J Genet Counsel DOI 10.1007/s10897-015-9829-5

ORIGINAL RESEARCH

The Impact of Neurofibromatosis Type 1 on the Health and Wellbeing of Australian Adults Hilda A. Crawford & Belinda Barton & Meredith J. Wilson & Yemima Berman & Valerie J. McKelvey-Martin & Patrick J. Morrison & Kathryn N. North

Received: 2 November 2014 / Accepted: 24 February 2015 # National Society of Genetic Counselors, Inc. 2015

Abstract The complications of neurofibromatosis type 1 (NF1) are widespread, unpredictable and variable and each person’s experience of this disorder is unique. However, few studies have addressed the impact of NF1 from an individual’s perspective. This qualitative study aims to identify the ways in which NF1 impacts upon affected Australian adults. Sixty adults with NF1, with a range of disease severity and visibility participated in a semi-structured interview about the ways in which NF1 impacted upon their life and health. Data were analyzed using grounded theory methodology. Results indicated that NF1 impacts upon affected adults in five major ways: 1) cosmetic burden of disease 2) learning difficulties 3) concerns about the risk of passing NF1 to offspring 4) uncertain disease progression, and 5) pain. Participants identified the aspects of NF1 that bothered them the most, creating a hierarchy of NF1 concerns H. A. Crawford : B. Barton The University of Sydney, Sydney, NSW 2006, Australia H. A. Crawford The Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia B. Barton (*) Children’s Hospital Education Research Institute (CHERI), The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia e-mail: [email protected] M. J. Wilson Department of Genetic Medicine, Westmead Hospital, Cnr Hawkesbury Road and Darcy Road, Westmead, NSW 2145, Australia M. J. Wilson Discipline of Genetics, University of Sydney, Sydney, NSW 2006, Australia

within the cohort. Importantly, mildly affected adults shared many of the same concerns as those more severely affected. This study enhances our current understanding of the impact of NF1 in adulthood, and augments existing recommendations for the care of these patients. Keywords Neurofibromatosis 1 . Adults . Lives . Wellbeing . Cosmetic . Uncertainty . Learning difficulties . Pain

Introduction NF1 is a common single-gene disorder with an autosomal dominant pattern of inheritance and a minimum birth

Y. Berman Department of Clinical Genetics, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia Y. Berman Discipline of Medicine, University of Sydney, Sydney, NSW 2006, Australia V. J. McKelvey-Martin : P. J. Morrison School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, Co. Londonderry BT52 1SA, Northern Ireland, UK P. J. Morrison Northern Ireland Regional Genetics Service, Department of Medical Genetics, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK K. N. North Murdoch Childrens Research Institute, Royal Children’s Hospital, 50 Flemington Rd, Parkville, VIC 3062, Australia

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incidence of 1 per 2700 in which approximately 50 % of cases arise as a new mutation in the NF1 gene (de novo) (Evans et al. 2010). Characteristic features include café au lait patches (CALs) and Lisch nodules (Huson et al. 1988). Cutaneous neurofibromas arise in early adulthood and continue to develop throughout life. The number of cutaneous neurofibromas in any individual can vary in number from a few to thousands (Jett and Friedman 2010). Although benign, the appearance of cutaneous neurofibromas can cause major psychological distress (Ferner 2010). Complications of NF1 in adulthood include disfiguring and sometimes symptomatic plexiform neurofibromas, hypertension, gastrointestinal tumors, bone abnormalities, pain from neurological symptoms and an increased lifetime risk of malignancy (in particular malignant peripheral nerve sheath tumor [MPNST] and breast cancer) (Creange et al. 1999; Evans et al. 2012; Jett and Friedman 2010; Sharif et al. 2007). The most frequent neurological complication of NF1 is cognitive dysfunction, which is highly variable, affecting up to 80 % of children (Hyman et al. 2005; Lehtonen et al. 2013) and has also been reported in adults (Ferner et al. 1996; Granstrom et al. 2014). There is an increased risk for learning disabilities and other neuropsychological impairments such as deficits in attention and executive functioning (Pride and North 2012). Attention deficit hyperactivity disorder (ADHD) has been widely documented in NF1, affecting 30–50 % of children, and symptoms are reported to persist into adulthood (Mautner et al. 2012; Pride et al. 2012). Social, emotional and psychological problems also occur in adults (Pride et al. 2013; Reichardt et al. 2013; Wang et al. 2012). Collectively, these complications contribute to the morbidity of NF1 and negatively impact on academic achievement, employment prospects, quality of life and mental health (Kodra et al. 2009; Page et al. 2004; Wolkenstein et al. 2001). Hallmark features of NF1 include the unpredictability of the disorder throughout life, and variability in disease expression (Ferner et al. 2007). Despite complete penetrance, interand intra-familial inconsistency is common (Rieley et al. 2011; Sabbagh et al. 2009; Samuelsson and Axelsson 1981). NF1 is a progressive disorder, and even in adults where NF1 has not previously impacted adversely upon their health, severe complications can occur unexpectedly and may arise at any time throughout life (Ferner et al. 2007). Patients’ reports of their disease experiences are therefore an important consideration to understand the physical and psychosocial effects of a disorder (Chren 2010). Despite this, there are few qualitative studies that explore the impact of NF1 upon the life and health of adults. Previous studies have identified negative impacts on social networks, worries about the unpredictability of disease, and concerns related to the cosmetic appearance of NF1 (Ablon 1999; Barke et al. 2014; Benjamin et al. 1993; Hummelvoll and Antonsen 2013; Mauger et al. 1999; Smith et al. 2013).

