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Disease Models & Mechanisms Feb 2022The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including... (Review)
Review
The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome and Legius syndrome, among others, have overlapping clinical features due to RAS/MAPK dysfunction. Although several of the RASopathies are very rare, collectively, these disorders are relatively common. In this Review, we discuss the pathogenesis of the RASopathy-associated genetic variants and the knowledge gained about RAS/MAPK signaling that resulted from studying RASopathies. We also describe the cell and animal models of the RASopathies and explore emerging RASopathy genes. Preclinical and clinical experiences with targeted agents as therapeutics for RASopathies are also discussed. Finally, we review how the recently developed drugs targeting RAS/MAPK-driven malignancies, such as inhibitors of RAS activation, direct RAS inhibitors and RAS/MAPK pathway inhibitors, might be leveraged for patients with RASopathies.
Topics: Animals; Costello Syndrome; Failure to Thrive; Humans; Neurofibromatosis 1; Noonan Syndrome; ras Proteins
PubMed: 35178568
DOI: 10.1242/dmm.049107 -
Nutrition in Clinical Practice :... Feb 2017The publication of the landmark paper "Defining Pediatric Malnutrition: A Paradigm Shift Toward Etiology-Related Definitions" launched a new era in diagnosing pediatric... (Review)
Review
The publication of the landmark paper "Defining Pediatric Malnutrition: A Paradigm Shift Toward Etiology-Related Definitions" launched a new era in diagnosing pediatric malnutrition. This work introduced the paradigm shift of etiology-related definitions-nonillness and illness related-and the use of anthropometric z scores to help identify and describe children with malnutrition (undernutrition) in the developed world. Putting the new definition into practice resulted in some interesting observations: (1) Etiology-related definitions result in etiology-related interventions. (2) Illness-related malnutrition cannot always be immediately "fixed." (3) Using z scores in clinical practice often puts the burden of proof on the clinician to show that a child is not malnourished, rather than the other way around. (4) Children with growth failure severe enough to be admitted with "failure to thrive" should always be assessed for malnutrition, and when they meet the criteria, malnutrition should be documented and coded. The publication of the consensus statement came next, announcing the evidence-informed, consensus-derived pediatric malnutrition indicators. Since the indicators are a work in progress, clinicians are encouraged to use them and give feedback through an iterative process. This review attempts to respond to the consensus statement's call to action by thoughtfully appraising the indicators and making recommendations for future review. Coming together as a healthcare community to identify pediatric malnutrition will ensure that this vulnerable population is not overlooked. Outcomes research will validate the indicators and result in new discoveries of effective ways to prevent and treat pediatric malnutrition.
Topics: Adolescent; Adolescent Development; Body Composition; Child; Child Development; Child Nutrition Disorders; Child, Preschool; Consensus; Deficiency Diseases; Evidence-Based Medicine; Failure to Thrive; Growth Charts; Humans; Infant; Infant Nutrition Disorders; Malnutrition; Nutrition Assessment; Pediatrics; Practice Guidelines as Topic; Severity of Illness Index
PubMed: 27765878
DOI: 10.1177/0884533616671861 -
American Family Physician Aug 2016Children with very low weight for age or height and those who do not maintain an appropriate growth pattern may have failure to thrive (FTT), also known as weight... (Review)
Review
Children with very low weight for age or height and those who do not maintain an appropriate growth pattern may have failure to thrive (FTT), also known as weight faltering. If confirmed by repeated valid measurements, FTT should prompt a search for causes of undernutrition, including neglect, family food insecurity, and underlying medical conditions. Inadequate caloric intake is the most common cause of FTT, but inadequate nutrient absorption or increased metabolism is also possible. Difficulty attaining or maintaining appropriate weight is the first indication of FTT, and sustained undernutrition can impede appropriate height, head circumference, and the development of cognitive skills or immune function in extreme cases. Early identification and management of the issues causing undernutrition are critical. In most cases, an appropriate growth velocity can be established with outpatient management based on proper nutrition and family support. Primary care physicians can effectively treat most children with FTT, and subspecialist consultation or hospitalization is rarely indicated.
