Anna Rosenberg

Adults with complex rare genetic syndromes (CRGS) have combined medical problems affecting multiple organ systems. Currently, many adults with CRGS do not receive the care they need. While the complexity and multi-morbidity of the syndromes require integrated multidisciplinary care, it is often fragmented and of poor quality. This is primarily due to lack of knowledge about these syndromes during adulthood. Since medical guidelines are frequently lacking, physicians do not know the pitfalls when treating these patients. This often results in poor healthcare efficiency, caused by under- and overdiagnostics and under- and overtreatment (like missed diagnoses and needless diagnostic procedures and treatments).

In this dissertation, we discussed different aspects related to diagnostics and medical treatment in adults with CRGS, in order to improve healthcare for these adults. Additionally, we provided practical recommendations on how to prevent under- and overdiagnostics and under- and overtreatment in these adults. Since our center is a center of reference for Prader-Willi syndrome (PWS), Neurofibromatosis type 1 (NFN) and Turner syndrome (TS), we paid special attention to these syndromes.

In chapter 1-3, we gave a general introduction on this dissertation, including a thorough overview of health problems in adults with PWS, NFN and TS. In chapter 4, we described common medical pitfalls when treating adults with CRGS and introduced an algorithm for the approach to physical health problems in these adults, including analysis of somatic, medication related, neuropsychological and other contextual factors. This algorithm can be used to decide whether further (invasive) diagnostic testing is really needed in adults with CRGS, thereby preventing unnecessary diagnostics. Apart from using this algorithm, we advise that all adults with CRGS should be treated by a multidisciplinary team and should be systematically screened for health problems. Ideally, the multidisciplinary team consists of an internist-endocrinologist, neuropsychologist, dietitian and physician for intellectual disabilities (ID), coordinated by a nurse practitioner. When needed, other disciplines, like gynecologists, cardiologists or physiotherapists, should also be consulted and included in the multidisciplinary team. The multidisciplinary approach is especially important in syndromes that are associated with (mild) ID or other neuropsychological alterations. In these patients, somatic health problems may well be caused by stress or other neuropsychological or contextual factors (e.g. lifestyle, inadequate nutritional status), for which a multidisciplinary approach is needed.

In chapters 5-7, we focused on the optimization of medical care for adults with PWS. PWS is a rare genetic syndrome that is caused by the lack of expression of the paternally expressed genes in the PWS region of chromosome 15q11.2-q13. It is associated with (mild) intellectual disabilities (ID), hypotonia, challenging behavior and hypothalamic dysfunction, resulting in hyperphagia and pituitary hormone deficiencies among others. In the past, it has been suggested that central adrenal insufficiency (CAI) might partly explain sudden death in young people with PWS. There was no consensus, however, on the prevalence of CAI in adults with PWS. Since untreated CAI can be life-threatening, stress-doses of hydrocortisone are often prescribed in adults with PWS during periods of physical or psychological stress. However, frequent hydrocortisone use may result in osteoporosis, weight gain, hypertension and diabetes mellitus, for which adults with PWS are already at risk. Therefore we tested the hypothalamic-pituitary-adrenal axis in a large international cohort of adults with PWS (chapter 5). We showed that the prevalence of CAI in adults with PWS is 1.2% (95% CI 0.2% - 6.6%), which is much lower than previously reported among children with PWS. Additionally, we found that none of the adults who underwent surgery without hydrocortisone displayed any symptoms of hypocortisolism or adrenal crisis. Therefore, we conclude that CAI is rare in adults with PWS and we advise to refrain from routine hydrocortisone administration during psychological stress, surgery or illness. When there is a clinical suspicion of hypocortisolism, we recommend to exclude CAI and to only administer hydrocortisone if CAI is confirmed by a metyrapone or insulin tolerance test.

In chapter 6, we analyzed the effects and safety of growth hormone (GH) treatment in adults with PWS. Currently, GH is only reimbursed in children with PWS or in adults with proven GH deficiency. Although virtually all adults with PWS exhibit features that overlap with features of GH deficiency, like small hands and feet, short stature, low lean body mass and reduced strength, GH deficiency often remains unproven due to infeasibility of provocative testing in most adults with PWS. In this dissertation, we showed that GH treatment is effective and safe in adults with PWS, also in those without proven GH deficiency. GH treatment improves body composition by reducing fat mass and increasing fat-free mass (‘lean body mass’). Since body composition plays an important role in the vicious circle of muscle weakness, poor exercise tolerance and reduced physical activity, improving body composition might be crucial to improve energy expenditure in adults with PWS. The results of studies assessing the effect of GH treatment on bone suggest that although bone mineral density remains similar during GH treatment, there might be a (small) positive effect on bone strength, bone geometry and maintenance of bone mass. Only a small number of studies assessed the effects of GH treatment on cardiovascular health, muscle strength, exercise tolerance, cognitive function and quality of life, with inconclusive results. Therefore, more research is needed to determine the effects of GH treatment on these health outcomes.

