":""},{"id":498930980,"identity":"5ba58a4d-2cb0-4bac-8855-6a0c9d07d1e8","order_by":14,"name":"Sophie Julia","email":"","orcid":"","institution":"Hôpital Purpan CHU Toulouse","correspondingAuthor":false,"prefix":"","firstName":"Sophie","middleName":"","lastName":"Julia","suffix":""},{"id":498930981,"identity":"598163d0-75da-4dc7-97fc-434810795bdc","order_by":15,"name":"Mélanie Fradin","email":"","orcid":"","institution":"Hôpital SUD","correspondingAuthor":false,"prefix":"","firstName":"Mélanie","middleName":"","lastName":"Fradin","suffix":""},{"id":498930982,"identity":"a94e9782-a88a-44ad-983b-44cf631d4578","order_by":16,"name":"Elise Brischoux-Boucher","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Besançon, Université de Franche-Comté","correspondingAuthor":false,"prefix":"","firstName":"Elise","middleName":"","lastName":"Brischoux-Boucher","suffix":""},{"id":498930983,"identity":"dd8d28a3-289c-4070-b98f-c9ea86fb7dc5","order_by":17,"name":"Juliette Piard","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Besançon, Université de Franche-Comté","correspondingAuthor":false,"prefix":"","firstName":"Juliette","middleName":"","lastName":"Piard","suffix":""},{"id":498930984,"identity":"285f5f28-cb5c-4748-85a6-65f8351bb04e","order_by":18,"name":"Anick Toutain","email":"","orcid":"","institution":"CHU Tours, UMR 1253, Université de Tours","correspondingAuthor":false,"prefix":"","firstName":"Anick","middleName":"","lastName":"Toutain","suffix":""},{"id":498930985,"identity":"a09b53fa-691a-4c55-9441-0caee1d63a44","order_by":19,"name":"Elise Schaefer","email":"","orcid":"","institution":"Institut de Génétique Médicale d’Alsace, Hôpitaux Universitaires de Strasbourg","correspondingAuthor":false,"prefix":"","firstName":"Elise","middleName":"","lastName":"Schaefer","suffix":""},{"id":498930986,"identity":"3fa6aa42-5b4e-4a93-b25a-e2b40be4036c","order_by":20,"name":"Pauline Burger","email":"","orcid":"","institution":"Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, INSERM U1258, CNRS UMR7104","correspondingAuthor":false,"prefix":"","firstName":"Pauline","middleName":"","lastName":"Burger","suffix":""},{"id":498930987,"identity":"e7777e48-c465-412f-9595-87269519ac16","order_by":21,"name":"Jean-Louis Mandel","email":"","orcid":"","institution":"Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, INSERM U1258, CNRS UMR7104","correspondingAuthor":false,"prefix":"","firstName":"Jean-Louis","middleName":"","lastName":"Mandel","suffix":""},{"id":498930988,"identity":"a1fb8b04-0a7b-4fa4-ba79-965a8dde2f2b","order_by":22,"name":"Charles-Patrick Edery","email":"","orcid":"","institution":"GH Est, Hospices Civils de Lyon","correspondingAuthor":false,"prefix":"","firstName":"Charles-Patrick","middleName":"","lastName":"Edery","suffix":""},{"id":498930989,"identity":"aa4a9b53-4fa9-4990-a716-141aa07d34cb","order_by":23,"name":"Karine Jobard-Garou","email":"","orcid":"","institution":"Association White–Sutton","correspondingAuthor":false,"prefix":"","firstName":"Karine","middleName":"","lastName":"Jobard-Garou","suffix":""},{"id":498930990,"identity":"f70eab6d-a9d4-4df6-8d98-900183e41080","order_by":24,"name":"Christel Thauvin-Robinet","email":"","orcid":"","institution":"CHU Dijon- Bourgogne","correspondingAuthor":false,"prefix":"","firstName":"Christel","middleName":"","lastName":"Thauvin-Robinet","suffix":""},{"id":498930991,"identity":"6c38d9e7-f81c-43b7-88a1-47ea04cd48d0","order_by":25,"name":"Frédéric Huet","email":"","orcid":"","institution":"CHU Dijon-Bourgogne","correspondingAuthor":false,"prefix":"","firstName":"Frédéric","middleName":"","lastName":"Huet","suffix":""},{"id":498930992,"identity":"4571f78c-b4d0-485e-96e6-81bfe685d980","order_by":26,"name":"Laurence Faivre","email":"","orcid":"","institution":"CHU Dijon-Bourgogne","correspondingAuthor":false,"prefix":"","firstName":"Laurence","middleName":"","lastName":"Faivre","suffix":""}],"badges":[],"createdAt":"2025-07-07 13:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7065996/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7065996/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88983034,"identity":"3bf54347-817b-487c-9c51-50d19f929f76","added_by":"auto","created_at":"2025-08-13 11:57:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":43735,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation of repeated vomiting, constipation, feeding difficulties and gastroesophageal reflux within our cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e15% of patients had four gastrointestinal disorders, 30% had three, 5% had two and 20% had one.\u003c/p\u003e\n\u003cp\u003eThe most frequent associations were:\u003c/p\u003e\n\u003cp\u003e− Constipation, feeding disorders, repeated vomiting and GERD in 15% of cases\u003c/p\u003e\n\u003cp\u003e− Constipation, feeding disorders and repeated vomiting in 10% of cases\u003c/p\u003e\n\u003cp\u003e− Constipation, repeated vomiting and GERD in 10% of cases\u003c/p\u003e\n\u003cp\u003e− Feeding difficulties and GERD in 10% of cases.\u003c/p\u003e\n\u003cp\u003eGastroesophageal reflux disease was never isolated within our cohort.\u003c/p\u003e\n\u003cp\u003eGERD, gastroesophageal reflux disease.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7065996/v1/839f443da59fadeca0098c11.png"},{"id":88983038,"identity":"5d0dfd21-960b-4e7d-912f-f859711e297f","added_by":"auto","created_at":"2025-08-13 11:57:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":55517,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of POGZ variants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA. \u003c/strong\u003eProtein model of POGZ with all identified variants within the reported cohort indicated. All variants have been annotated on the RefSeq transcript (GenBank: NM_015100.4) (POGZ). Protein domains are indicated on the structure. ***, three unrelated patients had the p.