Topics: Adolescent; Body Weight; Child; Child, Preschool; Early Diagnosis; Early Medical Intervention; Energy Intake; Failure to Thrive; Growth Charts; Humans; Infant; Infant, Newborn; Malabsorption Syndromes; Malnutrition; Practice Guidelines as Topic
PubMed: 27548594
DOI: No ID Found -
Best Practice & Research. Clinical... Feb 2011Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism,... (Review)
Review
Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects and hypertrophic cardiomyopathy, variable cognitive deficit and skeletal, ectodermal and hematologic anomalies. Noonan syndrome is transmitted as an autosomal dominant trait, and is genetically heterogeneous. So far, heterozygous mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie this disorder or clinically related phenotypes. Based on these recent discoveries, the diagnosis can now be confirmed molecularly in approximately 75% of affected individuals. Affected genes encode for proteins participating in the RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway, which is implicated in several developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations.
Topics: Adolescent; Child; Costello Syndrome; Ectodermal Dysplasia; Facies; Failure to Thrive; Heart Defects, Congenital; Humans; Infant; Intracellular Signaling Peptides and Proteins; LEOPARD Syndrome; Loose Anagen Hair Syndrome; Mitogen-Activated Protein Kinases; Neurofibromatosis 1; Noonan Syndrome; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-cbl; Proto-Oncogene Proteins c-raf; SOS1 Protein
PubMed: 21396583
DOI: 10.1016/j.beem.2010.09.002 -
Journal of Pediatric Gastroenterology... Jul 2023Faltering growth (FG) is a problem regularly seen by clinicians in infants and young children (<2 years of age). It can occur due to non-disease-related and...
Faltering growth (FG) is a problem regularly seen by clinicians in infants and young children (<2 years of age). It can occur due to non-disease-related and disease-related causes and is associated with a wide range of adverse outcomes, including shorter-term effects such as impaired immune responses and increased length of hospital stay, and longer-term consequences, including an impact on schooling and cognitive achievements, short stature, and socioeconomic outcomes. It is essential to detect FG, address underlying causes and support catch-up growth where this is indicated. However, anecdotal reports suggest misplaced fear of promoting accelerated (too rapid) growth may deter some clinicians from adequately addressing FG. An invited international group of experts in pediatric nutrition and growth reviewed the available evidence and guidelines on FG resulting from disease-related and non-disease-related effects on nutritional status in healthy term and small for gestational age infants and children up to the age of 2 years in low-, middle-, and high-income countries. Using a modified Delphi process, we developed practical consensus recommendations to provide clarity and practical recommendations for general clinicians on how FG should be defined in different young child populations at risk, how FG should be assessed and managed, and the role of catch-up growth after a period of FG. We also suggested areas where further research is needed to answer remaining questions on this important issue.
Topics: Infant, Newborn; Infant; Child; Humans; Child, Preschool; Expert Testimony; Infant, Small for Gestational Age; Nutritional Status; Risk Factors; Failure to Thrive
PubMed: 36976274
DOI: 10.1097/MPG.0000000000003784 -
Italian Journal of Pediatrics Mar 2021Failure to thrive is a common reason for referral to paediatric services. Malnutrition or inadequate caloric intake is the most common cause, while organic form is...
BACKGROUND
Failure to thrive is a common reason for referral to paediatric services. Malnutrition or inadequate caloric intake is the most common cause, while organic form is unlikely in children who are asymptomatic and healthy on examination. By this study we evaluate the application of a cost-effective flow chart that helps the clinician in a hospital setting discern accurately organic and non-organic failure to thrive.
METHODS
Conduct a prospective single-center study in children up to 2 years of age with growth faltering. The pediatricians used a practical flow chart, took the medical history, created a growth chart, performed clinical examinations, and requested blood test and consultations in a step by step approach.
