Eur J Pediatr (2014) 173:1727–1730 DOI 10.1007/s00431-014-2432-1
CASE REPORT
Congenital central hypoventilation syndrome and carbon dioxide sensitivity Thomas Rossor & Aung Soe & Ravindra Bhat & Anne Greenough
Received: 24 September 2014 / Accepted: 29 September 2014 / Published online: 17 October 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Congenital central hypoventilation syndrome (CCHS) is characterised by hypoventilation most marked during sleep and is often associated with abnormalities of the autonomic nervous system. We report an infant with severe CCHS and Hirschsprung disease in whom, while awaiting genotyping, the diagnosis was facilitated by the results of a carbon dioxide (CO2) sensitivity study in the neonatal period and was confirmed by paired-like homeobox 2B (PHOX2B) mutational analysis. The infant had no ventilatory response to increased inspired carbon dioxide levels when either awake or asleep suggesting he had a severe form for CCHS; indeed, he subsequently demonstrated to have the 20/31 genotype. This is the first case report of a genotypeconfirmed CCHS disease in a neonate with Hirschsprung disease further characterised by a ventilatory challenge. Communicated by Peter de Winter T. Rossor : R. Bhat : A. Greenough Division of Asthma, Allergy and Lung Biology, MRC Centre for Allergic Mechanisms in Asthma, King’s College London, London, UK T. Rossor e-mail: [email protected] R. Bhat e-mail: [email protected] A. Soe Neonatal Department, Medway Maritime Hospital, Gillingham, Kent, UK e-mail: [email protected] A. Greenough NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK A. Greenough (*) NICU, King’s College Hospital, 4th Floor Golden Jubilee Wing, Denmark Hill, London SE5 9RS, UK e-mail: [email protected]
Conclusion: CO2 sensitivity status may assist in determining the severity of the CCHS. Keywords Congenital central hypoventilation syndrome . Autonomic nervous system . Chemoreceptor . Ventilation Abbreviations CCHS Congenital central hypoventilation syndrome CO2 Carbon dioxide PHOX2B Homeobox 2B (human gene) Phox2b Homeobox 2B (mouse gene) RTN Retrotrapezoid nucleus SIMV Synchronised intermittent mandatory ventilation
Introduction Congenital central hypoventilation syndrome (CCHS), first described in 1970 [7], is characterised by hypoventilation, most marked during sleep. Affected individuals often present in the neonatal period with unexplained apnoea and respiratory failure. CCHS is frequently associated with abnormalities of the autonomic nervous system, particularly Hirschsprung disease and neural crest tumours [9]. Other autonomic nervous system abnormalities can result in a low baseline body temperature, failure to respond to environmental stressors such as exercise or pain and a lack of perception of dyspnoea. The paired-like homeobox 2B (Phox2b) gene is a transcription factor which is crucial to the development of autonomic nervous system reflex pathways. A mouse model carrying a mutation of the transcription factor Phox2b has been engineered [3]. The absence of a population of Phox2b-expressing retrotrapezoid nucleus (RTN) neurons was associated with the early death of the mice due to a lack of a ventilatory response to hypercapnia [3].
1728
Abnormalities in the RTN have been found at postmortem in infants with CCHS [9]. In the first published case series, heterozygous mutations in the human ortholog PHOX2B gene were reported in 18 of 29 individuals with CCHS [1]. In a larger, subsequent series, 65 of 67 individuals with a clinical diagnosis of CCHS, but none of 67 matched controls, showed a PHOX2B mutation. The mutations were primarily alanine expansions within a polyalanine tract. Of the remaining 2 cases, 1 was found to have a non-sense PHOX2B mutation and the other a polyalanine repeat mutation that was missed due to laboratory error [13]. It has subsequently been shown that the severity of the phenotype correlated with the number of expansions [9]. Further studies have demonstrated PHOX2B mutations in between 91 % [12] and 100 % [6] of cases. Most studies of ventilatory control in patients with CCHS were performed before PHOX2B genetic testing was available [9, 14]. Thus, the relationship between the various mutations and the results of physiological testing has not been clearly defined. Indeed, before genetic testing, the conditions labelled as CCHS may have included other diagnoses. For this reason, the American Thoracic Society statement on CCHS emphasised the need to correlate the results of ventilatory response testing with CCHS genotype [14]. We present a case report of an infant with a severe form of genotype-confirmed CCHS who also had Hirschsprung disease and was further characterised by their response to a ventilatory challenge.