(Met394ValfsTer9) variant. **, two related patients had this variant. Del, deletion; Fs, frameshift; HTH, helix-turn-helix; ZNF, zinc finger.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB.\u003c/strong\u003e Gastrointestinal disorders represented on a protein POGZ model according to genetic variants. Our cohort’s digestive phenotype/genetic variant is above and the literature one is below the protein model. CVS, cyclic vomiting syndrome; GERD, gastroesophageal reflux disease.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7065996/v1/065adc341d5391bb4f3fc263.png"},{"id":88986002,"identity":"271f55ca-a8a0-4481-84f6-7fe5349cd983","added_by":"auto","created_at":"2025-08-13 12:29:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":809817,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7065996/v1/8215a18a-588c-4762-8291-07d911321678.pdf"},{"id":88983035,"identity":"d653b243-cc11-4c2d-8cee-334dca4bfd31","added_by":"auto","created_at":"2025-08-13 11:57:33","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":46689,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e \u003cstrong\u003eDigestive phenotypes and molecular data of White–Sutton patients presenting with gastrointestinal disorders\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll HGVS were annotated on RefSeq transcript NM_015100.4; GrCh38.\u003c/p\u003e\n\u003cp\u003e+, present; -, not present; dark grey box, not concerned; del, deletion; fs, frameshift; PPI, proton-pump inhibitor; CVS, cyclic vomiting syndrome; GERD, gastroesophageal reflux disease; ND, no data; GID, gastrointestinal disorder.\u003c/p\u003e","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7065996/v1/e221ed08a01c6a78070badf8.docx"},{"id":88983036,"identity":"14ffce75-2004-44df-b6bd-03987d748054","added_by":"auto","created_at":"2025-08-13 11:57:33","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":33576,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e \u003cstrong\u003eReview of articles on White–Sutton syndrome containing information on gastrointestinal disorders\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGID, gastrointestinal disorder; CVS, cyclic vomiting syndrome; GER, gastroesophageal reflux; UKN, unknown; fs, frameshift; del, deletion.\u003c/p\u003e","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7065996/v1/e5471095213aa435fe76c392.docx"},{"id":88983640,"identity":"cd0dc128-5ea1-48e4-92a2-be503b24b720","added_by":"auto","created_at":"2025-08-13 12:05:34","extension":"pptx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":63265,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplemental 1. Representation of the main categories of patient history in our cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eENT, ear, nose, throat.\u003c/p\u003e","description":"","filename":"Supplemental1.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7065996/v1/74ce6e6b27f4ada08c722329.pptx"},{"id":88985142,"identity":"21459568-cbbd-44a8-8e68-c0edd934fc3b","added_by":"auto","created_at":"2025-08-13 12:21:34","extension":"pptx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":48030,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplemental 2.\u003c/strong\u003e \u003cstrong\u003eRepresentation of the evolution of cyclic vomiting syndrome over time among our cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient 2 presented with vomiting every month from two to six years old. He was not diagnosed during his symptomatic period.\u003c/p\u003e\n\u003cp\u003ePatient 3 presented with episodes of vomiting since the age of four years and six months. He has been treated for CVS since the age of nine years and six months and received transient parenteral nutrition. After a transient improvement, his symptoms have worsened since the age of eleven years and ten months.\u003c/p\u003e\n\u003cp\u003ePatient 5 presented with vomiting every four months for fifteen years, from five to twenty years old.\u003c/p\u003e\n\u003cp\u003ePN, parenteral nutrition; CVS, cyclic vomiting syndrome.\u003c/p\u003e","description":"","filename":"Supplemental2.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7065996/v1/220c8d2dc952c6335849cd7b.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cyclic vomiting and digestive symptoms in White–Sutton syndrome: a participatory study","fulltext":[{"header":"Background","content":"\u003cp\u003eWhite\u0026ndash;Sutton syndrome (WHSUS) (OMIM 616364) is a rare neurodevelopmental disorder (NDD) caused by a heterozygous variant affecting the \u003cem\u003ePOGZ\u003c/em\u003e gene. POGZ is involved in mitosis and expressed in the brain from the fetal period to adulthood (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). WHSUS is characterized by a broad spectrum of cognitive dysfunctions, global developmental delays, hypotonia and autism spectrum disorders (ASDs). Gastrointestinal disorders (GIDs) are among the other frequently reported symptoms in WHSUS (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) with a prevalence from 59% (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) to 89% (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis digestive comorbidity is increasingly described among patients with NDDs, particularly ASDs, with a prevalence ranging from 4.4\u0026ndash;96.8% and a median of 46.8% (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The most common digestive symptoms encountered are chronic functional constipation and abdominal pain associated or not with