Purpose of the Study The aim of this study was to examine the ways in which NF1 impacts upon the health and life of affected adults from an individual perspective. A qualitative approach was chosen to enable in-depth exploration of the life experiences of adults with NF1.

Method Participants Potential study participants were males and females with NF1 aged between 18 and 40 years who satisfied the diagnostic criteria for NF1 (Anon 1988). Affected patients or parents and relatives of children with NF1 attending one of the three hospital genetic clinics within the Sydney metropolitan area of New South Wales, Australia were approached directly by one of the investigators (HC) to participate in the study. The study was further verbally explained to adults and they were also given a study information sheet. They could enroll in the study when approached, or could contact the investigator by phone or email at a later date if they were interested in participating. A search of the NF1 databases of these three hospital clinics was also conducted and eligible patients were mailed a study invitation letter. In addition, an online study advertisement and the study information sheet was placed on the website of the support charity the Children’s Tumour Foundation of Australia (CTF Australia). Patients were excluded if they had a co-existing genetic disorder, did not speak English, or were mentally or physically unwell to participate in the study. Adults who had intractable hearing and/or vision deficits were also excluded, as this severity of sensory impairment would not be reflective of the experiences of most adults with NF1. Furthermore, the study was unable to support the additional communication needs of these individuals. Ethics approval for the study was granted by the relevant hospital and university ethics committees. Prior to enrolment, written informed consent was obtained from all participants according to the Declaration of Helsinki, and participants did not receive any incentive (World Med Association 2013). Disease Severity and Visibility Current overall disease severity was rated in participants from medical files, consultation with clinicians and patient history using the Riccardi scale, a 4 point severity scale ranging from minimal to severe (1 to 4) (Riccardi and Kleiner 1977), (Table 1). Prior to determining overall disease severity in all participants, two investigators (MW & HC) independently rated 20 of the same participants to establish inter-rater reliability and a high intra class coefficient equal to 0.93 was obtained. The remaining cases were rated by one investigator

Impact of NF1 on the Health and Wellbeing of Adults Table 1 Anatomical structural and functional disease severity of neurofibromatosis 1

Data Collection: Procedures and Interview Questions

Severity grade

Features of severity grade

Minimal grade 1

Absence of features, no compromise of health or well-being. Café-au-lait spots, iris Lisch nodules. Enough stigmata to make the disease a source of concern but without significant compromise of health. Facial café-au-lait spots, modest number of cutaneous or deep neurofibromas. Unequivocal compromise of health and wellbeing but the compromise can be reasonably well managed, is not intractable and will not lead to a shortened life span. Broad category spanning a large age range. Serious compromise that is intractable and is managed or treated only with difficulty. Mental retardation (intellectual disability), drug resistant seizures, brain tumors, malignant tumors.

Data were collected in 2012 and 2013. Eligible participants who consented to the study participated in a semi–structured face-to-face interview with one of the investigators (HC). Each participant was asked the following two open-ended questions: BCan you talk about the ways NF1 affects your health?^ and BCan you talk about the ways NF1 affects your life?^ These broad questions led to further discussion and guidance of questions by the interviewer (HC), to capture individual experiences and important issues, according to participants’ willingness to share their story. Initial analysis resulted in interview questions evolving, allowing interpretation to continue as the data were collected. As the interviews progressed it became evident when making data comparisons, that participants’ concerns about NF1 were numerous, complex and variable. Therefore, the interview schedule was extended to include asking participants, BWhat bothers you the most about NF1?^ as this was felt to be important in building emerging conceptual interpretations of the ways in which NF1 affected adults’ health and lives. Interviews lasted between 30 and 80 min. From a total of 94 interviews conducted, 60 were selected using a purposive sampling strategy which reflected grounded theory research methodology (Sbaraini et al. 2011), and demonstrated the age range, mode of inheritance, disease severity and visibility of the cohort. Thirty-nine interviews were conducted at a hospital clinic, 19 at participants’ homes and two via Skype ® where participants lived interstate. Interviews were audio recorded and were transcribed either by one of the investigator’s (HC) (n=15) or by a transcriber (n=45). Carefully selecting

Mild grade 2

Moderate grade 3

Severe grade 4

Adapted from Riccardi and Kleiner (1977)

(HC). In order to identify those participants with learning difficulties, self-reported childhood schooling was classified (Table 2). Lastly, one of the investigators (HC) used the Ablon visibility scale to grade the outwardly visible signs of participants’ NF1 as mild, moderate or severe (Ablon 1996) (Table 3).

Table 3 Table 2

Ablon visibility scale, neurofibromatosis 1

Self-reported schooling of adults with NF1

Self-reported schooling by grade

Features of grade

Minimal grade 1 Mild grade 2

No learning disability reported. No educational assistance but participants report they found learning difficult, felt they struggled with learning at school, or felt they were at the bottom of a mainstream class. Attended mainstream school but struggled with learning and received additional assistance in class, or were taken out of classes into smaller groups, or teacher’s aide. Attended mainstream school, received additional assistance at school and / or home, consistently struggled with work during most or all of their school years and failed to progress despite additional support.

Moderate grade 3

Severe grade 4

Severity grade

Features of severity grade

1. Mild

Essentially no visible tumors outside of normal clothing areas; gait and posture appear unremarkable when casually observed (this allows for heavy coating of neurofibromas on the body and some minor skeletal symptoms). Some tumors on the neck, face, hands, mild scoliosis or other skeletal features without noticeable limp. Numerous tumors on the face, optic glioma (tumor) that has affected sight and eye socket, severe scoliosis or skeletal features with noticeable limp.

