Highlight
– Gastrointestinal (GI) symptoms were reported in 64% of 50 individuals with CHARGE syndrome; constipation affected 48% and was more common in females.
– Constipation correlated with greater GI comorbidities and significantly lower GI-specific quality of life (PedsQL GI scores 56.0 vs 73.1, p = 0.04).
– Younger participants had more varied GI pathology and higher feeding-tube rates; older participants primarily presented with constipation.
– Early and ongoing involvement of GI/motility specialists is recommended; decreased gut motility is a plausible contributing mechanism warranting further study.
Background
CHARGE syndrome is a complex congenital condition characterized by Coloboma, Heart defects, choanal Atresia, Retardation of growth and/or development, Genital hypoplasia, and Ear anomalies. First described as a recognizable pattern of anomalies in the 1980s, pathogenic variants in the CHD7 gene account for the majority of molecularly confirmed cases and explain much of the multisystem developmental perturbation observed clinically (Pagon et al., 1981; Vissers et al., 2004). Gastrointestinal (GI) problems—ranging from feeding difficulties and aspiration risk to obstructive lesions and motility disorders—are known components of the CHARGE phenotype but have been incompletely quantified across ages. Understanding GI prevalence, patterns, and quality‑of‑life effects is essential for anticipatory care and targeted management in this vulnerable population.
Study design
The study by Kakamousias and Blake (2025) is a cross-sectional analysis using standardized questionnaires to ascertain GI symptoms, feeding status, and GI‑related quality of life in a sample of 50 participants with CHARGE syndrome (18 males, 31 females, 1 non-binary) aged 2–46 years (mean 16.2 years). Measures included descriptive symptom inventories, feeding assessments (including tube feeding status), and the PedsQL GI Symptoms Scale for GI‑specific health-related quality of life (HRQoL). Key comparisons focused on presence/absence of GI issues, constipation status, feeding modality (tube-fed vs orally fed), sex differences, and age-related patterns.
Key findings
Prevalence and demographics
Overall, 64% (32/50) of participants reported at least one GI issue, and 48% (24/50) reported constipation. The authors report a higher prevalence of GI problems and constipation in females than males. Tube feeding was present in a subset and was associated with younger age.
Constipation: comorbidity and quality of life
Constipation was associated with a greater burden of GI comorbidities. Importantly, participants with constipation had significantly worse GI‑specific quality of life: mean PedsQL GI Symptoms Scale scores were 56.0 in those with constipation versus 73.1 in those without (p = 0.04). This difference is clinically meaningful and suggests constipation contributes substantially to daily symptom burden and family impact in CHARGE.
Feeding modality and age relationships
Tube-fed participants were younger than orally fed participants (mean age 11.7 vs 18.7 years; p = 0.02). These tube‑fed individuals had significantly lower scores on the Pediatric Assessment Scale for Severe Feeding Problems (means 16.9 vs 35.1; p < 0.00001), consistent with more severe feeding impairment. The dataset revealed an age-related shift in phenotype: younger children exhibited a broader array of GI problems (e.g., reflux, dysphagia, anatomical issues, aspiration risk), while older individuals more often presented with chronic constipation as the dominant GI complaint.
Statistical considerations and effect sizes
Reported p‑values indicate statistical significance for the comparisons highlighted (PedsQL GI score difference p = 0.04; age difference by feeding modality p = 0.02; feeding score difference p < 0.00001). Exact confidence intervals were not provided in the summary data available here; however, the magnitude of the PedsQL difference (~17 points) and the highly significant feeding score disparity suggest clinically meaningful effects that merit attention in practice.
Mechanistic considerations: why is constipation common in CHARGE?
Several plausible, non–mutually exclusive mechanisms likely contribute to the high constipation prevalence in people with CHARGE syndrome:
- Developmental abnormalities: CHD7 is a chromatin‑remodeling gene involved in neural and neural crest development. Disruption of developmental pathways could impair enteric nervous system formation or vagal/cranial nerve function relevant to swallowing and upper GI motility.
- Neuromuscular dysfunction: Cranial nerve anomalies and hypotonia, common in CHARGE, may extend to pelvic floor or colonic neuromuscular control, reducing propulsive activity.
- Anatomic and surgical sequelae: Choanal atresia, esophageal anomalies, or previous corrective surgeries may alter feeding, mobility, and gut function, indirectly precipitating constipation.
- Medication effects: Polypharmacy—particularly opioid, anticholinergic, or antiepileptic medications—can exacerbate constipation.
- Behavioral and oral–motor feeding issues: Selective diets, limited fluid intake, and low fiber intake due to feeding difficulties can predispose to constipation.
While the study hypothesizes decreased gut motility as a contributing mechanism, direct physiologic testing (transit studies, manometry) in CHARGE populations remains limited and represents an important area for future research.
