Particularităţile terapiei medicale nutriţionale în sindromul Prader-Willi, sindromul de deleţie 22q11.2 și tulburările din spectrul autismului: fenotipuri alimentare, provocări nutriţionale și intervenţii bazate pe dovezi

Introduction

Feeding difficulties represent one of the most common reasons for referral to pediatric dietitians among children with genetic syndromes and neurodevelopmental disorders. These challenges frequently arise from complex interactions between structural abnormalities, neuromotor dysfunction, sensory processing differences, endocrine disturbances, gastrointestinal comorbidities and behavioral factors. Beyond their immediate impact on food intake, feeding difficulties may influence growth, body composition, metabolic health, neurodevelopment and quality of life across the lifespan^(1-9).

Medical nutrition therapy (MNT) plays a central role in the multidisciplinary management of these populations. Early nutritional assessment and individualized dietary intervention may contribute to the prevention of growth failure, nutritional deficiencies, obesity, metabolic complications and feeding-related psychosocial difficulties. However, nutritional management remains particularly challenging because feeding phenotypes differ substantially between disorders and often evolve throughout childhood and adolescence^(1-9).

Prader-Willi syndrome (PWS), 22q11.2 deletion syndrome (DiGeorge syndrome) and autism spectrum disorder (ASD) represent three distinct clinical models of feeding dysfunction. In PWS, the nutritional management is complicated by a unique biphasic feeding pattern characterized by neonatal hypotonia and feeding difficulties followed by progressive hyperphagia, impaired satiety and severe obesity risk^(1-3). In contrast, individuals with 22q11.2 deletion syndrome frequently present with structural feeding impairments related to palatal anomalies, velopharyngeal dysfunction, dysphagia and hypocalcemia secondary to hypoparathyroidism, all of which may compromise nutritional status from infancy^(4-6). Autism spectrum disorder is commonly associated with food selectivity, sensory-based food refusal, restricted dietary variety and gastrointestinal symptoms that may negatively affect dietary quality and nutritional adequacy^(7-9).

Despite major advances in pediatric nutrition, important challenges remain regarding the implementation of evidence-based MNT strategies in these populations. The available literature is characterized by considerable heterogeneity, limited syndrome-specific nutritional outcome data and a relative scarcity of large randomized controlled trials evaluating dietary interventions. Consequently, clinical decision-making often requires the integration of available evidence with multidisciplinary expertise and individualized patient-centered care^(1-9).

The purpose of this narrative review is to summarize current evidence regarding feeding phenotypes, nutritional deficiencies, growth and body composition abnormalities, gastrointestinal manifestations, metabolic complications and evidence-based medical nutrition therapy strategies in Prader-Willi syndrome, 22q11.2 deletion syndrome and autism spectrum disorder. Furthermore, this review aims to provide a comparative perspective on the nutritional challenges encountered across these conditions and to highlight the critical role of multidisciplinary care in optimizing long-term clinical outcomes.

Feeding phenotypes and eating behaviors across disorders

Prader-Willi syndrome: the transition from feeding difficulties to hyperphagia

Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by a distinctive evolution of feeding behavior throughout life. Unlike many pediatric conditions associated exclusively with overeating, individuals with PWS frequently present during infancy with severe hypotonia, weak sucking reflexes, feeding difficulties and impaired growth. These early manifestations often require nutritional support aimed at ensuring adequate energy and protein intake while promoting normal growth and development.

As children age, feeding behavior gradually shifts toward increased appetite, reduced satiety, and progressive hyperphagia. Dysfunction of hypothalamic pathways involved in appetite regulation contributes to persistent hunger and impaired control of food intake. Without appropriate intervention, excessive energy consumption frequently leads to obesity, insulin resistance, dyslipidemia, obstructive sleep apnea and cardiovascular complications.

