Anja Roubos

Endocrine and non-endocrine causes of fatigue in adults with Neurofibromatosis type 1

Frontiers in endocrinology, Mar 15, 2024

Context: Neurofibromatosis type 1 (NF1) is a complex system disorder, caused by alterations in RA... more Context: Neurofibromatosis type 1 (NF1) is a complex system disorder, caused by alterations in RAS pathways. NF1 adults often suffer from chronic and severe fatigue, for which they are frequently referred to Internal Medicine/ Endocrinology. Seeking medical help often leads to (invasive) diagnostic procedures. To prevent the personal and financial burden of this disabling fatigue, it is crucial to know the causes. Objective: To explore somatic causes and provide practical recommendations for the approach to fatigue in adults with NF1. Design: Cross-sectional. All adults with NF1 (N = 133) who visited our Endocrinology department underwent a systematic health screening, including a medical questionnaire, structured interview, complete physical examination, biochemical measurements and additional tests if indicated. Main outcome measure: Prevalence of endocrine and non-endocrine health problems between NF1 adults with and without fatigue. Results: In our cohort, 75% of NF1 adults experienced fatigue. The most frequent endocrine disorders were vitamin D deficiency (28%), obesity (18%) and hypothyroidism (8%). The most frequent non-endocrine internal disorder was high blood pressure (42%). None of the disorders differed significantly between adults with and without fatigue. Conclusions: Endocrine and non-endocrine disorders were equally present in our cohort of NF1 adults with and without fatigue. This suggests that the high prevalence of fatigue in NF1 adults is not explained by these somatic disorders. An Frontiers in Endocrinology frontiersin.org 01

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Behavior and cognitive functioning in <scp>Witteveen–Kolk</scp> syndrome

American Journal of Medical Genetics, Aug 11, 2020

Witteveen–Kolk syndrome (WITKOS) is a rare neurodevelopmental disorder characterized by developme... more Witteveen–Kolk syndrome (WITKOS) is a rare neurodevelopmental disorder characterized by developmental delay/intellectual disability, facial dysmorphisms, and short stature. The syndrome is caused by loss of function of switch‐insensitive 3 transcription regulator family member A (SIN3A). Regarding behavioral functioning, Autism Spectrum Disorders (ASD), obsessive–compulsive behaviors, as well as Attention‐Deficit/Hyperactivity Disorder symptoms (ADHD) have been suggested. The present study explores various aspects of neurocognitive functioning in five individuals (age range 10–23) with WITKOS. Medical records and results of extensive neuropsychological assessment are used to describe developmental trajectories and neurocognitive profiles. Systematic analysis of medical records displays developmental difficulties described as ASD or ADHD in childhood, sleep problems and internalizing problems during adolescence. Results of cognitive assessments indicate profoundly disabled (n = 1), mildly disabled (n = 2), borderline (n = 1), and average (n = 1) levels of intelligence. Furthermore, results indicate weaknesses in speed of information processing/sustained attention in all participants, and difficulties in planning and maintaining overview in three participants. Furthermore, parent reports of behavioral functioning primarily suggest problems in social functioning. Implications of both cognitive problems and social–emotional vulnerabilities for counseling are discussed and supplemented with suggestions for interventions.

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Supplementary data for: Missed Diagnoses and Health Problems in Adults With Prader-Willi Syndrome: Recommendations for Screening and Treatment

PWS home a N = 23 Non-PWS home b N = 61 Family c N=28 Age in years, median [IQR] 26 [21-32] 36 [2... more

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Hypertension with hidden causes: the cognitive and behavioral profile of an adult female with chronic stress and 16p11.2 microdeletion

Journal of Hypertension

This case report aims to alert physicians to neuropsychological features and chromosomal variants... more This case report aims to alert physicians to neuropsychological features and chromosomal variants that may underly resistant hypertension. We present a 35-year-old female patient with hypertensive crisis (BP 260/160 mmHg), initially treated with a combination of calcium antagonists, beta blockers, diuretics and angiotensin-converting enzyme (ACE)-inhibitors, though with little improvement. Cushing's syndrome, Conn's syndrome, and glucocorticoid receptor deficiency were ruled out. Multidisciplinary examination of medical history and (hetero)anamneses including psychosocial factors revealed mild dysmorphic body features, developmental delay, early diagnosis of autism spectrum disorder, a history of being bullied at school, little peer contact, learning disabilities, and special education. Neuropsychological assessment demonstrated below average to low average intelligence quotient, cognitive impairments, and psychopathology. Parallel genetic analyses revealed a rare 16p11.2 mi...

