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.

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.

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.

Diagnosing, discarding, or de-VUSsing: A practical guide to (un)targeted metabolomics as variant-transcending functional tests.

PURPOSE: For patients with inherited metabolic disorders (IMDs), any diagnostic delay should be avoided because early initiation of personalized treatment could prevent irreversible health damage. To improve diagnostic interpretation of genetic data, gene function tests can be valuable assets. For IMDs, variant-transcending functional tests are readily available through (un)targeted metabolomics assays. To support the application of metabolomics for this purpose, we developed a gene-based guide to select functional tests to either confirm or exclude an IMD diagnosis. METHODS: Using information from a diagnostic IMD exome panel, Kyoto Encyclopedia of Genes and Genomes, and Inborn Errors of Metabolism Knowledgebase, we compiled a guide for metabolomics-based gene function tests. From our practical experience with this guide, we retrospectively selected illustrative cases for whom combined metabolomic/genomic testing improved diagnostic success and evaluated the effect hereof on clinical management. RESULTS: The guide contains 2047 metabolism-associated genes for which a validated or putative variant-transcending gene function test is available. We present 16 patients for whom metabolomic testing either confirmed or ruled out the presence of a second pathogenic variant, validated or ruled out pathogenicity of variants of uncertain significance, or identified a diagnosis initially missed by genetic analysis. CONCLUSION: Metabolomics-based gene function tests provide additional value in the diagnostic trajectory of patients with suspected IMD by enhancing and accelerating diagnostic success.

Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: A retrospective cohort study.

Background: De novo variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI). Methods: This study explored the potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI that underwent patient-parent trio-based WES. Results: A (likely) molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic in silico IEI WES gene panel. Systematic evaluation of rare, non-synonymous DNVs in coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were found in IEI genes (NLRP3 and RELA) and in potentially novel candidate genes, including PSMB10, DDX1, KMT2C, and FBXW11. The FBXW11 canonical splice site DNV was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1ß production in primary immune cells extracted from the patient with autoinflammatory disease. Conclusions: Our findings in this retrospective cohort study advocate the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we provide functional evidence supporting a causal role for FBXW11 loss-of-function mutations in autoinflammatory disease. Funding: This research was supported by grants from the European Union, ZonMW and the Radboud Institute for Molecular Life Sciences.

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 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.

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.

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.

Lymphatic Abnormalities in Noonan Syndrome Spectrum Disorders: A Systematic Review.

Noonan syndrome spectrum disorders are a group of phenotypically related conditions, resembling Noonan syndrome, caused by germline pathogenic variants in genes within the Ras/mitogen-activated protein kinase (Ras/MAPK) signalling pathway. Lymphatic dysplasia with a clinical lymphatic abnormality is one of the major features. We performed a systematic review to get more insight in (1) the prevalence of clinically lymphatic abnormalities in patients with a genetically proven Noonan syndrome spectrum disorder, (2) if a genotype-lymphatic phenotype relation can be found and describe the clinical presentation and course of the lymphatic abnormality. Most studies report patients with Noonan syndrome. Prenatally, the prevalence of increased nuchal translucency differs from 7% in patients with pathogenic PTPN11 variants to 38% in patients with pathogenic RIT1 variants, and the prevalence of pleural effusions differed from 7% in patients with pathogenic SOS1 to 29% in patients with pathogenic RIT1 variants. Postnatally, the prevalence of lymphedema differs from 16% in patients with pathogenic PTPN11 variants to 44% in patients with pathogenic SOS1 variants, and the prevalence of acquired chylothorax is 4% in patients with pathogenic RIT1 variants. Lymphatic abnormalities do occur in patients with cardiofaciocutaneous syndrome and Costello syndrome. In conclusion, Noonan syndrome spectrum disorders, Noonan syndrome in particular, are associated with lymphatic abnormalities. Combining the available published literature about genetically proven Noonan syndrome spectrum disorders, it appears likely that the lifetime prevalence of these abnormalities in Noonan syndrome is higher than the 20% that were generally accepted so far. This is increasingly important, because the activation of the RAS/MAPK pathway can be inhibited by RAS/MAPK inhibitors, and clinically severe lymphatic abnormalities may improve.

The added value of the electrocardiogram in Noonan syndrome.

