Management of nutritional and gastrointestinal issues in RASopathies: A narrative review

Abstract

Noonan, Costello, and cardio-facio-cutaneous syndrome are neurodevelopmental disorders belonging to the RASopathies, a group of syndromes caused by alterations in the RAS/MAPK pathway. They are characterized by similar clinical features, among which feeding difficulties, growth delay, and gastro-intestinal disorders are frequent, causing pain and discomfort in patients. Hereby, we describe the main nutritional and gastrointestinal issues reported in individuals with RASopathies, specifically in Noonan syndrome, Noonan syndrome-related disorders, Costello, and cardio-faciocutaneous syndromes. Fifty percent of children with Noonan syndrome may experience feeding difficulties that usually have a spontaneous resolution by the second year of life, especially associated to genes different than PTPN11 and SOS1. More severe manifestations often require artificial enteral nutrition in infancy are observed in Costello syndrome, mostly associated to c.34G>A substitution in the HRAS gene.In cardio-facio-cutaneous syndrome feeding issues are usually present (90-100% of cases), especially in individuals carrying variants in BRAF, MAP2K1, and MAP2K2 genes, and artificial enteral intervention, even after scholar age, may be required.Moreover, disorders associated with gastrointestinal dysmotility as gastroesophageal reflux and constipation are commonly reported in all the abovementioned syndromes. Given the impact on growth and on the quality of life of these patients, early evaluation and prompt personalized management plans are fundamental.

The “FEEDS (FEeding Eating Deglutition Skills)” over Time Study in Cardiofaciocutaneous Syndrome

“…In the present cohort, feeding difficulties were a constant finding since before birth, as demonstrated by the high prevalence of reported polyhydramnios, namely a pathological increase in amniotic fluid, mainly due to disturbed foetal swallowing [28], as was described by Allanson et al [14]. Soon after birth, a high prevalence of scarce sucking ability leading to a need for enteral nutrition support has been noted in almost all published cohorts, analogous to what was also observed for most infants with CS [29][30][31][32]. Despite these common aspects shared by both CS and CFCS, CS children face an improvement in feeding abilities during growth [33], requiring the placement of a gastrostomy tube that is usually removed at 4 or 5 years of life [29].…”

“…The genotype-phenotype correlation between CFCS genes and feeding difficulties has been recently analysed [29], showing a relatively homogeneous and high prevalence of artificial enteral nutrition (with any kind of device), independent from the causative gene mutation (48-54%, BRAF; 40-67%, MAP2K1; 40-50%, MAP2K2) [14,15]. The prevalence of artificial enteral nutrition in our cohort is similar to the ones that have been previously reported in the literature.…”

“…Moreover, the administration of the I-MCH-FS allowed us to quantify feeding difficulties in the CFCS children, showing, in most cases, results above the normality range [24,25], confirming the extent of these issues experienced by the entire families and/or caregivers [13]. The described negative mealtime behaviours, including long feeding time and tendency to spit foods [29], are triggered by impaired oral sensory regulation, quantified in this study by the SP questionnaire. In addition to RASopathies [39], atypical sensory modulation has also been reported in other conditions, namely Smith-Magenis, Williams and X-fragile syndromes [40][41][42].…”

“…Soon after birth, a high prevalence of scarce sucking ability leading to a need for enteral nutrition support has been noted in almost all published cohorts, analogous to what was also observed for most infants with CS [29][30][31][32]. Despite these common aspects shared by both CS and CFCS, CS children face an improvement in feeding abilities during growth [33], requiring the placement of a gastrostomy tube that is usually removed at 4 or 5 years of life [29]. Such a finding is in contrast with what is observed in CFCS children who face persistent food aversion and oral hypersensitivity, therefore requiring enteral nutrition support even after early childhood [25].…”

Validation and cross‐cultural adaptation of the Italian version of the paediatric eating assessment tool (I‐PEDI‐EAT‐10) in genetic syndromes

“…Signs and symptoms of dysphagia include breathing difficulties during feeding, coughing and/or choking during or after swallowing, gagging, drooling, frequent respiratory illnesses, food refusal or difficulty chewing foods that are texturally appropriate for age (Harding et al., 2022; Prasse & Kikano, 2009). The child's inability to eat and drink safely may lead not only to undernutrition/malnutrition, dehydration and poor growth (Leoni et al., 2016; Onesimo et al., 2022), but also to aspiration pneumonia (Southall & Schwartz, 2000). There is a significant risk of the development of malnutrition in hospitalized children with abnormal swallowing (Ilgaz et al., 2018).…”