diarrhea. Other digestive symptoms include gastroesophageal reflux disease (GERD) and abdominal bloating (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The repeated vomiting (RV) prevalence ranges from 4.2\u0026ndash;11.4% (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn WHSUS, GIDs include feeding difficulties (FD) (52\u0026ndash;61%), functional constipation (30\u0026ndash;47%) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), GERD and RV, sometimes falling within the nosological framework of cyclic vomiting syndrome (CVS) (21\u0026ndash;42%) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). CVS is not generally described within the ASD/NDD population but 25% of patients with CVS have neurological comorbidities (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). It is characterized by acute, stereotyped and recurrent episodes of intense nausea accompanied by incoercible vomiting, lasting from a few hours to a few days. Prevalence in the general pediatric population is estimated at 1.9% (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). It is a diagnosis of exclusion with many differential diagnoses, including migraine spectrum disorders, GIDs such as chronic intestine obstruction or GERD (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTo our knowledge, no study has focused solely on the digestive symptoms presented by WHSUS patients, and more specifically on recurrent vomiting. The objective of this study was to describe gastrointestinal symptomatology in patients with WHSUS, and CVS in particular due to its uncommonness among ASD patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eEthics\u003c/p\u003e\u003cp\u003eIn accordance with French legislation, this research qualifies as a project not involving human subjects (RNIPH). The study was registered with the Health Data Hub under registration number 17992342 and was conducted following the guidelines of the CNIL (French Data Protection Authority) MR-004 framework, thus not requiring any specific Ethics committee decision. Furthermore, the study was carried out in accordance with the French Data Protection Act No. 78\u0026thinsp;\u0026minus;\u0026thinsp;17 of January 6, 1978, as amended, and to the European General Data Protection Regulation (GDPR) effective since May 25, 2018. This study is in compliance with the Helsinki declaration. Informed consent to participate was obtained from patients or their parents/legal guardians for any patient under the age of 16 years.\u003c/p\u003e\u003cp\u003ePatient recruitment and data collection\u003c/p\u003e\u003cp\u003eThis study took place between April 2024 and September 2024. A dedicated clinical questionnaire was sent by the Association White\u0026ndash;Sutton France (AWSF) to its members, 66 parents of 46 children with WHSUS and causal POGZ variants). This charity is highly representative of the French White-Sutton patients since 55 patients are currently included in the Banque Nationale de Donn\u0026eacute;es Maladies Rares (BNDMR) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Its members are also particularly interested in participatory medicine and the vast majority of its members contribute to GenIDA, an international participatory database designed to increase knowledge related to genetic forms of NDDs (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eQuestionnaire design\u003c/p\u003e\u003cp\u003eWe designed a questionnaire to screen for GIDs. It was divided into five sections.\u003c/p\u003e\u003cp\u003eThe first section addressed general questions including the children\u0026rsquo;s main medical and surgical histories, age at diagnosis, symptoms leading to the search for a genetic origin and the \u003cem\u003ePOGZ\u003c/em\u003e variant responsible for the syndrome. We asked the parents if their child had any GIDs and, if so, which ones. We then asked if they have ever consulted a physician for GIDs and which GID was the most impairing for their child. If the child did not have any GIDs, the questionnaire was ended.\u003c/p\u003e\u003cp\u003eThe second section sought repeated vomiting or nausea and then signs of CVS using Rome IV criteria (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), as well as details of age at onset, duration of symptoms, their impact on quality of life (using a scale ranging from 0 \u0026ndash; no impact to 5 \u0026ndash; major impact), their evolution over time, complementary examinations, treatments implemented and their efficacy. Migraine and abdominal migraine, which are differential diagnoses of CVS, were looked for using the ICHD-3 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). We also asked if they have ever consulted a physician for vomiting.\u003c/p\u003e\u003cp\u003eThe third section focused on constipation. The diagnosis was confirmed using Rome IV criteria (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). In cases of constipation, parents had to state if a treatment was prescribed and how effective it was.\u003c/p\u003e\u003cp\u003eThe fourth section focused on FD. If their child experienced FD, parents had to detail what kind, if enteral feeding was required, the age at onset and the duration.\u003c/p\u003e\u003cp\u003eThe fifth section focused on GERD. In the event of signs, extra-digestive symptoms were sought (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). We also asked whether any paraclinical examinations had been carried out, the results and the treatments used.\u003c/p\u003e\u003cp\u003eOpen-ended questions were asked at the ends of the second section and the questionnaire for parents to provide clarifications or add comments if necessary. A detailed questionnaire is available on request.