Late-onset Congenital Central Hypoventilation Syndrome and the Mutation of Phox2B Gene (CCHS)

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.

Study Overview

• Status: Completed
• Conditions: Congenital Central Hypoventilation Syndrome
• Intervention / Treatment: Device: positive airway pressure, Non-invasive mechanic ventilation

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 Type: Observational
• Enrollment (Actual): 1

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 04024-002
    • Disciplina de Medicina e Biologia do Sono, Departamento de Psicobiologia, Universidade Federal de São Paulo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

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.

Description

Inclusion Criteria:Family member

Exclusion Criteria:NA

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

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.

Device: positive airway pressure, Non-invasive mechanic ventilation; 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.; Other Names: There is no other intervention description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Describe the clinical case apresentation	Years of evolution

Collaborators and Investigators

• Sponsor: Associação Fundo de Incentivo à Pesquisa
• Investigators: Principal Investigator: Lia Rita A Bittencourt, PhD, Universidade Federal de São Paulo/UNIFESP

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: July 7, 2010
• First Submitted That Met QC Criteria: October 20, 2010
• First Posted (Estimate): October 21, 2010

Study Record Updates

• Last Update Posted (Estimate): February 6, 2014
• Last Update Submitted That Met QC Criteria: February 5, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: genetics; sleep; Congenital Central Hypoventilation Syndrome; Phox2B gene; invasive ventilation; late-onset; central sleep apnea
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Disease; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Respiratory Insufficiency; Syndrome; Hypoventilation; Sleep Apnea, Central
• Other Study ID Numbers: 512947

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No