Constipation in adults with neurofibromatosis type 1

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1 Ejerskov et al. Orhanet Journal of Rare Diseases (2017) 12:139 DOI /s RESEARCH Oen Access Constiation in adults with neurofibromatosis tye 1 Cecilie Ejerskov 1,2,3*, Klaus Krogh 4, John R. Ostergaard 1, Janne L. Fassov 4 and Annette Haageru 2,3 Abstract Background: Neurofibromatosis tye 1 (NF1) is an autosomal-dominant disease characterised by symtoms of the skin, eyes, nervous system and bones. A revious study indicated that constiation, large rectal diameters and rolonged colorectal transit times are common in children with NF1. The aim of the resent study was to investigate and comare the revalence of gastrointestinal symtoms in adult atients with NF1 to their unaffected relatives serving as the control grou. Patients with NF1 were recruited from one of two Danish National Centres of Exertise for NF1 and their unaffected relatives were invited to articiate as controls. Gastrointestinal symtoms were assessed with a web-based, self-administered, validated, Rome III diagnostic questionnaire. Logistic regression was used to estimate the revalence of functional dysesia, IBS and functional constiation in each grou and the grous were comared using their odds ratios. Results: The resonse rates for atients and controls were 66.4% and 82.4%, resectively. We comared 175 atients, median age 34.2 (IQR = 20.1) and 91 of their unaffected relatives, median age 42.0 (IQR = 12). The overall likelihood of fulfilling the diagnostic criteria for functional constiation,irritablebowelsyndromeorfunctional dysesia was 33.1% among atients vs. 14.3% among controls, (odds ratio (OR): 2.97; 95% CI: ) and after adjustment for age and gender (OR: 3.06; 95% CI: ). The likelihood of functional constiation was higher among atients (OR: 3.80; 95% CI: ), and this was still true after adjustment (OR: 3.49; 95% CI: ). The likelihood of irritable bowel syndrome (OR: 2.29; 95% CI: ) was evident after adjustment (OR: 2.46; 95% CI: ), whereas there was no difference in the likelihood of functional dysesia (OR: 2.35; 95% CI: ) after adjustment (OR:2.25; 95% CI: ). Conclusions: Overall, having symtoms usually attributed to either functional dysesia, IBS or functional constiation is more common in adults with NF1 comared to unaffected relatives. Of the three, the likelihood of constiation is markedly higher. The high revalence of constiation indicates that it is not functional but art of the NF1 disorder. Keywords: Neurofibromatosis tye 1, Functional gastrointestinal disorders, Self-reort questionnaire, Rome criteria, Functional constiation, Irritable bowel syndrome, Functional dysesia Background Neurofibromatosis tye 1 (NF1) is an autosomal dominant disease caused by a mutation in or a deletion of the neurofibromin gene on chromosome 17q11.2, causing inactivation of the tumor suressor gene neurofibromin [1]. The revalence of NF1 is 1:3000 [2]. Clinical and diagnostic features of NF1 include café au lait macules, cutaneous or lexiform neurofibromas, axillary and inguinal freckling, * Corresondence: CECILIE@EJERSKOV.DK 1 Centre for Rare Diseases, Pediatrics and Adolescent Medicine, Aarhus University Hosital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark 2 NIDO Danmark, Research in Education and Health, West Danish Hosital, HEV, Gl. Landevej 61, 7400 Herning, Denmark Full list of author information is available at the end of the article otic glioma, Lisch nodules and distinctive osseous lesions, such as shenoid dyslasia or seudoarthrosis [3]. The NF1 henotye shows great variability with both intra-family and inter-family exressivity [4]. Thus, some atients have only mild cutaneous manifestations while others have multi-organic involvement. Aart from the hysical features, common findings in atients with NF1 are slight mental imairment, learning disabilities and behavioral symtoms [5]. Studies on the gastrointestinal function in atients with NF1 are very rare. In a revious ilot study, we found that children with NF1 had abnormally large rectal diameters and a higher roortion than exected had rolonged colonic transit time [6]. A retrosective The Author(s) Oen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (htt://creativecommons.org/licenses/by/4.0/), which ermits unrestricted use, distribution, and reroduction in any medium, rovided you give aroriate credit to the original author(s) and the source, rovide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (htt://creativecommons.org/ublicdomain/zero/1.0/) alies to the data made available in this article, unless otherwise stated.