RESULTS
Among the 74 subjects included in the study, the diagnosis of organic failure to thrive was reached by 42%. Gastrointestinal and genetic diagnoses were the most frequent. Patients with organic failure to thrive had significantly lower gestational age and birth weight. Age at diagnosis and Z-score weight were lower in organic than in non-organic forms. Most patients with non-organic forms (88%) did not undergo in-depth blood test or specialist advice.
CONCLUSION
The flow chart we presented was accurate for diagnosing children with failure to thrive in a hospital setting and distinct organic and non-organic forms. It was cost-effective to avoid unnecessary blood test or consultations in most non-organic diagnoses.
Topics: Decision Support Techniques; Failure to Thrive; Female; Hospitals, Pediatric; Humans; Infant; Infant, Newborn; Male; Prospective Studies
PubMed: 33691756
DOI: 10.1186/s13052-021-01017-4 -
Clinical and Experimental Pharmacology... Nov 20071. For animals of all ages, during activation of skeletal muscles and the subsequent contraction, the balance between the force developed by the muscle and the external... (Review)
Review
1. For animals of all ages, during activation of skeletal muscles and the subsequent contraction, the balance between the force developed by the muscle and the external load determines whether the muscle shortens, remains at fixed length (isometric) or is lengthened. With maximum activation, the force developed is least during shortening, intermediate when muscle length is fixed and greatest during lengthening contractions. During lengthening contractions, when force is high, muscles may be injured by the contractions. 2. 'Frailty' and 'failure to thrive' are most frequently observed in elderly, physically inactive people. A 'frail' person is defined as one of small stature, with muscles that are atrophied, weak and easily fatigued. The condition of 'failure to thrive' is typified by a lack of response to well-designed programmes of nutrition and physical activity. 3. With ageing, skeletal muscle atrophy in humans appears to be inevitable. A gradual loss of muscle fibres begins at approximately 50 years of age and continues such that by 80 years of age, approximately 50% of the fibres are lost from the limb muscles that have been studied. For both humans and rats, the observation that the timing and magnitude of the loss of motor units is similar to that for muscle fibres suggests that the mechanism responsible for the loss of fibres and the loss of whole motor units is the same. The degree of atrophy of the fibres that remain is largely dependent on the habitual level of physical activity of the individual. 4. 'Master athletes' maintain a high level of fitness throughout their lifespan. Even among master athletes, performance of marathon runners and weight lifters declines after approximately 40 years of age, with peak levels of performance decreased by approximately 50% by 80 years of age. The success of the master athletes and of previously sedentary elderly who undertake well-designed, carefully administered training programmes provide dramatic evidence that age-associated atrophy, weakness and fatigability can be slowed, but not halted.
Topics: Adult; Aged; Aged, 80 and over; Aging; Animals; Exercise; Failure to Thrive; Frail Elderly; Humans; Life Style; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Strength; Muscle Weakness; Muscle, Skeletal; Muscular Atrophy
PubMed: 17880359
DOI: 10.1111/j.1440-1681.2007.04752.x -
American Journal of Medical Genetics.... Mar 2020Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of... (Review)
Review
Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of congenital heart disease (i.e., pulmonary valve stenosis, septal defects, left-sided lesions, and complex forms with multiple anomalies). Care includes attentiveness to several comorbidities, some directly impacting cardiac management (bleeding diatheses and lymphatic anomalies). More than 50% of patients with Noonan syndrome harbor PTPN11 pathogenic variation, which results in hyperactivation of RAS/mitogen-activated protein kinase signaling. Several other disease genes with similar biological effects have been uncovered for NS and phenotypically related disorders, collectively called the RASopathies. Molecular diagnosis with gene resequencing panels is now widely available, but phenotype variability and in some cases, subtlety, continues to make identification of Noonan syndrome difficult. Until genetic testing becomes universal for patients with congenital heart disease, alertness to Noonan syndrome's broad clinical presentations remains crucial. Genotype-phenotype associations for Noonan syndrome enable better prognostication for affected patients when a molecular diagnosis is established. We still lack Noonan syndrome-specific treatment; however, newly developed anticancer RAS pathway inhibitors could fill that gap if safety and efficacy can be established for indications such as pulmonary valve stenosis.