Associations Between Fatigue and Endocrine and Non-endocrine Health Problems in Turner Syndrome: Cohort Study and Review

The Journal of Clinical Endocrinology & Metabolism

Context Turner syndrome (TS) is a rare chromosomal disorder characterized by gonadal dysfunction,... more Context Turner syndrome (TS) is a rare chromosomal disorder characterized by gonadal dysfunction, short stature, and heart defects, among other features. Women with TS often suffer from severe fatigue, for which they are typically referred to endocrinologists. The diagnostic work-up is generally time-consuming and invasive, and it rarely solves the problem. To prevent the personal and financial burden of unnecessary diagnostic procedures, it is crucial to understand fatigue in TS. Objective To explore the association between fatigue and endocrine and non-endocrine comorbidities in a—for rare disorders—large group of women with TS. Methods 170 genetically confirmed women with TS who attended the TS Reference Center underwent a systematic health screening, including a structured interview, complete physical examination, biochemical measurements, perceived stress and fatigue questionnaires, and additional tests when indicated. Results Median (interquartile range) age was 32.6 (23.9-41....

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An exploratory study on somaesthetics: Judged beauty and difficulty of dance postures depends on the involvement of one's own body

Perception, 2016

Genetic Disorders and Dual Diagnosis: Building Clinical Management on Etiology and Neurocognition

Handbook of Dual Diagnosis, 2020

Major advances have been made in the identification of genetic neurodevelopmental disorders and p... more Major advances have been made in the identification of genetic neurodevelopmental disorders and psychological (dis)functioning among persons with intellectual disabilities. This chapter first provides an overview of developments on the topic. Thereafter, our preference to study “dual diagnosis” from a neuropsychological perspective is described, building upon the increasing opportunities in genetic testing and beyond classificatory diagnosis of psychiatric conditions (e.g., DSM, ICD) in genetic neurodevelopmental disorders. This implies a multimethod assessment of cognitive functioning and understanding behavior from a contextual perspective, across the life span. Applying this neuropsychological clinical research strategy provides opportunities for developing and implementing (multidisciplinary) treatment strategies, as is shown in the syndrome descriptions in Chap. 4. Common conditions such as Fragile X syndrome and Noonan syndrome are reviewed as well as several rare genetic syndromes (e.g., Kleefstra syndrome, KBG syndrome, and Phelan-McDermid syndrome) with typically co-occurring mental health disorders and/or challenging behaviors. Special attention is paid to Prader-Willi syndrome, because it typically illustrates the complex interplay of the syndrome-bound phenomena and the great benefits of interdisciplinary study thereof. Resulting clinical strategies that may emerge from the advocated genetic neuropsychological paradigm are shortly addressed, including future vistas on this dynamic and rapidly developing field.

Family Matters: Trauma and Quality of Life in Family Members of Individuals With Prader-Willi Syndrome

Frontiers in Psychiatry, Jun 28, 2022

Conclusions: Having a relative with PWS is associated with higher prevalence of traumatic experie... more Conclusions: Having a relative with PWS is associated with higher prevalence of traumatic experiences and greater vulnerability to PTSD. Raising awareness in health care professionals of trauma symptoms in PWS relatives may contribute to effective treatment of their psychosocial stress. In addition, timely interventions might prevent family members from developing psychopathology like PTSD.

