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The French Congenital Central Hypoventilation Syndrome Registry^*

General Data, Phenotype, and Genotype

Ha Trang, MD, PhD; Michel Dehan, MD; François Beaufils, MD; Isabelle Zaccaria, MD; Jeanne Amiel, MD and Claude Gaultier, MD, PhD; French CCHS Working Group

^* From the Service de Physiologie (Drs. Trang and Gaultier), INSERM E-9935, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris, France; Service de Réanimation Néonatale (Dr. Dehan), Hôpital Antoine Béclère, Clamart, France; Service de Réanimation Pédiatrique (Dr. Beaufils) and the Unité d’Epidémiologie Clinique (Dr. Zaccaria), Hôpital Robert Debré, Paris, France; and the Département de Génétique (Dr. Amiel), INSERM U-393, Hôpital Necker Enfants Malades, Paris, France. A list of participants in the French CCHS Working Group is located in the ^Appendix.

Correspondence to: Ha Trang, MD, PhD, Service de Physiologie, Hôpital Robert Debré, 48 Blvd Serurier, 75019 Paris, France; e-mail: ha.trang{at}rdb.ap-hop-paris.fr

Objective: To analyze the main clinical features, genetic mutations, and outcomes of patients of the French Congenital Central Hypoventilation Syndrome (CCHS) Registry.

Design: A country-wide cohort established throughout a long-term multicenter effort.

Patients: Seventy French patients with CCHS (29 male patients and 41 female patients).

Methods: The following items were analyzed: the most important moments of the disease course; the main clinical characteristics; associated pathologic conditions; management; clinical outcome; and genetic mutations.

Results: An average of four new cases of CCHS per year was observed in the last 5 years. Thus, the incidence may be estimated to be 1 per 200,000 live births in France. The median age at diagnosis was 3.5 months (range, 0.5 to 15 months) before 1995 and < 2 weeks in the last 5 years (p = 0.01). CCHS occurred in isolation in 58 of 70 patients. In the remainder, it was associated with Hirschsprung disease (HSCR) [nine patients], Hirschsprung and neural crest tumor (two patients), and growth hormone deficiency (one patient). Among the 50 patients who lived beyond 1 year of age, all but one received nighttime ventilation, with 10 of them (20%) receiving it noninvasively. Three patients (6%) required daytime ventilatory support in addition to nighttime ventilation. The overall mortality rate was 38% (95% confidence interval [CI], 27 to 49%). The median age at death was 3 months (range, 0.4 months to 21 years). The 2-year mortality rate was greater in male patients than in female patients (p = 0.02; relative risk [RR], 2.71; 95% CI, 1.14 to 6.47) but was not affected by HSCR (p = 0.93; RR, 0.95; 95% CI, 0.28 to 3.2). The 43 patients who are currently alive (11 men; sex ratio, 0.4) have a mean age of 9 years (range, 2 months to 27 years). Among the 34 patients tested thus far, heterozygous mutations of the paired-like homeobox gene 2B (PHOX2B) gene were found in 31 patients (91%).

Conclusion: Our four major findings are the extreme rarity of CCHS, the improved recognition over time, the lack of effect of HSCR on the mortality rate, and the high frequency of PHOX2B mutations.

Key Words: central alveolar hypoventilation syndrome • mortality • registry

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