Topics: Abnormalities, Multiple; Failure to Thrive; Heart Defects, Congenital; Humans; Mutation; Noonan Syndrome; Phenotype; Protein Tyrosine Phosphatase, Non-Receptor Type 11
PubMed: 32022400
DOI: 10.1002/ajmg.c.31765 -
Nutrients Jul 2020(1) Introduction: Current evidence on managing infants under six months with growth failure or other nutrition-related risk is sparse and low quality. This review aims...
(1) Introduction: Current evidence on managing infants under six months with growth failure or other nutrition-related risk is sparse and low quality. This review aims to inform research priorities to fill this evidence gap, focusing on breastfeeding practices. (2) Methods: We searched PubMed, CINAHL Plus, and Cochrane Library for studies on feeding interventions that aim to restore or improve the volume or quality of breastmilk and breastfeeding when breastfeeding practices are sub-optimal or prematurely stopped. We included studies from both low- and middle-income countries and high-income countries. (3) Results: Forty-seven studies met the inclusion criteria. Most were from high-income countries ( = 35, 74.5%) and included infants who were at risk of growth failure at birth (preterm infants/small for gestational age) and newborns with early growth faltering. Interventions included formula fortification or supplementation ( = 31, 66%), enteral feeds ( = 8, 17%), cup feeding ( = 2, 4.2%), and other ( = 6, 12.8%). Outcomes included anthropometric change ( = 40, 85.1%), reported feeding practices ( = 16, 34%), morbidity ( = 11, 23.4%), and mortality ( = 5, 10.6%). Of 31 studies that assessed formula fortification or supplementation, 30 reported anthropometric changes ( = 17 no effect, = 9 positive, = 4 mixed), seven morbidity ( = 3 no effect, = 2 positive, = 2 negative), five feeding ( = 2 positive, = 2 no effect, = 1 negative), and four mortality ( = 3 no effect, = 1 negative). Of eight studies that assessed enteral feed interventions, seven reported anthropometric changes ( = 4 positive, = 3 no effect), five feeding practices ( = 2 positive, = 2 no effect, = 1 negative), four morbidity ( = 4 no effect), and one reported mortality ( = 1 no effect). Overall, interventions with positive effects on feeding practices were cup feeding compared to bottle-feeding among preterm; nasogastric tube feed compared to bottle-feeding among low birth weight preterm; and early progressive feeding compared to delayed feeding among extremely low birth weight preterm. Bovine/cow milk feeding and high volume feeding interventions had an unfavourable effect, while electric breast pump and Galactagogue had a mixed effect. Regarding anthropometric outcomes, overall, macronutrient fortified formula, cream supplementation, and fortified human milk formula had a positive effect (weight gain) on preterm infants. Interventions comparing human breastmilk/donor milk with formula had mixed effects. Overall, only human milk compared to formula intervention had a positive effect on morbidity among preterm infants, while none of the interventions had any positive effect on mortality. Bovine/cow milk supplementation had unfavourable effects on both morbidity and mortality. (4) Conclusion: Future research should prioritise low- and middle-income countries, include infants presenting with growth failure in the post-neonatal period and record effects on morbidity and mortality outcomes.
Topics: Bottle Feeding; Breast Feeding; Enteral Nutrition; Failure to Thrive; Humans; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Milk, Human; Weight Gain
PubMed: 32660020
DOI: 10.3390/nu12072044 -
American Journal of Medical Genetics.... Jun 2021Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and... (Observational Study)
Observational Study
Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
Topics: Black People; Constipation; Failure to Thrive; Genetic Association Studies; Genetic Predisposition to Disease; Growth Disorders; Histone-Lysine N-Methyltransferase; Humans; Hypertrichosis; Intellectual Disability; Loss of Function Mutation; Myeloid-Lymphoid Leukemia Protein; Retrospective Studies; White People
PubMed: 33783954
DOI: 10.1002/ajmg.a.62124