1 Introduction

KBG syndrome (KBGS) (OMIM#148050) is a rare neurodevelopmental syndrome caused by heterozygous pathogenic ANKRD11 variants (Sirmaci et al. 2011). It is characterized by distinctive craniofacial features, macrodontia, short stature, skeletal abnormalities, intellectual and developmental disability, behavioral and psychiatric comorbidities, and sometimes association with seizures (Sirmaci et al. 2011). First described in 1975 and named after the surnames of the first families reported with the syndrome (Herrmann et al. 1975), it is now known to affect more than 500 families worldwide (based on estimates from patient groups and published cohorts).

With the increasing availability of new genomic techniques and reducing test costs, more individuals are being diagnosed with KBGS. International pediatric cohorts have been described in the literature, leading to a better understanding of the phenotypic spectrum in childhood (Loberti et al. 2022). However, when a child is diagnosed with KBGS, their parents are often concerned about long-term implications for their child, which also requires good knowledge of the adult phenotypic spectrum. Adults with syndromic neurodevelopmental disorders can experience fragmented care (Douzgou et al. 2022), and there is a need for more data on the natural history of KBGS into adulthood in order to improve care planning and inform future guidelines.

We recently reported a study of 36 adults with KBGS based on clinician-reported data (Bayat et al. 2024). The study presented here is the first to examine the long-term outcomes of KBGS into adulthood as reported by individuals with KBGS and/or their family members, with a particular focus on the impact of the disorder on daily life, employment, leisure, and relationships. We co-produced a survey designed to enable individuals with KBGS, their families and physicians to have a clearer picture of what they can expect for the future.

2 Methodology

The premise for this study was based on the report by Douzgou et al., and their survey formed the initial starting point for development. We then created an accessible questionnaire, designed for individuals with KBGS and their caregivers, to provide insight into how this condition affects a person's daily life. The questionnaire was designed to capture information that may have been missed by healthcare professionals. It was co-produced by an international network of physicians, researchers, and parents/carers of individuals with KBGS.

Between December 2023 and June 2024, the study was predominantly advertised via the KBG Foundation, on their website and social media channels. Adults with KBGS were recruited to participate in the survey, either independently or with the support of family or carers. An adult was defined as a person over the age of 16 years due to this being a common delineator between pediatric and adult care. International collaborators from five other countries also shared the study with their patients, which was available translated into other languages. Participants were required to understand English, Spanish, French, Dutch, or German to take part.

If an individual with KBGS was interested in participating, they were instructed to follow a URL link/QR code, which directed them to an online participant information sheet. If participants wished to continue, they were asked to complete an online consent form. All consent data was collected via a web-based data capture system for research called Research Electronic Data Capture (REDCap). Participants were then asked to answer a series of questions relating to their KBGS (see supplementary information). Participants were able to save and return to their survey at any time to allow for breaks, if needed. Upon finalization of data collection, outcome measurements were analyzed using a combination of descriptive and simple frequency or percentage analysis.

3 Results

There were 104 responses to the survey. Of these, 10 were excluded from analysis because they did not complete the survey to the end, and three were excluded due to the participant being aged below 16 years. This resulted in 91 responses for analysis. Some of these respondents did not answer every question, and the low response rate to individual questions was reflected upon during analysis.

Of the 91 responses, 66 were completed by caregivers and 25 were completed by the person with KBGS themselves. For the purpose of this paper, the person with KBGS is referred to as the “participant”.

The ages of the participants in this survey ranged from 16–86 years (median 22 years, mean 24.8 years). The ages were broken down into categories to enable further analysis of the data collected. There was a higher number of participants in the younger adult age range (see Table 1).

Forty-one participants were female, 44 were male, and six did not respond to the question asking the gender of the participant.

Participants lived in the following countries: USA (n = 25), United Kingdom (n = 14), Spain (n = 11), Netherlands (n = 9), Denmark (n = 7), Australia (n = 3), France (n = 3), Georgia (n = 2), Germany (n = 2), Italy (n = 2), Norway (n = 2), Belgium (n = 1), Canada (n = 1), Estonia (n = 1), Portugal (n = 1), and South Africa (n = 1), and this data was missing for six.

