Pupillary signs are associated with subsequent Hirschsprung disease diagnosis and malignant adrenal neoplasm in congenital central hypoventilation syndrome
Abstract
To evaluate the association between pupillary signs and the risk of late-diagnosed Hirschsprung disease (HD) and Malignant Neoplasm of the Adrenal Gland (MNAG) in pediatric patients with Congenital Central Hypoventilation Syndrome (CCHS), and to systematically review ocular manifestations in CCHS. We performed a retrospective cohort analysis with integrated systematic literature review. A cohort of 680 pediatric CCHS patients (2004–2024) was identified from the TriNetX US Collaborative Network. Patients with pre-existing HD or MNAG were excluded. CCHS patients with pupillary signs (ICD-10 codes H21.56, H57.0, G90.2) were compared to those without. Primary outcomes were subsequent HD diagnosis or MNAG at 3 and 5 years, assessed using adjusted Hazard Ratios (aHRs). A PRISMA-compliant systematic review of CCHS ocular findings was also performed. Among 680 CCHS patients (mean age 3.4 years), 38 (5.6%) had pupillary abnormalities. The presence of pupillary signs was significantly associated with an increased risk of subsequent HD diagnosis [5-year aHR, 4.93 (95% CI: 2.72–8.84; p < .001)] and MNAG [5-year aHR, 5.72 (95% CI: 2.31–14.33; p < .001)]. The systematic review (8 studies, n = 32 patients) found pupillary signs were present in 100% of tumor-positive patients and co-occurred with HD in 56%. Pupillary signs in pediatric CCHS were significantly associated with increased risk of subsequent HD diagnosis and MNAG. These findings are hypothesis-generating and support the incorporation of structured pupillary assessment into the multidisciplinary evaluation of pediatric CCHS patients, pending prospective validation.
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BibTeX
@article{eleiwa2026pupillary,
title = {{Pupillary signs are associated with subsequent Hirschsprung disease diagnosis and malignant adrenal neoplasm in congenital central hypoventilation syndrome}},
author = {Taher K. Eleiwa and Ahmed S. Bayoumy and Jamal O. Azhari and Ibrahim Abboud and Davina Malek and Eric D. Gaier and Paul H. Phillips and Abdelrahman M. Elhusseiny},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-67332-0},
url = {https://www.nature.com/articles/s41598-026-67332-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pupillary signs are associated with subsequent Hirschsprung disease diagnosis and malignant adrenal neoplasm in congenital central hypoventilation syndrome
AU - Taher K. Eleiwa
AU - Ahmed S. Bayoumy
AU - Jamal O. Azhari
AU - Ibrahim Abboud
AU - Davina Malek
AU - Eric D. Gaier
AU - Paul H. Phillips
AU - Abdelrahman M. Elhusseiny
PY - 2026
DA - 2026/10/22
JO - Scientific Reports
DO - 10.1038/s41598-026-67332-0
UR - https://www.nature.com/articles/s41598-026-67332-0
AB - To evaluate the association between pupillary signs and the risk of late-diagnosed Hirschsprung disease (HD) and Malignant Neoplasm of the Adrenal Gland (MNAG) in pediatric patients with Congenital Central Hypoventilation Syndrome (CCHS), and to systematically review ocular manifestations in CCHS. We performed a retrospective cohort analysis with integrated systematic literature review. A cohort of 680 pediatric CCHS patients (2004–2024) was identified from the TriNetX US Collaborative Network. Patients with pre-existing HD or MNAG were excluded. CCHS patients with pupillary signs (ICD-10 codes H21.56, H57.0, G90.2) were compared to those without. Primary outcomes were subsequent HD diagnosis or MNAG at 3 and 5 years, assessed using adjusted Hazard Ratios (aHRs). A PRISMA-compliant systematic review of CCHS ocular findings was also performed. Among 680 CCHS patients (mean age 3.4 years), 38 (5.6%) had pupillary abnormalities. The presence of pupillary signs was significantly associated with an increased risk of subsequent HD diagnosis [5-year aHR, 4.93 (95% CI: 2.72–8.84; p < .001)] and MNAG [5-year aHR, 5.72 (95% CI: 2.31–14.33; p < .001)]. The systematic review (8 studies, n = 32 patients) found pupillary signs were present in 100% of tumor-positive patients and co-occurred with HD in 56%. Pupillary signs in pediatric CCHS were significantly associated with increased risk of subsequent HD diagnosis and MNAG. These findings are hypothesis-generating and support the incorporation of structured pupillary assessment into the multidisciplinary evaluation of pediatric CCHS patients, pending prospective validation.
SN - 2045-2322
ER -