Medical nutrition therapy in PWS therefore presents a unique challenge, requiring a transition from strategies focused on supporting adequate intake during infancy to long-term energy restriction and obesity prevention. Nutritional management must balance growth requirements with strict environmental control of food access, structured meal routines, family education and regular monitoring of body composition. Current evidence supports the implementation of multidisciplinary interventions combining individualized dietary plans, physical activity promotion, behavioral support and growth hormone therapy when clinically indicated^(1-3).

22q11.2 deletion syndrome (DiGeorge syndrome): structural and functional feeding impairments

Feeding difficulties in 22q11.2 deletion syndrome differ substantially from those observed in PWS, being predominantly related to structural, neuromuscular and developmental abnormalities. Infants frequently present with cleft palate, velopharyngeal insufficiency, craniofacial anomalies, congenital heart defects and impaired coordination of sucking and swallowing, all of which may compromise feeding efficiency and nutritional status.

Dysphagia, prolonged feeding times, aspiration risk, gastroesophageal reflux and growth faltering are commonly reported during infancy and early childhood. In some cases, enteral feeding support may be required to ensure adequate nutrient intake and growth. Additional nutritional challenges may arise from endocrine abnormalities, particularly hypocalcemia secondary to hypoparathyroidism, necessitating careful biochemical monitoring and targeted nutritional interventions.

Medical nutrition therapy should prioritize growth optimization, prevention of nutrient deficiencies, management of feeding-related complications and support for developmental progression. Nutritional care often requires close collaboration between dietitians, pediatricians, gastroenterologists, speech-language therapists and otolaryngologists. Given the heterogeneity of clinical presentation, nutritional interventions must be highly individualized and adapted to the patient’s developmental stage and medical comorbidities^(4-6).

Autism spectrum disorder: food selectivity and sensory-driven feeding behaviors

Among the three conditions reviewed, autism spectrum disorder (ASD) is most strongly associated with food selectivity and restrictive eating patterns. Many children with ASD demonstrate heightened sensory sensitivity to food texture, color, smell, temperature, appearance and presentation, resulting in a limited dietary repertoire and significant mealtime challenges.

Food refusal, preference for specific brands or food presentations, repetitive eating behaviors, and strong reliance on highly palatable foods are frequently reported. These behaviors may contribute to inadequate intake of dietary fiber, fruits, vegetables, essential fatty acids, vitamins and minerals. Consequently, nutritional deficiencies involving iron, vitamin D, calcium, folate and other micronutrients have been described in this population.

Gastrointestinal symptoms such as constipation, abdominal pain, bloating and altered bowel habits are also highly prevalent and may further exacerbate feeding difficulties. Current evidence suggests that successful nutritional intervention requires a comprehensive and individualized approach that integrates nutritional assessment, gradual food exposure strategies, behavioral techniques, family involvement and management of gastrointestinal comorbidities. Rather than focusing solely on nutrient intake, medical nutrition therapy should aim to improve dietary variety, mealtime experiences, nutritional adequacy and long-term eating behaviors^(10-15).

Nutritional deficiencies and growth impairment

Growth disturbances and nutritional deficiencies represent important clinical concerns across Prader-Willi syndrome (PWS), 22q11.2 deletion syndrome (22q11.2DS) and autism spectrum disorder (ASD). However, the mechanisms leading to nutritional compromise differ considerably among these conditions and require individualized assessment and management strategies^(1-15).

In PWS, nutritional challenges evolve throughout life. During infancy, hypotonia and poor feeding may result in inadequate energy intake and growth failure. As hyperphagia emerges later in childhood, excessive caloric intake becomes the dominant concern. Despite increased body weight, individuals with PWS may still present with micronutrient inadequacies, particularly when energy restriction strategies are implemented without adequate nutritional planning. Reduced lean body mass, altered body composition and increased risk of obesity-related metabolic complications further complicate nutritional management^(1-3).