2. Moderate

3. Severe

Ablon (1996). Ratings are based on the appearance of the person fully dressed and how readily symptoms could be perceived in impersonal interaction. Many of those who display no visible tumors while wearing normal clothing could have numerous tumors or cafe au lait patches on the body, which would be visible in intimate situations

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participants in a purposive sampling manner enabled researchers to gain access to the richest data. In this sense saturation took place in that all of the concepts in the theoretical developments were well understood and could be supported by the data (Charmaz 2006, p.113).

Data Analysis The interview transcripts formed the basis of a grounded theory analysis, although the evaluation did not extend to the development of theory. Constructivist grounded theory was chosen as an appropriate methodology to examine the impact of NF1 upon the health and lives of adults with NF1 (Charmaz 2006; Sbaraini et al. 2011) as it facilitated the examination of how and why participants construct meanings in specific situations, and considers that both the data and the analysis are socially constructed. Analysis occurred in the following sequence: Interview transcripts were subjected to line-by-line coding by one investigator (HC). A second investigator (BB) coded transcripts independently and then both investigators met to discuss their analysis. In the analysis, decisions were made about which line by line codes made the most analytical sense and represented the data incisively and fully; memo writing also formed part of the analysis (Montgomery and Bailey 2007). Five major focused codes were developed, broadened and expanded; the situations in which focused codes appeared were examined, when they changed and the relationships among them. These five focused codes were evident across all transcripts, formed the foundation of explication of frameworks of meaning in the data, and informed a literature search which enabled us to situate our conceptualization within the context of the existing body of literature (Charmaz 2006, p.168; Sbaraini et al. 2011). This constant comparative method enabled the analysis to explain where more abstract concepts were related and addressed the research question, BWhat are the ways in which NF1 impacts on the health and lives of affected adults?^

Results The median age and disease severity of adults were 29 years (IQR=10) and 3 (IQR=1), respectively. Other clinical and demographic information of participants including gender, mode of inheritance, age categories, level of education, employment, marital status, disease severity and visibility and self-reported schooling are reported in Table 4. Results of the analysis of the transcripts and theoretical codes are provided below.

Table 4 (N=60)

Clinical and demographic characteristics of adults with NF1

Characteristics

Participants n (%)

Gender Female Male Inheritance

35 (58) 25 (42)

Sporadic Familial Age range 18–40 (yrs) 18–25 26–30 31–35 36–40 Level of education Less than high school graduate High school graduate Post high school educationa University graduate or higher Employment Full time employed Part time employed Unemployed Female at home with children Student Marital/partner status Married/partnered Single Separated Overall disease severity (Riccardi scale) Grade 1 minimal Grade 2 mild Grade 3 moderate Grade 4 severe Visibility (Ablon scale) Mild Moderate Severe Self-reported schooling by grade Grade 1 (no learning difficulty reported) Grades 2, 3 or 4 (learning difficulty reported)

36 (60) 24 (40) 20 (33) 13 (22) 15 (25) 12 (20) 20 (33) 40 (67) 13 (22) 15 (25) 30 (50) 8 (13) 7 (12) 8 (13) 7 (12) 32 (53) 25 (42) 3 (5) 10 (17) 17 (28) 26 (43) 7 (12) 28 (47) 17 (28) 15 (25) 20 (33) 40 (67)

a

TAFE Technical and Further Education; Armed Forces, Australian Apprenticeships

Code 1. The Visibility and Cosmetic Appearance of NF1 Cosmetic Disfigurement The cosmetic burden of NF1 was reported by women and men across all severity grades and ages. For many participants the

Impact of NF1 on the Health and Wellbeing of Adults

visible appearance of NF1 was the worst aspect of the condition and often caused emotional distress. BJust cosmetically. I don’t particularly like the lumps but there’s nothing I can do about that. ^ male 32, mildly affected BI pretty much don’t go out in public like swimming and stuff like that unless I cover up, unless I wear a rash vest or stuff like that that.^ male 32, moderately affected Many participants chose clothing specifically to cover the physical signs of NF1, restricted their clothing choices or grew their hair to disguise NF1. Neurofibromas and cafe au lait spots were frequently associated with feelings of embarrassment, shame and self-consciousness. One woman felt she was missing out on family life because of self-imposed restrictions on clothing to cover NF1: BThis [participant points to the blouse she is wearing] is probably the lowest thing I will ever wear because I am conscious of it. It’s just very hard. I’m very wary about when I go to a pool; I try to avoid the beach too. There is no way you could ever wear swimmers. Just doing those fun activities with your kids, I feel I’m missing out on them…I do cope with it on a day-to-day basis. Sometimes, say, you have a function on and what you wear… that’s when it brings you down; like why can’t I be like an average person and wear what I want? I could never wear a cocktail dress. I just can’t. Like you think, what have I done so wrong to have this?^ female, 39, severe visibility In women and men across all overall severity and visibility grades, the cosmetic appearance of NF1 affected their selfconfidence. BI don’t think it affects me health wise, I think it affects me confidence wise because of the whole like, always having to cover it up because it’s not that great to look at.^ female, 22, mild visibility

