Late-onset Congenital Central Hypoventilation Syndrome Research Articles

Research advances on late-onset congenital central hypoventilation syndrome

Research advances on late-onset congenital central hypoventilation syndrome

Two children with late-onset congenital central hypoventilation syndrome

Two children with late-onset congenital central hypoventilation syndrome were reported, one of whom was male and had no abnormal manifestations after birth, respiratory failure occurs at the age of 1 year and 6 months. After being hospitalized, he was treated with oxygen inhalation and non-invasive ventilation, but carbon dioxide retention could not be corrected. After one month of tracheal intubation, he was failure to wean from ventilator, so tracheostomy was performed. He needs a ventilator to help breath while sleeping, and can breath autonomously during the day without ventilator. The other case was a female, with no abnormalities after birth. At the age of 11 months, she developed respiratory failure. During sleep, the child needs non-invasive assisted ventilation through a nasal mask, and during the day, she breathed autonomously.Two patients were followed up forever 2 years and their growth and development were normal.

Late-onset congenital central hypoventilation syndrome :a case with RET gene mutation

Late-onset congenital central hypoventilation syndrome :a case with RET gene mutation

Generation of two hiPSC lines (UMILi027-A and UMILi028-A) from early and late-onset Congenital Central hypoventilation Syndrome (CCHS) patients carrying a polyalanine expansion mutation in the PHOX2B gene

Congenital Central Hypoventilation Syndrome (CCHS) is a rare disorder of the autonomic nervous system (ANS), characterized by inadequate control of autonomic ventilation and global autonomic dysfunction. Heterozygous polyalanine repeat expansion mutations in exon 3 of the transcription factor Paired-like homeobox 2B (PHOX2B) gene occur in 90% of CCHS cases. In this study, we describe the generation and characterization of two human induced pluripotent stem cell (hiPSC) lines from female CCHS patients carrying a heterozygous + 5 alanine expansion mutation. The generated iPSC lines show a normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.

Adult With PHOX2B Mutation and Late-Onset Congenital Central Hypoventilation Syndrome.

PHOX2B 20/27 polyalanine repeat mutation (PARM) in patients with congenital central hypoventilation syndrome (CCHS) is generally associated with full-time ventilator dependence, Hirschsprung disease, and increased risk for cardiac asystole. We follow a 14-year-old boy with CCHS PHOX2B 20/27 PARM who is full-time ventilator dependent via tracheostomy and has Hirschsprung disease. His mother, age 52 years, has a history of prolonged recovery from anesthesia and an elevated serum bicarbonate level of 45 mEq/L discovered on routine blood chemistry. PHOX2B gene mutation analysis was performed and showed an identical 20/27 PARM, diagnostic of CCHS. Late-onset CCHS has been reported in those with 20/24, 20/25 PHOX2B PARM, and in nonpolyalanine repeat mutations. This is the first report of a patient with PHOX2B 20/27 PARM with a mild phenotype diagnosed during adulthood. This unusual presentation supports the screening for PHOX2B mutations in parents of children with CCHS.

Conscious sedation with dexmedetomidine for implantation of a phrenic nerve stimulator in a pediatric case of late-onset congenital central hypoventilation syndrome

Patients with congenital central hypoventilation syndrome (CCHS) develop alveolar hypoventilation resulting from a failure of central ventilatory control. Late-onset CCHS (LO-CCHS), which may be precipitated by severe respiratory infection or exposure to sedatives or general anesthesia, presents after the neonatal period. Since CCHS patients require lifelong mechanical-assisted ventilation, in western countries, diaphragm pacing is used to provide adequate alveolar ventilation and oxygenation during rest and daily activities. The main anesthesia-related concern regarding CCHS is postoperative respiratory failure or apnea, and anesthetic agents should be minimized to avoid further respiratory depression after surgery. A 5-year-old girl with LO-CCHS was referred to our hospital for implantation of a phrenic nerve stimulator for diaphragm pacing. Respiratory infection triggered the need for permanent nocturnal ventilator support at age 3 years and tracheotomy was performed at age 4 years. Repeated self-dislodgement of the ventilator tube led to hypoxic ischemic encephalopathy. The patient was thought to require mechanical ventilation under minimum sedation and pain management during the early postoperative period. The co-administration of dexmedetomidine and morphine provided effective conscious sedation with protection of the surgical site and without adverse events. She was discharged from the intensive care unit with a home ventilator at 3 days post-operation.

Anesthetic Considerations for Patients With Congenital Central Hypoventilation Syndrome: A Systematic Review of the Literature.