2 Ejerskov et al. Orhanet Journal of Rare Diseases (2017) 12:139 Page 2 of 5 assessment of 126 children concluded that an abdominal migraine could be a significant cause of abdominal ain in children with NF1 [7]. For the resent study, we hyothesized that adult atients with NF1 have an increased revalence of gastrointestinal symtoms. The aim was to comare the revalence of gastrointestinal (GI) symtoms in adults with NF1 and a control grou consisting of their relatives without NF1. Methods Particiants Patients with NF1 were recruited from the outatient clinic at the Centre for Rare Diseases (CRD), Deartment of Paediatrics, Aarhus University Hosital, which is one of two Danish National Centres of Exertise for NF1. The centre takes care of all asects of NF1, regardless of the atient s age, income and disease severity. Patients were included if they fulfilled the diagnostic criteria of NF1 established by the National Institutes of Health Consensus Conference [3] and were 18 years or older. At the start of the roject in December 2015, the 268 atients fulfilling the inclusion criteria were invited to articiate between December 2015 and July The control grou comrised relatives without NF1; a artner, a sibling or a arent and who was 18 years or older with no diagnosis of NF1. A total of 125 relatives were invited to articiate. The invitations included a link to an online questionnaire and were issued to the eligible atients and their resective relatives during a) the atient s regular visits to the CRD or b) by letter to the atients who were not scheduled to attend the CRD during the recruitment eriod. Patients and controls were excluded if they had undergone major abdominal surgery or had known disease affecting their bowel function. Protocol The study was based on the self-administered, validated, Rome III diagnostic questionnaires comrehensively investigating GI symtoms via the three questionnaire modules; functional dysesia, irritable bowel syndrome (IBS) and constiation. It is ossible to score and correlate them to the following adult functional GI disorders: functional dysesia, IBS, functional constiation, ostrandial distress syndrome, eigastric ain syndrome and functional gallbladder, shincter Oddi disorders and functional defecation disorders [8]. Furthermore, an additional questionnaire described the usage of medicine, exercise, organic GI disease, and major abdominal surgery, the last two being a reason for exclusion. The articiants were introduced to the confidentiality rocedures and to the use of the questionnaires by the first author. The atients articiated on even terms but reading assistance was needed for 17 atients who showed roblems with reading or understanding words (n = 15), had dyslexia (n = 1) or was blind (n = 1). The Rome questionnaire had been translated from English to Danish accordingly to the guidelines dislayed on the Rome Foundation website [9] in the year 2014; a rocess of six translators active in forward translation, reconciliation, backward translation and finally a consensus meeting was held. Informed consent was collected from atients. Details that might identify the articiants have been omitted. The study was aroved by the Danish Data Protection Agency ( ). According to the Ethics Committee of Denmark, no aroval was needed for this questionnaire-based investigation. Data analysis We scored the questionnaires accordingly to the Rome III scoring algorithm devised by the Rome Foundation for functional dysesia, ostrandial distress syndrome, eigastric ain syndrome, functional gallbladder and shincter of Oddi disorders, IBS including subtyes, functional constiation, and functional defecation disorders. Study data were collected and managed using RED- Ca electronic data cature tools hosted at the Deartment of Clinical Medicine at Aarhus University. REDCa (Research Electronic Data Cature) is a secure, web-based alication designed to suort data cature for research studies [10]. Statistical analyses were erformed with Stata 12 software (StataCor, College Station, TX). Median and interquartile range of the age were reorted in each grou and the grous were comared using a ermutation test for Mann-Whitney for continuous variables. The variables gender, regular exercise and the usage of laxatives in each grou were reorted as frequencies and the grous were comared using chi-square test. Logistic regression was used to estimate the revalence of functional dysesia, IBS and functional constiation in atients and controls. The grous were comared using their odds ratios (ORs). The crude revalence and the crude and adjusted ORs were reorted along with their 95% confidence intervals. Secific gastrointestinal symtoms in each grou were reorted as frequencies and the grous were comared using chi-square test. No corrections were made for the multile comarisons. Particiants from the same family were assumed to be more homogeneous than those from the other family and hence the between-family variation was taken into account in the logistic regression model. Results A total of 178 atients (66.4%) and 103 controls (82.4%) resonded. Three articiants in the NF1 grou were excluded due to inflammatory bowel disease (n = 2)or colonic cancer (n = 1). Two articiants in the control