Strangers Commenting on the Cosmetic Appearance of NF1 Participants experienced situations as they went about daily life outside the home, where strangers approached them, made comments or taunted them about their physical appearance or stared, or touched their skin. This was a distressing and humiliating experience. BLike I went shopping one time … and the shop assistant asked me, ‘Why are you out? You have the measles and you are spreading it.’ I just turned around and said, ‘Look

it’s not contagious, it’s a skin condition and it’s not contagious.’ But I walked out of there and I burst into tears.^ female, 39, severe visibility In contrast some participants were less bothered by cosmetic disfigurement. A young woman with a facial plexiform neurofibroma commented on how NF1 affected her cosmetically and how she came to accept her appearance. BBecause my face is asymmetrical…you get asked all the time… not that it bothers me and sometimes its just like, the way that they ask… some people are abrupt about it and some people are just genuinely interested. Like it’s never affected me making friends in a certain sense. I did get bullied a bit at school like. I did get called ‘shovel face’ when I was in school which was, you know, fairly mean. For a while you know I did get a bit weird about my café au lait spots even though I don’t go to the beach that often. But I just don’t care anymore, I just do whatever I want to, I just show people my face, you know it doesn’t bother me.^ female, 22, severe visibility For several participants, the cosmetic appearance of NF1 was perceived to affect employment prospects. BI got sick of being turned down for jobs… I’d go into an interview and sit down, I’d be very nicely dressed, you know? And then they’d just look at you, and you’d know you hadn’t got the job because of the way you look.^ female, 29, moderate visibility

Finding Partners and Disclosing the Diagnosis of NF1 Some men perceived NF1 affected them socially and was the reason for their inability to find partners and form relationships. They attributed rejection to disclosure of their diagnosis of NF1. For those in their late 20’s and 30’s, the inability to find partners was linked to a feeling of being left behind in the normal stages of life. Participant: BSeeing everyone else having fun and enjoying life and I’m not…. sort of thing… its sort of… I just sort of… being… drifted by like…. all my friends are married and all of them are starting to get a house together and I’m not, and that’s hard.^ Interviewer: BWhy is that, do you think?^ Participant: BCan’t form a relationship I think… yeah.^ Interviewer: BWhat’s the reason for that, do you think?^ Participant: BJust self-confidence in meeting people. Meeting the potential partner or whatever…yeah, that’s got a lot to do with it.^ male, 33, moderate visibility

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While none of the women explicitly reported difficulties finding partners this does not mean that they did not experience these difficulties. Women tended to talk about their relationships and rejection within those relationships. One woman’s experience of rejection in a relationship came as a result of her partner at the time meeting her affected mother who had a high cosmetic burden of neurofibromas. BI was in the last relationship and the person didn’t want to be with me because I had NF, he met my parents, and mum’s really bad, it’s really bad with mum. He didn’t want to be with me after he met mum basically.^ female, 29, moderate visibility

Sexual Relationships Women appeared to have less difficulty finding partners, however they expressed negative feelings about their body image and concerns about sexual intimacy; in contrast, none of the men discussed intimacy. Women harbored feelings of shame and revulsion and anticipated rejection as a consequence of body neurofibromas becoming visible to a partner in intimate situations. BMy physical appearance is probably the most obvious one. I guess the by-product of that is that psychologically I fear being intimate with a man. I’m scared that when we get our clothes off he is going to see it and freak out. It did affect a relationship, there was a really lovely guy I met, but I found it so difficult to be really open about that.^ female, 29, moderate visibility

Lack of Awareness and Knowledge of NF1 in Society Lack of awareness and understanding of NF1 in society was mentioned by participants. This led to some individuals finding themselves in situations where they were drawn into explaining NF1 to others; the visible symptoms of NF1 were usually the trigger for unwanted questioning. One participant commented that this was a situation to be avoided as it was like, Bopening a can of worms.^ Code 2. Cognition and Behavior Difficulties Learning and/or attention difficulties were self-reported in two-thirds of participants. Some individuals with learning difficulties who were mostly in their 30’s had vivid recollections of negative school experiences. These were related to school failure and were often accompanied by bullying and teasing and were associated with low self-esteem and negative selfimage.

BI used to get picked on all the time at school… I was so depressed at school it wasn’t funny. It was the worst time of my life.^ male 30, moderate severity, moderate learning difficulties One man proposed that a poor understanding of how NF1 impacts on learning explained the lack of support he received when he was at school. Interviewer: BWere there ways in which school was a struggle?^ Participant: BOh shockingly. I hated school. Teachers didn’t care. No it wasn’t that they didn’t care, they didn’t understand. I look back now and I think that I wish I had a teacher that would sit and just explain things a bit better to me. But I understand …there wasn’t the help there that there could be now. So I just left at the end of year nine and refused to go. Just got a job. I would say I definitely needed help. I would have loved it.^ male, 38, moderate severity, moderate learning difficulties In contrast, some participants who did not report learning difficulties described mostly positive school experiences, while others remembered a struggle to achieve average grades at school. Participants who found school difficult and who later participated in tertiary education programs reported that the adult learning environment was a more positive experience. One woman perceived that this was due to being able to adapt better to learning as she became older, and that the mature learning environment was easier.