Congenital central hypoventilation syndrome (CCHS) is a form of sleep-disordered breathing characterized by a diminished drive to breathe during sleep, despite progressive hypercapnia and hypoxia. The condition results from mutations in the paired-like homeobox 2B (PHOX2B) gene. The aim of this review was to conduct a systematic search of the current data on CCHS as it relates to perioperative considerations and to discuss the classification, prevalence, pathophysiology, presentation, genetics, and management of the condition. A systematic search of Medline, EMBASE, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials was done up to October 2015. The results were limited to human studies published in the English language. Study titles and abstracts were screened to identify studies relating to CCHS relevant to anesthetic care. All study designs including randomized controlled trials, observational studies, case reports, or case series were included. The searches yielded 165 articles, of which 45 were relevant to perioperative considerations. There were 15 relevant case reports categorized as pertaining to the following: (1) novel presentations of the condition after sedation/anesthesia; (2) anesthetic techniques used in patients with established CCHS; and (3) patients with CCHS who experienced anesthetic complications. Review of the case reports showed that patients ranged from neonates up to 59 years of age. Novel presentations of the disease after sedation or anesthesia for minor procedures often led to diagnosis. The sequelae of undiagnosed CCHS led to complications, such as hypoxia, desaturations, apneas, seizures, unplanned intensive care admissions, prolonged hospital stays, and long-term tracheostomies. There appeared to be few postoperative complications in patients with known CCHS. Anesthesiologists need to be aware of undiagnosed late-onset CCHS and include this condition in the differential diagnosis of patients with unexplained postoperative respiratory depression. Anesthetic techniques should minimize the use of agents that further depress respiration postprocedure and ensure adequate monitoring to detect postoperative apneas.

Late-onset congenital central hypoventilation syndrome and a rare PHOX2B gene mutation

Congenital central hypoventilation syndrome (CCHS) is a rare lifelong disorder characterized by an abnormal ventilatory response with persistent hypercapnia and hypoxia, which worsen during sleep. About 90% of CCHS individuals are heterozygous for a mutation in the exon 3 of the PHOX2B gene. With higher awareness and better diagnostic tools, cases are identified in late childhood and adulthood, often with distinct mutations. The authors present a 4-year-old girl admitted to the intensive care unit at 9, 11 and 13months suffering from severe hypercapnic respiratory failure during viral respiratory infections. Hypercapnia during sleep improved with wakefulness. CCHS was confirmed genetically (heterozygous insertion of an adenine at position 23, leading to a premature stop codon in exon 1 of the PHOX2B gene). The parents' DNA showed no PHOX2B mutations. Hypoventilation was observed by polysomnography, with no autonomic response to declining oxygen or increasing carbon dioxide values. A subsequent sleep study showed less hypoxia and hypercapnia. The patient has been on non-invasive ventilation during sleep, showing good growth and neurocognitive development. A greater awareness is required to diagnose late-onset CCHS. A respiratory infection can trigger the disease, with a significant difference in CO2 between sleep and wakefulness as the warning signal. Given the clinical suspicion, a genetic study should be performed. Polysomnography is essential for patient characterization. Follow-up and ventilator support adjustment prevent serious hypoxia and hypercapnia, which impair cardiovascular and neurocognitive functions. This patient's mutation has not been previously described; hence, clinical evolution cannot be predicted.

Le syndrome d’hypoventilation alvéolaire central congénital (CCHS) : un cas de révélation tardive

The congenital central hypoventilation syndrome (CCHS) or Ondine's curse is a rare autosomal dominant disease, characterized by disorders of the autonomic nervous system, with abnormal ventilatory responses to hypercapnia and hypoxia. PHOX2B has been identified as the major gene causing CCHS. It results from polyalanine repeat expansion mutations. It typically presents in the newborn period but some cases have been described in adults (late onset CCHS) reflecting the variable penetrance of PHOX2B mutations. A 48 year-old woman presented, after ovarian cyst surgery, with severe hypoventilation requiring intubation. Arterial blood gases revealed a PaO2 of 6.6kPa (50mmHg), a PaCO2 of 10kPa (80mmHg) and a pH of 7.22. The past medical history revealed nocturnal symptoms for a few years. These included apnoeas, fitful sleep and awakening with headaches. Physical examination, pulmonary function tests, lung tomography and magnetic resonance imaging of the brainstem were all normal. Polysomnography revealed numerous central and obstructive apnoeas and hypopnoeas, with severe hypoxaemia and hypercapnia. Hypoxic and hypercapnic stimulation tests showed no adaptation of the ventilatory responses. Genetic analysis showed a heterozygous five alanine expansion mutation of the 20-residue polyalanine tract in exon 3 of the PHOX2B gene. The diagnosis of late onset CCHS should be considered in patients with unexplained hypoventilation, and physiological evaluation should be undertaken to document the abnormal ventilatory responses. The presence of a PHOX2B mutation confirms the diagnosis.