In contrast, growth impairment is a prominent concern in 22q11.2DS. Feeding inefficiency, dysphagia, gastroesophageal reflux, congenital heart disease and increased metabolic demands may contribute to inadequate nutrient intake and poor growth during infancy and childhood. Calcium and vitamin D deficiencies may occur secondary to hypoparathyroidism, while prolonged feeding difficulties can negatively affect overall nutritional status and developmental outcomes. Regular monitoring of growth trajectories, biochemical parameters, and feeding abilities is therefore essential^(10-12).

Children with ASD frequently exhibit selective eating patterns that may substantially reduce dietary variety. Restricted consumption of fruits, vegetables, whole grains and protein-rich foods has been associated with lower intakes of dietary fiber, iron, calcium, vitamin D, folate, zinc and omega-3 fatty acids. Although growth may remain within normal ranges in many cases, nutritional inadequacies can persist despite apparently adequate energy intake. The coexistence of gastrointestinal symptoms may further increase the risk of suboptimal nutritional status^(11,12).

Given these differences, nutritional assessment should extend beyond anthropometric measurements and include dietary intake evaluation, feeding behavior assessment, biochemical monitoring and body composition analysis when available. Early identification of nutritional risk factors allows the implementation of targeted interventions aimed at supporting growth, preventing deficiencies and at optimizing long-term health outcomes across all three conditions^(13-15).

Gastrointestinal manifestations and the gut-brain axis

Gastrointestinal manifestations are highly prevalent in Prader-Willi syndrome (PWS), 22q11.2 deletion syndrome (22q11.2DS) and autism spectrum disorder (ASD), although their clinical presentation and underlying mechanisms differ considerably. Beyond their direct impact on feeding behavior and nutrient intake, gastrointestinal disturbances may influence nutritional status, growth, metabolic health, and quality of life. Increasing evidence also highlights the potential role of the gut-brain axis in mediating interactions between gastrointestinal function, neurodevelopment, endocrine regulation, and eating behaviors^(16-20).

In PWS, gastrointestinal complications may include delayed gastric emptying, reduced gastrointestinal motility, constipation, abdominal distension and an increased risk of gastric dilatation. Hypotonia and autonomic dysfunction may contribute to impaired gastrointestinal function throughout life. These abnormalities can further complicate nutritional management by affecting satiety perception, feeding behaviors and gastrointestinal comfort. Given the high prevalence of obesity and metabolic dysfunction in PWS, gastrointestinal symptoms should be routinely assessed during nutritional follow-up^(1-3,16).

Children with 22q11.2DS frequently experience gastrointestinal symptoms secondary to structural and functional abnormalities affecting the upper digestive tract. Oropharyngeal dysphagia, gastroesophageal reflux disease, feeding inefficiency, aspiration risk and prolonged feeding times are commonly reported. Gastrointestinal manifestations may contribute to inadequate energy intake, growth impairment and feeding-related anxiety in both children and caregivers. Early recognition and multidisciplinary management are therefore essential to prevent nutritional deterioration and support developmental progress^(4-6,10-12).

Among the three conditions, ASD has been most extensively investigated in relation to gastrointestinal dysfunction and the gut-brain axis. Constipation, abdominal pain, bloating, diarrhea and altered bowel habits are frequently reported. Several studies have suggested alterations in gut microbiota composition, intestinal permeability, immune function and microbial metabolite production in individuals with ASD. Although causal relationships remain incompletely understood, gastrointestinal symptoms appear to interact bidirectionally with feeding behaviors, sensory sensitivities and behavioral manifestations^(7-9,13-20).

Emerging evidence indicates that dietary patterns may influence gut microbial composition across all three conditions. Reduced dietary diversity, limited intake of plant-based foods and inadequate fiber consumption may contribute to lower microbial diversity and altered production of beneficial metabolites such as short-chain fatty acids. These changes may influence inflammatory pathways, gastrointestinal function, and metabolic regulation, further emphasizing the importance of comprehensive nutritional assessment and individualized dietary interventions^(16-20).