Aspirations and Self-Esteem There was an expressed lack of belief amongst individuals in what they could aspire to and achieve in life. Other emotional effects such as anxiety were reported. The legacy of school failure continued into adulthood, affecting further education, career and employment choices and opportunities. One woman recalled her school experiences and how they affected her in adult life: BI failed school, miserably…It’s not just school performance, it’s the whole thing because once you have that issue with the learning, it affects everything. Affects self-confidence, and that’s what destroyed me at school....my schooling was that bad it affected my self esteem that much that I left school, I got a job as a cashier, and then I went and got married cause I thought, I’m not capable of doing anything else.^ female, 39, moderate severity, moderate learning difficulties

Impact of NF1 on the Health and Wellbeing of Adults

Another man felt his learning difficulties and low selfesteem affected him in adulthood. BMy self-esteem is nowhere near where it used to be. I just lack confidence. Fear of failing all the time, do you know?^ male 33, moderate severity, moderate learning difficulties

Code 3. Inheritance There was accurate awareness amongst adults (with and without children), that NF1 could be passed on to their offspring and disease severity could not be predicted. At least four participants had chosen to undergo either prenatal genetic diagnosis (PND) or pre-implantation genetic diagnosis (PGD), and other participants expressed similar intentions. BWe decided on IVF because I couldn’t face a pregnancy and having to decide to terminate. But we decided we didn’t want a child with NF1. I’m pretty ok with it and if it was like me that would be ok, but if it was severely affected with it…^ female 28, moderate severity Younger participants felt that the risk of passing NF1 on to offspring would be an issue in the future when they found partners, but not something they were overly concerned with in the present. Mildly affected participants understood that children with NF1 could be more severely affected than their parents.

Worries about their Child with NF1 A number of mothers but not fathers expressed concerns about which symptoms and complications of NF1 would develop in their affected children.

Code 4. Unpredictable Disease Progression throughout Adult Life The unpredictable, unknown course of NF1 was a source of concern for many participants, and the most frequently expressed worry was the growth of neurofibromas and other tumours. BNo just fearing of what’s to come. Just where they might grow. The eyes, the ears, maybe the brain.^ male 34, moderate severity BProbably the unknown more so that anything that’s happening at the moment. Probably more so, you know how many more lumps am I going to get, are they going to turn cancerous or you know grow on the spine or anything like that, so that’s probably the most concern health wise. It’s always at the back of my mind but it’s certainly not front of mind, so I just get on. male 39, mild severity

Acceptance and Awareness of NF1 as a Life Long Disorder

Several mothers expressed worries about having additional children. For one woman, the emotional effects of PND resulted in a decision not to have another child.

Many participants of all ages referred to NF1 as being, Bpart of them.^ One participant, who had a limb amputation in childhood because of pseudoarthrosis, self-rated his disease severity as mild, as his prosthetic limb allowed him to function normally in his working and family life. There was also recognition that NF1 is a life long disorder. Few participants reported feeling angry about having NF1. One woman felt emotionally upset, questioning what she had done to deserve a severe neurofibroma burden. Others expressed hurt and annoyance at having NF1, but had a determination to get on with life that overcame those feelings. Overall there was a stoic attitude to living with NF1, not letting the disorder take over life, and not being held back in life.

BOnly that I’d really like to have another child, but it’s just too much for me I think. I just don’t want to put myself through it again… because I would hate to have to terminate a pregnancy. It makes me sad thinking about it, and I just don’t want to have to make that choice. And I’ve got two beautiful kids so… [participant cries] sorry, I didn’t mean to get emotional.^ female 32, mild severity

BI sometimes think, it’s a bit unfair, like why was it me out of everyone else in the family? But it’s not gonna consume me because I’m not gonna let it. Sometimes I feel annoyed about it all or I worry a bit about the lumps but not particularly, there’s nothing I can do about it so…You’ve either got to… you’ve just got to get on with it…. I can’t change it, you just have to deal with it.^ female 39, moderate severity

BThere is a 50/50 chance that I could pass it onto my children and they could be a lot worse than me. I wouldn’t really want them to go through what I have been through, and I have a very mild case. For them to be worse than me and to have more set backs and difficulties than I have had....^ male 31, mild severity

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In some mildly affected participants who perceived that NF did not affect them, there remained a constant awareness of the presence or potential consequences of NF1.

by men were associated with lack of success in forming relationships and in one man, learning difficulties. Hierarchy of NF1 Concerns

BNo you know it’s more awareness. I’ll still do something, it just hurts me that I do have something different and I’m not like everyone else on the beach but other than that not greatly. I’m always aware of it, always every day you’re aware of it.^ male 39, mild severity Physical and Mental Health Participants across all severity grades felt NF1 did not have negative effects on their general health. However, the exception to this was participants who were affected by chronic pain. To a much lesser degree, itching and fatigue were also reported as negative health effects. Many participants reported their general health was good. BThere is nothing wrong with me. I’m not sick or anything…I seem to be a lot less affected if affected at all.^ female 20, moderate severity BI don’t feel it affects my health at all, I feel healthy.^ male 34, moderate severity Most participants felt they were not held back doing what they wanted in life because of the physical effects of NF1 on their health. A young woman with an optic pathway tumor remarked, BI don’t really have any problems… oh, I’m blind in one eye…that’s not really stopped me from doing anything.^ female 27, moderate severity Code 5. Pain For those who had pain, this was severe in several participants and impacted significantly upon health and daily functioning, and was associated with low mood and depressive symptoms. Some participants felt NF1 pain was impossible to control. BThere are times when I feel quite down but I try not to think about it but there are certainly bad days. Especially when I have pain that I just can’t get it off my mind.^ female 27, severe disease BJust pain. Just constant pain. I have bad days. I have really bad days where I am depressed.^ female 26, severe disease A number of participants reported emotional symptoms such as anxiety, stress and low mood. In women, these symptoms were associated with pain. Emotional symptoms reported

