Exploring the Value of an Assessment for the Professional Coaching of Residents.

Background Research on how tools can support coaching of residents is lacking. We hypothesized that an electronic assessment (EA) tool presently applied in selection for residency training, which measures cognitive capacities, personality, motivational drivers, and competencies, could be a valuable tool to support coaching of residents. Objective This study explored the value and limitations, as perceived by residents and coaches, of using the EA to facilitate a single coaching session. Methods This qualitative study took place in the East-Netherlands Training District from August 2022 to April 2023. Volunteer residents and professionally trained coaches engaged in a single coaching session, using the EA. A purposive sample of 7 residents in different training years from 3 specialties were recruited via the training secretariats. Individual interviews with residents were conducted 1 week and 3 months after the coaching session. Data collection ceased when data sufficiency was considered reached. A focus group interview was held with the 3 participating coaches. Thematic analysis was employed to identify themes. Results Participants considered the EA a supportive tool, but not the core focus in the coaching process. Coaching sessions remained guided by residents' individual needs. The EA was considered supportive in fostering residents' self-reflection and awareness, accelerating the coaching process by enhancing preparedness and fostering familiarity among residents and coaches. The perceived value of the EA for the coaching process was affected by residents' and coaches' attitudes toward the tool. Conclusions The EA played a supportive but nonprominent role in the coaching of residents.

Nerve enlargement in patients with Noonan syndrome: A retrospective cohort study.

Noonan syndrome (NS) is an autosomal dominant condition characterized by facial dysmorphism, congenital heart disease, development delay, growth retardation and lymphatic disease. It is caused by germline pathogenic variants in genes encoding proteins in the Ras/mitogen-activated protein kinase signaling pathway. Nerve enlargement is not generally considered as a feature of NS, although some cases have been reported. High-resolution nerve ultrasound enables detailed anatomical assessment of peripheral nerves and can show enlarged nerves. This retrospective cohort study aims to describe the sonographic findings of patients with NS performed during a 1-year time period. Data on the degree of enlargement, the relation to increasing age, pain in extremities, genotype on the gene level and clinical features were collected. Twenty-nine of 93 patients visiting the NS Center of Expertise of the Radboud University Medical Center Nijmegen underwent high-resolution ultrasound. In 24 patients (83%) nerve enlargement was found. Most of them experienced pain. We observed a weak correlation with increasing age and the degree of nerve enlargement but no association with pain, genotype at the gene level or clinical features. This study shows that patients with NS have a high predisposition for sonographic nerve enlargement and that the majority experience pain.

Trametinib restores the central conducting lymphatic flow in a premature infant with Noonan syndrome.

We describe a premature hydropic infant with Noonan syndrome and a therapy refractory chylothorax. This was shown to be due to a central conducting lymphatic anomaly. After therapy with a MEK-inhibitor the infant recovered clinically and radiologically completely, possibly by restoring lymphatic valve function.

Reframing selection as a learning experience: Insights from a residency selection assessment.

PURPOSE: Selection for postgraduate medical training is high-stakes and complex. The learning value of assessments for selection has, thus far, been underexplored, limiting their uptake as potentially meaningful learning experiences. The aim of this study was to explore the learning value residency applicants derive from an intelligence, personality, motivation and competency selection assessment and what factors influence the experienced learning value. METHODS: In Autumn 2020 and Spring 2021, we conducted individual semi-structured interviews with sixteen applicants for pediatric residency training. Selection outcomes were unknown at the time of the interview. Interviews were transcribed verbatim and thematically analyzed. RESULTS: Participants reported that the assessment was valuable in fostering self-reflection and self-awareness, embracing self-acceptance, pursuing development goals, assessing professional fit, and harnessing motivational drivers in work. The experienced learning value was influenced by applicants' ability to interpret its results, their focus on the high-stakes selection process and concerns regarding the acceptability and credibility of the selection tool. CONCLUSIONS: While the selection assessment showed learning potential, its learning value was impeded by a preoccupation with the high-stakes nature of the selection procedure. Intentional integration of the selection assessment in the learning curriculum may play a pivotal role in realizing its learning potential.

Differentiating primary sarcomeric hypertrophic cardiomyopathy from Noonan syndrome: can the electrocardiogram be of use?