From a clinical perspective, the evaluation of gastrointestinal symptoms should be considered a routine component of medical nutrition Therapy in children with PWS, 22q11.2DS and ASD. Addressing gastrointestinal dysfunction may improve feeding tolerance, dietary variety, nutrient absorption, growth outcomes, and overall quality of life while supporting the long-term effectiveness of nutritional interventions^(16-20).

Evidence-based medical nutrition therapy

Medical nutrition therapy (MNT) represents a fundamental component of multidisciplinary care in Prader-Willi syndrome (PWS), 22q11.2 deletion syndrome (22q11.2DS) and autism spectrum disorder (ASD). Although the nutritional goals differ substantially among these conditions, early identification of feeding difficulties, comprehensive nutritional assessment, and individualized intervention remain essential for optimizing growth, nutritional status, metabolic health, and quality of life^(1-20).

Medical nutrition therapy in Prader-Willi syndrome

Nutritional management in PWS requires adaptation to the evolving feeding phenotype observed throughout the lifespan. During infancy, the primary objectives include supporting adequate growth, preventing malnutrition and addressing feeding difficulties associated with hypotonia and poor sucking ability. As hyperphagia develops later in childhood, therapeutic priorities shift toward obesity prevention and long-term metabolic risk reduction.

Current evidence supports structured meal schedules, environmental control of food access, portion regulation and individualized energy prescriptions. Dietary approaches generally emphasize nutrient-dense foods, adequate protein intake, high dietary quality, and careful monitoring of body composition. Because individuals with PWS often exhibit reduced energy expenditure and altered body composition, nutritional recommendations should be adjusted according to growth patterns, physical activity levels, and clinical evolution. Collaboration with endocrinologists is particularly important when growth hormone therapy is implemented^(1-3).

Medical nutrition therapy in 22q11.2 deletion syndrome

The nutritional management of 22q11.2DS focuses primarily on ensuring adequate growth and preventing nutritional deficiencies. Feeding interventions are frequently required during infancy due to dysphagia, velopharyngeal dysfunction, gastroesophageal reflux, prolonged feeding times and increased energy requirements associated with congenital comorbidities.

Nutritional assessment should include evaluation of growth parameters, feeding efficiency, nutrient intake and biochemical markers, particularly calcium and vitamin D status. In selected cases, texture modification, specialized feeding techniques, oral nutritional supplementation, or enteral nutrition may be necessary. Nutritional interventions should be integrated within a multidisciplinary care model involving pediatricians, gastroenterologists, speech-language therapists, otolaryngologists and dietitians^(4-6,10-12).

Medical nutrition therapy in autism spectrum disorder

In ASD, nutritional management is primarily directed toward improving dietary variety, correcting nutritional inadequacies, and addressing feeding-related behavioral challenges. Food selectivity frequently results in restricted dietary repertoires characterized by limited consumption of fruits, vegetables, whole grains and protein-rich foods.

Successful intervention often requires a gradual and individualized approach based on repeated food exposure, sensory adaptation strategies, positive reinforcement, caregiver education and behavioral support. Nutritional assessment should evaluate dietary diversity, nutrient adequacy, growth status, gastrointestinal symptoms and feeding behaviors. Particular attention should be given to nutrients commonly at risk, including iron, calcium, vitamin D, folate, zinc and omega-3 fatty acids.

The management of gastrointestinal symptoms such as constipation, abdominal discomfort and altered bowel habits may further contribute to improvements in food acceptance and overall nutritional status. Interdisciplinary collaboration between dietitians, psychologists, occupational therapists, pediatricians and gastroenterologists is frequently required to achieve sustainable outcomes^(7-9,13-20).

Shared principles of medical nutrition therapy across disorders

Despite important differences in clinical presentation, several nutritional principles are applicable across all three conditions. These include early nutritional screening, regular monitoring of growth and body composition, assessment of dietary quality and nutrient adequacy, management of gastrointestinal symptoms, caregiver education and integration of nutritional care within a multidisciplinary framework.