\u003c/p\u003e\u003cp\u003e After an initial review of the questionnaire responses, families and/or referring practitioners were contacted by email and/or telephone in the event of repeated vomiting that might fall within the nosological framework of cyclic vomiting. The same procedure was followed for incomplete responses to avoid missing data.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e 33 parents answered the questionnaire for 34 patients, two being siblings (72% of members of the AWSF). 2 children were not monitored in France, meaning our cohort represents 58% (32/55) of French White\u0026ndash;Sutton patients according to the BNDMR survey (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The main medical and surgical histories are summarized in Supplemental 1. The median age at diagnosis was 9.5 years and 12 years at the time of last follow-up. The sex ratio was 1:1. The disease was diagnosed because of an ASD or another NDD in all patients. 59% (20/34) suffered from GIDs. The digestive phenotypes and molecular data are summarized in Table\u0026nbsp;1. Among them, 45% (9/20) had consulted a specialist at least once for these conditions.\u003c/p\u003e\u003cp\u003e35% (12/34) suffered from RV. 10 patients were declared by their parents as suffering from CVS. To verify the CVS criteria, we contacted parents or physicians (with the parents\u0026rsquo; written consent) for all patients. Finally, three (8,8%) suffered from CVS according to Rome IV criteria (3/34). According to the ICHD-3, two had migraines and one suffered from abdominal migraines associated with vomiting. Two had vomiting associated with gastritis or constipation, one described signs of GERD, two had nausea associated or not with epigastralgia (without CVS or abdominal migraine criteria), and the last suffered from treatment-induced nausea. 58% (7/12) had never consulted a specialist physician including one with CVS. Two declared that they had never consulted for vomiting. The impact of RV on quality of life was assessed to be an average 4.25/5 and CVS 5/5. The two patients who had never consulted a physician put the impact on quality of life at 5/5. The mean age of symptom onset for RV was 6.7 years and 3.7 years for CVS. RV\u0026rsquo;s evolution showed improvement in 67% (6/9, now aged 8, 12, 16, 17, 24, 38 years) of cases, stability in 22% (2/9, now aged 9 and 25 years) and worsening in 11% (1/9, now aged 11 years). Concerning the management of the three patients presenting with CVS, all had been hospitalized on several occasions for episodes of vomiting, requiring parenteral hydration. CVS was not diagnosed during patient 2\u0026rsquo;s symptomatic period. He was hospitalized on a regular basis for uncontrollable vomiting over a period of four years, with vomiting every month from the ages of two to six, and required parenteral hydration followed by progressive refeeding. Patient 3 presented with a serious case of WHSUS, combining severe intellectual development disorder, absence of speech and a predominant digestive phenotype. He has a medical history of incomplete common mesentery and stomach volvulus. Since the age of four years and six months, he repeatedly presented with episodes of vomiting requiring recurring hospitalizations. His symptoms were long attributed to his severe constipation before CVS was diagnosed. He has been treated for CVS since the age of nine years and six months and received transient parenteral nutrition. He had background therapy with Levocarnitine and crisis treatment with Hydroxyzine, Niflumic Acid, PPI and Ondansetron. Cyproheptadine was tried as a background treatment but was not well tolerated. After a transient improvement, his symptoms have worsened since the age of eleven years and ten months, requiring transient parenteral nutrition. Patient 5 presented with vomiting every four months for fifteen years, from the ages of five to twenty, and had background therapy with Flunarizine and crisis treatment with Ibuprofen, Paracetamol and Ondansetron. The evolution of CVS among our patients is represented in Supplemental 2.\u003c/p\u003e\u003cp\u003e35% (12/34) suffered from constipation. 50% (6/12) met Rome IV criteria for functional constipation. Of these, four were treated with polyethylene glycol (PEG), one followed dietary rules and one had no treatment. Of the remaining six patients who did not meet Rome IV criteria, four were treated with PE (two requiring occasional enemas), one with a combination of osmotic laxative and lubricant, and one had no treatment.\u003c/p\u003e\u003cp\u003e29% of patients reported FD (10/34). Parents described chewing problems in 70% of cases (7/10), swallowing difficulties in 60% (6/10), gastroesophageal reflux responsible for the difficulties in 60% (6/10), hypersensitivity of the oral region in 30% (3/10) and allergy to cow milk proteins in one patient (10%). In all cases, several symptoms were associated. Two patients (5.9%, 2/34) required enteral nutrition: patient 3 because of FD during the neonatal period for a duration of eight months. He then required enteral nutrition later, from the age of nine years, and now parenteral nutrition. Patient 10 was fed by nasogastric tube for several months from the age of sixteen months.\u003c/p\u003e\u003cp\u003e29% (10/34) showed signs of GERD. Four described extra-digestive symptoms. 40% (4/10) reported sleeping difficulties linked to GERD. Five patients underwent complementary examinations. One had pH and esogastroduodenal transit monitoring confirming the diagnosis and discovering hiatal hernia. He benefited from a gastric fundoplication. Three patients underwent esogastroduodenal fibroscopy confirming the diagnosis, with one suffering from Barrett\u0026rsquo;s esophagus. One patient underwent pH monitoring without showing signs of acid reflux but was treated with PPIs. In total, six patients were treated with PPIs.