0
Selected Reports |

PHOX2B Mutation-Confirmed Congenital Central Hypoventilation Syndrome in a Chinese Family: Presentation From Newborn to Adulthood FREE TO VIEW

Peilin Lee, MD; Yi-Ning Su, MD, PhD; Chong-Jen Yu, MD, PhD; Pan-Chyr Yang, MD, PhD, FCCP; Huey-Dong Wu, MD, FCCP
Author and Funding Information

*From the Center of Sleep Disorder (Dr. Lee), the Department of Internal Medicine (Drs. Yu and Yang), and the Department of Integrated Diagnostics and Therapeutics (Dr. Wu), National Taiwan University Hospital; and the Graduate Institute of Clinical Medicine (Dr. Su), College of Medicine, National Taiwan University, Taipei, Taiwan.

Correspondence to: Huey-Dong Wu, MD, Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, 7 Chung-Shan South Rd, Taipei 100, Taiwan; e-mail: hdwu@ntuh.gov.tw


The authors have no conflicts of interest to disclose.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2009;135(2):537-544. doi:10.1378/chest.08-1664
Text Size: A A A
Published online

Background:  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.

Methods:  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.

Results:  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.

Conclusions:  Transmission of late-onset CCHS is autosomal-dominant. Genetic screening of family members of CCHS probands allows for early diagnosis and treatment.

Figures in this Article

Congenital central hypoventilation syndrome (CCHS) is characterized by compromised central and peripheral chemoreflexes in the absence of primary neuromuscular, lung, cardiac, or metabolic diseases that lead to hypoventilation in sleep.18 In more severely affected patients, hypoventilation can be detected even when they are awake.5,9

Symptoms of CCHS usually develop early in the newborn, within weeks or months after birth.5,7,1013 Patients may have central hypoventilation alone or with associated Hirschsprung disease or tumors of neural crest origin. Symptoms of diffuse autonomic system dysregulation include esophageal dysmotility, decreased heart rate variability, poor temperature regulation, and decreased perception of discomfort and anxiety.3,57,1316 In rare instances, patients remain asymptomatic until an older age and receive a diagnosis of late-onset congenital central hypoventilation syndrome (LOCHS).3,1720

An autosomal-dominant inherited heterozygous paired-like homeobox 2B (PHOX2B) gene de novo mutation has been identified2,7,11,14,21 in 92 to 95% of CCHS cases. This gene encodes a highly conserved transcription factor devoted to the formation of autonomic medullary reflex pathways.4,21,22 Most PHOX2B gene mutations consist of + 5 to + 13 alanine expansions within a 20-repeat polyalanine tract resulting from a nonhomologous recombination.2,7,21,2325 The size of this polyalanine repeat expansion correlates closely with the severity of the clinical phenotype.7,11,14,20,23 The + 5 alanine expansions are not fully penetrant for the ventilatory phenotype and do not lead to either Hirschsprung disease or to tumor formation, but comprise the most frequent mutation in LOCHS.11,20,26,27 Nonpolyalanine repeat mutations include point and frameshift mutations that produce more severe disruptions of PHOX2B function and are associated with continuous ventilatory dependence, Hirschsprung disease, and tumors of neural crest origin.7,10,11,14,23,28,29

In this study, we report a Chinese family with CCHS that had a clinical spectrum ranging from newborn fatality (secondary to respiratory failure) to adults who were either asymptomatic or had hypoventilation while awake. Genetic analysis was used to confirm the presence of the PHOX2B expansion mutation.

Case Identification

After identifying central hypoventilation in an adult man (index case), a detailed evaluation was performed of the complete family, which consisted of the parents, five siblings, and five offspring (Fig 1). The father of the index patient died of colon cancer at 79 years of age, while an older sister died of breast cancer at 30 years of age. His first and fourth children died of respiratory failure 35 and 58 days after birth, respectively.

Figure Jump LinkFigure 1 The pedigree of a case of familial CCHS. Patients II-4, III-1, and III-2 are the index patient and his second and third children, respectively.Grahic Jump Location

Aside from full clinical assessment that included an evaluation of daytime sleepiness, anxiety symptoms, and signs of autonomic system dysregulation,17,18 additional tests included pulmonary function tests (PFTs), overnight attained polysomnography (PSG), arterial blood gas (ABG) levels, and hypercapnia ventilatory response. Brain MRI, 24-h Holter recording, and echocardiography were also performed on members with clinically diagnosed central hypoventilation syndrome. All living family members were screened for the PHOX2B gene mutation. The study protocol was approved by the Ethics Committee of the National Taiwan University Hospital, and all of the subjects provided written informed consent.