Clinical implications and recommendations
Screening and surveillance
Given the high GI burden documented, routine screening for GI symptoms should be standard in CHARGE care pathways. Simple targeted questions at each visit should include stool frequency and consistency, painful or withheld stools, abdominal pain, vomiting, feeding tolerance, and signs of aspiration.
Multidisciplinary management
Early referral to pediatric gastroenterology, dietetics, speech and language therapy (for oral–motor/feeding evaluations), and developmental pediatrics is advisable. For constipation specifically, management should follow established pediatric constipation guidelines (ESPGHAN/NASPGHAN) with individualized plans for behavioral modification, disimpaction when needed, maintenance osmotic laxatives, and attention to hydration and fiber where feasible (Tabbers et al., 2014).
When to pursue specialized testing
Consider transit studies, colonic manometry, or anorectal manometry when constipation is refractory to standard therapy, when there are red flags (failure to thrive, severe abdominal distension, vomiting, passage of blood), or when surgical causes are suspected. For younger patients with complex feeding disorders, video fluoroscopic swallow studies and endoscopic evaluation for anatomic lesions are commonly indicated.
Expert commentary and study limitations
The study provides valuable patient-centered data on GI prevalence and quality-of-life impact in a relatively large single-cohort sample of individuals with CHARGE. Strengths include use of standardized instruments (e.g., PedsQL GI Symptoms Scale) and exploration of age-related patterns and feeding status. However, several limitations should be considered when interpreting the findings:
- Cross-sectional design limits causal inference and may not capture symptom trajectories over time.
- The sample size (n = 50) constrains subgroup analyses and precision of estimates; confidence intervals were not provided in the current summary.
- Potential selection bias: participants may have been recruited through specialty clinics or family networks, possibly enriching for symptomatic individuals.
- Reliance on questionnaire data and caregiver report (where used) can introduce recall or reporting bias; objective physiologic testing was not systematically reported.
Despite these limitations, the consistent signal—high GI symptom prevalence and a clear association between constipation and reduced GI‑specific HRQoL—supports the study’s clinical relevance.
Gaps and future research priorities
Key unanswered questions include:
- What are the pathophysiologic mechanisms linking CHD7 variants to GI dysmotility or enteric nervous system dysfunction?
- How do GI symptom patterns evolve longitudinally across childhood into adulthood in CHARGE?
- What are the optimal diagnostic pathways and therapeutic algorithms for refractory constipation and feeding disorders in this population?
- Could targeted therapies (e.g., prokinetics, neuromodulation) play a role in selected patients, and how should trials be designed?
Conclusion
Kakamousias and Blake (2025) highlight that GI problems affect a majority of individuals with CHARGE syndrome and that constipation—present in nearly half—has a significant and measurable adverse effect on GI‑specific quality of life. Age stratification suggests a transition from diverse early-life GI morbidity and feeding support needs toward chronic constipation as a predominant problem in older children and adults. Clinicians should proactively screen for GI symptoms, involve multidisciplinary teams early, and apply guideline-based constipation management while recognizing the need for individualized care plans. Further mechanistic and longitudinal studies are needed to clarify pathophysiology and inform targeted interventions.
Funding and clinicaltrials.gov
The primary article (Kakamousias & Blake, 2025) should be consulted for specific funding disclosures and trial registrations. No clinicaltrials.gov identifier was provided in the study summary here.
References
1. Kakamousias A, Blake K. Gastrointestinal Issues in CHARGE Syndrome: Prevalence, Patterns, and Constipation-Related Quality of Life. Am J Med Genet A. 2025 Nov;197(11):e64141. doi: 10.1002/ajmg.a.64141. PMID: 40525699.
2. Pagon RA, Graham JM Jr, Zonana J, Yong SL. Coloboma, congenital heart disease, choanal atresia, and hypothalamic-pituitary dysfunction: a single syndrome? J Pediatr. 1981 Nov;99(5):757-7. PMID: 6971296.
3. Vissers LE, van Ravenswaaij CM, Admiraal R, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004 Apr;36(9):955-7. doi:10.1038/ng1426. PMID: 15322537.
4. Tabbers MM, Di Lorenzo C, Berger MY, et al.; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN). Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN. J Pediatr Gastroenterol Nutr. 2014 Feb;58(2):258-74. doi:10.1097/MPG.0000000000000235. PMID: 23963179.
5. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the Pediatric Quality of Life Inventory. Med Care. 1999 Feb;37(2):126-39. PMID: 10024117.
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Clinical thumbnail prompt: “A pediatric clinician and a parent reviewing a PedsQL questionnaire and a growth chart at a clinic desk; a young child sits on the examination table with a calm expression. Background includes a soft schematic overlay of the gastrointestinal tract. Warm, professional lighting; inclusive, diverse family; clinically realistic setting.”