\u003c/p\u003e\u003cp\u003e30% of patients (6/20) had only one GID, 25% (5/20) had two, 25% (5/20) had three and 20% (4/20) had four. The different combinations of GIDs are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. RV was associated with other GIDs in 89% of cases (8/9). It was the most important GID in 62.5% (5/8) of cases. CVS was associated with other GIDs in 67% of cases (2/3) and, was the most important GID in 100% of cases (2/2). Among patients with RV, 56% (5/9) suffered from constipation, and among patients with CVS, 67% (2/3) suffered from constipation.\u003c/p\u003e\u003cp\u003eThe following additional digestive symptoms were reported by parents: one inguinal hernia, one rectal prolapse (associated with constipation), one intestinal malrotation, and one Hirschsprung\u0026rsquo;s disease requiring surgery.\u003c/p\u003e\u003cp\u003eThe total 34 patients carried 30 different variants, occurring de novo for 32 patients. The c.1180_1181del variant recurred in three patients and the c.1524-3C\u0026thinsp;\u0026gt;\u0026thinsp;G one was shared by siblings and inherited from the affected father. Variants identified were frameshift (43% \u0026ndash; 13/30), nonsense (33% \u0026ndash; 10/30), missense (17% \u0026ndash; 5/30), splice-site (10% \u0026ndash; 3/30), small in-frame deletion (3% \u0026ndash; 1/30) and larger deletions encompassing the whole gene (6% \u0026ndash; 2/30). 43% (13/30) of variants were predicted to escape nonsense-mediated RNA decay (NMD). Among the 20/34 patients presenting with GIDs, 7/20 (35%) of nonsense variants, 6/20 (30%) frameshift variants, 2/20 (10%) missense variants, 2/20 (10%) splice-site, 2/20 (10%) larger deletions encompassing the whole gene and 1/20 (5%) small-in frame deletions. 9/20 variants were predicted to escape NMD. The different variants and their respective digestive presentations are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.a.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first study to focus solely on GIDs in patients suffering from WHSUS. Few studies are based on the parent\u0026rsquo;s perspective while there is good correlation with the specialist on GID (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). We obtained a very satisfying response rate from members of the AWSF, allowing us to describe more than half of French patients known to the BNDMR. We carried out a literature review on PubMed by selecting all known articles with information on GIDs presented by WHSUS patients (19 articles), accounting for a total of 103 patients (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). The information about the presence and/or subtype of GID was available for 84 patients and we found a prevalence of 65% (55/84), as can be seen in Table\u0026nbsp;2, close to the prevalence in our study.\u003c/p\u003e\u003cp\u003eIf we focus on vomiting, we report for the first time on other causes of vomiting than CVS (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Our 8.8% (3/34) prevalence of CVS approaches the 14.8% we found in the literature review (12/81), confirming its higher prevalence compared to the general population (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) or patients with ASD (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The median age of CVS onset coincided with that of the general population (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) as did the 66% positive evolution (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The management of CVS in our patients appeared to partially follow current pediatric recommendations (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Diagnosing CVS is difficult because of a periodicity sometimes difficult to identify, the absence of confirmatory testing and its status as an exclusion diagnosis. It relies entirely on diagnosis criteria, for which three main sets are available (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). We chose to use Rome IV, which is tailored to the pediatric population and widely used in the literature, as in Batzir \u003cem\u003eet al\u003c/em\u003e. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). We were not able to find how CVS was diagnosed in other studies (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Diagnosing CVS seems to be even more challenging among WHSUS patients. First because of the association of several GIDs. Indeed, diagnosing CVS is complex when a patient presents with several digestive symptoms, some of which may cause vomiting, such as constipation (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Furthermore, patients with ASD can have limited verbal ability and/or abnormal sensory perception, making it difficult for them to localize or describe the sources of their discomfort (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). However, pain is an important symptom of GIDs, helping to guide or rule out diagnoses, including the differential diagnosis of CVS, such as gastritis, abdominal migraine, etc. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). These difficulties also apply to the etiological diagnosis of repeated vomiting. Therefore, it was surprising to find that more than half of patients presenting with RV had never consulted a specialist physician. Furthermore, parents described the strong impact of RV and even stronger impact of CVS on their child\u0026rsquo;s quality of life. When several GIDs were associated, the majority of parents described RV and CVS as the most important GID. This shows the prominent place that RV and CVS have in patients\u0026rsquo; lives.