Noonan syndrome is a genetic disorder characteried by short stature, typical facial features, developmental delay, and CHD. In this single-centre retrospective study, we analysed typical Noonan syndrome-related electrocardiographic features in 95 patients with clinically and molecularly confirmed Noonan syndrome. Typical Noonan syndrome-related electrocardiographic features are left axis deviation, small left precordial R-waves, large right precordial S-waves, abnormal Q-wave, and abnormal wide QRS complex. In this representative cohort, CHD was found in 59 patients (62.1%) and typical Noonan syndrome-related electrographic features in 60 patients (63.2%). The typical Noonan syndrome-related electrographic features were also increased over baseline in patients without CHD (41.7%). Of all 95 patients, left axis deviation was seen in 46.3%, small left precordial R-waves in 30.5%, large right precordial S-waves in 5.3%, and abnormal Q-wave and wide QRS complex in 2.1%. There was no significant difference in the frequency of the individual-specific electrographic features between the group with CHD and the group without CHD. However, there were significantly more patients with a small left precordial R-wave in the subgroup with pulmonary stenosis compared to patients without pulmonary stenosis. Conclusion: Specific Noonan syndrome-related electrographic features are frequently present in patients with Noonan syndrome, also in the absence of CHD. These results suggest that there may be a continuum of cardiac anomalies from overt CHD to milder abnormalities that are only seen on electrocardiogram.

Patient engagement in the design of clinical research in Noonan syndrome spectrum disorders: a scoping review.

BACKGROUND: Noonan syndrome spectrum disorders are a group of disorders caused by mutations in several genes of the RAS/MAPK pathway. Because of a highly heterogeneity and variable phenotypical manifestations of the disorders, these children and adults have a variable number of symptoms. Inclusion of their perceived experience of their health and developmental problems in research (design) could contribute to increased relevance of the research process and outcomes. The aim of this study is to get insight in what way patients with a Noonan syndrome spectrum disorder have been involved in the research process in order to learn for future engagement practices. METHODS AND RESULTS: To that end, the degree of engagement was measured by the eight levels of the participation ladder of Arnstein. Using a scoping review approach, 18 articles were selected in which patient engagement in the design of studies in patients with Noonan syndrome spectrum disorders was described over the past twenty years. Six of these articles reported engagement on the level of informing (level 3), 8 on the level of consultation (level 4), 2 on the level of placation (level 5)and 2 on the level of partnership (level 6). CONCLUSIONS: The current results do show a positive albeit still modest development of patient engagement over the last few years. A promising way to stimulate engagement is aiming to yield insights in the most important patients' needs by developing a patient guided research agenda. However, this is not automatically followed by patient engagement at higher levels of participation in subsequent research steps. For this reason, in the Netherlands for example, a Dutch Noonan syndrome spectrum disorders research agenda is being developed, in a collaboration between the Dutch Noonan Syndrome Foundation and national scientific and clinical professionals.

TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility.

Deletions that include the gene TAB2 and TAB2 loss-of-function variants have previously been associated with congenital heart defects and cardiomyopathy. However, other features, including short stature, facial dysmorphisms, connective tissue abnormalities and a variable degree of developmental delay, have only been mentioned occasionally in literature and thus far not linked to TAB2. In a large-scale, social media-based chromosome 6 study, we observed a shared phenotype in patients with a 6q25.1 deletion that includes TAB2. To confirm if this phenotype is caused by haploinsufficiency of TAB2 and to delineate a TAB2-related phenotype, we subsequently sequenced TAB2 in patients with matching phenotypes and recruited patients with pathogenic TAB2 variants detected by exome sequencing. This identified 11 patients with a deletion containing TAB2 (size 1.68-14.31 Mb) and 14 patients from six families with novel truncating TAB2 variants. Twenty (80%) patients had cardiac disease, often mitral valve defects and/or cardiomyopathy, 18 (72%) had short stature and 18 (72%) had hypermobility. Twenty patients (80%) had facial features suggestive for Noonan syndrome. No substantial phenotypic differences were noted between patients with deletions and those with intragenic variants. We then compared our patients to 45 patients from the literature. All literature patients had cardiac diseases, but syndromic features were reported infrequently. Our study shows that the phenotype in 6q25.1 deletions is caused by haploinsufficiency of TAB2 and that TAB2 is associated not just with cardiac disease, but also with a distinct phenotype, with features overlapping with Noonan syndrome. We propose the name "TAB2-related syndrome".

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype.

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.

Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications.