In chapter 7, we analyzed physical health problems in relation to genetic subtypes in PWS. We showed that health problems differ between adults with PWS due to a paternal deletion and maternal uniparental disomy (mUPD) and that these differences mainly apply to the psychological domain. Especially psychotic episodes were more common among adults with an mUPD. Adults with a paternal deletion had a higher BMI and were slightly more often diagnosed with scoliosis. Other physical health problems did not differ between the deletion and mUPD subtypes. Within the deletion group, there were no differences in health problems between adults with a type 1 or type 2 deletion. Additionally, we found that 13% of the people with PWS have an atypical microdeletion, which is higher than previously reported. More research on these atypical microdeletions is needed to further unravel the influence of the genes in the chromosome 15q11.2-13 region on the PWS phenotype.

In chapters 8 and 9, we focused on the prevention of under- and overdiagnostics and under- and overtreatment during the diagnostic work-up of fatigue in adults with NFN and TS. NFN (prevalence 1:3000) is a ‘more common’ rare genetic neurocutaneous syndrome that is caused by loss-of-function mutations in the NFN gene on chromosome 17q11.2, resulting in RAS pathway alterations. Although NFN is associated with endocrine disorders like short stature (with or without growth hormone deficiency), central precocious puberty, growth hormone excess and endocrine tumors like pheochromocytomas, the most prominent features are non-endocrine tumors (neurofibromas), café-au-lait macules, bone deformities and learning problems. The other ‘more common rare disorder’, TS (prevalence 1:2000-2500) is a sex chromosome aneuploidy that is caused by partial or complete loss of one of the X-chromosomes. It usually only occurs in women and is associated with short stature, premature ovarian insufficiency, cardiovascular health problems, autoimmune diseases and learning difficulties among others. At our outpatient clinic, many adults with NFN and TS suffer from (severe) fatigue. Since people with NFN and TS have a complicated phenotype with multiple comorbidities, they are usually referred to the internal medicine department for analysis of their fatigue. The diagnostic work-up of fatigue can be very time-consuming and invasive and may include multiple diagnostic procedures and/or ‘trial’ treatments. In this dissertation, we systematically explored somatic causes of fatigue in adults with NFN and TS and provided recommendations for the approach to fatigue in these adults. In chapter 8, we showed that somatic health disorders are equally present in NFN adults with and without fatigue, which suggests that those somatic problems are not the (only) explanation for their fatigue. We hypothesize that neuropsychological factors might contribute to the (onset or aggravation of) fatigue in these adults. In chapter 9, we showed that somatic disorders are not associated with fatigue in women with TS, apart from high total bilirubin and BMI. We found a high correlation between perceived stress and fatigue. This suggests that, also in women with TS, neuropsychological processes may play an important role in the onset or aggravation of fatigue. We introduced clinical algorithms for the approach to fatigue in adults with NFN and TS, including both somatic and psychological assessment. Using this algorithm may help to reduce the burden of under- and overdiagnostics and under- and overtreatment in adults with NFN and TS.

The previous chapters mostly concerned adults with known CRGS. However, under- and overdiagnostics and under- and overtreatment may also occur in people with unrecognized and undertreated genetic syndromes, which could partly be prevented by improving the recognition of ID among healthcare professionals. Since many CRGS are associated with (mild) ID, increased recognition of ID might reduce the number of people with unrecognized and undertreated CRGS. Moreover, better recognition of ID will likely also reduce the burden of unnecessary diagnostic procedures in patients in whom diagnostic procedure are performed to find a cause for health problems that are related to their ID or genetic syndrome. Therefore, increasing awareness and recognition of ID is important to prevent under- and overdiagnostics and under- and overtreatment. In chapter 10, we showed that adults with ID have a higher BMI, shorter stature, are more frequently diagnosed with epilepsy and musculoskeletal problems and are less frequently diagnosed with neoplasms, more often use psychotropic drugs and are more often hospitalized than adults without ID. These differences may aid in the development of an ID alert, which could lead to an improved awareness of ID among healthcare professionals. Especially the combination of different health problems should alarm the professional that (mild) ID might be present, after which the Screener for Intelligence and Learning Disability (SCIL) or the SCAF (Screener for Adaptive Functioning) can provide a first global indication of cognitive impairment. When this is suggestive for ID, neuropsychological assessment should be discussed with the patient to confirm the presence of ID. Hereafter, appropriate care and psychosocial support can be arranged when needed.

In chapter 11, we discussed the results of the studies and how they contribute to the prevention of under- and overdiagnostics and under- and overtreatment in adults with CRGS. Furthermore, future perspectives were discussed and conclusions were drawn. The results of this dissertation can be seen as a first step towards improved medical care for adults with CRGS in and outside the Netherlands.