Measurements
Sleepiness and Perception of Anxiety:

Daytime sleepiness was measured using the Epworth sleepiness scale and was defined by a score ≥ 11.30 The quality of life and perception of discomfort and anxiety were measured using the Medical Outcomes Study 36-item short form (SF-36) and the Hospital Anxiety and Depression Scale (HADS), respectively.18,3133

PFTs and ABGs:

PFTs, spirometry, diffusing capacity measurements, and testing of respiratory muscle strength (Autobox 6200; SensorMedics; Yorba Linda, CA) were performed with the patient in a sitting position. The percentage of predicted values was obtained from the literature,34,35 while analysis of ABGs was made from blood obtained by radial arterial puncture.

Hypercapnia Ventilatory Response:

Ventilatory responsiveness to progressive hypercapnia was measured using the rebreathing technique,36 where the subject was seated and connected to a rebreathing circuit through a mouthpiece. The patient then breathed into an airtight 7-L bag containing a mixture of 5% carbon dioxide and 95% oxygen. The spirometer technology used to monitor ventilation was based on a heated wire flow sensor, which was calibrated by a 3-L syringe prior to testing. Before the rebreathing test, the subjects breathed room air through the same mouthpiece for baseline data. The partial pressure at end-tidal carbon dioxide (Petco2) was continuously measured with a capnograph connected to the mouthpiece (Autobox 6200; SensorMedics) and pulse oximetric saturation (Spo2) [Criticare CSI 503; Criticare Systems Inc; Milwaukee, WI].

When ventilatory response was assessed, Spo2 was maintained > 96%. Breathing rate, tidal volume, and minute ventilation (̇Ve) were noted together with their corresponding Spo2 and Petco2 values. Rebreathing continued for 4 to 6 min or until the onset of discomfort. Chemoreflex sensitivity to hypercapnia was obtained from the slopes of the linear regression of ̇Ve vs Petco2.

Overnight PSG:

All overnight PSG (Embla; Medcare; Reykjavik, Iceland) were recorded for > 6 h with the following channels: electroencephalography, electrooculogram, chin and tibia electromyogram, oronasal airflow by thermocouples and nasal pressure, thoracic and abdominal excursions, ECG, snoring sound, body position, and Spo2. Apnea was defined as the absence of airflow for ≥ 10 s, while hypopnea was defined as decreased airflow > 50% associated with Spo2 reduction in 4% or an arousal. The apnea-hypopnea index was defined as the sum of the number of apneas and hypopneas per hour of sleep, while the arousal index was the number of arousals per hour of sleep. An oxygen desaturation event was defined as the amount of 4% Spo2 reductions per hour.37,38

Genetic Testing:

Genomic DNA was collected from peripheral whole blood using a kit (QIAamp Blood MiniKit; QIAGEN; Hilden, Germany) according to the manufacturer's instructions. PHOX2B gene mutations were screened using polymerase chain reaction and direct sequencing as mentioned in the authors' previous work.23

Clinical Characteristics
Index Patient:

The index patient was a 53-year-old man who required medical attention at the age of 30 years for primary alveolar hypoventilation.39 He was rushed to the emergency department (ED) for shortness of breath and cyanotic spells with symptoms of minor upper respiratory tract infection. ABG levels revealed hypoxia and hypercapnia (Pao2, 59.3 mm Hg; Paco2, 64.2 mm Hg; HCO3, 34.4; and pH 7.34) while awake and breathing room air, which worsened during sleep but could be corrected with voluntary hyperventilation. Body mass index at hospital admission was 18.8 kg/m2, hematocrit was 49%, and PFT was normal. Pulmonary angiography disclosed patent pulmonary vasculature and normal pulmonary artery pressure (mean pressure, 27 mm Hg). He received a diagnosis of primary alveolar hypoventilation, but PSG was not available at that time. Thereafter, he adapted well and had an uneventful life.

However, 23 years after the episode of respiratory failure, polycythemia was noted during a medical checkup. He was referred to the hospital and received a diagnosis of secondary polycythemia with high hematocrit (70%) and erythropoietin level (41 IU; normal 9 to 12 IU). He denied symptoms of shortness of breath, exercise intolerance, daytime sleepiness, or awakening with headaches. Physical examination revealed a slim stature (body mass index, 23 kg/m2), cyanotic lips and fingernails, and clubbing of fingers. He had no clinical features of autonomic nervous system dysfunction.

