Congenital Central Hypoventilation SyndromeCCHSNCT01225679
Late-onset Congenital Central Hypoventilation Syndrome and the Mutation of Phox2B Gene
An observational study of Congenital Central Hypoventilation Syndrome, run by Associação Fundo de Incentivo à Pesquisa at 1 site in Brazil.
Trial summary
Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory control characterized by ventilatory impairment that results in arterial hypoxemia. Although patients typically present this disease as newborns and rarely in later infancy, there have been reports of patients presenting with CCHS in… Read more about this study
- Who is it for?
- Ages 5 years and older, men onlyHealthy volunteers can take part
- Conditions the study is for
- Congenital Central Hypoventilation Syndrome
- What is being tested?
- positive airway pressure, Non-invasive mechanic ventilation
- Type of treatment
- Medical device
- How many people
- 1 participants
- Where
- 1 siteBrazil
- Study dates
- Jul 2010to Sep 2010
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 years and older
- Men only
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: familial case in which the father (proband) presented late-onset CCHS with an expansion mutation of the Phox2B gene that was confirmed by genetic analysis.
Inclusion Criteria:Family member
Exclusion Criteria:NA
Trial locations and contacts
1 site in 1 country.
Brazil1 site
Disciplina de Medicina e Biologia do Sono, Departamento de Psicobiologia, Universidade Federal de São Paulo
São Paulo, São Paulo, 04024-002
About this study
Official title: Late-onset, Insidious Course and Invasive Treatment of Congenital Central Hypoventilation Syndrome in a Case With the Phox2B Mutation
Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory control characterized by ventilatory impairment that results in arterial hypoxemia. Although patients typically present this disease as newborns and rarely in later infancy, there have been reports of patients presenting with CCHS in adulthood.
The present study reports a unique familial case in which the father (proband) presented late-onset CCHS with an expansion mutation of the Phox2B gene that was confirmed by genetic analysis. Surprisingly, the proband did not report any manifestation of the disease during childhood, and the disease progressed following an insidious course until adulthood. At the time of diagnosis, he did not present signs of pulmonary hypertension and right-side heart failure. The patient responded well to nocturnal invasive ventilation. In contrast, his son presented CCHS as a newborn with the full complement of symptoms while his daughter did not.
The present report shows that CCHS cases characterized by a mutated Phox2 gene can progress without many symptoms and that the treatment approach used here was efficient for controlling the course of the disease. Furthermore, this case indicates that incomplete penetrance can occur. Genetic screening of family members is mandatory to evaluate the reproductive risk of the disease, especially because asymptomatic mutation carriers may be at high risk to develop the disease and transmit it to the next generation.
Read the detailed description
Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory control characterized by ventilatory impairment that results in arterial hypoxemia. This condition worse during sleep and occurs in patients with normal mechanical properties of the lung. It is diagnosed in the absence of primary neuromuscular disease, identifiable brainstem lesions, and other sleep disturbances or substance use.
Amiel et al. (2003) identified a mutation in the Phox2B gene associated with CCHS, characterized by 5 to 9 alanine expansions within a 20-residue polyalanine region in exon 3 of the Phox2B gene. Several reports confirmed the findings of Amiel et al., supporting the view that this gene is a master switch for the development of the autonomic nervous system network linked to respiratory control. Transgenic animals carrying the human Phox2B mutation develop a similar phenotype and lack glutamatergic neurons located in the parafacial region in the brainstem, which are involved in breathing control.
Although patients typically present with CCHS as newborns and rarely in later infancy, there have been reports of patients presenting with CCHS in adulthood. In cases of late-onset CCHS, most patients report having had some symptoms since childhood, and they have parents with a history of CCHS. Symptoms of right-side heart failure are generally observed at the time of diagnosis, and nocturnal noninvasive ventilation is frequently indicated.
The present study reports a unique familial case of CCHS in which the father (proband) presented late-onset CCHS linked to a Phox2B gene expansion mutation. The presentation, course of development and treatment response for this patient was unique His son presented CCHS as a newborn, while his daughter did not.
- Being tested
- positive airway pressure, Non-invasive mechanic ventilation
- Keywords
- Congenital Central Hypoventilation Syndrome, Phox2B gene, invasive ventilation, genetics, late-onset, sleep, central sleep apnea
- Medical subject headings
- Congenital central hypoventilation syndrome, Sleep Apnea, Central
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
positive airway pressure, Non-invasive mechanic ventilationDevice
Also called There is no other intervention description
Vpap: 16 cm H2O inspiratory and 8 cm H2O expiratory pressures, 20 irpm.
Mechanic ventilation: tidal volume of 850 ml; 16 irpm; inspiratory pressure of 40 mmHg; PEEP: 5 cm H2O.