Case history The infant was born at 41 weeks of gestation following an unremarkable pregnancy. This was the mother’s third pregnancy and she had a planned home delivery. The infant was born in good condition with an Apgar score of 9 at both 1 and 5 min of age, but he then developed apnoea and cyanosis and hence was transferred to the neonatal unit. The infant arrived at 3 h of age and was immediately intubated and ventilated as the initial blood gas demonstrated a pH of 7.04. He was commenced on trophic feeds while still ventilated but developed worsening abdominal distension and bilious aspirates. On day 5, there was an abnormal gas pattern on an abdominal X-ray, and an upper gastrointestinal contrast study was performed. This demonstrated delay of contrast passing the duodeno-jejunal junction, with to and fro peristalsis seen in the duodenum suggestive of mechanical obstruction, with no evidence of malrotation. Hence, he was transferred to the King’s College Hospital NHS Foundation Trust for further investigation. Histological examination of a rectal biopsy demonstrated no ganglion cells, and a diagnosis of Hirschsprung disease was made. He was managed initially with rectal washouts but continued to have bilious aspirates
Eur J Pediatr (2014) 173:1727–1730
and was taken to theatre on day 26 after birth where a short section of aganglionic ileum was resected and an ileostomy undertaken and a mucous fistula created. At no time did abdominal distension impair his ventilation. At 9 months of age, he was fully bottle fed and had no evidence of gastrooesophageal reflux. Once extubated on day 8 after birth, the infant had significant apnoeas with desaturation. Polysomnography was performed using an Alice 4 Sleep system. The sleep study comprised 35 % active and 65 % quiet sleep. All but one clinically significant central apnoea (more than 20 s in duration and/or associated with desaturation or bradycardia) occurred during quiet sleep, at a rate of 16 per hour. Respiratory pauses of more than 2 s occurred on average 45 times per hour. During the polysomnography study, the infant’s respiratory rate was 30 breaths per minute and his mean end tidal carbon dioxide (CO2) level was 56 mmHg. An EEG showed no abnormal activity associated with the apnoeas. The results of a brain MRI examination were unremarkable. The infant’s central chemoreceptor sensitivity was assessed by determining his ventilatory response (as indicated by changes in minute volume) to air, 2 and 4 % CO2. The ventilatory response to CO2 was measured using a steadystate technique as described by Rigatto et al. [10]. A nasal mask was placed over the infant’s nose which was connected to a pneumotachograph and a side-sampling capnograph. Respiratory gas was delivered with a bias flow of 4 l/min through a non-return valve to a pneumotachograph attached to either a snugly fitting nasal mask or the endotracheal tube. A side-sampling capnograph provided a continuous readout of both inspired CO2 and end tidal CO2. Each level of CO2 was maintained for 5 min and the mean of the results of the last minute of exposure was calculated. He was assessed while self-ventilating in quiet sleep and also on a ventilator providing synchronised intermittent mandatory ventilation (SIMV), both while he was awake and asleep. During SIMV, his respiratory rate was greater than the backup rate of 25 bpm; hence, we were able to differentiate the infant’s breathing efforts from ventilator inflations. During testing, in no period was there increases in minute volume in response to increasing levels of inspired CO2 (Fig. 1). The PHOX2B mutational analysis was subsequently reported as abnormal; there was a heterozygous increase in alanine repeats confirming the diagnosis of severe CCHS with the 20/ 31 genotype. The infant subsequently underwent a tracheostomy and remained ventilator dependent at 9 months of age.