The quality of life and perception of anxiety, as measured by the SF-36 and HADS, respectively, did not deviate from age- and sex-matched healthy subjects.32,33 ABG levels revealed hypoxia and hypercapnia while awake (Table 1), while overnight PSG revealed marked central hypoventilation with Spo2 nadir of 50% while breathing room air (Table 2). Though there were some episodes of obstructive apnea, the patient had no symptoms related to obstructive sleep apnea syndrome, such as snoring or excessive daytime sleepiness. The findings of chest radiography, PFTs, and brain MRI were unremarkable, while echocardiography showed a dilated right ventricle, mild tricuspid regurgitation, and pulmonary hypertension (estimated pulmonary pressure, 54 mm Hg). Holter recording revealed sinus rhythm with 64 to 120 beats/min and occasional ventricular ectopic beats.

Table Graphic Jump Location
Table 1 Clinical Features of the Index Case and His Family*

*NA = not applicable; MVV = maximum voluntary ventilation; Pimax = maximal inspiratory pressure; Pemax = maximal expiratory pressure; ESS = Epworth sleepiness score.

Table Graphic Jump Location
Table 2 Polysomnographic Findings of the Index Case and His Family*

*TST = total sleep time; AHI = apnea-hypopnea index.

For nocturnal ventilatory support, the patient was started on therapy using a ventilator support system (bilevel positive airway pressure [BPAP]) [BiPAP; Respironics Inc; Murrysville, PA], which markedly improved the central hypoventilation and desaturation. After 6 months of BPAP treatment, the polycythemia, daytime hypoxia, hypercapnia, and quality of life also improved (Table 3). However, repeated hypercapnic ventilatory response tests showed no change in chemosensitivity (Fig 3, top, A).

Table Graphic Jump Location
Table 3 Clinical Features and Polysomnographic Findings of the Two Adult-Onset CCHS After 6 Months of BPAP Treatment*

*See Tables 1 and 2 for expansion of abbreviations.

Family Details:

An inquiry on the immediate family revealed that four of five children had either a history or objective findings suggestive of CCHS, which were not present in the parents or siblings. The first child required medical attention at the age of 35 days. The mother recalled that he had repeated episodes of cyanotic spells and feeding difficulties. He was sent to the ED because of cyanosis and poor activity, and eventually died of respiratory failure.

The fourth child needed medical attention at the age of 31 days, 4 years after her father had received a diagnosis of primary alveolar hypoventilation. She was rushed to the ED because of repeated cyanotic spells, which were relieved by crying. Her ABG levels disclosed severe hypoxia and respiratory acidosis (Table 1). The findings of a brain CT scan were unremarkable, while echocardiography showed an enlarged right ventricle, severe tricuspid regurgitation, and moderate pulmonary hypertension. There were no neuromuscular, pulmonary, or GI diseases identified.

During hospitalization, she had episodic apnea, bradycardia, and hypothermia during sleep, which led to repeated intubations. The diagnosis was central hypoventilation. When she was 58 days old, her parents decided to cease all medical treatment after repeated respiratory failure and bradycardia.

The second and third children were 23 and 22 years old, respectively, at the time of this study. Both were asymptomatic, had no childhood history suggestive of CCHS, and no clinical features of autonomic system dysfunction (Table 1). The findings of their chest radiographs and PFTs were unremarkable. ABG levels were normal in the second child, but borderline hypercapnia (Paco2, 47.2 mm Hg) with elevated HCO3 was observed in the third child. The PSG findings of the second child demonstrated short episodic oxygen desaturation without associated central or obstructive apnea, but in the third child, PSG disclosed nocturnal hypoventilation with Spo2 nadir of 59% while breathing room air (Table 2). Brain MRI, 24-h Holter recording, and echocardiography findings were unremarkable in both children.

Hypercapnic ventilatory response was reduced in both children in comparison to that of the healthy population (Fig 2).36 Surprisingly, ventilatory response was more reduced in the second child even though she had no nocturnal sleep hypoventilation. She was observed for lack of evidence indicating hypoventilation in sleep and was observed at the clinic every 6 months. The findings of overnight sleep studies and hypercapnic ventilatory response tests repeated 6 months apart showed that her chemosensitivity did not worsen.

Figure Jump LinkFigure 2 Ventilatory response to progressive hypercapnia via the rebreathing technique of the index patients and his three living children. Ventilatory response was impaired in the index patient and in his second and third children, but was normal in the fifth child (filled triangle = index patient; circle = second child; square = third child; star = fifth child).Grahic Jump Location

The third child received BPAP for nocturnal ventilatory support but was not compliant with therapy. Repeated PSGs revealed that central hypoventilation and desaturation could be resolved under BPAP. However, ABG levels measured 6 months later revealed increased Paco2 (from baseline at 47.2 mm Hg to 54 mm Hg) [Table 3]. Repeated hypercapnic ventilatory response tests revealed deteriorating chemosensitivity (Fig 3, bottom, B).