RASopathies are caused by variants in genes encoding components or modulators of the RAS/MAPK signaling pathway. Noonan syndrome is the most common entity among this group of disorders and is characterized by heart defects, short stature, variable developmental delay, and typical facial features. Heterozygous variants in SOS2, encoding a guanine nucleotide exchange factor for RAS, have recently been identified in patients with Noonan syndrome. The number of published cases with SOS2-related Noonan syndrome is still limited and little is known about genotype-phenotype correlations. We collected previously unpublished clinical and genotype data from 17 individuals carrying a disease-causing SOS2 variant. Most individuals had one of the previously reported dominant pathogenic variants; only four had novel changes at the established hotspots for variants that affect protein function. The overall phenotype of the 17 patients fits well into the spectrum of Noonan syndrome and is most similar to the phenotype observed in patients with SOS1-related Noonan syndrome, with ectodermal anomalies as common features and short stature and learning disabilities as relatively infrequent findings compared to the average Noonan syndrome phenotype. The spectrum of heart defects in SOS2-related Noonan syndrome was consistent with the known spectrum of cardiac anomalies in RASopathies, but no specific heart defect was particularly predominating. Notably, lymphatic anomalies were extraordinarily frequent, affecting more than half of the patients. We therefore conclude that SOS2-related Noonan syndrome is associated with a particularly high risk of lymphatic complications that may have a significant impact on morbidity and quality of life.

Young children with Noonan syndrome: evaluation of feeding problems.

Noonan syndrome (NS) is a common genetic syndrome with a high variety in phenotype. Even though genetic testing is possible, NS is still a clinical diagnosis. Feeding problems are often present in infancy. We investigated the feeding status of 108 patients with clinically and genetically confirmed NS. Only patients with a documented feeding status before the age of 6 were included. A distinction was made between patients with early onset feeding problems (< 1 year) and children with late onset feeding problems (> 1 year). Seventy-one of 108 patients had feeding problems, of which 40 patients required tube feeding. Children with a genetic mutation other than PTPN11 and SOS1 had significantly more feeding problems in the first year. Fifty-two of all 108 patients experienced early onset feeding problems, of which 33 required tube feeding. A strong decrease in prevalence of feeding problems was found after the first year of life. Fifteen children developed feeding problems later in life, of which 7 required tube feeding.Conclusion: Feeding problems occur frequently in children with NS, especially in children with NS based on genetic mutations other than PTPN11 and SOS1. Feeding problems develop most often in infancy and decrease with age. What is Known: • Young children with Noonan syndrome may have transient feeding problems. • Most of them will need tube feeding. What is New: • This is the first study of feeding problems in patients with clinically and genetically proven Noonan syndrome. • Feeding problems most often develop in infancy and resolve between the age of 1 and 2.

Cancer prevention by aspirin in children with Constitutional Mismatch Repair Deficiency (CMMRD).

Constitutional MisMatch Repair Deficiency (CMMRD) is caused by homozygous or compound heterozygous germline variants in one of the mismatch repair (MMR) genes (MSH2, MSH6, PMS2, MLH1). This syndrome results in early onset colorectal cancer, leukemia and lymphoma, brain tumors and other malignancies. Children with CMMRD are at high risk of developing multiple cancers and cancer surveillance does not guarantee detection of cancer at a curable stage. The development of a preventive treatment strategy would be a major step forward. Long-term daily use of acetylsalicylic acid (ASA) has been shown to reduce cancer risk in individuals with Lynch syndrome (LS). LS is caused by heterozygous germline variants of MSH2, MSH6, PMS2 and MLH1 and characterized by an increased risk of developing colorectal and endometrial cancer at adult age. Here we discuss the potential use of ASA for cancer prevention in patients with CMMRD.

Low- versus High-Dose and Early versus Late Parenteral Amino-Acid Administration in Very-Low-Birth-Weight Infants: A Systematic Review and Meta-Analysis.

OBJECTIVES: Providing parenteral amino acids to very-low-birth-weight infants during the first weeks of life is critical for adequate growth and neurodevelopment. However, there is no consensus about what dose is appropriate or when to initiate supplementation. As a result, daily practice varies among neonatal intensive care units. The objective of our study was to determine the effects of early parenteral amino-acid supplementation (within 24 h of birth) versus later initiation and high dose (>3.0 g/kg/day) versus a lower dose on growth and morbidities. METHODS: A systematic review and meta-analysis of publications identified by searching PubMed, EMBASE, and Cochrane databases was conducted. Randomized controlled studies were eligible if information on growth was available. RESULTS: The search identified 14 studies. No differences were observed in growth or morbidity after early or high-dose amino-acid supplementation, but for several outcomes, meta-analysis was not possible due to study heterogeneity. Initiation of amino acids within the first 24 h of life appeared to be safe and well tolerated, and leads more rapidly to a positive nitrogen balance. CONCLUSIONS: Administering a high dose (>3.0 g/kg/day) or an early dose (≤24 h) of parenteral amino acids is safe and well tolerated but does not offer significant benefits on growth. Further large-scale randomized controlled trials in preterm infants are needed to study the effects of early and high-dose amino acids on growth and morbidity more consistently and extensively.