Noonan syndrome is a multi-system genetic disorder and patients may suffer from hypertrophic cardiomyopathy. Previous studies have identified electrocardiographic features that may support a diagnosis of Noonan syndrome. In this two-centre retrospective study, we analysed typical Noonan syndrome-related electrocardiographic features in 30 patients with Noonan syndrome with hypertrophic cardiomyopathy and compared these with the electrocardiographic features in 15 children with sarcomeric hypertrophic cardiomyopathy. Typical Noonan syndrome-related electrocardiographic features are a negative aVF, small left precordial R-waves, large right precordial S-waves, and abnormal Q-wave. We also analysed electrocardiographic features of hypertrophic cardiomyopathy: ST-segment abnormalities and T-wave abnormalities. A negative aVF was seen in 83% of patients with Noonan syndrome-related hypertrophic cardiomyopathy in contrast to 27% of patients with primary sarcomeric hypertrophic cardiomyopathy (p < 0.001). An extreme QRS axis in the north-west was seen only in patients with Noonan syndrome-related hypertrophic cardiomyopathy. This QRS axis deviation is likely to be determined by the Noonan syndrome-related hypertrophic cardiomyopathy and not by the type of hypertrophic cardiomyopathy. There were no differences between the two groups in the frequency of large right precordial S-waves and small R-waves in the left precordial leads V5 and V6. However, an abnormal R/S ratio was more often seen in patients with Noonan syndrome-related hypertrophic cardiomyopathy (p < 0.001). Pathologic Q-waves were seen statistically more frequently in patients with sarcomeric hypertrophic cardiomyopathy (p = 0.009). The occurrence of ST-segment and T-wave pathology did not statistically differ between the two groups. Electrography can be of use in differentiating sarcomeric hypertrophic cardiomyopathy from Noonan syndrome-related hypertrophic cardiomyopathy.

Bone quality in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a one-year prospective natural history study.

Fragility fractures are frequently reported in neuromuscular diseases and negatively influence functional prognosis, quality of life and survival. In LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related congenital myopathy (SELENON-RM) cross-sectional and prospective natural history studies on bone quality and fragility long bone fractures (LBFs) are lacking. We therefore aim to systematically assess bone quality and provide recommendations for clinical care. We performed a one-year prospective natural history study in 21 LAMA2-MD and 10 SELENON-RM patients including a standardized fracture history and bone quality assessment through dual energy Xray absorptiometry scan (DEXA-scan) and/or bone health index (BHI). Ninety percent of the LAMA2-MD and SELENON-RM patients showed low bone quality. Eight (38%) LAMA2-MD and five (50%) SELENON-RM patients had a history of fragility LBFs. During the one-year follow-up period, one LAMA2-MD patient (female, 3 years) experienced a fragility LBF of the right humerus. We found no difference in bone mineral density between baseline and one-year follow-up. Based on general international guidelines for osteoporosis, we advise adequate vitamin D and calcium intake, and standardized clinical follow-up through a DEXA-scan or BHI in all LAMA2-MD and SELENON-RM patients. On indication, patients should be referred to the pediatrics or internal medicine for consideration of additional treatments.

Unravelling underlying processes in intraprofessional workplace learning in residency.

BACKGROUND: To deliver high-quality collaborative care, residents need to be trained across the boundaries of their medical specialty (intraprofessional learning). The current literature does not provide insights into the underlying processes that influence intraprofessional learning. The aim of this study was to gain insight into the processes that occur during intraprofessional workplace learning in residency training, by exploring everyday intraprofessional interactions experienced by residents, with the ultimate objective of improving collaborative practice. METHOD: We conducted a focused ethnography using field observations and in-depth interviews with residents at an academic children's hospital in the Netherlands. In 2022, nine residents from four different medical specialties were shadowed and/or interviewed. In total, >120 hours of observation and 10 interviews were conducted. Data collection and analysis were conducted iteratively and discussed in a research team with diverse perspectives, as well as with a sounding board group of stakeholders. RESULTS: Residents were involved in numerous intraprofessional interactions as part of their daily work. We identified three themes that shed light on the underlying processes that occur during intraprofessional workplace learning: (1) residents' agency, (2) ingroups and outgroups and (3) communication about intraprofessional collaboration. CONCLUSIONS: Collaborative practice offers many intraprofessional learning opportunities but does not automatically result in learning from, with and about other specialties to improve intraprofessional collaborative care. Overarching the identified themes, we emphasise the pivotal role of the resident-supervisor dyad in facilitating residents' engagement in the learning opportunities of complex intraprofessional care. Furthermore, we propose that promoting deliberate practice and shared responsibility in collaborative care are crucial to better prepare residents for their roles and responsibilities in delivering high-quality collaborative patient care.

SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness.

BACKGROUND: SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness. OBJECTIVE: We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care. METHODS: This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry. RESULTS: Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3-42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%. Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures. CONCLUSIONS: We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression.

Short-term effects of an elimination diet and healthy diet in children with attention-deficit/hyperactivity disorder: a randomized-controlled trial.

An Elimination Diet (ED) may be effective in reducing symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD), but has never been compared to an active control condition [i.e., Healthy Diet (HD)]. In a two-armed RCT, a total of N = 165 children (5-12 years) with ADHD were randomized by means of minimization (1:1) to either an ED (N = 84) or HD (N = 81) within two Dutch child and adolescent psychiatry centers. The design included a non-randomized comparator arm including N = 58 children being treated with Care as Usual (CAU). Treatment allocation was unblinded. The primary outcome was a 5-point ordinal measure of respondership based on a combination of parent and teacher ratings on ADHD and emotion regulation, determined after 5 weeks of treatment. Ordinal regression analyses were done on an intention-to-treat basis. Fewer ED (35%) than HD (51%) participants showed a partial to full response, despite overall good-to-excellent treatment adherence (> 88%) and comparable high parental prior believes. A younger age and higher problem severity predicted a better respondership. CAU-preferring participants responded more often favorably (56%) compared to ED-but not HD-participants. Small-to-medium improvements in physical health (blood pressure, heart rate, and somatic complaints) were found in response to ED/HD versus decrements in response to CAU (74% received psychostimulants). The lack of superiority of the ED versus HD suggests that for the majority of children, dietary treatment response is not rooted in food-allergies/-sensitivities. The comparable results for treatment with HD and CAU are remarkable given that CAU participants were probably 'easier to treat' than HD (and ED) participants with proportionally fewer with a (suboptimal/non-response to) prior treatment with medication (4% versus 20%). Further assessment of long-term effects is needed to evaluate the potential place of dietary treatment within clinical guidelines. The trial is closed and registered in the Dutch trial registry, number NL5324 ( https://www.onderzoekmetmensen.nl/en/trial/25997 ).

LAMA2-Related Muscular Dystrophy Across the Life Span: A Cross-sectional Study.

Background and Objectives: LAMA2-related muscular dystrophy (LAMA2-MD) is a rare neuromuscular disease characterized by proximal and axial muscle weakness, rigidity of the spine, scoliosis, and respiratory impairment. No curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data, and appropriate clinical and functional outcome measures are needed. We aim for deep clinical phenotyping, establishment of a well-characterized baseline cohort for prospective follow-up and recruitment for future clinical trials, improvement of clinical care, and selection of outcome measures for reaching trial readiness. Methods: We performed a cross-sectional, single-center, observational study. This study included neurologic examination and functional measurements among others the Motor Function Measure 20/32 (MFM-20/32) as primary outcome measure, accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electrocardiography and echocardiography, and dual-energy X-ray absorptiometry. Results: Twenty-seven patients with genetically confirmed LAMA2-MD were included (21 ± 13 years; M = 9; ambulant = 7). Axial and proximal muscle weakness was most pronounced. The mean MFM-20/32 score was 42.0% ± 29.4%, with domain 1 (standing and transfers) being severely affected and domain 3 (distal muscle function) relatively spared. Physical activity as measured through accelerometry showed very strong correlations to MFM-20/32 (Pearson correlation, -0.928, p < 0.01). Muscle ultrasound showed symmetrically increased echogenicity, with the sternocleidomastoid muscle most affected. Respiratory function was impaired in 85% of patients without prominent diaphragm dysfunction and was independent of age. Ten patients (37%) needed (non)invasive ventilatory support. Cardiac assessment revealed QRS fragmentation in 62%, abnormal left ventricular global longitudinal strain in 25%, and decreased left ventricular ejection fraction in 14% of patients. Decreased bone quality leading to fragility fractures was seen in most of the patients. Discussion: LAMA2-MD has a widely variable phenotype. Based on the results of this cross-sectional study and current standards of care for congenital muscular dystrophies, we advise routine cardiorespiratory follow-up and optimization of bone quality. We propose MFM-20/32, accelerometry, and muscle ultrasound for assessing disease severity and progression. For definitive clinical recommendations and outcome measures, natural history data are needed. Clinical Trials Registration: This study was registered at clinicaltrials.gov (NCT04478981, 21 July 2020). The first patient was enrolled in September 2020.