Figure Jump LinkFigure 3 Changes in hypercapnic ventilatory responses within 6 months of BPAP treatment in the index patient ( top, A) and the third child (bottom, B). Ventilatory response was similar in the index patient but worsened in the third child (top, A: solid triangle = baseline; open triangle = 3-month BPAP treatment; diamond = 6-month BPAP treatment) [bottom, B: solid square = baseline; open square = 3-month BPAP treatment; triangle = 6-month BPAP treatment].Grahic Jump Location

The fifth child was also asymptomatic. The PSG did not disclose any evidence of hypoventilation in sleep (Table 2), and the hypercapnia ventilatory test results were normal (Fig 2).40 ABG levels were not checked, because the mother did not consent to ABG analysis. For the three living children, the SF-36 and HADS scores did not deviate from results for age- and sex-matched healthy subjects.32,33

Genetic Mutation

PHOX2B gene mutation analysis in this family revealed expanded alleles containing 25 repeat polyalanine expansions (20/25 genotype) in the index patient and in his second and third children. The other family members had normal polyalanine repeats (20/20 genotype). Results of genetic analyses further supported the diagnosis of three adult-onset CCHS of + 5 alanine expansions.

This study on CCHS in a Chinese family underscores its wide clinical spectrum, from newborn fatality due to respiratory failure to an adulthood that can be asymptomatic or with hypoventilation while awake and asleep. Genetic screening of living family members identified 25 repeat polyalanine expansions (20/25 genotype) of the PHOX2B gene in three cases of adult-onset CCHS.

Previous literature5,41 has revealed that CCHS is underdiagnosed because of its rarity and because practitioners lack experience with this disease. In the present study, despite a history of episodic cyanotic spells and medical consults for respiratory failure, CCHS was not diagnosed in the first child. CCHS was also not diagnosed in the fourth child until she repeatedly needed mechanical ventilation for respiratory failure. These experiences corroborate findings on the underdiagnosis or delayed diagnosis of CCHS. This report, therefore, seeks to increase awareness of CCHS by demonstrating its varied manifestations.

In addition to a detailed history and physical examination, a detailed evaluation of spontaneous breathing during sleep and wakefulness in a sleep laboratory can help make the diagnosis.24 For example, in the third child, who showed no symptom of CCHS since birth, overnight PSG allowed for the early detection of hypoventilation in sleep and the early implementation of BPAP treatment.

The PHOX2B + 5 alanine expansions were detected in the index patient and his two children, but not in his mother and siblings. Although this gene mutation is more likely to have been de novo and passed on as an autosomal-dominant trait to the offspring, a genetic mutation inherited from the father still cannot be ruled out due to the lack of available material for genetic analysis.

The size of the polyalanine repeat expansion is directly linked to the severity of autonomic nervous system dysfunction and ventilatory dependence.14,20,29 The three patients with adult-onset CCHS had the shortest expansions and only had isolated central hypoventilation with no accompanying neurocristopathy, enabling them to survive into adulthood without succumbing early to respiratory failure.11,14 This finding is compatible with previous literature11,17,20,26,27,42 that the + 5 alanine expansion is the most common mutation found in LOCHS to date.

Patients with untreated, mild CCHS have subtle respiratory abnormalities in the early newborn period, which progress unnoticed and turn into LOCHS.7,24 Since carriers of the PHOX2B mutations may remain asymptomatic but still have alveolar hypoventilation develop, their identification through genetic screening of family members with the CCHS proband will allow for appropriate monitoring and early diagnosis and treatment.7,29 In this study, the second child, who was asymptomatic and had a normal finding on a sleep study report, had a high probability of being undiagnosed but could be identified early through PHOX2B gene mutation screening and then could be continuously monitored.

Treatment of CCHS includes life-long ventilatory support, at least during sleep, and diaphragm pacing.8,9,24,43 Although diaphragm pacing has been reported to work well in pediatric CCHS patients, it is not commonly used for adult CCHS patients.44 Moreover, it requires surgical implantations of bilateral phrenic nerve electrodes, which are costly and require careful management. Therefore, BPAP was chosen as the ventilatory support during sleep for the index patient and the third child. Central hypoventilation and desaturation resolved well with BPAP, and daytime hypercapnia was exacerbated in the third child mainly because of poor compliance with therapy.

In conclusion, this study confirms that the transmission of LOCHS is autosomal-dominant. Genetic screening of family members of CCHS probands will allow for early diagnosis and treatment.

