Abstract
Study Objectives:
Congenital central hypoventilation syndrome (CCHS) is caused by the paired-like homeobox 2B (PHOX2B) mutation and predominantly diagnosed during the neonatal period. Although late-onset CCHS and PHOX2B mutation carriers have been reported, the features of these disease states in adults remain uncertain. This study aimed to identify the characteristics of adult-onset CCHS and PHOX2B-mutation carriers in adult.
Methods:
We mainly searched the PubMed/Medline and Cochrane Databases and classified our target patients into 2 groups: group A, symptomatically diagnosed with late-onset CCHS in adulthood; group B, adult PHOX2B-mutation carriers. Then, clinical characteristics, including the onset, treatment, long-term course, and pattern of the PHOX2B mutation in both groups were analyzed. Additionally, a new adult-case of late-onset CCHS was added to the analysis.
Results:
Group A was comprised of 12 patients. The onset triggers of illness included a history of respiratory compromise following general anesthesia and respiratory tract infections. All patients in group A had 20/25 polyalanine repeat mutations and required some chronic ventilatory support at least during sleep, including portable positive pressure ventilator via tracheostomy or noninvasive positive pressure ventilation. In these patients with ventilatory support during sleep, sudden death or poor prognosis was not reported. Group B was comprised of 33 adults from 24 families with PHOX2B mutations. Nine patients in group B were confirmed with the diagnosis of CCHS. Although polyalanine repeat mutations 20/25 represented the most common gene mutation, diverse mutations, including mosaicism, were observed. Hypoventilation of several cases in group B were underdiagnosed by overnight polysomnography without monitoring for CO2.
Conclusion:
Alveolar hypoventilation with unknown origin can be caused by the PHOX2B mutation even in adult cases. Both the identification of the PHOX2B mutation and the incorporation of capnography in polysomnography are important for adult cases with unexplained alveolar hypoventilation or asymptomatic mutation carriers.
Citation:
Hino A, Terada J, Kasai H, et al. Adult cases of late-onset congenital central hypoventilation syndrome and paired-like homeobox 2B-mutation carriers: an additional case report and pooled analysis. J Clin Sleep Med. 2020;16(11):1891–1900.
Keywords: congenital central hypoventilation syndrome, PHOX2B, transcutaneous carbon dioxide monitoring, polysomnography, CCHS, late-onset CCHS
BRIEF SUMMARY
Current Knowledge/Study Rationale: Although late-onset congenital central hypoventilation syndrome (CCHS) and paired-like homeobox 3B (PHOX2B)-mutation carriers have been reported in recent years, the characteristics of adult-onset CCHS remain uncertain. Moreover, clinical information of the PHOX2B-mutation carriers who were identified by familial screening for patients with CCHS is particularly insufficient.
Study Impact: This was the first pooled analysis that evaluated adult-onset CCHS and PHOX2B-mutation carriers in adults. For cases with unexplained alveolar hypoventilation or the family of proband, both the identification of the PHOX2B mutation and the incorporation of capnography in polysomnography are important to improve outcomes, even in adults.
INTRODUCTION
Congenital central hypoventilation syndrome (CCHS) is a rare and life-threating disorder due to the mutation of the paired-like homeobox 2B (PHOX2B) gene, presenting as an abnormal ventilatory response to hypercapnia and hypoxia.1 Most patients with CCHS are diagnosed with hypoventilation that requires assisted ventilation during the neonatal period. The PHOX2B gene, which is located on chromosome 4p12 and has 3 exons, is a transcription factor that is involved in the differentiation of the respiratory control system and the autonomic nervous system.2,3 To date, CCHS studies have revealed that PHOX2B mutations mainly occur de novo but can be inherited in an autosomal dominant with variable penetrance,4 and the mutation patterns (eg, expansion length of the polyalanine tracts in exon 3) are associated with disease phenotype or severity.5
Since the American Thoracic Society published and updated the statement on CCHS,6,7 CCHS and the diagnostic modality of PHOX2B mutations became of interest to pediatricians, physicians, and pulmonologists in the following years. Recently, cases diagnosed beyond the newborn period have been sporadically reported as late-onset CCHS (LO-CCHS).8–10 According to these reports, the majority of the patients with LO-CCHS appear to carry mild mutations of the PHOX2B gene (ie, 20/24 or 20/25 polyalanine repeat mutation [PARM]). However, the prognosis, treatment method, and onset factors of adult-onset CCHS (≥ 20 years old) are not fully understood. Furthermore, regarding PHOX2B-mutation carriers who were identified by familial screening for patients with symptomatic CCHS, detailed information, including clinical course, the future development of hypoventilation, and mutation pattern with/without mosaicism, is insufficient.