\u003c/p\u003e\u003cp\u003eOur 18% prevalence of constipation according to Rome IV criteria approaches the one reported in the literature (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) and remains higher than that of the general European population (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) and is closer to the one among ASD patients (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). 83% (5/6) of patients suffering from constipation according to their parents but not meeting Rome IV criteria were treated. This indicates some difficulties in applying those criteria to NDD/ASD patients, which have been reported in previous publications (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Several questionnaires have been developed in the past few years to assess GIDs among the ASD population (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) but literature lacks uniformity in that regard and Rome IV are still the most used criteria.\u003c/p\u003e\u003cp\u003eConcerning FD, our 29% prevalence was below the 52% reported in the literature (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The lack of a clear definition of FD leads us to suppose that parents might not have considered some symptoms as such. FDs can be severe enough to require enteral nutrition and we report here a case of parenteral nutrition lasting several months, which has never been previously discussed to our knowledge.\u003c/p\u003e\u003cp\u003eSeveral studies have already signaled the presence of GERD among WHSUS patients (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) without giving a prevalence. If we only consider patients whose diagnosis was confirmed by complementary examinations or who were treated by PPIs, our prevalence of GERD was 17.6% (6/34). It is higher than among the general pediatric population (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e) but less than among children suffering from neurological disorders (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). It is an important feature that can lead to FDs, and an organic etiology should not be neglected as one of our patients had a hiatal hernia and required fundoplication.\u003c/p\u003e\u003cp\u003eWe report an additional case of malrotation, bringing the total number of cases in the literature to four (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) and the prevalence to 3.3%, which is higher than among the general population (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). We also report a case of Hirschsprung\u0026rsquo;s disease, which has never been discussed among WHSUS patients. It will be interesting to follow this up to identify whether WHSUS is a predisposing syndrome for Hirschsprung\u0026rsquo;s disease.\u003c/p\u003e\u003cp\u003eConcerning genetic variants, Nagy \u003cem\u003eet al\u003c/em\u003e. (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e) showed that missense variants were more often associated with milder phenotypes and truncating variants predicted to escape NMD were associated with more severe phenotypes. We had more missense variants compared to Nagy \u003cem\u003eet al\u003c/em\u003e. (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e) and we had less variants predicted to escape NMD than in Batzir \u003cem\u003eet al\u003c/em\u003e. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). This could explain why they had higher GID prevalences. The variants and digestive phenotypes of patients presenting with GIDs are represented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.b.\u003c/p\u003e\u003cp\u003eWe believe that conducting a participatory study gave us a more comprehensive description of patients\u0026rsquo; digestive phenotype and its consequences on their daily life. We used validated criteria to confirm a diagnosis suspected by the parents in order to limit bias. Concerning CVS, when the diagnosis was suggested, we crossed data from the questionnaire to medical data available from physicians or given by families, enabling us to obtain more precise information and sometimes to rule out the diagnosis. However, the data available were not uniform and not always exhaustive. The use of a questionnaire we designed, even if based on validated criteria, is also a limitation to our study.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOurs is the first study focused solely on the GIDs presented by patients with WHSUS. We took a particular interest in CVS, which has been previously described in the literature because of its unusual presentation among patients suffering from ASDs or NDDs.\u003c/p\u003e\u003cp\u003eOur study confirms the remarkable prevalence of GIDs, repeated vomiting and CVS in particular. This disease, its major impact on quality of life, plus the delays and difficulties in diagnosis must be addressed to improve the care of affected children and referrals to a gastroenterologist pediatrician need to be more systematic. The reason why so many WHSUS patients experience GIDs is yet to be discovered, and further studies are needed to find if phenotype\u0026ndash;genotype correlations exist.