ABG

arterial blood gas

BPAP

bilevel positive airway pressure

CCHS

congenital central hypoventilation syndrome

ED

emergency department

HADS

Hospital Anxiety and Depression Scale

LOCHS

late-onset congenital central hypoventilation syndrome

Petco2

partial pressure at end-tidal carbon dioxide

PFT

pulmonary function test

PHOX2B

paired-like homeobox 2B

PSG

polysomnography

SF-36

Medical Outcomes Study 36-item short form

Spo2

pulse oximetric saturation

e

minute ventilation

The authors express their gratitude to Mei-Hui Tai (National Taiwan University Hospital, Taipei, Taiwan) for performing the PFTs.

Macey PM, Woo MA, Macey KE, et al. Hypoxia reveals posterior thalamic, cerebellar, midbrain, and limbic deficits in congenital central hypoventilation syndrome. J Appl Physiol. 2005;98:958-969. [PubMed] [CrossRef]
 
Trochet D, O'Brien LM, Gozal D, et al. PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Am J Hum Genet. 2005;76:421-426. [PubMed]
 
Or SF, Tong MF, Lo FM, et al. PHOX2B mutations in three Chinese patients with congenital central hypoventilation syndrome. Chin Med J (Engl). 2006;119:1749-1752. [PubMed]
 
Stornetta RL, Moreira TS, Takakura AC, et al. Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat. J Neurosci. 2006;26:10305-10314. [PubMed]
 
American Thoracic Society Idiopathic congenital central hypoventilation syndrome: diagnosis and management. Am J Respir Crit Care Med. 1999;160:368-373. [PubMed]
 
O'Brien LM, Holbrook CR, Vanderlaan M, et al. Autonomic function in children with congenital central hypoventilation syndrome and their families. Chest. 2005;128:2478-2484. [PubMed]
 
Berry-Kravis EM, Zhou L, Rand CM, et al. Congenital central hypoventilation syndrome: pHOX2B mutations and phenotype. Am J Respir Crit Care Med. 2006;174:1139-1144. [PubMed]
 
Chen ML, Tablizo MA, Kun S, et al. Diaphragm pacers as a treatment for congenital central hypoventilation syndrome. Expert Rev Med Devices. 2005;2:577-585. [PubMed]
 
Sritippayawan S, Hamutcu R, Kun SS, et al. Mother-daughter transmission of congenital central hypoventilation syndrome. Am J Respir Crit Care Med. 2002;166:367-369. [PubMed]
 
Trang H, Dehan M, Beaufils F, et al. The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype. Chest. 2005;127:72-79. [PubMed]
 
Antic NA, Malow BA, Lange N, et al. PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood. Am J Respir Crit Care Med. 2006;174:923-927. [PubMed]
 
Khalifa MM, Flavin MA, Wherrett BA. Congenital central hypoventilation syndrome in monozygotic twins. J Pediatr. 1988;113:853-855. [PubMed]
 
Haddad GG, Mazza NM, Defendini R, et al. Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore). 1978;57:517-526. [PubMed]
 
Weese-Mayer DE, Berry-Kravis EM. Genetics of congenital central hypoventilation syndrome: lessons from a seemingly orphan disease. Am J Respir Crit Care Med. 2004;170:16-21. [PubMed]
 
Ou-Yang MC, Yang SN, Hsu YM, et al. Concomitant existence of total bowel aganglionosis and congenital central hypoventilation syndrome in a neonate with PHOX2B gene mutation. J Pediatr Surg. 2007;42:e9-e11. [PubMed]
 
Katz ES, McGrath S, Marcus CL. Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome. Pediatr Pulmonol. 2000;29:62-68. [PubMed]
 
Weese-Mayer DE, Berry-Kravis EM, Zhou L. Adult identified with congenital central hypoventilation syndrome: mutation in PHOX2b gene and late-onset CHS. Am J Respir Crit Care Med. 2005;171:88. [PubMed]
 
Doherty LS, Kiely JL, Deegan PC, et al. Late-onset central hypoventilation syndrome: a family genetic study. Eur Respir J. 2007;29:312-316. [PubMed]
 
Windisch W, Vogel M, Sorichter S, et al. Normocapnia during nIPPV in chronic hypercapnic COPD reduces subsequent spontaneous PaCO2. Respir Med. 2002;96:572-579. [PubMed]
 
Matera I, Bachetti T, Puppo F, et al. PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset central hypoventilation syndrome. J Med Genet. 2004;41:373-380. [PubMed]
 