In this study, we investigated the characteristics of adult-onset CCHS and PHOX2B-mutation carriers in adults by pooling outcomes from past studies. We also added to this analysis a new case of a 60-year-old Japanese woman diagnosed with LO-CCHS, who required ventilatory assistance via tracheostomy.
CASE REPORT
A 60-year-old women was referred to our hospital for further examination of alveolar hypoventilation with unknown origin. Before the age of 58, she did not have any specific medical history. Two years before admission to our hospital, she was admitted to another hospital for pneumonia, and moderate hypercapnia was discovered. However, no clinical abnormalities were identified except for the hypercapnia. Afterward, 8 months before admission to our hospital, she was hospitalized with bacterial pneumonia and acute respiratory distress syndrome after she was infected with influenza. She was temporarily ventilated due to disturbed consciousness and hypercapnic respiratory failure. Although her pneumonia improved after treatment with antibiotics, the hypercapnia persisted, especially during sleep. Examinations, including chest imaging, electroencephalography, pulmonary function testing, and head magnetic resonance imaging were conducted; however, no obvious abnormalities were observed. Noninvasive positive airway pressure ventilation (NPPV) was started during the night for her nocturnal ventilatory disorder, but after polysomnography (PSG) was performed, she was switched to continuous positive airway pressure (CPAP) due to a suspicion of obstructive sleep apnea and hypopnea.
Two months before admission to our hospital, the patient underwent bilateral mastectomy under general anesthesia for breast cancer. After the anesthesia, she had refractory and severe respiratory failure with hypercapnia (Paco2 97 mm Hg). She was extubated, but after that, hypercapnia was uncontrolled in her spontaneous breathing (PaCO2 106.9 mmHg, pH 7.201). Furthermore, since she presented with bradycardia and 12-second sinus pauses during sleep and reached asystole, a pacemaker was implanted. Finally, she underwent tracheostomy and required continuous, assisted ventilation during sleep. Therefore, she was referred to our hospital for further examination of unexplained alveolar hypoventilation.
Clinical, radiological, and neurologic examinations were performed at our hospital, but we did not detect any abnormalities in the patient’s respiratory system, chest, nerves, muscles, central nervous system, or physique. The patient’s body mass index was 19.6 kg/m2 and she had never smoked, and a history of drug use causing her hypercapnia was not reported. After reanalyzing the PSG data from the previous hospital (Figure 1), we identified a mixture of obstructive sleep apnea and sustained hypopnea without respiratory effort (apnea-hypopnea index, 76.5 events/h; hypopnea index, 39.0 events/h). We investigated the cause and trend of her hypercapnia via transcutaneous carbon dioxide monitoring (TCM 5, IMI, Japan). Transcutaneous carbon dioxide monitoring revealed persistent hypercapnia (50–80 mm Hg), which worsened during sleep despite the use of NPPV (Figure 2, A and B). Her symptoms of hypercapnia got worse when she was watching television or reading books during the daytime (ie, less wakefulness stimulation) than when she was chatting or eating. During sleep, we adjusted the ventilator pressure setting according to the transcutaneous carbon dioxide monitor (Figure 2C) to treat her hypercapnia.
Figure 1. PSG performed at the former hospital before the diagnosis of CCHS.
Parameters measured during PSG (left). Mixed patterns of obstructive apnea (top right) and hypopnea (bottom right). We did not monitor transcutaneous CO2 during PSG. CCHS = congenital central hypoventilation syndrome, PSG = polysomnography, REM = rapid eye movement.
Figure 2. Trend of Ptcco2 monitoring.
Monitoring in the daytime (A), at night (B), and at night after NPPV adjustments (C). NPPV = noninvasive positive pressure ventilation, Ptcco2 = transcutaneous CO2.