The most important problems and needs of rasopathy patients with a noonan syndrome spectrum disorder.

BACKGROUND: Noonan syndrome spectrum disorders (NSSDs) constitute a group within the Rasopathies, and are one of the largest groups of syndromes with impact on multi-organ involvement known. The extreme variability of the clinical phenotype is, among others, due to the numerous different genes that are involved, and the differences in clinical presentation over the life span. We have studied the needs of patients and their relatives aiming to develop, evaluate and choose focus in research, medical care and policy to better meet their perspectives. METHODS: Using the participatory and interactive Dialogue method, 80 patients and relatives mentioned 53 different problems or needs (topics) that were categorized into eight themes. These themes and the topics within each theme, were subsequently prioritized by putting them in order of importance methodologically. RESULTS: The four highest prioritized themes were: (1) Physical problems (non-musculoskeletal related); (2) Social, emotional and behavioral problems; (3) Cognitive functioning and information processing; and (4) Problems related to the musculoskeletal system. Nineteen out of the 53 topics were physical problems. According to the total group of respondents, the top 3 prioritized topics within theme 1 were coagulation problems, heart problems, and feeding problems. Also data stratified by age groups, phenotype (NS and other NSSDs) and gender showed some remarkable results. For instance, feeding problems were prioritized as the most important topic of the highest prioritized theme, according to patients aged 0-12 years. Also feeding problems show a significant difference in its prioritization according to female patients (2) compared to male patients (7). On the other hand, heart problems were not mentioned in the top three prioritized topics in the youngest age groups, although heart problems are generally considered most important for patients with NSSD. CONCLUSIONS: With our results we underline the importance of methodologically inventorying the needs of NSSD patients, not only at the group level, but to also focus on specific needs according to e.g. age, phenotype and gender. For instance, it is remarkable that both the current Clinical Guidelines and the Noonan Syndrome diagnostic criteria give little to no attention to feeding problems, though our results indicate that, to the youngest patients, these problems have top priority. A similar situation appears to apply to the clinical management of e.g. coagulation, neuropsychological and musculoskeletal problems (like physiotherapy or occupational therapy) and to a need for (educational) tools to support patients at school or at work. Our study may help to shape targeted (clinical) management, research and policy inside and outside medical (research) institutes and shed light on the complex phenotypes of NSSDs, the families' and patients' perspectives on the everyday consequences of the many different problems, as well as their needs.

Learning for doctor-to-doctor collaboration: a qualitative study exploring the experiences of residents and supervisors with intraprofessional workplace learning in complex tertiary care.

BACKGROUND: To deliver high-quality care for individuals with complex medical conditions, residents need to be trained across the boundaries of their specialties. This study aimed to explore learning activities and influencing factors in intraprofessional workplace learning by residents in complex tertiary care. METHODS: This qualitative study was conducted in a tertiary care children's hospital. In September - December 2017, fourteen individual and two focus group interviews were conducted with a purposive sample of residents and supervisors of various specialties. Transcribed interviews were thematically analyzed to describe learning activities and influencing factors that play a role in intraprofessional workplace learning in complex tertiary care settings during residency training. RESULTS: Respondents described numerous activities that they considered opportunities for intraprofessional learning, both directly and not directly related to patient care. However, deliberate attention to intraprofessional learning often seemed to be lacking in clinical practice. Influencing factors on a system (macro), organization (meso) and personal and interpersonal level (micro) level were identified. Factors on the macro and meso level mainly determined whether intraprofessional learning opportunities arose, while micro level factors mainly influenced whether opportunities were seized. CONCLUSIONS: There are ample opportunities for intraprofessional workplace learning in complex tertiary care for residents. Residents may benefit more from intraprofessional learning opportunities if these are made more intentional and deliberate. Influencing factors at the macro, meso and micro level provide targets for interventions aimed at enhancing intraprofessional workplace learning in postgraduate medical training.