When participants were asked what bothered them most about NF1, the most frequent concern was the presence of visible cutaneous neurofibromas particularly on exposed areas of the body that could not be hidden such as the face, neck and lower arms. There were also worries about neurofibromas increasing in number and size, and where on the body they would grow. BIt would be the lumps. If it was just the brown marks I wouldn’t worry at all, but it’s the lumps that keep growing. That’s the biggest issue…it’s a bit scary. I don’t want any to come all over my face… that would be a worry. If it was just hidden under clothes on your stomach and back I wouldn’t worry. But when it comes on your arms and legs and your neck it is a worry. Yeah, it is a worry.^ female 36, moderate severity Several mildly affected men reported being most bothered by the cosmetic affects of NF1. BThe lesions side of it. Just the marks and the birthmarks, I know it’s superficial sometimes you know.^ male 32, mild severity The second area of greatest disturbance was learning difficulties. BI don’t find it affected my health over the years. It’s more like the learning side of things, I felt like it didn’t hold me back fully, but some things I just didn’t understand and otherwise I had to ask to have things repeated a couple of times. I think it’s just the way I interpret things, I interpret them a bit differently to other people.^ male 31, mild severity For those participants who had chronic pain, this was the complication of NF1 that bothered them most. The risk of having an affected child was also a concern but one where adults believed they had some control. BTo me the worst part is the tumors and the surgeries to remove them. Because I’m now well informed about the decisions I have to make about pregnancy it’s not a concern but not really an easy or a cheap fix, but it’s something, there’s a way around it. I can’t stop myself getting tumors, but I know I can stop children having NF.^ female, 23 moderate severity In those adults who had severe disease, a minority found the effects of NF1 so great that they were unable to identify a

Impact of NF1 on the Health and Wellbeing of Adults

feature of greatest concern, as all features were equally bothersome and distressing. In contrast, minimally and some mildly affected individuals reported that little or nothing bothered them physically about NF1, however in their thoughts there remained a constant awareness of the disorder and concerns about disease progression, potential symptoms and the risks of passing NF1 on to their offspring.

Discussion This is the first study to describe the impact of NF1 on the life and health of variably affected Australian adults. The most significant impact of NF1 on adults was in the following five areas: 1. Cosmetic burden of NF1 Previous studies in conditions other than NF1 have shown that disorders that affect the skin and change appearance can result in negative emotional, psychological and functional effects (Chren 2010; Krueger et al. 2001; Lasek and Chren 1998; Odonnell et al. 1997). Similar findings have been demonstrated in NF1, where cosmetic visibility negatively affected quality of life (Kodra et al. 2009; Page et al. 2004; Wolkenstein et al. 2001), and appearance concerns were found to be highly prevalent in women with NF1 (Smith et al. 2013). In this study, we found that many participants across all grades of visibility and disease severity were bothered by the cosmetic signs of NF1, and its affect upon their appearance. The growth of cutaneous neurofibromas (actual or feared) bothered adults the most. Conversely, a smaller number of participants with moderate to severe visibility appeared to have accepted their cosmetic appearance suggesting that they may have a more positive body image and may cope better with the visible signs of NF1. It might be assumed that individuals with mild visible cosmetic signs of NF1 would be bothered by the cosmetic impact less than those more severely affected, however we found this not to be the case; indeed it is recognized that the visibility of a disorder affecting the skin may not be the same as the burden experienced by the patient (Chren 2012). In addition, we did not find gender differences, with men and women equally bothered by the appearance of NF1 amongst our participants. This is in contrast to a previous study conducted in Norway where the appearance of NF1 was a major concern for women, whereas men expressed little concern about the visible manifestations of NF1 (Hummelvoll and Antonsen 2013). Our findings may reflect the body image concerns of Australian men, a greater awareness of male body image ideals and different climates (Agliata and TantleffDunn 2004; Fildes et al. 2014). As a mechanism to cope

with the visibility of NF1, men and women explained how they dressed specifically to conceal cutaneous neurofibromas. Such action also enabled participants to avoid having to explain NF1 to others. Similar findings regarding concealment have been found in another NF1 study (Benjamin et al. 1993). In the area of employment, several women felt discriminated against in job interviews because of the visibility of NF1. Adults with other disfiguring medical conditions have also reported that they felt their appearance negatively impacted upon their likelihood of being employed (Sarwer et al. 1999). Consistent with this, studies of healthy adults have found that being physically attractive increases the chances of successfully securing employment (Shannon and Stark 2003; Tews et al. 2009). For those adults with moderate to severe visibility, they perceived that their appearance negatively influenced their ability to secure employment and their prospects for promotion. The impact of the visibility of NF1 extended to adults’ capacity to form relationships. Men reported NF1 caused them difficulties socially in finding partners. In a previous study, the social lives and relationships of men with NF1 were reported to be different from those of women, with some men withdrawing from social life in young adulthood (Ablon 1996; Pride et al. 2013). In this study, women did not appear to have difficulty finding partners. However, in situations of physical intimacy where body neurofibromas were exposed, women reported a negative body image, felt self-conscious and feared rejection. This is similar to another NF1 study where women experienced sexual/body self-consciousness about their appearance (Smith et al. 2013). Men did not report these same feelings; this could have been because of reluctance to discuss this subject with the (female) interviewer, or because men did not have the same feelings of self-consciousness as women. Our findings are consistent with other studies of people with visible disfigurement, where appearance related concerns were associated with difficulties forming relationships or with sexual partners, and the development of low self-esteem and a negative body image (Rumsey and Harcourt 2004; Thompson and Kent 2001). 2. Learning difficulties An individual’s school years are fundamental for educational preparation but also for social interaction and development (Ablon 1999, p. 45). Deficits in cognition and social functioning have been identified in children and adults with NF1 (Ferner et al. 1996; Pride et al. 2013). These deficits can create hardship throughout school life for affected children and adolescents, with learning disabilities reported to affect later achievement and unhappiness at school (Benjamin et al. 1993). Adults with NF1 frequently recall painful school experiences including harrowing teasing and social assaults