Initially, idiopathic central alveolar hypoventilation was considered her disease. We obtained written informed consent from her and submitted a genetic test. The PHOX2B mutation was investigated using blood samples at Yamagata University, and it was revealed that there was a heterozygous, 5-alanine expansion mutation of the 20-residue polyalanine tract (ie, 20/25 PARM) in exon 3 of the PHOX2B gene. Finally, she was diagnosed with LO-CCHS at the age of 60. After discharge, she continued to use ventilation via tracheostomy (inspiratory positive airway pressure, 12 cm H2O; expiratory positive airway pressure, 5 cm H2O, 2L) during sleep. When we asked her about her medical history in more detail, she recalled that she stopped breathing at night on the day she gave birth by cesarean section and received temporary ventilation management. Furthermore, we obtained informed consent from her 2 daughters and submitted genetic tests; both daughters had no somatic mutation of the PHOX2B (ie, PARM20/20) from their blood tests.
METHODS
To identify LO-CCHS cases (> 20 year old), we searched English or Japanese literature via PubMed/Medline, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews using the keywords “late-onset”, “congenital central hypoventilation syndrome”, “CCHS”, “paired-like homeobox 2B”, and/or “PHOX2B”. Additional records that were found through other literature searches were also investigated. We finally identified 31 records from the PubMed database and 9 records from other sources. After screening the titles and abstracts, we excluded non-CCHS records (2 records), nonadult records (15 records), duplicate records (2 records), and review articles (4 records). As a result, 17 records of adult case reports of LO-CCHS were included in our analysis (Figure 3). Adult patients who were children at the time of diagnosis were excluded from the study. Additionally, we investigated patients’ families who carried PHOX2B mutations. Patients were divided into 2 groups; 1) group A, symptomatic patients who were diagnosed with CCHS in adulthood, and 2) group B, adult cases who carry the PHOX2B mutation (mutation was identified by familial search in CCHS patients). Group B consisted of patients with genetic mutations regardless of whether they had a final diagnosis of CCHS. Patients diagnosed later with familial LO-CCHS were also included. We extracted detailed information of patients and their family members from the literature, including age, sex, symptoms, type of PHOX2B mutation, results of the sleep study, results of PSG data, therapy, onset triggers of CCHS, and other complications.
Figure 3. Study flow chart of the literature search and screening process.
CCHS = congenital central hypoventilation syndrome.
If the term CCHS was clearly described in the reports or when the condition met the definition of sleep-related hypoventilation from the test results, such cases in group B (ie, PHOX2B-mutation carriers) are described with “the definitive diagnosis” of CCHS. According to the International Classification of Sleep Disorders, Third Edition (ICSD-3) of the American Academy of Sleep Medicine,1 sleep-related hypoventilation in adults is defined as follows: sleep hypoventilation is scored when the arterial Pco2 (or surrogate) is > 55 mm Hg for ≥ 10 minutes or when there is an increase in the arterial Pco2 (or surrogate) ≥ 10 mm Hg (in comparison to an awake supine value) to a value exceeding 50 mm Hg for ≥ 10 minutes. Given the absence of generally available continuous CO2 monitoring modalities for the diagnosis of sleep-related hypoventilation over the last 20 years, CO2 ventilatory response was partly included as the CO2 assessment/monitoring in Table 1 and Table 2.
Table 1.
Group A: Patients symptomatically diagnosed with LO-CCHS in adulthood.
| Case | Reference | Reported Year | Age of Diagnosis, y | Sex | Triggering Factor | Lethal Arrythmia | ANS Dysfunction | CO2 Monitoring System | Ventilatory Support | Tracheostomy | Genetics |
|---|---|---|---|---|---|---|---|---|---|---|---|
| #A-1 | Weese-Mayer et al20 | 2005 | 35 | M | anesthesia | (−) | (+) | ND | unclear | (+) | PARM 20/25 |
| #A-2 | Antic et al4 | 2006 | 22 | M | anesthesia, infection | (+) | ND | Tc | nocturnal NPPV | (−) | PARM 20/25 |
| #A-3 | Antic et al4 | 2006 | 22 | M | unknown | (−) | ND | Tc | nocturnal NPPV | (−) | PARM 20/25 |
| #A-4 | Antic et al4 | 2006 | 27 | F | unknown | (−) | ND | ND | nocturnal NPPV | (−) | PARM 20/25 |
| #A-5 | Barratt et al21 | 2007 | 41 | M | infection | (−) | (−) | (−) | nocturnal NPPV | (−) | PARM 20/25 |
| #A-6 | Trochet et al10 | 2008 | 25 | M | unknown | (−) | ND | ND | ventilatory assistance | unknown | PARM 20/25 |
| #A-7 | Trochet et al10 | 2008 | 55 | F | anesthesia | (−) | ND | ND | unclear | unknown | PARM 20/25 |
| #A-8 | Lee et al22 | 2009 | 53 | M | infection | (−) | (−) | V’R | nocturnal NPPV | (−) | PARM 20/25 |
| #A-9 | Bittencourt et al23 | 2012 | 49 | M | unknown | (−) | ND | Et | nocturnal invasive ventilation | (+) | PARM 20/25 |
| #A-10 | Lamon et al19 | 2012 | 48 | F | anesthesia | ND | ND | (+) | unclear | unknown | PARM 20/25 |
| #A-11 | Visser et al11 | 2013 | 55 | F | unknown | ND | ND | V’R | nocturnal NPPV | (−) | Mild PHOX2B mutation |
| #A-12 | Our case | 2019 | 60 | F | anesthesia, infection | (+) | (−) | Tc | nocturnal invasive ventilation | (+) | PARM 20/25 |
(−) = not present, (+) = present, Et = end-tidal CO2 monitoring, genetics = information regarding PHOX2B mutations, ND = no specific description, Tc = transcutaneous CO2 monitoring system, therapy = maintenance chronic treatment, V’R = ventilatory response test.