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eASD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eautism spectrum disorder\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAWSF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eassociation White-Sutton France\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBNDMR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebanque nationale de donn\u0026eacute;es maladies rares\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCVS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecyclic vomiting syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003efeeding difficulties\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGERD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003egastroesophageal reflux disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGID\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003egastrointestinal disorders\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHP1\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eheterochromatin binding protein\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eICHD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003einternational classification of headache disorders\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNASPGHAN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNorth American society for pediatric gastroenterology, hepatology and nutrition\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNDD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eneurodevelopmental disorder\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNMD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003enon-sens mediated decay\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePEG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epolyethylene glycol\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eparenteral nutrition\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cem\u003ePOGZ\u003c/em\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epogo transposable element with ZNF domain\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePPI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eproton pump inhibitor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003erepeated vomiting\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWHSUS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWhite-Sutton syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eZNF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ezinc finger fonction\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn accordance with French legislation, this research qualifies as a project not involving human subjects (RNIPH). The study was registered with the Health Data Hub under registration number 17992342 and was conducted following the guidelines of the CNIL (French Data Protection Authority) MR-004 framework, thus not requiring any specific Ethics committee decision. Furthermore, the study was carried out in accordance with the French Data Protection Act No. 78-17 of January 6, 1978, as amended, and to the European General Data Protection Regulation (GDPR) effective since May 25, 2018.This study is in compliance with the Helsinki declaration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed consent to participate was obtained from patients or their parents/legal guardians for any patient under the age of 16 years.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients/families agreed for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors do not declare any conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was provided for this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCC: conception and design, acquisition of data, analysis and interpretation of data, article drafting\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAL, RM, MG, PB, JLM, FH: conception and design\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAG: acquisition of data\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCR: interpretation of data\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMM, CTR: acquisition and interpretation of data\u003c/p\u003e\n\u003cp\u003eJA, EG, SO, LP, CC, RC, AV, SJ, MF, EB, JP, AT, ES, CPE, KJG: acquisition of data \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLF: conception and design, acquisition and interpretation of data\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Laura Grayston for proofreading and editing the manuscript. We are grateful to the patients and their families for their participation in this study.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNozawa RS, Nagao K, Masuda HT, et al. Human POGZ modulates dissociation of HP1α from mitotic chromosome arms through Aurora B activation. Nat Cell Biol. 2010;12(7):719\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAssia Batzir N, White J, Sutton VR et al. White-Sutton Syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, editors. GeneReviews\u0026reg; [Internet]. Seattle (WA): University of Washington, Seattle; 2021. 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Clin Genet. 2021;99(3):407\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDal S, Hopper B, Du Chattel MVR. A case of White\u0026ndash;Sutton syndrome with previously described loss-of‐function variant in DDE domain of \u003cem\u003ePOGZ\u003c/em\u003e (p.Arg1211*) and Kartagener syndrome. Am J Med Genet A. 2021;185(3):1006\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWright CM, Guter SJ, Cook EH. Case Report: Association of Comorbid Psychiatric Disorders and Sigmoid Prolapse with de novo POGZ Mutation. J Autism Dev Disord. 2022;52(3):1408\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDuan J, Ye Y, Liao J, Chen L, et al. White-Sutton syndrome and congenital heart disease: case report and literature review. BMC Pediatr. 2023;23(1):158.