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(Ablon 1999, p.47). In our study, older participants reported feeling depressed, unhappy and inadequate as well as being misunderstood, and labeled by teachers as lazy. Learning difficulties continued to hinder participants in adult life, in career choices and in seeking employment, but also in their day-to-day experiences of learning new things. Adults reported feelings of low self-esteem and self-confidence, which they felt to be consequences of learning difficulties. Overall, older adults aged in their thirties had worse school experiences than those in their twenties. This may suggest improved awareness of NF1, or changes in the way bullying is addressed in schools. One encouraging finding is that tertiary education was reported as a different and more positive learning experience than high school. Moreover, participants did not report the same negative experiences in the workplace as they did in school. Similar to rates reported in a recent study (Granstrom et al. 2014), almost two thirds of participants self-reported learning difficulties. There were striking differences in the school experiences reported; some adults found school was a struggle, while others who did not find learning difficult reported largely positive school experiences. This finding lends support to the early identification and treatment of NF1 learning disorders in school (Lehtonen et al. 2013). Overall, the levels of participants in employment, in full time education, as well as participants graduating from high school and entering tertiary education suggests that learning difficulties in NF1 are not necessarily a barrier to achievement (Table 4). 3. Inheritance The absence of genotype-phenotype correlations in NF1 means that the clinical severity of the disease in any affected pregnancy cannot be predicted (Ferner 2007). Although there is a 50 % risk of passing NF1 on to offspring, the likelihood of having a severely affected child is estimated to be about 1 in 12 (Ferner et al. 2007; Terzi et al. 2009). In this study, concerns about the risks of passing NF1 on to children fell into two groups; older adults and younger individuals who did not yet have children. The younger group was aware of the available reproductive choices, with most being informed at a genetic clinic consultation. Some participants had already made a decision to avoid passing NF1 on to offspring when planning their family. All those who discussed having children in the future or who were planning a pregnancy, indicated that they would undertake interventions such as PND or PGD to avoid passing NF1 on to their offspring. No participants expressed a willingness to undertake a pregnancy without intervention. This was not the subject of investigation in the study, but is worthy of further research. Of those participants who were planning to have children, several were undergoing or had undergone PGD. Two participants reported having undergone PND; one

was a woman who after having two unaffected children chose not to have further children, due to the emotional stress of possibly having to make a decision whether to terminate a pregnancy or not. Similarities are also found in an analysis of demand for prenatal diagnosis among French patients with NF1, in which increased demand was associated with a younger age group who did not yet have children, who had been followed up in clinics and who had higher education. Disease severity was not associated with demand for prenatal diagnosis (Farhi et al. 2008), a finding similar to this study. Findings are also comparable to a recent study of Marfan disease, a disorder also characterized by phenotypic variability, in which the majority of participants were in favor of prenatal diagnosis (Coron et al. 2012). Of those participants who had affected children, similar to previous studies we found that mothers worried how the disease will progress (Hummelvoll and Antonsen 2013). Concerns about affected children’s future wellbeing were more often expressed than feelings of guilt at passing NF1 on to their offspring. Overall, findings of this study demonstrated that adults had a desire to avoid passing NF1 on to children, an awareness and understanding of inheritance risk in NF1, and an interest in PND or PGD. 4. Uncertain disease progression In NF1, uncertainty exists around life long and ongoing disease complexity (Skirton and Bylund 2010). In this study, the unknown, uncertain and unpredictable progression of NF1 was a concern to adults of all ages and severity. It was notable that in most cases worries about what could happen in the future were of greater concern than current disease symptoms. Many participants, some of whom had severe physical manifestations of NF1, perceived that NF1 did not impact upon their health and did not hold them back in life. Even for minimally affected individuals there was a high level of awareness of potential complications in NF1. The greatest source of worry amongst participants was the potential growth in number and size of cutaneous neurofibromas, particularly those growing on the face or other exposed areas. Many participants expressed particular concern about the uncertainty as to when and where new visible lesions may develop. These findings are similar to another study of NF1 where fears related to disfigurement were the primary concern, despite the coexistence of other problems of greater clinical severity (Ablon 1999, p. 100). Uncertainty is a central feature of many chronic disorders and may be best managed by strategies that promote coping with, rather than reducing uncertainty (Babrow and Kline 2000). This is appropriate in the context of NF1, where the meaning of uncertainty can change with disease progression throughout life. Theories of communication and uncertainty suggest that