KBGS was diagnosed at ages 6–9 years for six participants, 10–17 years old for 37, and 18 years or older for 41, while the age at diagnosis was missing for seven participants.

3.1 Everyday Life

3.1.1 Living Arrangements

In total, 60 (66%) participants lived with their main caregiver, while nine (10%) were in supported living. Eleven (12%) lived independently, six (7%) reported there were “other” arrangements, and the data were missing for five (5%).

The data were analyzed to look at the frequency of these living arrangements within each age category (see Figure 1). For 16–24 year olds, 90% (n = 47) lived with their main caregiver, 8% (n = 4) in supported living, and 2% (n = 1) independently. For 25–34 year-olds the proportion of individuals living with their main caregiver decreased to 40% (n = 8), with 15% (n = 3) in supported living, 35% (n = 7) independently, and 10% (n = 2) “other.” The proportion of participants living at home with their main caregiver decreased further for 35–44 year-olds to 27% (n = 3). This trend did not continue into the older age categories; however, there were fewer participants in these groups.

3.1.2 Grocery Shopping

In total, 47 (52%) participants were able to do their grocery shopping independently, and 34 (37%) reported they were not. The data were missing for 10 (11%) participants. The responses were analyzed according to the age category of the participants (see figure 2). The proportion of individuals able to do their grocery shopping independently increased from 44% (n = 23) in the 16–24 year-olds, to 70% (n = 14) in the 25–34 year-olds, to 73% (n = 8) in the 35–44 year-olds, and 100% (n = 2) in the 45–54 year-olds. The individual in the 55+ age group was unable to do their grocery shopping independently.

3.1.3 Driving

Seventy-one participants (78%) could not drive a car, 10 (11%) could and data for 10 (11%) was missing. Responses were analyzed according to the age categories (see figure 3). The proportion able to drive a car increased from 2% (n = 1) in the 16–24 year olds to 20% (n = 4) in the 25–35year olds, 36% (n = 4) in the 35–44 year olds and 50% (n = 1) in the 45–54year olds.

3.1.4 Education

Eleven participants (12%) were currently enrolled in school, while 18 (20%) had completed high school or college. Twenty-four (26%) described requiring a special educational setting or had some modifications to the curriculum. Sixteen (18%) had undertaken vocational training. One (1%) was currently attending university, one (1%) had obtained an undergraduate degree, and one (1%) had earned a master's degree. Furthermore, two participants (2%) did not attend any educational institution. Data regarding educational attainment was missing for 50 participants (55%).

3.1.5 Employment

Thirty participants (33%) were employed. There were a range of careers in the following job categories: Hospitality and food (n = 6), environment and land (n = 4), retail and sales (n = 4), home services (n = 3), social care (n = 3), teaching and education (n = 2), administration (n = 2), animal care (n = 1), creative and media (n = 1), delivery and storage (n = 1), healthcare (n = 1), and sports and leisure (n = 1). One participant was employed at a sheltered workshop but did not specify the type of activities performed.

Twenty-nine reported whether the person with KBGS had any kind of support at work. Of these, 16 reported no specific support, while three responded “yes” without further detail. Two mentioned having support persons on their team, one reported receiving support from teachers, three noted having one-to-one support, and four described working in sheltered workshops for people with disabilities under adapted or protected conditions.

3.1.6 Leisure

Fifty-four respondents (60%) reported the person with KBGS maintained social activities. Of these, nine reported attending organized social activities/outings, and nine participated in sports, with one competing at an elite level. Six described involvement in creative arts: four in music, one in drama and one in dance. Nine respondents went out with friends, going to the cinema (n = 2), swimming (n = 1), and sleepovers (n = 1). Two respondents played computer games, three maintained social connections through living and/or working with others, and two through religious groups.

Two individuals reported their social activities were limited, and two enjoyed going out with family but did not socialize with friends. Two respondents described their challenges to accessing leisure activities; one did not like being in large groups of people alone, and the other expressed they did not like change in routine or unpredictable events.

