The French Congenital Central Hypoventilation Syndrome Registry

doi:10.1378/chest.127.1.72

Chest

Volume 127, Issue 1, January 2005, Pages 72-79

https://doi.org/10.1378/chest.127.1.72 Get rights and content

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.

Section snippets

Materials and Methods

In 1993, we initiated a national survey among neonatal and pediatric ICUs, as well as anesthesia care units, to identify the patients in whom CCHS has been diagnosed. Fifty-eight postal questionnaires were sent, and 45 responses obtained. One of us (H.T.) reviewed all medical records and sleep tracings whenever they were available. This allowed us to identify 32 patients who fulfilled the criteria for CCHS.¹ In 1996, the number of recorded patients was 34. An update was performed yearly using

Results

The 70 French CCHS patients consisted of 29 male patients and 41 female patients (sex ratio, 0.7). All but two patients were born as a result of spontaneous pregnancies. There were one drug-induced pregnancy (clomiphene citrate) and one in vitro fertilization using the biological father's sperm (not using intracytoplasmic sperm injection). The eldest patient was born in 1976. There was an average of four new CCHS cases per year in the last 5 years. This number was nearly twice as high as that

Discussion

This study provides data from a unique, country-wide cohort of patients with CCHS. This is the first description of the French CCHS population as a whole.

The French CCHS Working Group

Groupe Francophone de Réanimation et Urgences Pédiatriques: J. Camboulives (Marseille); B. Delaporte (Le Havre); J.L. Demarquez (Bordeaux); D. Devictor (Paris); L. Egreteau (Reims); G. Ensel (Rouen); D. Floret (Lyon); P. Hubert (Paris); F. Leclerc (Lille); J. Messer (Strasbourg); M. Moktari (Paris); G. Moriette (Paris); D. Oriot (Poitiers); J.C. Rozé (Nancy); D. Rieu (Montpellier). All are physicians from neonatal and pediatric ICUs.

INSERM U-393, Départment de Génétique, Hôpital Necker Enfants

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Cited by (167)