Discussion We report a detailed CO2 sensitivity study undertaken in a neonate with severe CCHS confirmed by PHOX2B analysis. The 20/31 genotype, which is a relatively rare genotype, in
Eur J Pediatr (2014) 173:1727–1730
1729
Fig. 1 Ventilatory responses (as indicated by the change in minute volume) to increased inspired CO2 levels. The infant with CCHS: blue circle asleep (self ventilating), blue box asleep (synchronised intermittent mandatory ventilation), grey diamond awake (synchronised intermittent mandatory ventilation) and grey triangle a healthy term control with no respiratory problems
association with Hirschsprung disease (which occurs in up to 50 % of cases) comprises Haddad’s syndrome [4]. Since genotyping has been available, reports that included assessments of CO2 sensitivity have been described in individuals with milder genotypes (20/25, 20/27), and in all but one case, the individuals were studied in late childhood or adulthood. In a case report, carbon dioxide levels were assessed and compared to the infant’s respiratory rate [5]. The infant’s respiratory rate remained low (usually less than 20 breaths per minute) despite a severe respiratory acidosis [5]. In addition, techniques used to evaluate CO2 sensitivity were rebreathing or responses to spontaneous hypercapnoea. Those techniques may incorporate a period of CO2 exposure too brief to result in a maximal ventilatory response, unlike the steady-state challenge we have used. A further advantage of the method we used to assess CO2 sensitivity was that we were able to apply it when the infant was awake, asleep, ventilated or spontaneously breathing. On all study occasions, there was no ventilatory response to increasing CO2 levels, reflecting the severity of the infant’s abnormality. The management of CCHS remains supportive, with artificial ventilation required in most cases. Diaphragmatic pacing has been successfully used, but respiratory support may still be required during sleep. Respiratory stimulants such as caffeine or doxapram have been shown to be ineffective in the treatment of CCHS [11]. As these may work via enhanced central chemoreceptor sensitivity, their lack of efficacy may be explained by the “total” disruption of the pathway in severely affected individuals. Medroxyprogesterone was reported to successfully improve the response to carbon dioxide in two
children (aged 1 and 20 months) with hypoventilation syndrome [8]. Neither, however, had genotyping to confirm (or refute) the diagnosis, and we are unaware of subsequent confirmatory studies since that initial report in 1985. Studies in older infants, children and adults have suggested there may be partial preservation on central nervous system networks. Carroll et al. [2] demonstrated graded dysfunction in cardiovascular regulation in association with genotype in 32 infants, children and older adults with CCHS and suggested this could represent differential effects on the autonomic system. In addition, there were also differences between the cases of 15 young adult controls with regard to their cerebrovascular responses to chemosensory challenge which the authors suggested might indicate alteration in cerebral autoregulation [2]. This finding may suggest targets for potential pharmacologic interventions. Genotyping is essential to the diagnosis [12], but CO2 sensitivity studies could be used to facilitate identification of infants with milder phenotypes of CCHS as indicated by a partial response to increased CO2 levels and who may respond to respiratory stimulants. Acknowledgments Conflict of interest None. Funding AG is an NIHR Senior Investigator. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
1730 Contributor statement Dr. Rossor undertook the physiological assessments under Professor Greenough and Dr. Bhat’s guidance. All authors contributed to the writing of the manuscript.