Table 2.
Group B: PHOX2B-mutation carriers in adults.
| Case | Reference | Reported Year | Relationship | Age | Sex | Definitive Diagnosis | Description of Symptom | Description of PSG Finding or Sleep Related Disordered Breathing | CO2 Monitoring System | Genetics | Therapy |
|---|---|---|---|---|---|---|---|---|---|---|---|
| #B-1 | Antic et al4 | 2006 | mother | 36 | F | (+) | Seizure | PSG: alveolar hypoventilation with hypoxemia and hypercarbia during sleep | Tc | PARM 20/25 | Nocturnal NPPV |
| #B-2 | Doherty et al12 | 2007 | father | 41 | M | (+) | (-) | Nocturnal hypoventilation 5 years later: elevated apnea-hypopnea index | V’R | PARM 20/25 | U |
| #B-3 | Trochet et al10 | 2008 | mother | 43 | F | (−) | (−) | (−) | (−) | PARM 20/25 | U |
| #B-4 | 2008 | father | 39 | M | (−) | (−) | (−) | (−) | PARM 20/25 | U | |
| #B-5 | 2008 | father | 34 | M | (−) | (−) | (−) | (−) | PARM 20/27 (mosaicism) | U | |
| #B-6 | 2008 | father | 27 | M | (−) | (−) | (−) | (−) | PARM 20/26 (mosaicism) | U | |
| #B-7 | 2008 | father | 43 | M | (−) | (−) | (−) | (−) | PARM 20/28 (mosaicism) | U | |
| #B-8 | 2008 | mother | 26 | F | (−) | (−) | (−) | (−) | PARM 20/26 (mosaicism) | U | |
| #B-9 | 2008 | mother | 43 | F | (−) | (−) | (−) | (−) | PARM 20/26 (mosaicism) | U | |
| #B-10 | 2008 | father | 57 | M | (−) | (−) | (−) | (−) | PARM 20/25 (mosaicism) | U | |
| #B-11 | 2008 | mother | 25 | F | (−) | (−) | (−) | (−) | PARM 20/31 (mosaicism) | U | |
| #B-12 | 2008 | father | 39 | M | (−) | (−) | (−) | (−) | NPARM (c.691_698dup) | U | |
| #B-13 | 2008 | father | 33 | M | (−) | (−) | (−) | (−) | NPARM (c.722 del35) (mosaicism) | U | |
| #B-14 | 2008 | mother | U | F | (−) | (−) | (−) | (−) | PARM 20/27 (mosaicism) | U | |
| #B-15 | 2008 | mother | 48 | F | (−) | (−) | (−) | (−) | PARM 20/25 (mosaicism) | U | |
| #B-16 | 2008 | mother | 37 | F | (-) | (−) | PSG: normal ventilation during sleep | ND | PARM 20/26 (mosaicism) | U | |
| #B-17 | 2008 | father | 45 | M | (+) | Sleep apnea | U | ND | PARM 20/28 (mosaicism) | Ventilatory support | |
| #B-18 | Trivedi et al13 | 2011 | paternal grandmother | U | F | U | (−) | U | ND | PARM 20/25 | Nocturnal NPPV |
| #B-19 | Meguro et al14 | 2012 | mother | 35 | F | (+) | (−) | PSG (+) | ND | PARM 20/25 | U |
| grandmother | 68 | F | (+) | (−) | PSG (+) | ND | PARM 20/25 | U | |||
| uncle | 31 | M | (+) | Cardiac failure at age of 35 | PSG (+) | ND | PARM 20/25 | U | |||
| #B-20 | Bygarski et al18 | 2013 | father | 42 | M | (−) | Diaphoresis | A low resting oxygen saturation level and mild obstructive sleep apnea | ND | NPARM (c.391 delC) | nocturnal CPAP |