The complexity of feeding difficulties observed in PWS, 22q11.2DS and ASD highlights the need for individualized treatment plans that address not only nutrient intake but also behavioral, developmental, medical and psychosocial factors influencing feeding and nutritional outcomes^(1-20).

Discussion

The present review highlights the substantial heterogeneity of feeding difficulties encountered in Prader-Willi syndrome, 22q11.2 deletion syndrome and autism spectrum disorder. Although these conditions are frequently associated with nutritional compromise, the mechanisms driving feeding dysfunction differ considerably. PWS is characterized by a unique progression from early feeding difficulties to hyperphagia and obesity risk, whereas 22q11.2DS is predominantly associated with structural and functional feeding impairments. In contrast, ASD is commonly characterized by food selectivity, sensory-based food refusal and restricted dietary diversity.

Despite these differences, all three conditions share a common vulnerability to nutritional inadequacies, growth disturbances, gastrointestinal symptoms and reduced quality of life. The findings reviewed suggest that feeding difficulties should not be viewed as isolated symptoms but rather as multidimensional clinical manifestations that require integrated nutritional, medical, developmental and behavioral management^(1-20).

The role of early nutritional intervention

Early nutritional intervention represents one of the most important determinants of long-term outcomes across all three conditions. Feeding difficulties often emerge during infancy or early childhood, a period characterized by rapid growth, neurodevelopment and establishment of lifelong eating behaviors. Delayed recognition of feeding challenges may contribute to growth impairment, nutritional deficiencies, maladaptive feeding patterns, gastrointestinal complications and unfavorable metabolic trajectories later in life^(1-20).

In PWS, early nutritional intervention facilitates the transition between nutritional phases and may help prevent excessive weight gain before the onset of severe hyperphagia. In 22q11.2DS, timely identification of feeding and swallowing difficulties may reduce the risk of growth failure, aspiration-related complications and micronutrient deficiencies. In ASD, early intervention may increase food acceptance, improve dietary variety and reduce the long-term consequences of restrictive eating patterns and nutritional inadequacies^(4-20).

Beyond its effects on nutritional status, early medical nutrition therapy may contribute to improved family functioning and reduced caregiver burden. Feeding difficulties frequently generate parental stress, mealtime conflict and anxiety regarding growth and development. Family-centered nutritional counseling and multidisciplinary support may therefore provide benefits that extend beyond traditional clinical outcomes^(7-20).

Growing evidence also suggests that early dietary exposures may influence gut microbiota development, immune regulation, metabolic health and feeding behaviors. Although causal relationships remain incompletely understood, these findings further support the importance of early identification and management of nutritional challenges in vulnerable pediatric populations^(15-20).

Gastrointestinal health as a therapeutic target

The review also emphasizes the growing importance of gastrointestinal health in the management of these conditions. Gastrointestinal symptoms are highly prevalent across all three disorders and may directly influence feeding behaviors, nutrient intake and the quality of life. Emerging evidence suggests that alterations in gut microbiota composition, intestinal function and inflammatory pathways may contribute to both gastrointestinal and behavioral manifestations, particularly in ASD^(15,19).

Although current evidence remains insufficient to establish definitive causal relationships, the gut-brain axis represents a promising area for future research. Improved understanding of these interactions may facilitate the development of more targeted nutritional interventions and individualized treatment strategies^(15-17,19).

Toward personalized medical nutrition therapy

The findings of this review further support the concept of personalized medical nutrition therapy. Given the considerable variability in clinical presentation, nutritional status, feeding behaviors and comorbidities, standardized dietary recommendations are unlikely to adequately address the needs of all patients. Individualized nutritional care plans should therefore be developed according to syndrome-specific characteristics, developmental stage, growth patterns, gastrointestinal symptoms and family context^(1-15).