3 Ejerskov et al. Orhanet Journal of Rare Diseases (2017) 12:139 Page 3 of 5 Table 1 Basic characteristics of atients and controls -value Age, median (IQR) 34.2 (20.6) 42.0 (12) Gender, female, n (%) 109 (62%) 41 (45%) Regular exercise, n (%) 55 (31.4%) 38 (41.8%) Usage of laxatives, n (%) 8 (4.6%) 5 (5.6%) NF1 neurofibromatosis tye 1 grou were excluded due to inflammatory bowel disease (n = 2) and ten controls were omitted from the analyses since the information on the family association was lost during the data collection. For basic characteristics on age, gender, exercise and the usage of laxatives on the 175 atients and the 91 controls, see Table 1. When comared to the articiating atients the atients who declined to articiate were younger, median age 28.2 (IQR = 18.5) ( = 0.013) but did not differ in gender ( = 0.160). When comared to the articiating controls, the relatives who declined to articiate did not differ in gender ( = 0.095), whereas there was no record of the age of those not resonding. Gastrointestinal symtoms The roortion of articiants fulfilling the criteria for at least one of the three most common functional gastrointestinal disorders (functional dysesia, IBS or functional constiation) was 33.1% in the atient grou vs. 14.3% the control grou, see Table 2. Uer gastrointestinal symtoms The secific uer gastrointestinal symtoms described in the questionnaire are shown in Table 3. There was no difference in the roortion fulfilling the criteria for functional dysesia (atients 7.4% (n = 13) and controls 3.3% (n = 3)), see Table 2. The roortion fulfilling the criteria for ostrandial distress syndrome was 5/175 among atients vs. 1/91 among controls ( = 0.360). In both grous, none fulfilled the criteria for eigastric ain syndrome or functional gallbladder and shincter of Oddi disorders. Lower gastrointestinal symtoms The secific symtoms described in the questionnaire are shown in Tables 4 and 5. The roortion fulfilling the criteria for functional constiation was significant higher in atients (atients 14.9% (n = 26) and controls 4.4% (n = 4)), see Table 2. The roortion fulfilling the criteria for IBS was in atients 16.0% (n =28)andincontrols 7.7% (n = 7), see Table 2. There was no difference in IBS subtyes; IBS with constiation (atients 21% (n = 6) and controls 14%(n = 1)( = 0.260)), IBS with diarrhea (atients 32% (n = 9) and controls 57%(n =4),( =0.790)), mixed IBS (atients 39% (n = 11) and controls 14% (n =1),( = 0.055)), and un-subtyed IBS (atients 7% (n = 2) and controls 14% (n = 1), ( = 0.380)). Among the atients and controls with constiation 65% (n = 17) and 25% (n = 1),( = 0.125), resectively, were identified as cases who would require further investigation to confirm functional defecation disorders. Discussion Theresentstudyrovidesthefirstsystematicallycollected data on gastrointestinal symtoms among adults with NF1. The atients had a higher revalence of symtoms usually characterized as functional gastrointestinal disorders. Overall, their likelihood of fulfilling the criteria for functional constiation, IBS, or functional dysesia was higher with an OR of three comared to their relatives without NF1. For each of the three conditions functional dysesia, IBS and chronic functional constiation, adults with NF1 had a higher likelihood of IBS after adjustment and a markedly higher both crude and adjusted likelihood of functional constiation comared to their relatives. Functional gastrointestinal disorders are common in the general oulation. In our study, we exlored and assessed the GI symtoms as functional gastrointestinal disorders, which enables us to comare the results to the literature. The revalence of subjects fulfilling the criteria for functional constiation was 14.9% among adults with NF1 and 4.4% among relatives. In comarable studies using the Rome III criteria, revalence rates in the general oulation of 4 7.6% are reorted [11 13]. Thus, the occurrence of GI symtoms corresonding to functional constiation seems Table 2 The revalence of gastrointestinal disorders within the grous and comared using the odds ratios Odds ratio,, crude Odds ratio,, adjusted for age and gender Functional gastrointestinal disorder a 33.1% (CI: ) 14.3% (CI: ,8) 2.97 (CI: ), (CI: ), Functional constiation 14.9% (CI: ) 4.4% (CI: ) 3.80 (CI: ), (CI: ), Irritable bowel syndrom 16.0% (CI: ) 7.7% (CI: ) 2.29 (CI: ), (CI: ), Functional dysesia 7.4% (CI: ) 3.3% (CI: 0 6.9) 2.35 (CI: ), (CI: ), a Any of the three; functional dysesia, IBS or functional constiation Legend: The revalence reorted within the grou of atients with NF1 and the control grou and comared using the odds ratio