| paternal grandfather | 80 | M | (−) | Cardiac arrest Chronic constipation | Severe obstructive sleep apnea | ND | NPARM (c.391 delC) | CPAP | |||
| paternal aunt | 44 | F | (−) | Recurrent bronchitis and photophobia | Unexplained low resting saturation levels during a hospital admission for a cholecystectomy at the age of 25 | ND | NPARM (c.391 delC) | CPAP | |||
| Sign of Pulmonary hypertension | Severe obstructive sleep apnea | ||||||||||
| paternal aunt | 46 | F | (−) | Sleep apnea and occasional episodes of diaphoresis | U | ND | NPARM (c.391 delC) | U | |||
| paternal aunt | 48 | F | (−) | U | U | ND | NPARM (c.391 delC) | U | |||
| daughter of paternal aunt | 28 | F | (−) | Recurrent abdominal pains and chronic constipation as a child | U | ND | NPARM (c.391 delC) | (-) | |||
| #B-21 | Chuen-im et al16 | 2014 | mother | U | F | (−) | Snoring and recurrent sinusitis | PSG; respiratory disturbance index of 9.3 events/h of sleep and an apnea-hypopnea index of 4.8 events/h | Et | PARM 20/24 | (-) |
| The lowest SpO2 was 92%. The SpO2 ranged from 96 to 98% during non-REM sleep. Et-CO2 was 40–48 mm Hg | |||||||||||
| maternal grandmother | U | F | (+) | Idiopathic central hypersomnia and chronic respiratory failure | PSG: complex sleep apnea | ND | PARM 20/24 | Nocturnal NPPV | |||
| #B-22 | Low et al17 | 2014 | mother | U | F | (+) | (−) | Central hypoventilation | Et | NPARM (c.691_698dup) | (-) |
| grandfather | U | M | (−) | Daytime somnolence | Subtle abnormalities with short central apneas not associated with desaturation | ND | NPARM (c.691_698dup) | (-) | |||
| #B-23 | Klaskova et al15 | 2016 | father | 40 | M | (−) | Severe headache | PSG: moderate obstructive sleep apnea desaturation | ND | PARM 20/25 | Nocturnal CPAP |
| Excessive daytime sleepiness | |||||||||||
| #B-24 | Kasi et al8 | 2018 | mother | 52 | F | (+) | Hard to wean from oxygen led to headache and desaturation after surgery | PSG without capnography: obstructive sleep apnea and sleep-related hypoxemia | (−) | PARM 20/27 | NPPV |
(−) = not present, (+) = present, Et = end-tidal CO2 monitoring, Genetics = gene mutation of CCHS, ND = no specific description, Tc = transcutaneous CO2 monitoring system, Therapy = maintenance chronic treatment, U = unknown, V’R = ventilatory response test.
RESULTS
Twelve patients, including the patient who was described in our case report, were assigned to group A (Table 2), and 33 patients from 24 families were assigned to group B (Table 2). All cases were reported in the literature between 2004 and 2018 because the PHOX2B mutation was identified in 2003.