| Study group | Role | What they receive |
|---|---|---|
| polysomnography | Overnight supervised polysomnography (Embla System®) was performed in a sleep laboratory, which included capnometry. Arterial blood gas analysis was performed by radial arterial puncture. Ventilatory response to progressive hypercapnia was measured using the Read breathing technique. Briefly, subjects rebreathed into an air tight 5-L bag containing a mixture of 8% carbon dioxide (CO2) and 40% oxygen (O2). The spirometer technology used to monitor ventilation was based on a bi-directional rotating vane principle (flow sensitive). A continuous record of CO2 concentration in the expired gas was obtained by a CO2 analyzer within the circuit. The ventilatory hypercapnic drive was calculated from the slope produced by changes in ventilation (L. min-1) and changes in end-tidal PCO2. Receives: Device: positive airway pressure, Non-invasive mechanic ventilation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Describe the clinical case apresentation
Measured: Years of evolution
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2010 (estimated)
- Study startJul 2010
- Primary completionJul 2010
- Study completionSep 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Congenital Central Hypoventilation SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Retrospective
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- Associação Fundo de Incentivo à Pesquisa
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Prof. Dr. Lia Azeredo-Bittencourt, Associação Fundo de Incentivo à Pesquisa
- Investigators
- Lia Rita A Bittencourt, PhD, Principal investigator, Universidade Federal de São Paulo/UNIFESP
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01225679
- Sponsor's protocol ID
- 512947
- Acronym
- CCHS
- Status last verified
- Feb 2014
- First submitted
- 7 Jul 2010
- Last updated
- 6 Feb 2014
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Feb 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Late-onset, Insidious Course and Invasive Treatment of Congenital Central Hypoventilation Syndrome in a Case With the Phox2B Mutation
- ClinicalTrials.gov ID
- NCT01225679
- Acronym / sponsor ID
- CCHS / 512947
- Keywords
- Congenital Central Hypoventilation Syndrome, Phox2B gene, invasive ventilation, genetics, late-onset, sleep, central sleep apnea
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 1 participants (actual)
- Lead sponsor
- Associação Fundo de Incentivo à PesquisaUniversity, hospital or other
- Study start
- Jul 2010
- Primary completion
- Jul 2010 (actual)
- Study completion
- Sep 2010 (actual)
- First posted
- 21 Oct 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory control characterized by ventilatory impairment that results in arterial hypoxemia. Although patients typically present this disease as newborns and rarely in later infancy, there have been reports of patients presenting with CCHS in adulthood.
The present study reports a unique familial case in which the father (proband) presented late-onset CCHS with an expansion mutation of the Phox2B gene that was confirmed by genetic analysis. Surprisingly, the proband did not report any manifestation of the disease during childhood, and the disease progressed following an insidious course until adulthood. At the time of diagnosis, he did not present signs of pulmonary hypertension and right-side heart failure. The patient responded well to nocturnal invasive ventilation. In contrast, his son presented CCHS as a newborn with the full complement of symptoms while his daughter did not.
The present report shows that CCHS cases characterized by a mutated Phox2 gene can progress without many symptoms and that the treatment approach used here was efficient for controlling the course of the disease. Furthermore, this case indicates that incomplete penetrance can occur. Genetic screening of family members is mandatory to evaluate the reproductive risk of the disease, especially because asymptomatic mutation carriers may be at high risk to develop the disease and transmit it to the next generation.
Detailed description
Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory control characterized by ventilatory impairment that results in arterial hypoxemia. This condition worse during sleep and occurs in patients with normal mechanical properties of the lung. It is diagnosed in the absence of primary neuromuscular disease, identifiable brainstem lesions, and other sleep disturbances or substance use.
Amiel et al. (2003) identified a mutation in the Phox2B gene associated with CCHS, characterized by 5 to 9 alanine expansions within a 20-residue polyalanine region in exon 3 of the Phox2B gene. Several reports confirmed the findings of Amiel et al., supporting the view that this gene is a master switch for the development of the autonomic nervous system network linked to respiratory control. Transgenic animals carrying the human Phox2B mutation develop a similar phenotype and lack glutamatergic neurons located in the parafacial region in the brainstem, which are involved in breathing control.
Although patients typically present with CCHS as newborns and rarely in later infancy, there have been reports of patients presenting with CCHS in adulthood. In cases of late-onset CCHS, most patients report having had some symptoms since childhood, and they have parents with a history of CCHS. Symptoms of right-side heart failure are generally observed at the time of diagnosis, and nocturnal noninvasive ventilation is frequently indicated.
The present study reports a unique familial case of CCHS in which the father (proband) presented late-onset CCHS linked to a Phox2B gene expansion mutation. The presentation, course of development and treatment response for this patient was unique His son presented CCHS as a newborn, while his daughter did not.
Study design
- Observational model
- Case only
- Time perspective
- Retrospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| polysomnography | – | Device: positive airway pressure, Non-invasive mechanic ventilationOvernight supervised polysomnography (Embla System®) was performed in a sleep laboratory, which included capnometry. Arterial blood gas analysis was performed by radial arterial puncture. Ventilatory response to progressive hypercapnia was measured using the Read breathing technique. Briefly, subjects rebreathed into an air tight 5-L bag containing a mixture of 8% carbon dioxide (CO2) and 40% oxygen (O2). The spirometer technology used to monitor ventilation was based on a bi-directional rotating vane principle (flow sensitive). A continuous record of CO2 concentration in the expired gas was obtained by a CO2 analyzer within the circuit. The ventilatory hypercapnic drive was calculated from the slope produced by changes in ventilation (L. min-1) and changes in end-tidal PCO2. |
Who may qualify
- Ages
- 5 years and older
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- familial case in which the father (proband) presented late-onset CCHS with an expansion mutation of the Phox2B gene that was confirmed by genetic analysis.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| positive airway pressure, Non-invasive mechanic ventilationAlso: There is no other intervention descriptionVpap: 16 cm H2O inspiratory and 8 cm H2O expiratory pressures, 20 irpm. Mechanic ventilation: tidal volume of 850 ml; 16 irpm; inspiratory pressure of 40 mmHg; PEEP: 5 cm H2O. | Device | polysomnography |
Primary outcome
Describe the clinical case apresentation
Time frame: Years of evolution
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Feb 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lia Rita A Bittencourt, PhD principal investigator
Universidade Federal de São Paulo/UNIFESP
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Congenital Central Hypoventilation Syndrome, run by Associação Fundo de Incentivo à Pesquisa at 1 site in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Describe the clinical case apresentation (time frame: Years of evolution). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2014.