4 Ejerskov et al. Orhanet Journal of Rare Diseases (2017) 12:139 Page 4 of 5 Table 3 The revalence for secific symtoms of functional dysesia Pain or discomfort in the middle of the chest (not related to heart roblems) 13.7% (CI: ) 6.6% (CI: ) Heartburn 12.6% (CI: %) 9.8% (CI: ) Feeling uncomfortably full after a regular sized meal Unable to finish a regular size meal Pain or burning in the middle of the abdomen 17.1% (CI: ) 4.4% 18.3% (CI: ) 4.4% 5.7% (CI: ) 3.3% (CI: ) higher among adults with NF1, both when comared to their relatives and to the general oulation. In our grou of adults with NF1, the revalence of IBS was 16.0%. This is close to the revalence found in two other Danish studies using the Rome III criteria in a self-administrated questionnaire to define IBS. One study found a revalence of 16% among year olds and another found a revalence of 10.5%. Even though the revalence of functional dysesia (7.4%) is close to that in the background oulation (7.7%) [14], early satiety was more common in adults with NF Legend: The revalence for secific symtoms of functional dysesia resent at least once er week within the grou of atients with NF1 and the control grou Table 4 The revalence for secific symtoms of irritable bowel syndrome Discomfort or ain 35.2% anywhere in the abdomen? a (CI: ) Discomfort or ain get better or sto after a bowel movement? More frequent bowel movements when Less frequent bowel movements when Looser stools when Harder stools when 25.1% (CI: ) 6.3% (CI: ) 12.7% (CI: ) 13.1% (CI: ) 11.4% (CI: ) Often hard or lumy stools 14.3% (CI: ) Often loose, mushy or watery stools 13.7% (CI: ) 16.5% (CI: ) 4.3% (CI: ) 7.7% (CI: ) 8.9 (CI: ) 7.7% (CI: ) 2.2% (CI: ) 4.4% 8.8% (CI: ) a At least two to three days a month Legend: The revalence for secific symtoms of irritable bowel syndrome resent at least most of the time within the grou of atients with NF1 and the control grou Table 5 The revalence for secific symtoms of functional constiation Fewer than three bowel movements a week Hard or lumy stools 15.4% (CI: ) Straining during bowel movements Feeling of incomlete emtying after bowel movements Sensation that the stool cannot be assed, (i.e. blocked) Press on or around bottom or remove stool in order to comlete a bowel movement Difficulty relaxing or letting go during a bowel movement 10.9% (CI: ) 2.2% 17.7% (CI: ) 20.6% (CI: ) 2.2% 5.5% (CI: ) 9.9% (CI: ) 13.1% (CI: ) 2.2% 4.6% (CI: ) 0% % (CI: ) 2.2% Legend: The revalence for secific symtoms of functional constiation resent at least often within the grou of atients with NF1 and the control grou than in controls. This could indicate delayed gastric emtying, either rimary or secondary to constiation. The strengths of our study are that all the invited atients have been assessed and given the diagnosis NF1 by a secialist hysician at our center; the use of standardized and validated questionnaires used for collection of data; and the use of relatives as controls by which variations in eating habits as a robable reason for differences should be minimized. Additionally, access to the Danish health system is free which means that atients from all socioeconomic backgrounds reresenting all NF1 severity grades are followed at our centre. The latter reduces the risk of selection bias. The study has some limitations. Differences in socioeconomic factors that make eating habits and the intensity of exercise suscetible cannot be excluded nor can unidentified morbidity of the atients. The Rome criteria define functional dysesia given that organic disease of the esohagus and the stomach has been excluded with a gastroscoy. Our knowledge of organic uer GI disease is limited to the information from articiants given in the questionnaires and the atients medical files. The revalence of functional constiation is greater among women and increases with age [11], and since the roortion of females were higher among atients and the controls were older than the atients we took the differences in age and gender into account in the analysis and reorted adjusted ORs. The resent study comrising adults with NF1 was insired by our revious ilot study among children with NF1 [6]. In that study, children with NF1 had a higher revalence of constiation, abnormally large diameter of