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What Every Internist-Endocrinologist Should Know about Rare Genetic Syndromes in Order to Prevent Needless Diagnostics, Missed Diagnoses and Medical Complications: Five Years of ‘Internal Medicine for Rare Genetic Syndromes’

Journal of Clinical Medicine

Patients with complex rare genetic syndromes (CRGS) have combined medical problems affecting mult... more Patients with complex rare genetic syndromes (CRGS) have combined medical problems affecting multiple organ systems. Pediatric multidisciplinary (MD) care has improved life expectancy, however, transfer to internal medicine is hindered by the lack of adequate MD care for adults. We have launched an MD outpatient clinic providing syndrome-specific care for adults with CRGS, which, to our knowledge, is the first one worldwide in the field of internal medicine. Between 2015 and 2020, we have treated 720 adults with over 60 syndromes. Eighty-nine percent of the syndromes were associated with endocrine problems. We describe case series of missed diagnoses and patients who had undergone extensive diagnostic testing for symptoms that could actually be explained by their syndrome. Based on our experiences and review of the literature, we provide an algorithm for the clinical approach of health problems in CRGS adults. We conclude that missed diagnoses and needless invasive tests seem common...

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Effects of Childhood Multidisciplinary Care and Growth Hormone Treatment on Health Problems in Adults with Prader-Willi Syndrome

Journal of Clinical Medicine, 2021

Prader-Willi syndrome (PWS) is a complex hypothalamic disorder. Features of PWS include hyperphag... more Prader-Willi syndrome (PWS) is a complex hypothalamic disorder. Features of PWS include hyperphagia, hypotonia, intellectual disability, and pituitary hormone deficiencies. The combination of growth hormone treatment and multidisciplinary care (GHMDc) has greatly improved the health of children with PWS. Little is known about the effects of childhood GHMDc on health outcomes in adulthood. We retrospectively collected clinical data of 109 adults with PWS. Thirty-nine had received GHMDc during childhood and adolescence (GHMDc+ group) and sixty-three had never received growth hormone treatment (GHt) nor multidisciplinary care (GHMDc− group). Our systematic screening revealed fewer undetected health problems in the GHMDc+ group (10%) than in the GHMDc− group (84%). All health problems revealed in the GHMDc+ group had developed between the last visit to the paediatric and the first visit to the adult clinic and/or did not require treatment. Mean BMI and the prevalence of diabetes mellitu...

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Missed Diagnoses and Health Problems in Adults With Prader-Willi Syndrome: Recommendations for Screening and Treatment

The Journal of Clinical Endocrinology & Metabolism, 2020

Context Prader-Willi syndrome (PWS) is a complex hypothalamic disorder, combining hyperphagia, hy... more Context Prader-Willi syndrome (PWS) is a complex hypothalamic disorder, combining hyperphagia, hypotonia, intellectual disability, and pituitary hormone deficiencies. Annual mortality of patients with PWS is high (3%). In half of the patients, the cause of death is obesity related and/or of cardiopulmonary origin. Health problems leading to this increased mortality often remain undetected due to the complexity and rareness of the syndrome. Objective To assess the prevalence of health problems in adults with PWS retrospectively. Patients, Design, and Setting We systematically screened 115 PWS adults for undiagnosed health problems. All patients visited the multidisciplinary outpatient clinic for rare endocrine syndromes at the Erasmus University Medical Center, Rotterdam, Netherlands. We collected the results of medical questionnaires, interviews, physical examinations, biochemical measurements, polygraphy, polysomnography, and radiology. Main outcome measures Presence or absence of ...

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Intellectual Profiles in KBG-Syndrome: A Wechsler Based Case-Control Study

by Anja Roubos and Linde van Dongen

Frontiers in Behavioral Neuroscience, 2017

KBG syndrome is a neurodevelopmental disorder (NDD) caused by loss-of-function of the ANKRD11 gen... more KBG syndrome is a neurodevelopmental disorder (NDD) caused by loss-of-function of the ANKRD11 gene. The core phenotype comprises developmental delay (DD)/ intellectual disability (ID) and several specific facial dysmorphisms. In addition, both ADHD-and ASD-related symptoms have been mentioned. For the correct understanding of these developmental and behavioral characteristics however, it is of great importance to apply objective measures, which seldom has been done in patients with KBG syndrome. In this study, intelligence profiles of patients with KBG syndrome (n = 18) were compared with a control group comprising patients with NDD caused by various other genetic defects (n = 17), by means of the Wechsler scales. These scales were also used to measure speed of information processing, working memory, verbal comprehension and perceptual reasoning. No significant differences were found in the global level of intelligence of patients with KBG syndrome as compared to the patient genetic control group. The same was true for Wechsler subtest results. Hence, behavioral problems associated with KBG syndrome cannot directly be related to or explained by a specific intelligence profile. Instead, specific assessment of neurocognitive functions should be performed to clarify the putative behavioral problems as observed in this syndrome.