Hypertrophic neuropathy: a possible cause of pain in children with Noonan syndrome and related disorders.

This study is aimed at describing the findings of high-resolution nerve ultrasound in children with Noonan syndrome (NS) and related disorders experiencing pain in their legs. This retrospective cohort study was conducted in the NS expert center of the Radboud University Medical Center in the Netherlands. Patients were eligible if they were younger than 18 years, clinically and genetically diagnosed with NS or a NS related disorder, and experienced pain in their legs. Anamneses and physical examination were performed in all children. In addition, high-resolution nerve ultrasound was used to assess nerve hypertrophy and, if needed, complemented spinal magnetic resonance imaging was performed. Over a period of 6 months, four children, three with NS and one child with NS with multiple lentigines, who experienced pain of their legs were eligible for inclusion. Muscle weakness was found in two of them. High-resolution nerve ultrasound showed (localized) hypertrophic neuropathy in all patients. One child underwent additional spinal magnetic resonance imaging, which showed profound thickening of the nerve roots and plexus.  Conclusion: In the four children included with a NS and related disorders, pain was concomitant with nerve hypertrophy, which suggests an association between these two findings. The use of high-resolution nerve ultrasound and spinal magnetic resonance imaging might result in better understanding of the nature of this pain and the possible association to nerve hypertrophy in patients with NS and related disorders. What is Known: • Children with Noonan syndrome and related disorders may report pain in their legs, which is often interpreted as growing pain. • Some adults with Noonan syndrome and related disorders have hypertrophic neuropathy as a possible cause of neuropathic pain. What is New: • This is the first study using high-resolution nerve ultrasound in children with Noonan syndrome and related disorders experiencing pain in their legs. • Hypertrophic neuropathy was diagnosed as possible cause of pain in four children with Noonan syndrome and related disorders.

Bone Quality in Patients with a Congenital Myopathy: A Scoping Review.

BACKGROUND: Congenital myopathies are rare neuromuscular disorders presenting with a wide spectrum of clinical features, including long bone fractures (LBFs) that negatively influence functional prognosis, quality of life and survival. Systematic research on bone quality in these patients is lacking. OBJECTIVE: This scoping review aims to summarize all evidence on bone quality and to deduce recommendations for bone quality management in congenital myopathies. METHODS: Five electronic databases (Pubmed, Embase, Cochrane, Web of Science, CINAHL) were searched. All studies on bone quality in congenital myopathies were included. Decreased bone quality was defined as low bone mineral density and/or (fragility) LBFs. Study selection and data extraction were performed by three independent reviewers. RESULTS: We included 244 single cases (mean: 4.1±7.6 years; median: 0 years) diagnosed with a congenital myopathy from 35 articles. Bone quality was decreased in 93 patients (37%) (mean: 2.6±6.8 years; median: 0 years). Low bone mineral density was reported in 11 patients (4.5%) (mean: 10.9±9.7; median: 11 years). Congenital LBFs were reported in 64 patients (26%). (Fragility) LBFs later at life were described in 24 patients (9.8%) (mean: 14.9±11.0; median: 14 years). Four cases (1.6%) were reported to receive vitamin D and/or calcium supplementation or diphosphonate administration. CONCLUSION: LBFs are thus frequently reported in congenital myopathies. We therefore recommend optimal bone quality management through bone mineral density assessment, vitamin D and calcium suppletion, and referral to internal medicine or pediatrics for consideration of additional therapies in order to prevent complications of low bone mineral density.

Healthcare professionals' knowledge of the systematic ABCDE approach: a cross-sectional study.