Group A: Patients symptomatically diagnosed with LO-CCHS in adulthood (adult-onset CCHS)
The age of the 12 patients in group A ranged from 22 to 60 years and the group consisted of 7 men and 5 women. Onset triggers of illness included a history of respiratory compromise following general anesthesia in 5 cases and respiratory tract infections in 4. As for their chronic ventilatory support identified in the literature, 6 patients used bilevel positive airway pressure ventilation by mask or nasal prongs (ie, nocturnal NPPV), 3 required a tracheostomy, and 2 used portable positive pressure ventilator via tracheostomy during the night. The treatment regimen of 1 patient with a tracheostomy was unknown. Two patients had been diagnosed with mental retardation before CCHS was confirmed in adulthood, but both patients had hypoventilation-related symptoms that began in childhood.4 All confirmed genetic mutations in group A were PARM 20/25, and only 1 case was unclear.11
Symptoms included snoring (1 patient), daytime sleepiness (3), headache (4), cyanosis (4), autonomic symptoms (1), memory impairment (2), and convulsive symptoms (3). Patients with convulsive symptoms were poorly responsive to drugs. Autonomic nervous system dysfunction was seen in 1 patient only. Laboratory findings showed elevated hematocrit levels in 6 patients, right heart dilatation in 7, and pulmonary hypertension in 3. While 2 patients had the capability of being immersed in water for a long time, and additional 2 had cyanosis and apnea that began in childhood. Although poor prognosis and sudden death were not particularly described in the searched literature, a careful follow-up for adult-onset CCHS is warranted, considering that the sinus syndrome was reported in 2 patients (#A-2, our case #A-12). The use of the CO2 monitoring system for diagnosis was clearly reported in 6 patients (3 in transcutaneous, 1 in end-tidal, and 2 in ventilatory response tests).
Group B: Adult cases with PHOX2B-mutation carrier
The age of the 33 patients with genetic mutations ranged from 25 to 80 years. Seven cases had mild respiratory symptoms, and the remaining 26 cases did not. Nine cases were confirmed with the diagnosis of CCHS. The gene mutations in group B were diverse compared to those in group A, including PARM 20/25 (8 families),4,10, 12,13,14,15 PARM 20/26 (4 families),10 PARM 20/27 (4 families),8,10 PARM 20/28 (2 families),10 PARM 20/24 (1 family),16 PARM 20/31 (1 family),10 and nonpolyalanine repeat expansion mutation (NPARM) (4 families). All carriers with a severe form of PARM (ie, genotypes 20/26–20/33) seemed to have mosaicisms of the mutation except for #B-24. Only 1 carrier case, whose genotype was PARM20/27, was reported to develop CCHS in adulthood. The NPARMs were: c.691_698dup mutation (2 families),10,17 c.722 del35 mutation (1 family), and c.391 delC mutation (1 family).10 While autonomic nervous system dysfunction was reported in #B-20, no detailed description was provided in the remaining literature.
Three cases were not diagnosed with CCHS; however, they had been clinically diagnosed with obstructive sleep apnea (OSA).18 Accurate examinations using the CO2 monitoring system were not carried out or described in many of the undiagnosed cases. Polysomnographic abnormalities were identified in several cases; however, these abnormalities did not lead to a diagnosis (Table 2). There were 2 cases in which no abnormalities were identified in PSG or end-tidal CO2 (#B-21, #B-16). Additionally, 1 patient who had normal PSG values developed CCHS at the 5-year follow-up (#B-2).
No patients required tracheostomy for treatment. Eight patients used nocturnal NPPV or CPAP management. Six of these eight patients were not diagnosed with CCHS, but they had been treated with CPAP for a different disease, such as OSA syndrome. Only 1 patient had a definitive diagnosis of CCHS without interventions (#B-22).
DISCUSSION
In the present study, we conducted a pooled analysis regarding the symptoms or clinical courses of adults (> 20 years old) with LO-CCHS and/or PHOX2B-mutation carriers. Additionally, our new case of a 60-year-old patient diagnosed with adult-onset CCHS was added to the analysis. This analysis is the first study that focused on and summarized adult-onset CCHS and cases of adult PHOX2B-mutation carriers.