Impact of NF1 on the Health and Wellbeing of Adults

adaptation to chronic uncertainty can occur over time through developing structures or routines (Brashers 2001); in NF1 these include encouraging health surveillance and seeking advice for new symptoms (Radtke et al. 2007). Participants in this study were determined to, Bmake the best of things,^ even though there was a perception that nothing could be done for the clinical symptoms of NF1. This suggests a capacity for acceptance of NF1 in some adults, and reinforces the idea that healthcare practitioners may have a role in supporting adults as they adapt to living with uncertainty (Skirton and Bylund 2010). 5. Pain Pain is a significant cause of morbidity in NF1 and was found to be a disabling concern in a study of neurological complications in adults with NF1 (Creange et al. 1999). One quarter of participants in this study reported pain. With the exception of pain associated with MPNST, the source of pain in NF1 is mostly benign but can be variable according to its origin and can be difficult to treat (Korf and Rubenstein 2005, pp. 223–224). In this study, participants reported back pain and headaches; one female lived with headaches on a daily basis. Another study reported headache, back and also neurofibroma pain which were common, chronic and debilitating yet inadequately managed symptoms of NF1 in adults (Oates et al. 2013). In this study, there was a gender difference, with significantly more women reporting pain than men. It may be that men underreported pain, or that the pain experiences of men were different to that of women. Furthermore, it has been suggested that a psychological or depressive component should be considered in patients with NF1 who have pain, as there is evidence that a higher prevalence and severity of pain exists in patients with depressive symptoms (Bair et al. 2003; Creange et al. 1999). In this study, three female patients who had severe intractable tumor related pain reported effects on mood. Psychological therapies such as Acceptance and Commitment Therapy may be beneficial in helping adolescents and young adults with NF1 cope with chronic pain (ClinicalTrials.gov 2012)

Hierarchy of NF1 Concerns The principal concern amongst participants was cosmetic neurofibromas, followed by learning difficulties. In those patients with severe pain, this was the symptom of NF1 that bothered them most. Mothers expressed concerns about the progression of NF1 in their affected children. Across all age groups and gender, there were hypothetical concerns, such as worries about future disease progression, and concerns in mildly affected individuals about the risk of having severely affected children.

Implications for Practice Current guidelines provide a framework for counseling patients and families with NF1 (Radtke et al. 2007), and results of this study increase the body of knowledge about the specific impacts of NF1 on the life and health of affected adults. Of particular significance, is the awareness that each individual with NF1 may harbor a personal hierarchy of concerns and that even where adults share the same symptoms, the impact may differ from person to person. Our findings also suggest that the impact of cosmetic burden in NF1 should not be underestimated in any patient, regardless of gender, disease severity or visibility. The cosmetic burden of CALs and cutaneous neurofibromas in NF1 is an area of patient care that may be overlooked by clinicians due to the absence of any associated risk of mortality or medical morbidity. The emotional effects of learning difficulties may persist into adulthood and early intervention and educational support where required, seems to be important to promote positive school experiences, foster self-esteem and self-confidence. Chronic uncertainty is an unavoidable feature of NF1; adaptation to uncertainty may be possible in some individuals and or families, and psychological interventions may assist some families to cope with uncertainty. Adults may worry about passing NF1 on to offspring, and may wish to discuss the reproductive choices available to them. This may be the one area where uncertainty can be reduced and patients may be empowered to make informed decisions. Lastly, health professionals should be aware that some individuals with NF1 live with intractable pain; patients should be encouraged to seek medical advice to ensure NF1 associated pain is investigated and appropriately managed. Study Strengths, Limitations and Future Research The adults who participated in this study may be a self-selecting group with a higher level of education and potentially better coping skills than other affected persons. Those who chose not to participate may have different experiences. Women were more willing to participate than men; however this has been found in other studies of NF1 (Page et al. 2004). In addition, the research was limited to one age group; the life experiences of older adults may be different. A particular strength of the study is the wide recruitment base, which included relatives of probands, some of whom had never come to medical attention, thus facilitating the inclusion of mildly affected adults. This gave a depth to the study allowing new insights across a wider spectrum of disease severity than other studies which recruit from hospital centers, and more accurately reflects the natural history of NF1 (Sorensen et al. 1986). A key finding of this study is that the effects of visible cutaneous neurofibromas on appearance are at the heart of NF1 disturbance in the lives of adults across all grades of disease severity. Future research is needed in developing

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effective cosmetic treatments, and ensuring that existing therapies are available to patients with NF1, as our study suggests this may have the greatest potential to have a positive impact on the lives of adults. In many individuals cosmetically corrective medical treatment is currently not possible, therefore other psychotherapeutic interventions may be appropriate and may assist patients in developing coping skills to manage this most distressing aspect of the disorder. However there is a lack of reports of any such interventions in this patient group to date.

Conclusion This study offers a unique perspective on the ways in which NF1 impacts upon the life and health of affected adults across the spectrum of disease severity and visibility. Of the many potential impacts of NF1, some may cause greater disturbance for each affected adult than others. The primary areas of concern to adults in this study were disfiguring cosmetic neurofibromas, followed by learning difficulties. Importantly, results of this study challenge assumptions that more severe and/or visible NF1 implies a greater impact on the individual. In this study we found that mildly affected adults equally experienced significant negative effects of NF1 as those more severely affected. These key messages offer new insights into our understanding of NF1 in adulthood, and could enhance existing guidelines for the care of these patients. Acknowledgments The authors wish to sincerely thank the individuals and families who gave their time to participate in this research. This study was supported by a research grant, the Wingfield George Anderson Bequest from The University of Ulster, Coleraine, Northern Ireland, United Kingdom (Ms Crawford) with additional funding by the Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, NSW, Australia. Funding This study was funded by The Wingfield George Anderson Bequest, Ulster University, Coleraine, UK. Conflict of Interest Authors Crawford, Barton, Wilson, Berman, McKelvey-Martin, Morrison and North declare that they have no conflict of interest. Human Studies and Informed Consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study. Animal Studies No animal studies were carried out by the authors for this article.

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