3.1.7 Relationships

Seventy-four participants (81%) had never been in a romantic relationship. Of these, 25 expressed a desire for a relationship, while another 25 stated they were not interested in romantic relationships. Seventeen (19%) had been in a romantic relationship in the past, with nine of these currently in a relationship. Eleven (12%) reported currently having a long-term partner or spouse, while six (7%) had previously been in a long-term relationship.

When asked about sexual activity, 12 (13%) respondents confirmed they were sexually active, and 10 (6 Females/4 Males) (11%) reported having children. Fifty-one indicated they were not sexually active, while three were unsure, three preferred not to answer, and 12 did not respond. Regarding self-stimulation, six respondents confirmed engaging in this behavior, and nine indicated doing so with a partner.

4 Discussion

This study found independent living, grocery shopping, and driving skills were acquired by some adults with KBGS and that the prevalence of skill attainment was mostly highest in the 35–44 age group. This is important information for individuals with KBGS, their families, and genetic counselors when planning for the future. However considering the cross sectional study design and difference in absolute numbers of each age category, it is difficult to conclude the timescale of skill acquisition.

In this cohort, 33% reported employment, comparable to the 28% in our previous physician-reported data and in contrast to only 8% in the literature group from the same study (Bayat et al. 2024). We recognize that socioeconomic circumstances are likely to be a significant factor in an individual's ability to live and work, and that furthermore there is potential bias, whereby those with more support will have been more able to respond to this survey.

Some adults with KBGS will have only received genetic testing due to having children with more complex problems, and given some of the difficulties experienced with this condition can be mild and non-specific, there can be delays in diagnosis (Low et al. 2016). Most individuals with KBGS have a mild intellectual disability, but in a small proportion, this can vary from no intellectual disabilities to severe (Loberti et al. 2022). The responses demonstrate that high educational attainment is possible in KBGS, and it is plausible that there are further very mildly affected undiagnosed individuals in this category.

None of the participants aged 45+ in this data set lived independently, which could correlate with a testing bias. Given the changes in the availability of genetic testing, it is likely that there are unidentified older adults with KBGS who will never undergo genetic testing and that the older adults in this group have been diagnosed due to having a more significant set of problems. These figures may change in the future as the diagnosed children grow up. We hope the impact of an early diagnosis with appropriate support and interventions may also result in some further positive shift of these figures. Using the information from our results, we have considered the types of support that could be needed, along with possible early interventions to maintain long-term health and well-being outcomes.

Given the high burden of psychiatric and behavioral difficulties, we recommend that adults with KBGS are provided psychosocial support to optimize their mental health. This may include onward referral to psychiatry for assessment and treatment. We recognize best practice is a holistic approach, where support can be provided by wider members of multidisciplinary teams, such as the positive behavioral approach, in line with NICE guidelines for behaviors that challenge (National Institute for Health and Care Excellence 2015). Reasonable adjustments to work and education should be made to ensure individuals have the best chance of achieving their potential. Sensory needs assessments could inform these when indicated. Annual hearing and vision checks should be aimed for annually due to the high rates of hearing and visual problems, which can also be contributing factors to psychiatric and behavioral difficulties and sensory-seeking/avoiding behaviors.

This study found 21 (23%) participants were currently experiencing seizures, compared to our previous study where 28% of the adults with KBGS had epilepsy (Bayat et al. 2024). For the participants in this study, none of those who currently experienced seizures were found to be living independently. Although other factors, such as cognitive function and social support, could also influence independence, this observation suggests that seizures significantly impact daily living capabilities, limiting independence and necessitating additional support and supervision.

Unfortunately, a question about the impact of musculoskeletal problems on quality of life in adulthood was not asked in this survey, but we have inferred the high proportion of skeletal issues to indicate these are having an impact and would advise optimizing bone health, maintaining healthy physical activity, and appropriate investigation and treatment of painful joints.

Congenital heart disease and dilatation of the aorta were reported at higher rates than expected from the general population. In our previous study, we also identified cardiovascular abnormalities relating to the ascending aorta (n = 2) and/or aortic valve (n = 3) (Bayat et al. 2024). We acknowledge some individuals are likely to be reported in both our papers. However, these associations have also been reported in the wider literature and warrant further investigation (Digilio et al. 2022, Nicolini et al. 2009). Based on this, we recommend consideration of cardiac ECHO, including a measurement of the aortic diameter, at least once in adulthood (or more regularly if abnormalities are identified requiring monitoring or if symptomatic).