Regarding the onset age of the disease, the majority of the patients with adult-onset CCHS (ie, group A) were diagnosed in their twenties to fifties. The 60-year-old woman shown in the present study appears to be the oldest patient among those with symptoms diagnosed with LO-CCHS. This indicates that patients with unexplained alveolar hypoventilation should be screened for the PHOX2B mutation, even in middle age or above. In most of the symptomatic patients, the clinical course included a rapid and severe respiratory impairment as described in our case (#A-12). However, although detailed information from 2 patients in group A were not detected,10,19 the prognosis of patients who used NPPV during sleep seemed fair because of modern techniques of home ventilation. In the analysis, indeed 3 patients required tracheostomy, but they did not require all-day ventilatory support. Concerning the disease trigger, most patients with symptomatic LO-CCHS did not have a distinct history of general anesthesia4,10,19,20 and ventilatory management.4,19–21 Thus, anesthesia and ventilatory management can be the main pivotal risk factors for adult-onset CCHS in PHOX2B-mutation carriers. Additionally, an increase in respiratory demand, such as lower respiratory tract infection,4,21,22 can also manifest in adult-onset CCHS. However, we did not observe any obvious trigger in 2 patients (#A-610 and #A-923). Patient #A-6 had convulsions and patient #A-9 had chronic symptoms, including severe headache, excessive daytime sleepiness, memory deficits, and cyanosis. In the disease identification, most cases in group A were diagnosed after they became serious, except for patient #A-8.22 Patient #A-8 was originally diagnosed with primary central hypoventilation syndrome and had a symptom of headache. Our case (#A-12) was diagnosed before the initiation of assisted ventilatory support when she had either a respiratory infection or a respiratory disturbance during sleep. These facts indicate that the identification of the PHOX2B mutation and the incorporation of capnography in PSG are important for cases with unexplained alveolar hypoventilation, even in adults. In particular, the diagnosis should be carefully considered in patients presenting sinus pause or asystole prior to CCHS confirmation, eg, cases #A-24 and #A-12 reported here. Regarding the mutation pattern of PHOX2B, the most common genotypes in cases of CCHS during infancy are PARM 20/27 and PARM 20/26, followed by PARM 20/25.24 However, all of the symptomatic adult cases exhibited the PARM 20/25 genotype.
Among the 33 adult PHOX2B-mutation carriers (ie, group B), 9 cases were diagnosed with LO-CCHS. This highlights the importance of screening family members of patients with CCHS to minimize the future incidence of pulmonary compromise. Abnormalities on the PSG findings in 5 of the remaining 27 undiagnosed patients in group B were observed,10,15–18 but the abnormal findings of PSG in patient #B-16 were not detected.10 This might suggest that usual overnight PSG (ie, without monitoring for CO2) will not sufficiently detect the alveolar hypoventilation associated with CCHS. Regarding the PHOX2B-mutation pattern in group B, since the mutation includes mosaicism in some of the asymptomatic carriers (see Table 2), mutations were more variable than those in group A. Additionally, although PARM 20/25 gene mutations are more common in adult-onset CCHS (ie, group A), 8 out of the 24 families with PARM 20/25 gene mutations in group B were asymptomatic.10,12,13,14 That might indicate that these carriers will be diagnosed with LO-CCHS later. There are still differences in the age of onset and severity within families regardless of having the same genetic mutation. The patients carrying long PARMs (26 or more PARM) or most non-PARMs usually present with neonatal onset and are complicated frequently with Hirschsprung’s disease and occasionally with neural crest tumors. Cases diagnosed or cases with CCHS during adulthood generally carry mild 20/24 or 20/25 PARM and non-PARMs (eg, #A1–12, #B-1, 2, 19, 21, 22). These mutations are also detected in asymptomatic individuals, indicating incomplete penetrance. Trochet and colleagues10 described in their report that a patient with somatic mosaicism of 20/28 PARM developed the symptoms in his forties (#B-17). They mentioned in the report that patients with somatic mosaicism of PARM may develop their symptoms later and that germline alanine expansions are not fully penetrant in the ventilatory phenotype.10 Kasi and colleagues8 reported that a patient with adult-onset CCHS had 20/27 PARM (#B-24; the patient’s mother had been also diagnosed with PHOX2B mutation PARM 20/27 positive and LO-CCHS). Thus, patients with adult-onset CCHS were not severely complicated probably because the deleterious effect of the mutations was reduced by genetic or nongenetic factors. Conversely, carriers with non-PARM fully penetrate and can develop CCHS even if it presents somatic mosaicism.