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Exploring the behavioral and cognitive phenotype of KBG syndrome

Genes, Brain and Behavior, 2019

KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is c... more KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD-symptoms and social-emotional impairments. In this study, the behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 patients with other genetic disorders with comparable intelligence levels, completed neuropsychological assessment. Age-appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen's d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.

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What Every Internist Should Know About Rare Genetic Syndromes in Order to Prevent Needless Diagnostics, Missed Diagnoses and Medical Complications: Five-Year Experience of Internal Medicine for Complex Rare Genetic Syndromes

Journal of the Endocrine Society, 2021

Introduction: Patients with complex rare genetic syndromes (CRGS) have, by definition, combined m... more Introduction: Patients with complex rare genetic syndromes (CRGS) have, by definition, combined medical problems affecting multiple organ systems. Intellectual disability (ID) is often part of the syndrome. During childhood, most patients with CRGS receive multidisciplinary (MD) and specialized pediatric care in tertiary centers. As improvement of medical care has improved life expectancy, more and more patients are now reaching adult age. While the complexity of the syndromes persist into adulthood, adequate multidisciplinary syndrome-specific care is rarely available for adults with CRGS. Although multiple organ systems are usually affected, internists are rarely involved. Pediatricians have expressed the urgent need for adequate, syndrome-specific, MD tertiary healthcare for adults with CRGS. Methods: In 2015 we have launched the Center for Adults with CRGS, a specialized MD outpatient clinic (MOPC) within the Endocrinology unit of the department of Internal Medicine. As adult ma...

Behavior and cognitive functioning in Witteveen–Kolk syndrome

Witteveen–Kolk syndrome (WITKOS) is a rare neurodevelopmental disorder characterized by developme... more Witteveen–Kolk syndrome (WITKOS) is a rare neurodevelopmental disorder characterized by developmental delay/intellectual disability, facial dysmorphisms, and short stature. The syndrome is caused by loss of function of switch‐insensitive 3 transcription regulator family member A (SIN3A). Regarding behavioral functioning, Autism Spectrum Disorders (ASD), obsessive–compulsive behaviors, as well as Attention‐Deficit/Hyperactivity Disorder symptoms (ADHD) have been suggested. The present study explores various aspects of neurocognitive functioning in five individuals (age range 10–23) with WITKOS. Medical records and results of extensive neuropsychological assessment are used to describe developmental trajectories and neurocognitive profiles. Systematic analysis of medical records displays developmental difficulties described as ASD or ADHD in childhood, sleep problems and internalizing problems during adolescence. Results of cognitive assessments indicate profoundly disabled (n = 1), m...

Genetic Disorders and Dual Diagnosis: Building Clinical Management on Etiology and Neurocognition

Major advances have been made in the identification of genetic neurodevelopmental disorders and p... more Major advances have been made in the identification of genetic neurodevelopmental disorders and psychological (dis)functioning among persons with intellectual disabilities. This chapter first provides an overview of developments on the topic. Thereafter, our preference to study “dual diagnosis” from a neuropsychological perspective is described, building upon the increasing opportunities in genetic testing and beyond classificatory diagnosis of psychiatric conditions (e.g., DSM, ICD) in genetic neurodevelopmental disorders. This implies a multimethod assessment of cognitive functioning and understanding behavior from a contextual perspective, across the life span. Applying this neuropsychological clinical research strategy provides opportunities for developing and implementing (multidisciplinary) treatment strategies, as is shown in the syndrome descriptions in Chap. 4. Common conditions such as Fragile X syndrome and Noonan syndrome are reviewed as well as several rare genetic synd...

Supplementary data for: The iceberg of missed diagnoses and untreated health problems in a large cohort of adults with Prader-Willi syndrome – recommendations for screening and treatment

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