Later Onset Congenital Central Hypoventilation Syndrome
2024, Medical Clinics of North America
Pregnancy in congenital central hypoventilation syndrome
2020, American Journal of Obstetrics and Gynecology MFM
Citation Excerpt :
These patients with late-onset CCHS are often diagnosed because of development of cor pulmonale or when apnea becomes evident during exposure to a secondary physiological stressor such as general anesthesia or lower respiratory tract infection.5,6 CCHS is estimated to occur in 1 in 148,000 to 200,000 live births, although the true incidence is likely higher owing to underdiagnosis of individuals with mild phenotypes.7,8 CCHS is a neurocristopathy caused by mutations in the paired-like homeobox (PHOX2B) gene.
Congenital central hypoventilation syndrome is a rare genetic disorder of autonomic regulation of breathing resulting from mutations in the paired-like homeobox gene. Individuals with congenital central hypoventilation syndrome demonstrate an absent or diminished physiological response to hypercapnia and hypoxia that is most severe during sleep and depend on mechanical ventilation to maintain normal gas exchange. Increased disease awareness and availability of paired-like homeobox gene testing has improved congenital central hypoventilation syndrome morbidity and mortality, and patients are now living into adulthood. During pregnancy, delivery, and the postpartum period, women with congenital central hypoventilation syndrome are vulnerable to developing respiratory insufficiency. Currently, there is no standardized approach to monitoring ventilatory status and anticipating the need for changes to existing ventilatory support for women with congenital central hypoventilation syndrome during pregnancy, labor, and delivery.
This study aimed to characterize current practices for monitoring ventilatory status and managing ventilatory needs in women with congenital central hypoventilation syndrome during pregnancy; identify specific circumstances through which ventilation may be compromised during pregnancy, delivery, and postpartum; evaluate utilization of prenatal congenital central hypoventilation syndrome testing; and report any adverse pregnancy outcomes.
We conducted an anonymous cross-sectional survey of women with congenital central hypoventilation syndrome with current or prior pregnancy. The 26-item electronic questionnaire included questions on congenital central hypoventilation syndrome genotype; number and outcome of pregnancies; use of mechanical ventilation; and issues with or adjustments made to ventilation during pregnancy, delivery, and the postpartum period.
We received 10 responses. Three patients were not diagnosed with congenital central hypoventilation syndrome until after pregnancy and delivery. The 7 patients with a preexisting congenital central hypoventilation syndrome diagnosis reported information on 10 total pregnancies. At baseline, patients relied on various types of ventilatory support including positive pressure ventilation via tracheostomy, bilevel noninvasive positive pressure ventilation, and diaphragm pacing by phrenic nerve stimulation. Polysomnography for objective assessment of nocturnal ventilation was not consistently utilized. Changes to baseline ventilatory support were required during 3 out of 10 pregnancies. In addition, 2 patients using diaphragm pacing reported discomfort with pacing during the third trimester or after cesarean delivery, prompting discontinuation of diaphragm pacing. In 1 instance, discontinuation of diaphragm pacing and lack of recognition of need for an alternative support method led to respiratory arrest and need for emergent resuscitation. All patients who were offered prenatal congenital central hypoventilation syndrome testing chose to undergo testing. Of note, 9 out of 10 pregnancies were carried successfully to term and 5 infants were diagnosed with congenital central hypoventilation syndrome.
Women with congenital central hypoventilation syndrome may experience issues maintaining adequate ventilation during pregnancy, necessitating an adjustment of ventilator settings or use of an alternative type of ventilation. Objective assessment of nocturnal ventilation by means of polysomnography is an important part of congenital central hypoventilation syndrome pregnancy care to optimize maintenance of adequate gas exchange. Patients who rely on diaphragm pacing may experience discomfort with pacing during the later stages of pregnancy and after cesarean delivery. Anticipatory guidance and contingency planning for changing ventilatory needs should be discussed early in pregnancy. Prenatal congenital central hypoventilation syndrome testing should be offered to pregnant patients with congenital central hypoventilation syndrome to inform delivery decisions and prepare for the provision of advanced neonatal care.
Clinical features of children with Haddad syndrome: A single-center experience
2020, Journal of Pediatric Surgery
Haddad syndrome (HS) is a very rare disease considered a form of neurocristopathy. It is characterized by a combination of congenital central hypoventilation syndrome (CCHS) and Hirschsprung's disease (HD). We report the clinical features and disease progression of HS to provide better care for HS patients by achieving an earlier diagnosis and optimal treatment.
Medical records of patients diagnosed with HS from 2005 to 2016 were retrospectively reviewed. Demographic data including gestational age, birth weight and height, and paired-like homeobox 2b (PHOX2B) gene mutation were collected.
Seven males and three females were identified (mean gestational age 39.76 ± 1.49 weeks, mean birth weight 3117.5 ± 288.9 g). PHOX2B gene mutation was identified in all patients. Immediate ventilation care after birth was required in five patients due to poor respiration. The current median age of the children is 5.4 years (range, 1.8–10.1). Tracheostomy was performed in nine patients. Eight patients required sleep ventilation and two patients, 24-h continuous ventilation support. Six patients showed rectosigmoid aganglionosis and four patients exhibited total colonic aganglionosis, of these one had aganglionosis extended to the distal small bowel. Soiling was observed in seven patients (5 with laparoscopy-assisted transanal endorectal pull-through and 2 with Duhamel procedure) and one patient showed grade 2 constipation with Duhamel procedure. Six patients had developmental delay. All patients are alive.
HS may require lifelong medical care. This study could be helpful to understand the clinical features of HS including associated abnormalities and disease progression. By assisting to understand the clinical features, we could provide better care for HS patients by achieving an earlier diagnosis and appropriate treatment.
Prognosis study.
Level IV.
Congenital central hypoventilation syndrome and Hirschsprung disease: A retrospective review of the French National Registry Center on 33 cases
2019, Journal of Pediatric Surgery
Congenital Central Hypoventilation Syndrome (CCHS) is a rare affection associated to Hirschsprung disease (HD) in 20% of the cases. Using the French CCHS registry, we described the population of patients suffering from both CCHS and HD reporting the outcome on these patients.
Medical records were reviewed. Epidemiological, clinical, histological and genetic data were analyzed and extracted from the national French registry data.
33 patients had CCHS and HD. Thirty percent had a severe form of CCHS (Death owing to CCHS or 24/24 ventilation beyond 1 year old). Fifty four percent required tracheotomy. HD's pathologic segment was classic (Rectosigmoid and left colic form) in 20% and long (Above the splenic flexure) in 80%. Twenty four percent were treated with daily irrigation, 21% had colostomy without undergoing pullthrough, and 55% underwent optimal treatment (pull through). We failed to demonstrate a correlation between severity of CCHS and HD's length. The rate of mortality was 57% and was higher in the long HD group (p = 0.0005). Fourteen patients were still alive, aged 1 to 31 years old. Ninety two percent were weaned off the 24/24 ventilation. Regarding the intestinal function, 38% presented with soiling and 30% with chronic diarrhea. Hundred percent had CCHS follow-up while only 35% had no surgical follow-up in regard to the HD.
This is the largest study regarding the CCHS / HD association and its long-term followup. Mortality is high demonstrating that a multidisciplinary follow-up on respiratory and intestinal function is necessary to improve outcome.
Level III study.
Characteristics and outcomes in children with congenital central hypoventilation syndrome on long-term mechanical ventilation in the Netherlands
2024, European Journal of Pediatrics
Elevated transaminases in congenital central hypoventilation syndrome
2024, ERJ Open Research

View all citing articles on Scopus

This research was supported by a grant from GIS-Institut des Maladies Rares.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]).

A list of participants in the French CCHS Working Group is located in the Appendix.

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Chest

Clinical Investigations: Sleep and BreathingThe French Congenital Central Hypoventilation Syndrome Registry

Objective

Design

Patients

Methods

Results

Conclusion

Section snippets

Materials and Methods

Results

Discussion

The French CCHS Working Group

J Pediatr

J Pediatr

J Pediatr

Failure of automatic control of ventilation (Ondine's curse)

Medicine (Baltimore)

Congenital central hypoventilation syndrome: an update

Pediatr Pulmonol

Idiopathic congenital central hypoventilation syndrome: diagnosis and management

Am J Respir Crit Care Med

Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate

Medicine (Baltimore)

Congenital central hypoventilation syndrome and Hirschsprung's disease

Arch Dis Child

Polyalanine expansion and frameshift mutations of the paired-liked homeobox genePHOX2Bin congenital central hypoventilation syndrome

Nat Genet

Exclusion ofRNXas a major gene in congenital central hypoventilation syndrome

Am J Med Genet

Epidemiologic survey of 196 patients with congenital central hypoventilation syndrome

Pediatr Pulmonol

Hirschsprung disease, associated syndromes, and genetics: a review

J Med Genet

Clinical Investigations: Sleep and Breathing
The French Congenital Central Hypoventilation Syndrome Registry