Five of the PHOX2B-mutation carriers were treated with NPPV or CPAP for obstructive sleep apnea syndrome or other unreported reasons.15,16,18 However, since these carriers are at risk of developing CCHS, close monitoring, investigation, and early initiation of the therapy (particularly with illness or exposure to sedative medications) are warranted. In addition, although CPAP has been introduced for the treatment of OSA in some carriers, we think that its use would be insufficient to treat hypoventilation (ie, no increase in minute ventilation with hypercapnia and hypoxia; no backup rate) if an association with CCHS is likely. Regarding the clinical course of PHOX2B-mutation carriers, patient #B-212 had a PHOX2B mutation and was asymptomatic. Although the PSG of patient #B-2 did not previously reveal hypoventilation, this patient was diagnosed with CCHS at the 5-year follow-up visit. This suggests that long-term follow-up is necessary for people with PHOX2B mutations even if they do not exhibit any symptom. Previous reports suggest that even if patients have few or mild symptoms of CCHS, they might have a specific medical history or an episode of hypoventilation-related symptoms, including capability of being immersed in water and ability of holding their breath.8,16,18 In fact, some asymptomatic patients of CCHS were previously undiagnosed because the PSG results indicated a diagnosis of OSA.18 Additionally, previous studies reported that asymptomatic, undiagnosed PHOX2B-mutation carriers were initially diagnosed with OSA.12,17 Similarly, we initially suspected that the patient in our case report presented OSA. This misdiagnosis may be explained by the lack of CO2 monitoring. It is important to note that some patients may exhibit symptoms and findings that could also be seen in patients with OSA. Since it is difficult to identify hypoventilation in certain patients with obstructive apnea or hypopnea, we believe that transcutaneous CO2 values should be monitored during PSG investigations. In fact, some studies described patients who did not wear a CO2 monitor and had not yet been diagnosed with CCHS.12
Some patients with LO-CCHS are asymptomatic or less symptomatic; therefore, the prevalence of CCHS may be higher than what we currently expect. In addition, it is impossible to clinically differentiate symptomatic cases of CCHS from idiopathic central hypoventilation syndrome, and genetic mutations must be examined. Since PHOX2B-mutation carriers may develop hypoventilation later,12 we suggest that regular follow-ups using PSG and CO2 monitoring should be conducted for all carriers, including those without an established respiratory issue.
The present study had several limitations. First, most of the selected articles were single case reports, and the number of studies was limited because confirmed cases of adult-onset CCHS are rare. Thus, the present analysis may have been biased due to limited information. Second, we were unable to verify the detailed results of PSG or other information related to hypoventilation in some cases. Third, some PHOX2B-mutation carriers lacked detailed clinical information because such reports were generally for familial searches. Fourth, given that the number of pediatric cases is larger and that their diagnosis is likely accurate, such cases were excluded from this study as our primary aim was to increase awareness of LO-CCHS among internal and respiratory physicians. Nevertheless, findings from the present study may be useful for pulmonologists and/or physicians because we demonstrated that CCHS may be diagnosed in adulthood.
CONCLUSIONS
This is the first report that focused on adult cases of PHOX2B mutations. Alveolar hypoventilation can be caused by the PHOX2B mutation even in adulthood. Both the identification of the PHOX2B mutation and the incorporation of capnography in PSG are important for adult cases with unexplained alveolar hypoventilation or asymptomatic mutation carriers.
DISCLOSURE STATEMENT
All authors have seen and approved this manuscript. Work for this study was performed at Chiba University Hospital. This study was partly supported by the Japanese Ministry of Health, Labour and Welfare research grants specifically designated to the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group.
ACKNOWLEDGMENTS
The authors thank Sinobu Ikeda in Chiba University Hospital and medical staffs in Kawasaki Municipal Hospital for the technical support, analysis of polysomnography, and the clinical information. We also thank the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, especially the Alveolar Hypoventilation Research group in the Ministry of Health, Labour and Welfare Japan for their dedicated scientific support.
Author Contributions: A.H., H.S., H.K., K.O., A.S., K.H., and J.T. performed data collection and analyzed the data, and A.H., J.T., A.S., K.H., and K.T. contributed to the writing of the manuscript. J.T. and K.T. planned and designed the study.
ABBREVIATIONS
- ANS
autonomic nervous system
- ARDS
acute respiratory distress syndrome
- ATS
The American Thoracic Society
- CCHS
congenital central hypoventilation syndrome
- CPAP
continuous positive airway pressure
- ICSD-3
International Classification of Sleep Disorders, Third Edition
- LO-CCHS
late-onset congenital central hypoventilation syndrome
- MRI
magnetic resonance imaging
- NPARM
non-polyalanine repeat mutation
- NPPV
non-invasive positive pressure ventilation
- OSA
obstruct sleep apnea
- OSAS
obstructive sleep apnea syndrome
- PARM
polyalanine repeat mutation
- PHOX2B
paired-like homeobox 2B
- PSG
polysomnography
- PtcCO2
transcutaneous carbon dioxide
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