BACKGROUND: The Airway, Breathing, Circulation, Disability and Exposure (ABCDE) approach is a universal, priority-based approach for the assessment and treatment of critically ill patients. Although the ABCDE approach is widely recommended, adherence in practice appears to be suboptimal. The cause of this non-compliance is unknown. As knowledge is a prerequisite for adherence, the aim of this study was to assess healthcare professionals' knowledge of the ABCDE approach. METHODS: A cross-sectional study was conducted at the Radboud University Medical Center, the Netherlands. A digital multiple-choice assessment tool of the ABCDE approach was developed by an expert panel through a mini-Delphi method and validated by performing test item statistics and an expert-novice comparison. The validated test was sent to healthcare professionals (nurses, residents and medical specialists) of the participating departments: Anaesthesiology, Paediatrics, Emergency Department and the Neonatal, Paediatric and Adult Intensive Care Units. Primary outcome was the test score, reflecting individual level of knowledge. Descriptive statistics, regression analysis and ANOVA were used. RESULTS: Test validation showed a Cronbach's alpha of 0.71 and an expert-novice comparison of 91.9% (standard deviation (SD) 9.1) and 72.4% (15.2) respectively (p < 0.001). Of 954 eligible participants, 240 filled out the questionnaire. The mean (SD) test score (% of correct answers) was 80.1% (12.2). Nurses had significantly lower scores (74.9% (10.9)) than residents (92.3% (7.5)) and medical specialists (88.0% (8.6)) (p < 0.001). The Neonatal Intensive Care Unit (75.9% (12.6)) and Adult Intensive Care Unit (77.4% (11.2)) had significantly lower scores than Paediatric Intensive Care Unit (85.6% (10.6)), Emergency Department (85.5% (10.4)) and Anaesthesiology (85.3% (10.6)) (p < 0.05). Younger participants scored higher than older participants (-0.30% (-0.46;-0.15) in test score/year increase in age). CONCLUSION: Scores of a validated knowledge test regarding the ABCDE approach vary among healthcare professionals caring for critically ill patients. Type of department, profession category and age had a significant influence on the test score. Further research should relate theoretical knowledge level to clinical practice. Tailored interventions to increase ABCDE-related knowledge are recommended.

Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study.

Noonan syndrome (NS) has been associated with an increased risk of lymphatic anomalies, with an estimated prevalence of 20%. The prevalence of lymphatic anomalies seems to differ between pathogenic variants. Therefore, this study aims to describe the clinical presentation, prevalence and genotype-phenotype correlations of lymphatic anomalies during life in patients with NS. This retrospective cohort study included patients (n = 115) who were clinically and genetically diagnosed with NS and visited the Noonan expertise Center of the Radboud University Medical Center between January 2015 and March 2021. Data on lymphatic anomalies during lifetime were obtained from medical records. Lymphatic anomalies most often presented as an increased nuchal translucency, chylothorax and/or lymphedema. Prenatal lymphatic anomalies increased the risk of lymphatic anomalies during infancy (OR 4.9, 95% CI 1.7-14.6). The lifetime prevalence of lymphatic anomalies was 37%. Genotype-phenotype correlations showed an especially high prevalence of lymphatic anomalies during infancy and childhood in patients with a pathogenic SOS2 variant (p = 0.03 and p < 0.01, respectively). This study shows that patients with NS have a high predisposition for developing lymphatic anomalies during life. Especially patients with prenatal lymphatic anomalies have an increased risk of lymphatic anomalies during infancy. Genotype-phenotype correlations were found in pathogenic variants in SOS2.

Cognitive Phenotype and Psychopathology in Noonan Syndrome Spectrum Disorders through Various Ras/MAPK Pathway Associated Gene Variants.

Cognitive difficulties are argued to be common in patients with Noonan syndrome spectrum disorders (NSSDs), but findings are based on studies in which patients with variants in PTPN11 (prevalence ~50%) were overrepresented. The current study, using a structured clinical approach, describes the cognitive phenotype and psychopathology of 100 patients (aged 6 to 61 years) with nine different gene variants in the Ras/MAPK pathway underlying NSSDs (PTPN11n = 61, PTPN11 Noonan syndrome with multiple lentigines n = 3, SOS1n = 14, KRASn = 7, LZTR1n = 5, RAF1n = 4, SHOC2n = 2, CBLn = 2, SOS2n = 2). After weighted assessment and bootstrapping of the results of individual neuropsychological assessments and measures of psychopathology, cognitive performances in most variant groups were within the ranges of expectation. IQs were significantly lower in patients with variants in PTPN11, KRAS, RAF1, and SHOC2, but no specific cognitive impairments were found. The performances of younger participants (<16 years of age) did not differ from those of adults. Alexithymia and internalizing problems were more frequent in patients with variants in PTPN11 and SOS1, while PTPN11 patients also showed higher levels of externalizing problems. These results stress the need to take intelligence into account when interpreting lower cognitive performances in individual neuropsychological assessments, which is crucial for an adequate understanding and guidance of patients with NSSDs.