Late-onset, insidious course and invasive treatment of congenital central hypoventilation syndrome in a case with the Phox2B mutation: case report

Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory control characterized by ventilatory impairment that results in arterial hypoxemia. This condition is 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 [1]. Amiel et al. [2] identified a mutation in the Phox2B gene associated with CCHS, characterized by five to nine 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 [3–6]. 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 [7]. 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-sided heart failure are generally observed at the time of diagnosis, and nocturnal noninvasive ventilation is frequently indicated [8–15]. L. R. A. Bittencourt (*) :M. Pedrazzoli : F. Yagihara : G. P. Luz : S. Garbuio :G. A. Moreira : S. Tufik Disciplina de Medicina e Biologia do Sono, Departamento de Psicobiologia, Universidade Federal de Sao Paulo, Rua Napoleao de Barros, 925, 04024-002 Sao Paulo, Sao Paulo, Brazil e-mail: lia@psicobio.epm.br

PHOX2B Mutation-Confirmed Congenital Central Hypoventilation Syndrome in a Chinese Family

Congenital central hypoventilation syndrome (CCHS) is characterized by compromised chemoreflexes resulting in sleep hypoventilation. We report a Chinese family with paired-like homeobox 2B (PHOX2B) mutation-confirmed CCHS, with a clinical spectrum from newborn to adulthood, to increase awareness of its various manifestations. After identifying central hypoventilation in an adult man (index case), clinical evaluation was performed on the complete family, which consisted of the parents, five siblings, and five offspring. Pulmonary function tests, overnight polysomnography, arterial blood gas measurements, hypercapnia ventilatory response, and PHOX2B gene mutation screening were performed on living family members. Brain MRI, 24-h Holter monitoring, and echocardiography were performed on members with clinically diagnosed central hypoventilation. The index patient and four offspring manifested clinical features of central hypoventilation. The index patients had hypoxia and hypercapnia while awake, polycythemia, and hematocrit levels of 70%. The first and fourth children had frequent cyanotic spells, and both died of respiratory failure. The second and third children remained asymptomatic until adulthood, when they experienced impaired hypercapnic ventilatory response. The third child had nocturnal hypoventilation with nadir pulse oximetric saturation of 59%. Adult-onset CCHS with PHOX2B gene mutation of the + 5 alanine expansions were confirmed in the index patient and the second and third children. The index patient and the third child received ventilator support system bilevel positive airway pressure treatment, which improved the hypoxemia, hypercapnia, and polycythemia without altering their chemosensitivity. Transmission of late-onset CCHS is autosomal-dominant. Genetic screening of family members of CCHS probands allows for early diagnosis and treatment.

A 2-Year Old With No Ventilator Requirement but Who Cannot Be Extubated

A 2-year-old boy was intubated during treatment for pneumonia. After resolution of the infection, he had no pulmonary requirement for ventilation and could function without it while awake. When he slept, however, he would have decreasing respiratory effort, increasing hypercapnia, and episodic apnea. This report provides an example of late-onset congenital central hypoventilation syndrome.

Late-onset central hypoventilation syndrome: a family genetic study

Congenital central hypoventilation syndrome is a rare disorder characterised by chronic alveolar hypoventilation, which becomes more pronounced during sleep and may be associated with neurocristopathies, such as Hirchsprung's disease. A mutation in the PHOX2B gene has recently been identified. In a family of both parents and five offspring, detailed clinical assessment, pulmonary function testing, overnight sleep studies and ventilatory responsiveness to progressive hypercapnia (V'(R,CO(2))) were performed, in addition to analysis of known genetic loci for this condition. The father and four of the offspring demonstrated features of central hypoventilation with nonapnoeic oxygen desaturation during sleep and diminished V'(R,CO(2)), despite normal pulmonary function. The lowest sleep saturation was median (range) 79% (67-83%) and V'(R,CO(2)) was 2.1 (0.03-4.3) L x min(-1) x kPa(-1). The normal values for the authors' centre (St Vincent's University Hospital, Dublin, Ireland) are 15-40 L x min(-1) x kPa(-1). An in-frame five amino acid polyalanine expansion of the PHOX2B gene was found in all affected subjects, while the mother and fifth child, who did not have features of central hypoventilation, had a normal PHOX2B gene. Magnetic resonance imaging of the brainstem in one severely affected child was normal. The present study of a unique family confirms that transmission of late-onset congenital central hypoventilation syndrome is autosomal dominant in nature.

Diaphragm pacing in infants and children. A life-table analysis of implanted components.

Since 1976, we have implanted bilateral phrenic nerve electrodes for diaphragm pacing in 33 infants and children. This population includes 23 patients with congenital central hypoventilation syndrome (CHS), two with late onset CHS and hypothalamic dysfunction, three with hypoventilation associated with Chiari II malformation and myelomeningocele, and five with quadriplegia. Our experience, totalling 192 system-years and 96 patient-years of pacing, has enabled us to document the nature and frequency of problems related to the implanted components of the Avery Laboratories (S-232-1) pacemaker system when used in a pediatric population. By life table analysis, the mean time to need for replacement of any implanted component was 56.3 months. A total of 26 failures requiring component replacement occurred and were classified into four types: (1) receiver failure (15 cases), (2) electrode wire or wire insulation breakage (six cases), (3) infection requiring diaphragm pacer system removal (three cases), and (4) mechanical nerve injury (two cases). We conclude that the present diaphragm pacing system is effective but not without risk of biomedical component failure. The present system might be substantially improved by (1) a modified receiver design with a hermetic seal to prevent fluid penetration, (2) stronger, better insulated electrode wires, and (3) modifications of surgical technique and electrode type to prevent phrenic nerve damage.