Amiel J, Laudier B, Attie-Bitach T, et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003;33:459-461. [PubMed]
 
Dauger S, Pattyn A, Lofaso F, et al. Phox2b controls the development of peripheral chemoreceptors and afferent visceral pathways. Development. 2003;130:6635-6642. [PubMed]
 
Hung CC, Su YN, Tsao PN, et al. Unequal crossover recombination-population screening for PHOX2B gene polyalanine polymorphism using CE. Electrophoresis. 2007;28:894-899. [PubMed]
 
Maitra A, Shine J, Henderson J, et al. The investigation and care of children with congenital central hypoventilation. Curr Paediatr. 2004;14:354-360
 
Barratt S, Kendrick AH, Buchanan F, et al. Central hypoventilation with PHOX2B expansion mutation presenting in adulthood. Thorax. 2007;62:919-920. [PubMed]
 
Trang H, Laudier B, Trochet D, et al. PHOX2B gene mutation in a patient with late-onset central hypoventilation. Pediatr Pulmonol. 2004;38:349-351. [PubMed]
 
Trochet D, Hong SJ, Lim JK, et al. Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Hum Mol Genet. 2005;14:3697-3708. [PubMed]
 
Ramanantsoa N, Vaubourg V, Matrot B, et al. Effects of Temperature on Ventilatory Response to Hypercapnia in Newborn Mice Heterozygous for Transcription Factor Phox2b. Am J Physiol Regul Integr Comp Physiol. 2007;290:R1691-R1696
 
Weese-Mayer DE, Berry-Kravis EM, Zhou L, et al. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Am J Med Genet A. 2003;123:267:278
 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14:540-545. [PubMed]
 
Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 1983;67:361-370. [PubMed]
 
Lu JR TH, Tsai YJ. Assessment of health-related quality of life in Taiwan (I): development and psychometric testing of SF-36 Taiwan version. Taiwan J Public Health. 2003;22:501-511
 
Caci H, Bayle FJ, Mattei V, et al. How does the Hospital and Anxiety and Depression Scale measure anxiety and depression in healthy subjects? Psychiatry Res. 2003;118:89-99. [PubMed]
 
Pesola GR, Huggins G, Sherpa TY. Abnormal predicted diffusion capacities in healthy Asians: an inequality with a solution. Respiration. 2006;73:799-807. [PubMed]
 
Yang SC. Re-evaluation of the ventilatory function in a normal Chinese: comparison with the results of a survey conducted 15 years ago. J Formos Med Assoc. 1993;92suppl:S152-S159. [PubMed]
 
Read DJ. A clinical method for assessing the ventilatory response to carbon dioxide. Aust Ann Med. 1967;16:20-32. [PubMed]
 
American Academy of Sleep Medicine Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research: the Report of an American Academy of Sleep Medicine task force. Sleep. 1999;22:667-689. [PubMed]
 
Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. 1968; Los Angeles, CA UCLA Brain Information Service/Brain Research Institute
 
Hsu KL, Chen JJ, Chen JH, et al. Primary alveolar hypoventilation: a case report. Taiwan Yi Xue Hui Za Zhi. 1984;83:705-713. [PubMed]
 
Strauss SG, Lynn AM, Bratton SL, et al. Ventilatory response to CO2in children with obstructive sleep apnea from adenotonsillar hypertrophy. Anesth Analg. 1999;89:328-332. [PubMed]
 
Kerbl R, Litscher H, Grubbauer HM, et al. Congenital central hypoventilation syndrome (Ondine's curse syndrome) in two siblings: delayed diagnosis and successful noninvasive treatment. Eur J Pediatr. 1996;155:977-980. [PubMed]
 
Trochet D, de Pontual L, Straus C, et al. PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome. Am J Respir Crit Care Med. 2008;177:906-911. [PubMed]
 
Weese-Mayer DE, Silvestri JM, Kenny AS, et al. Diaphragm pacing with a quadripolar phrenic nerve electrode: an international study. Pacing Clin Electrophysiol. 1996;19:1311-1319. [PubMed]
 
Chen ML, Keens TG. Congenital central hypoventilation syndrome: not just another rare disorder. Paediatr Respir Rev. 2004;5:182-189. [PubMed]
 