Lymphatic Phenotype of Noonan Syndrome: Innovative Diagnosis and Possible Implications for Therapy.

Dysregulation of the Ras/Mitogen-activated protein kinase (MAPK) signaling pathway is suggested to play a pivotal role in the development of the lymphatic system in patients with Noonan Syndrome (NS). Pathogenic gene variants in the Ras/MAPK pathway can therefore lead to various lymphatic diseases such as lymphedema, chylo-thorax and protein losing enteropathy. Diagnosis and treatment of the lymphatic phenotype in patients with NS remain difficult due to the variability of clinical presentation, severity and, probably, underlying unknown pathophysiologic mechanism. The objective of this article is to give an overview of the clinical presentation of lymphatic disease in relation to central conducting lymphatic anomalies (CCLA) in NS, including new diagnostic and therapeutic options. We visualized the central conducting lymphatic system using heavily T2-weighted MR imaging (T2 imaging) and Dynamic Contrast-enhanced MR Lymphangiography (DCMRL) and compared these results with the lymphatic clinical presentation in seven patients with NS. Our results show that most patients with NS and lymphatic disease have CCLA. Therefore, it is probable that CCLA is present in all patient with NS, presenting merely with lymphedema, or without sensing lymphatic symptoms at all. T2 imaging and DCMRL can be indicated when CCLA is suspected and this can help to adjust therapeutic interventions.

The lymphatic system throughout history: From hieroglyphic translations to state of the art radiological techniques.

A comprehensive lymphatic system is indispensable for a well-functioning body; it is integral to the immune system and is also interrelated with the digestive system and fluid homeostasis. The main difficulty in examining the lymphatic system is its fine-meshed structure. This remains a challenge, leaving patients with uninterpreted symptoms and a dearth of potential therapies. We review the history of the lymphatic system up to the present with the aim of improving current knowledge. Several findings described throughout history have made fundamental contributions to elucidating the lymphatic system. The first contributions were made by the ancient Egyptians and the ancient Greeks. Vesalius obtained new insights by dissecting corpses. Thereafter, Ruysch (1638-1731) gained an understanding of lymphatic flow. In 1784, Mascagni published his illustration of the whole lymphatic network. The introduction of radiological lymphography revolutionized knowledge of the lymphatic system. Pedal lymphangiography was first described by Monteiro (1931) and Kinmonth (1952). Lymphoscintigraphy (nuclear medicine), magnetic resonance imaging, and near-infrared fluorescence lymphography further improved visualization of the lymphatic system. The innovative dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) transformed understanding of the central lymphatic system, enabling central lymphatic flow disorders in patients to be diagnosed and even allowing for therapeutic planning. From the perspective of the history of lymph visualization, DCMRL has ample potential for identifying specific causes of debilitating symptoms in patients with central lymphatic system abnormalities and even allows for therapeutic planning.

Feeding Problems in Patients with Noonan Syndrome: A Narrative Review.

Noonan syndrome (NS) belongs to the group of Noonan syndrome spectrum disorders (NSSD), which is a group of phenotypically related conditions. Feeding problems are often present not only in infancy but also in childhood, and even beyond that period. We describe the different aspects of feeding problems using a (theoretical) concept proposed in 2019. More than 50% of infants with NS develop feeding problems, and up to half of these infants will be tube-dependent for some time. Although, in general, there is a major improvement between the age of 1 and 2 years, with only a minority still having feeding problems after the age of 2 years, as long as the feeding problems continue, the impact on the quality of life of both NS infants and their caregivers may be significant. Feeding problems in general improve faster in children with a pathogenic PTPN11 or SOS1 variant. The mechanism of the feeding problems is complex, and may be due to medical causes (gastroesophageal reflux disease and delayed gastric emptying, cardiac disease and infections), feeding-skill dysfunction, nutritional dysfunction with increased energy demand, or primary or secondary psychosocial dysfunction. Many of the underlying mechanisms are still unknown. The treatment of the feeding problems may be a medical challenge, especially when the feeding problems are accompanied by feeding-skill dysfunction and psychosocial dysfunction. This warrants a multidisciplinary intervention including psychology, nutrition, medicine, speech language pathology and occupational therapy.