References 1. Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual L, Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich A, Gaultier C, Lyonnet S (2003) Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHO2B in congenital central hypoventilation syndrome. Nat Genet 33:459–461 2. Carroll MS, Patwari PP, Kenny AS, Brogadir CD, Stewart TM, Weese-Mayer DE (2014) Residual chemosensitivity to ventilatory challenges in genotyped congenital central hypoventilation syndrome. J Appl Physiol 116:439–450 3. Dubreuil V, Ramanantsoa N, Trochet D, Vaubourg V, Amiel J, Gallego J, Brunet JF, Goridis C (2008) A human mutation in Phox2B causes lack of CO2 chemosensitivity, fatal central apnea and specific loss of parafacial neurons. Proc Natl Acad Sci U S A 105:1067–1072 4. Haddad GG, Mazza NM, Defendini R, Blanc WA, Driscoll JM, Epstein MA, Mellins RB (1978) Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore) 57:517–526 5. Lingappa L, Panigrahi NK, Chirla DK, Burton-Jones S, Williams MM (2012) Congenital central hypoventilation syndrome with PHOX2B gene mutation. Indian J Pediatr 79:1526–1528 6. Da L, Rand CM, Zhou L, Berry-Kravis EM, Jennings LJ, Yu M, Weese-Mayer DE (2009) Paired-like homeobox gene 2B (PHOX2B) and congenital central hypoventilation syndrome (CCHS): genotype/ phenotype correlation in cohort of 347 cases. Am J Respir Crit Care Med 179:A6341
Eur J Pediatr (2014) 173:1727–1730 7. Mellins RB, Balfour HH Jr, Turino GM, Winters RW (1970) Failure of automatic control of ventilation (Ondine’s curse). Report of an infant born with this syndrome and review of the literature. Medicine 49:487–504 8. Milerad J, Lagercrantz H, Lofgren O (1985) Alveolar hypoventilation treated with medroxyprogesterone. Arch Dis Child 60:150–155 9. Patwari PP, Carroll MS, Rand CM, Kumar R, Harper R, Weese-Mayer DE (2010) Congenital central hypoventilation syndrome and the PHOX2B gene: a model of respiratory and autonomic dysregulation. Respir Physiol Neurobiol 173:322– 335 10. Rigatto H, Brady JP, de la TorreVerduzco R (1975) Chemoreceptor reflexes in preterm infants: II. The effect of gestational and postnatal age on the ventilatory response to inhaled carbon dioxide. Pediatrics 55:614–620 11. Spengler CM, Gozal D, Shea SA (2001) Chemoreceptive mechanisms elucidated by studies of congenital central hypoventilation syndrome. Respir Physiol 129:247–255 12. Trang H, Dehan M, Beaufils F, Zaccaria I, Amiel J, Gaultier C, French CCHS Working Group (2005) The French congenital central hypoventilation syndrome registry: general data, phenotype, and genotype. Chest 127:72–79 13. Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, Marazita ML (2003) 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 123:267–278 14. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H (2010) An official ATS clinical policy statement: congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med 181: 626–644
CASE REPORT
Congenital central hypoventilation syndrome and carbon dioxide sensitivity Thomas Rossor & Aung Soe & Ravindra Bhat & Anne Greenough
Received: 24 September 2014 / Accepted: 29 September 2014 / Published online: 17 October 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Congenital central hypoventilation syndrome (CCHS) is characterised by hypoventilation most marked during sleep and is often associated with abnormalities of the autonomic nervous system. We report an infant with severe CCHS and Hirschsprung disease in whom, while awaiting genotyping, the diagnosis was facilitated by the results of a carbon dioxide (CO2) sensitivity study in the neonatal period and was confirmed by paired-like homeobox 2B (PHOX2B) mutational analysis. The infant had no ventilatory response to increased inspired carbon dioxide levels when either awake or asleep suggesting he had a severe form for CCHS; indeed, he subsequently demonstrated to have the 20/31 genotype. This is the first case report of a genotypeconfirmed CCHS disease in a neonate with Hirschsprung disease further characterised by a ventilatory challenge. Communicated by Peter de Winter T. Rossor : R. Bhat : A. Greenough Division of Asthma, Allergy and Lung Biology, MRC Centre for Allergic Mechanisms in Asthma, King’s College London, London, UK T. Rossor e-mail: [email protected] R. Bhat e-mail: [email protected] A. Soe Neonatal Department, Medway Maritime Hospital, Gillingham, Kent, UK e-mail: [email protected] A. Greenough NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK A. Greenough (*) NICU, King’s College Hospital, 4th Floor Golden Jubilee Wing, Denmark Hill, London SE5 9RS, UK e-mail: [email protected]