5 Ejerskov et al. Orhanet Journal of Rare Diseases (2017) 12:139 Page 5 of 5 the rectum and a larger roortion than exected had rolonged colorectal transit time. This may indicate that constiation develos early in the life of atients with NF1, and may be a lifelong illness if not addressed. Presumably, atients with NF1 are undertreated since 14.9% of atients were found constiated but only 4.6% atients were using laxatives. A study on gastrointestinal symtoms in children and adolescents with NF1 is awaited and further studies should focus on treatment of constiation and consecutive measurements of constiation characteristics. The athohysiology behind a higher revalence of GI symtoms redominantly correlated to constiation in NF1 is unknown. If constiation develos early in life as indicated by our revious ilot study, we would exect that it is caused by NF1 er se. This makes the term functional misleading with resect to bowel symtoms in NF1. It is well established that atients with NF1 often have abnormalities within the nervous system. Abnormalities within the enteric, the eriheral or the central nervous system could cause chronic constiation. Further studies are needed to determine whether constiation in NF1 is mainly associated with rolonged transit through the colon, blunted rectoanal reflexes or by a hyosensate rectum. However, the high revalence of early satiety found in our grou of atients with NF1 could indicate a generalized gastrointestinal motility disorder. Conclusion In conclusion, we found that adults with NF1 have a higher likelihood of having symtoms of constiation (adjusted OR 3.5). This deserves further attention in future studies and in clinical ractice. Constiation has consequences for quality of life [15]. Thus, rofessionals taking care of atients with NF1 should be aware of gastrointestinal symtoms. Abbreviations CRD: Centre for rare diseases; GI: Gastrointestinal; IBS: Irritable bowel syndrome; NF1: Neurofibromatosis tye 1 Acknowledgements We are grateful for the assistance from Bias, biostatistical advisory service, Deartment of Public Health, Aarhus University, Denmark. Funding Aarhus University, Health. NF Denmark - The Danish NF atient association. The Danish Medical Research Grant. The funding bodies have had no role in the design of the study, collection, analysis or interretation of the data nor in the writing of the manuscrit. Availability of data and materials The datasets generated and analysed during the current study are not ublicly available due ongoing studies on the datasets since the current study is a art of a thesis but are available from the corresonding author on reasonable request. Authors contributions Concetion and design: CE, KK, AH, JF. Data collection: CE. Data analysis and interretation: CE, KK, JO, AH. Manuscrit writing: CE, KK. Final aroval of manuscrit: All authors. Ethics aroval and consent to articiate The study was aroved by the Danish Data Protection Agency ( ). Informed consent was collected from atients. According to the Ethics Committee of Denmark, no aroval was needed for this questionnaire-based investigation. Consent for ublication Not alicable. Cometing interests The authors declare that they have no cometing interests. Publisher s Note Sringer Nature remains neutral with regard to jurisdictional claims in ublished mas and institutional affiliations. Author details 1 Centre for Rare Diseases, Pediatrics and Adolescent Medicine, Aarhus University Hosital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. 2 NIDO Danmark, Research in Education and Health, West Danish Hosital, HEV, Gl. Landevej 61, 7400 Herning, Denmark. 3 Deartment of Clinical Medicine, Health, Aarhus University, Incuba/Skejby, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark. 4 Deartment of Heatology and Gastroenterology, Aarhus University Hosital, Noerrebrogade 44 Bygn. 7, 8000 Aarhus C, Denmark. Received: 6 February 2017 Acceted: 8 August 2017 References 1. OMIM. Online Mendelian Inheritance in Man, OMIM. Johns Hokins University, Baltimore, MD. MIM Number: {162200}: {29/03/2013}: 2013; Available at: htt://omim.org/. Accessed 29 Mar Ferner RE. Neurofibromatosis 1. Eur J Hum Genet. 2007;15(2): Neurofibromatosis SD. Conference statement. National Institutes of Health consensus develoment conference. Arch Neurol. 1988;45(5): Duuis L, Nezarati MM. Neurofibromatosis tye 1 as an examle of autosomal dominant inheritance. Pediatr Dermatol. 2001;18(5): Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century ersective. 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