Future advances in pediatric nutrition may increasingly incorporate precision nutrition approaches, including detailed dietary assessment, body composition monitoring, microbiota evaluation and individualized behavioral interventions. Such strategies have the potential to improve both clinical outcomes and quality of life for affected children and their families^(16-20).

A key finding emerging from the present review is that feeding difficulties should not be viewed solely as nutritional problems but as complex clinical phenotypes that may influence growth, metabolic health, neurodevelopment, gastrointestinal function and long-term quality of life. Although the mechanisms differ among PWS, 22q11.2 deletion syndrome and ASD, early recognition and individualized medical nutrition therapy may represent an important opportunity to improve both short- and long-term health outcomes^(1-20).

Clinical implications for dietitians and multidisciplinary teams

The management of feeding difficulties in Prader-Willi syndrome, 22q11.2 deletion syndrome and autism spectrum disorder extends beyond the correction of nutritional deficiencies and requires a comprehensive, multidisciplinary approach. The heterogeneity of feeding phenotypes observed across these conditions highlights the need for individualized nutritional assessment and tailored intervention strategies throughout childhood and adolescence^(1-20).

Clinical dietitians play a central role in the identification of nutritional risk factors, assessment of dietary adequacy, monitoring of growth and body composition, management of gastrointestinal symptoms and the development of individualized nutrition care plans. However, optimal outcomes are rarely achieved through isolated nutritional interventions. Effective management frequently requires close collaboration between pediatricians, endocrinologists, gastroenterologists, psychologists, speech-language therapists, occupational therapists and other healthcare professionals involved in the child’s care^(1-20).

Early intervention appears particularly important, as feeding difficulties may influence growth, neurodevelopment, nutritional status, metabolic health, psychosocial functioning and quality of life. Routine nutritional screening and longitudinal monitoring should therefore be integrated into standard care pathways for children with PWS, 22q11.2DS and ASD^(1-20).

Furthermore, caregiver education represents a critical component of successful intervention. Parents and caregivers often face significant challenges related to feeding management, food-related behaviors, and long-term adherence to nutritional recommendations. Providing practical guidance, behavioral support and realistic therapeutic goals may improve both nutritional outcomes and family quality of life^(7-9,13-15).

Limitations and future research directions

Several limitations should be considered when interpreting the findings presented in this review. Firstly, the available evidence varies considerably across the three conditions, with a greater volume of research available for autism spectrum disorder compared with Prader-Willi syndrome and 22q11.2 deletion syndrome. Secondly, substantial heterogeneity exists regarding study design, outcome measures, nutritional assessment methods and intervention protocols, limiting direct comparisons between studies^(1-20).

In addition, many published studies involve relatively small sample sizes, reflecting the rarity and clinical complexity of these populations. High-quality randomized controlled trials evaluating long-term nutritional interventions remain limited, particularly for 22q11.2 deletion syndrome and syndrome-specific nutritional outcomes^(1-20).

Future research should focus on the development of standardized nutritional assessment protocols, evaluation of long-term medical nutrition therapy outcomes and investigation of the interactions between feeding behaviors, gastrointestinal function, gut microbiota, metabolic health and neurodevelopment. Greater attention should also be directed toward personalized nutrition approaches and multidisciplinary intervention models capable of addressing the complex nutritional needs of these populations^(16-20).

Conclusions

Feeding difficulties represent a major clinical challenge in Prader-Willi syndrome, 22q11.2 deletion syndrome and in autism spectrum disorder, although the underlying mechanisms and nutritional consequences differ substantially across conditions. Early nutritional assessment, individualized medical nutrition therapy, management of gastrointestinal symptoms and multidisciplinary collaboration are essential for optimizing growth, nutritional status, metabolic health and the quality of life. Despite growing evidence supporting targeted nutritional interventions, additional research is required to establish standardized syndrome-specific protocols and to better understand the long-term impact of nutritional care in these populations.

Conflict of interests: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.