Figures

Figure Jump LinkFigure 1 The pedigree of a case of familial CCHS. Patients II-4, III-1, and III-2 are the index patient and his second and third children, respectively.Grahic Jump Location
Figure Jump LinkFigure 2 Ventilatory response to progressive hypercapnia via the rebreathing technique of the index patients and his three living children. Ventilatory response was impaired in the index patient and in his second and third children, but was normal in the fifth child (filled triangle = index patient; circle = second child; square = third child; star = fifth child).Grahic Jump Location
Figure Jump LinkFigure 3 Changes in hypercapnic ventilatory responses within 6 months of BPAP treatment in the index patient ( top, A) and the third child (bottom, B). Ventilatory response was similar in the index patient but worsened in the third child (top, A: solid triangle = baseline; open triangle = 3-month BPAP treatment; diamond = 6-month BPAP treatment) [bottom, B: solid square = baseline; open square = 3-month BPAP treatment; triangle = 6-month BPAP treatment].Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Clinical Features of the Index Case and His Family*

*NA = not applicable; MVV = maximum voluntary ventilation; Pimax = maximal inspiratory pressure; Pemax = maximal expiratory pressure; ESS = Epworth sleepiness score.

Table Graphic Jump Location
Table 2 Polysomnographic Findings of the Index Case and His Family*

*TST = total sleep time; AHI = apnea-hypopnea index.

Table Graphic Jump Location
Table 3 Clinical Features and Polysomnographic Findings of the Two Adult-Onset CCHS After 6 Months of BPAP Treatment*

*See Tables 1 and 2 for expansion of abbreviations.

References

Macey PM, Woo MA, Macey KE, et al. Hypoxia reveals posterior thalamic, cerebellar, midbrain, and limbic deficits in congenital central hypoventilation syndrome. J Appl Physiol. 2005;98:958-969. [PubMed] [CrossRef]
 
Trochet D, O'Brien LM, Gozal D, et al. PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Am J Hum Genet. 2005;76:421-426. [PubMed]
 
Or SF, Tong MF, Lo FM, et al. PHOX2B mutations in three Chinese patients with congenital central hypoventilation syndrome. Chin Med J (Engl). 2006;119:1749-1752. [PubMed]
 
Stornetta RL, Moreira TS, Takakura AC, et al. Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat. J Neurosci. 2006;26:10305-10314. [PubMed]
 
American Thoracic Society Idiopathic congenital central hypoventilation syndrome: diagnosis and management. Am J Respir Crit Care Med. 1999;160:368-373. [PubMed]
 
O'Brien LM, Holbrook CR, Vanderlaan M, et al. Autonomic function in children with congenital central hypoventilation syndrome and their families. Chest. 2005;128:2478-2484. [PubMed]
 
Berry-Kravis EM, Zhou L, Rand CM, et al. Congenital central hypoventilation syndrome: pHOX2B mutations and phenotype. Am J Respir Crit Care Med. 2006;174:1139-1144. [PubMed]
 
Chen ML, Tablizo MA, Kun S, et al. Diaphragm pacers as a treatment for congenital central hypoventilation syndrome. Expert Rev Med Devices. 2005;2:577-585. [PubMed]
 
Sritippayawan S, Hamutcu R, Kun SS, et al. Mother-daughter transmission of congenital central hypoventilation syndrome. Am J Respir Crit Care Med. 2002;166:367-369. [PubMed]
 
Trang H, Dehan M, Beaufils F, et al. The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype. Chest. 2005;127:72-79. [PubMed]
 
Antic NA, Malow BA, Lange N, et al. PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood. Am J Respir Crit Care Med. 2006;174:923-927. [PubMed]
 
Khalifa MM, Flavin MA, Wherrett BA. Congenital central hypoventilation syndrome in monozygotic twins. J Pediatr. 1988;113:853-855. [PubMed]
 
Haddad GG, Mazza NM, Defendini R, et al. Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore). 1978;57:517-526. [PubMed]
 
Weese-Mayer DE, Berry-Kravis EM. Genetics of congenital central hypoventilation syndrome: lessons from a seemingly orphan disease. Am J Respir Crit Care Med. 2004;170:16-21. [PubMed]
 
Ou-Yang MC, Yang SN, Hsu YM, et al. Concomitant existence of total bowel aganglionosis and congenital central hypoventilation syndrome in a neonate with PHOX2B gene mutation. J Pediatr Surg. 2007;42:e9-e11. [PubMed]
 
Katz ES, McGrath S, Marcus CL. Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome. Pediatr Pulmonol. 2000;29:62-68. [PubMed]
 
Weese-Mayer DE, Berry-Kravis EM, Zhou L. Adult identified with congenital central hypoventilation syndrome: mutation in PHOX2b gene and late-onset CHS. Am J Respir Crit Care Med. 2005;171:88. [PubMed]
 
Doherty LS, Kiely JL, Deegan PC, et al. Late-onset central hypoventilation syndrome: a family genetic study. Eur Respir J. 2007;29:312-316. [PubMed]
 