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMerriweather A, Murdock DR, Rosenfeld JA, et al. A novel, de novo intronic variant in \u003cem\u003ePOGZ\u003c/em\u003e causes White\u0026ndash;Sutton syndrome. Am J Med Genet A. 2022;188(7):2198\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGiraldo-Ocampo S, Pacheco-Orozco RA, Pachajoa H. A Novel POGZ Variant in a Patient with Intellectual Disability and Obesity. Appl Clin Genet 2022;Volume 15:63\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFitzpatrick E, Bourke B, Drumm B. The Incidence of Cyclic Vomiting Syndrome in Children: Population-Based Study.: CME. Am J Gastroenterol. 2008;103(4):991\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi BU, Lefevre F, Chelimsky GG, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Consensus Statement on the Diagnosis and Management of Cyclic Vomiting Syndrome. 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Dig Liver Dis. 2024;S1590865824007771.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMargolis KG, Buie TM, Turner JB, et al. Development of a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism Spectrum Disorder. J Autism Dev Disord. 2019;49(1):349\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKleinert J. Pediatric Feeding Disorders and Severe Developmental Disabilities. Semin Speech Lang. 2017;38(02):116\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchwarz SM, Corredor J, Fisher-Medina J. Diagnosis and Treatment of Feeding Disorders in Children With Developmental Disabilities. Pediatrics. 2001;108(3):671\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBaraskewich J, Von Ranson KM, McCrimmon A. Feeding and eating problems in children and adolescents with autism: A scoping review. Autism. 2021;25(6):1505\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRuig\u0026oacute;mez A, Wallander MA, Lundborg P. Gastroesophageal reflux disease in children and adolescents in primary care. Scand J Gastroenterol. 2010;45(2):139\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMartigne L, Delaage PH, Thomas-Delecourt F. Prevalence and management of gastroesophageal reflux disease in children and adolescents: a nationwide cross-sectional observational study. Eur J Pediatr. 2012;171(12):1767\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDewan T, Turner J, Lethebe BC. Gastro-oesophageal reflux disease in children with neurological impairment: a retrospective cohort study. BMJ Paediatr Open. 2022;6(1):e001577.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAdams SD, Stanton MP. Malrotation and intestinal atresias. Early Hum Dev. 2014;90(12):921\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNagy D, Verheyen S, Wigby KM, et al. Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring. Genes. 2022;13(1):154.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"POGZ, neurodevelopmental disorders, gastrointestinal disorders, cyclic vomiting syndrome, white-sutton syndrome","lastPublishedDoi":"10.21203/rs.3.rs-7065996/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7065996/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eWhite\u0026ndash;Sutton syndrome is a neurodevelopmental condition with a high prevalence of gastrointestinal disorders (89%), including cyclic vomiting (21\u0026ndash;37.5%). Our objective was to better characterize repeated vomiting, cyclic vomiting syndrome in particular, and other digestive symptoms by conducting a participatory study.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eFrench White\u0026ndash;Sutton Association members received a questionnaire to identify and describe repeated vomiting, constipation, feeding difficulties and gastroesophageal reflux. Families or physicians were contacted in the event of missing or unclear answers.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e34 patients out of 46 participated in our study, of whom 59% presented with digestive symptoms. 35% (12/34) reported repeated vomiting and 9% (3/34) met Rome IV criteria for cyclic vomiting syndrome, with a significant quality of life impact. 35% (12/34) reported constipation (18% \u0026ndash; 6/34 meeting Rome IV criteria for functional constipation), 29% (10/34) feeding difficulties and 29% (10/34) symptoms of gastroesophageal reflux disease. In 70% of cases, patients presented with more than one gastrointestinal disorder.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eOur participatory study is the first focusing on gastrointestinal disorders. It allowed us to obtain very precise information about the digestive phenotype and its consequences for patients. Further studies are required to evaluate if a genotype\u0026ndash;phenotype correlation exists.\u003c/p\u003e","manuscriptTitle":"Cyclic vomiting and digestive symptoms in White–Sutton syndrome: a participatory study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-13 11:57:29","doi":"10.21203/rs.3.rs-7065996/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"326087191981107768466420010508055054167","date":"2025-08-18T06:41:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-08T07:16:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-05T08:36:46+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-18T08:22:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-17T22:26:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-07-17T18:05:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ec93799a-ba44-4672-ab40-4469cb0aa31a","owner":[],"postedDate":"August 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-08-13T11:57:29+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-13 11:57:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7065996","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7065996","identity":"rs-7065996","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}