We found a high burden of gastrointestinal issues into adulthood, including cyclical vomiting and abdominal migraine, which has also been reported in the literature (Lyon et al. 2022). Constipation and reflux were identified in our previous study and again were common complaints in this cohort. This information could be used to raise awareness for practitioners who should treat as per condition on a case-by-case basis. See figure 4 for our recommendations for healthcare interventions for adults with KBGS.

There are limitations to this study that require consideration when making wider conclusions about the outcomes of KBGS. Sixty-six (73%) of surveys were completed by the caregiver rather than the individual with KBGS, which could infer a level of intellectual disability that would make completing such a survey difficult or unachievable. We note that educational attainment responses were missing in 50 cases—this could be because of limited educational attainment or because of problems understanding the questions. If this sort of survey is used in the future, the specific questions regarding intellectual disability and educational attainment should be revised and, ideally, tested first with a small group to ensure they provides a better response rate and a better reflection of intellectual disability. It is also possible there were questions that respondents felt embarrassed or uncomfortable answering, for example, around sexual relationships, and further refining these questions through consultation with individuals with KBGS would be beneficial.

This method of using adult/caregiver responses is vulnerable to recall bias and subjectivity, along with potential challenges arising from limited medical knowledge of the respondents. We found during analysis we were not able to ascertain in all responses whether an individual's medical problem or surgery occurred in childhood or adulthood and that our questions could have been misunderstood. There were also inconsistencies in respondents reporting whether conditions were autoimmune disorders, which has limited comparisons we have been able to make with our previous paper in this area. Due to the paucity of data, we have reported the majority of our findings and acknowledge that some of the rates of these will not be out of keeping with the general population. However, the strengths of this method of online questionnaire participation have included our success in recruitment of a large cohort across a number of countries and identification of implications for clinical management along with areas for further exploration. The method of our patient/carer questionnaire is likely to be of interest to researchers in a variety of other settings in the field of rare genetic syndromes.

5 Conclusion

Our study has clearly shown the wide range of education and employment that can be achieved by individuals with KBGS, along with social activities and relationships that they can have. It can therefore be concluded that since KBGS can affect people's lives in such varied ways, the diagnosis alone should not influence an individual's future aspirations. There are, however, high rates of comorbidities, which continue to affect people's quality of life into adulthood. Support will need to be tailored to the individual's needs and most likely will require the input of professionals from multiple specialties in order to optimize their health and well-being into adulthood. This study, through utilizing the adult's and caregiver's perspectives, provides valuable insights into the real-world needs of adults with this condition. This knowledge can be used to enhance counseling, clinical decision-making, care coordination and inform the development of holistic, evidence-based guidelines.

Author Contributions

Low Karen J: conceptualization, methodology, formal analysis, investigation, resources, data curation, writing–review and editing, supervision, funding acquisition. Walker Moira: formal analysis, writing–original draft, writing–review and editing. Treneman-Evans Georgia: methodology, formal analysis, resources, data curation, writing–original draft, writing–review and editing, project administration. Bramswig Nuria C: resources, writing–review and editing. Herlin Morten K: resources, writing–review and editing. Lesca Gaetan: resources, writing–review and editing. Scarano Emanuela: resources, writing–review and editing. Ockeloen Charlotte W: Resources, writing–review and editing. Bayat Allan: conceptualization, methodology, writing–review and editing, supervision, funding acquisition.

Ethics Statement

We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The study complies with the principles laid out in the Declaration of Helsinki. The study was approved by the faculty of health research ethics committee at the University of Bristol, UK, in November 2023 (ref. 16025). Written informed consent was collected from all respondents prior to completing the questionnaire, using research protocols approved by the ethics committee at the University of Bristol. The data gathered via the questionnaire was designed to allow anonymity and confidentiality.

Conflicts of Interest

The authors declare no conflicts of interest.