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Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome
D E Weese-Mayer1, J M Silvestri, M L Marazita
1Department of Pediatrics, Rush Medical College, Rush University, Chicago, Illinois.
Insights
Genetic analysis of congenital central hypoventilation syndrome (CCHS) families suggests multifactorial or major locus inheritance. The study also noted an intriguing link between CCHS, Hirschsprung disease, and sudden infant death syndrome (SIDS) in relatives.
Area of Science:
- Genetics
- Pediatrics
- Medical History
Background:
- Congenital central hypoventilation syndrome (CCHS) is a rare disorder affecting autonomic breathing control.
- The genetic basis and associated conditions of CCHS require further elucidation.
- Hirschsprung disease (HD) and sudden infant death syndrome (SIDS) are conditions sometimes observed in CCHS families.
Purpose of the Study:
- To investigate genetic hypotheses for CCHS.
- To explore the relationship between CCHS and Hirschsprung disease (HD).
- To examine the incidence of other clinical findings, such as SIDS, in CCHS relatives.
Main Methods:
- A questionnaire-based study of 50 CCHS families, including 1,482 relatives across three generations.
- Statistical genetic analysis using a unified mixed model (multifactorial [MF] and major locus [ML] components).
- Subgroup analyses were performed based on the presence of HD or constipation, and on the absence of HD or constipation.
Main Results:
- Genetic analysis indicated that both multifactorial (MF) and major locus (ML) inheritance models were plausible for CCHS.
- No significant familiality was detected in families without HD or constipation.
- A notably higher incidence of SIDS (11.2/1,000) was observed in relatives of CCHS patients with HD or constipation compared to those without (1.8/1,000).
Conclusions:
- The findings support the familial aggregation of CCHS, consistent with either MF or ML inheritance models.
- The recurrence risk for CCHS is estimated to be less than 5%.
- The observed association between CCHS, HD, and a higher familial incidence of SIDS warrants further investigation.
Abstract:
We evaluated the families of 50 children with idiopathic congenital central hypoventilation syndrome (CCHS) to 1) test genetic hypotheses, 2) explore the relationship to Hirschsprung disease (HD), and 3) examine other clinical findings including sudden infant death syndrome (SIDS) in relatives of CCHS patients. A questionnaire was administered to parents of each proband to determine a detailed pedigree and medical history for 3 generations including 1,482 relatives. The data were analyzed under the unified mixed model method (assumes individual genotype composed of multifactorial [MF] and major locus [ML] components). Analysis was made of the Total dataset and on subdivided data sets: HIR1 = families of probands with HD (n = 8) vs. HIR2 = families of probands without HD; then under a premise that severe, chronic constipation may be a milder form of HD (i.e., ganglion cells present but dysfunctional), CON1 = families of probands with HD or constipation (n = 13) vs. CON2 = families of probands without HD or constipation. By statistical genetic analysis of the Total, HIR1, and CON1 datasets, the MF and ML hypotheses were about equally likely, with the MF model slightly more parsimonious. Although HIR2 and CON2 datasets indicated no familiality, statistical evidence of heterogeneity between the results of HIR1 and HIR2, or between CON1 and CON2 was lacking. A SIDS incidence of 11.2/1,000 was documented among the relatives of CON1 vs. 1.8/1,000 among relatives of CON2. Our results are consistent with familiality by either MF or ML models. Recurrence risk is likely < 5%. The relationship of CCHS to the high familial incidence of SIDS is intriguing and demands further investigation.