Windisch W, Vogel M, Sorichter S, et al. Normocapnia during nIPPV in chronic hypercapnic COPD reduces subsequent spontaneous PaCO2. Respir Med. 2002;96:572-579. [PubMed]
 
Matera I, Bachetti T, Puppo F, et al. PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset central hypoventilation syndrome. J Med Genet. 2004;41:373-380. [PubMed]
 
Amiel J, Laudier B, Attie-Bitach T, et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003;33:459-461. [PubMed]
 
Dauger S, Pattyn A, Lofaso F, et al. Phox2b controls the development of peripheral chemoreceptors and afferent visceral pathways. Development. 2003;130:6635-6642. [PubMed]
 
Hung CC, Su YN, Tsao PN, et al. Unequal crossover recombination-population screening for PHOX2B gene polyalanine polymorphism using CE. Electrophoresis. 2007;28:894-899. [PubMed]
 
Maitra A, Shine J, Henderson J, et al. The investigation and care of children with congenital central hypoventilation. Curr Paediatr. 2004;14:354-360
 
Barratt S, Kendrick AH, Buchanan F, et al. Central hypoventilation with PHOX2B expansion mutation presenting in adulthood. Thorax. 2007;62:919-920. [PubMed]
 
Trang H, Laudier B, Trochet D, et al. PHOX2B gene mutation in a patient with late-onset central hypoventilation. Pediatr Pulmonol. 2004;38:349-351. [PubMed]
 
Trochet D, Hong SJ, Lim JK, et al. Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Hum Mol Genet. 2005;14:3697-3708. [PubMed]
 
Ramanantsoa N, Vaubourg V, Matrot B, et al. Effects of Temperature on Ventilatory Response to Hypercapnia in Newborn Mice Heterozygous for Transcription Factor Phox2b. Am J Physiol Regul Integr Comp Physiol. 2007;290:R1691-R1696
 
Weese-Mayer DE, Berry-Kravis EM, Zhou L, et al. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Am J Med Genet A. 2003;123:267:278
 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14:540-545. [PubMed]
 
Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 1983;67:361-370. [PubMed]
 
Lu JR TH, Tsai YJ. Assessment of health-related quality of life in Taiwan (I): development and psychometric testing of SF-36 Taiwan version. Taiwan J Public Health. 2003;22:501-511
 
Caci H, Bayle FJ, Mattei V, et al. How does the Hospital and Anxiety and Depression Scale measure anxiety and depression in healthy subjects? Psychiatry Res. 2003;118:89-99. [PubMed]
 
Pesola GR, Huggins G, Sherpa TY. Abnormal predicted diffusion capacities in healthy Asians: an inequality with a solution. Respiration. 2006;73:799-807. [PubMed]
 
Yang SC. Re-evaluation of the ventilatory function in a normal Chinese: comparison with the results of a survey conducted 15 years ago. J Formos Med Assoc. 1993;92suppl:S152-S159. [PubMed]
 
Read DJ. A clinical method for assessing the ventilatory response to carbon dioxide. Aust Ann Med. 1967;16:20-32. [PubMed]
 
American Academy of Sleep Medicine Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research: the Report of an American Academy of Sleep Medicine task force. Sleep. 1999;22:667-689. [PubMed]
 
Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. 1968; Los Angeles, CA UCLA Brain Information Service/Brain Research Institute
 
Hsu KL, Chen JJ, Chen JH, et al. Primary alveolar hypoventilation: a case report. Taiwan Yi Xue Hui Za Zhi. 1984;83:705-713. [PubMed]
 
Strauss SG, Lynn AM, Bratton SL, et al. Ventilatory response to CO2in children with obstructive sleep apnea from adenotonsillar hypertrophy. Anesth Analg. 1999;89:328-332. [PubMed]
 
Kerbl R, Litscher H, Grubbauer HM, et al. Congenital central hypoventilation syndrome (Ondine's curse syndrome) in two siblings: delayed diagnosis and successful noninvasive treatment. Eur J Pediatr. 1996;155:977-980. [PubMed]
 
Trochet D, de Pontual L, Straus C, et al. PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome. Am J Respir Crit Care Med. 2008;177:906-911. [PubMed]
 
Weese-Mayer DE, Silvestri JM, Kenny AS, et al. Diaphragm pacing with a quadripolar phrenic nerve electrode: an international study. Pacing Clin Electrophysiol. 1996;19:1311-1319. [PubMed]
 
Chen ML, Keens TG. Congenital central hypoventilation syndrome: not just another rare disorder. Paediatr Respir Rev. 2004;5:182-189. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543