Conclusion: CO2 sensitivity status may assist in determining the severity of the CCHS. Keywords Congenital central hypoventilation syndrome . Autonomic nervous system . Chemoreceptor . Ventilation Abbreviations CCHS Congenital central hypoventilation syndrome CO2 Carbon dioxide PHOX2B Homeobox 2B (human gene) Phox2b Homeobox 2B (mouse gene) RTN Retrotrapezoid nucleus SIMV Synchronised intermittent mandatory ventilation
Introduction Congenital central hypoventilation syndrome (CCHS), first described in 1970 [7], is characterised by hypoventilation, most marked during sleep. Affected individuals often present in the neonatal period with unexplained apnoea and respiratory failure. CCHS is frequently associated with abnormalities of the autonomic nervous system, particularly Hirschsprung disease and neural crest tumours [9]. Other autonomic nervous system abnormalities can result in a low baseline body temperature, failure to respond to environmental stressors such as exercise or pain and a lack of perception of dyspnoea. The paired-like homeobox 2B (Phox2b) gene is a transcription factor which is crucial to the development of autonomic nervous system reflex pathways. A mouse model carrying a mutation of the transcription factor Phox2b has been engineered [3]. The absence of a population of Phox2b-expressing retrotrapezoid nucleus (RTN) neurons was associated with the early death of the mice due to a lack of a ventilatory response to hypercapnia [3].
1728
Abnormalities in the RTN have been found at postmortem in infants with CCHS [9]. In the first published case series, heterozygous mutations in the human ortholog PHOX2B gene were reported in 18 of 29 individuals with CCHS [1]. In a larger, subsequent series, 65 of 67 individuals with a clinical diagnosis of CCHS, but none of 67 matched controls, showed a PHOX2B mutation. The mutations were primarily alanine expansions within a polyalanine tract. Of the remaining 2 cases, 1 was found to have a non-sense PHOX2B mutation and the other a polyalanine repeat mutation that was missed due to laboratory error [13]. It has subsequently been shown that the severity of the phenotype correlated with the number of expansions [9]. Further studies have demonstrated PHOX2B mutations in between 91 % [12] and 100 % [6] of cases. Most studies of ventilatory control in patients with CCHS were performed before PHOX2B genetic testing was available [9, 14]. Thus, the relationship between the various mutations and the results of physiological testing has not been clearly defined. Indeed, before genetic testing, the conditions labelled as CCHS may have included other diagnoses. For this reason, the American Thoracic Society statement on CCHS emphasised the need to correlate the results of ventilatory response testing with CCHS genotype [14]. We present a case report of an infant with a severe form of genotype-confirmed CCHS who also had Hirschsprung disease and was further characterised by their response to a ventilatory challenge.
Case history The infant was born at 41 weeks of gestation following an unremarkable pregnancy. This was the mother’s third pregnancy and she had a planned home delivery. The infant was born in good condition with an Apgar score of 9 at both 1 and 5 min of age, but he then developed apnoea and cyanosis and hence was transferred to the neonatal unit. The infant arrived at 3 h of age and was immediately intubated and ventilated as the initial blood gas demonstrated a pH of 7.04. He was commenced on trophic feeds while still ventilated but developed worsening abdominal distension and bilious aspirates. On day 5, there was an abnormal gas pattern on an abdominal X-ray, and an upper gastrointestinal contrast study was performed. This demonstrated delay of contrast passing the duodeno-jejunal junction, with to and fro peristalsis seen in the duodenum suggestive of mechanical obstruction, with no evidence of malrotation. Hence, he was transferred to the King’s College Hospital NHS Foundation Trust for further investigation. Histological examination of a rectal biopsy demonstrated no ganglion cells, and a diagnosis of Hirschsprung disease was made. He was managed initially with rectal washouts but continued to have bilious aspirates
Eur J Pediatr (2014) 173:1727–1730
and was taken to theatre on day 26 after birth where a short section of aganglionic ileum was resected and an ileostomy undertaken and a mucous fistula created. At no time did abdominal distension impair his ventilation. At 9 months of age, he was fully bottle fed and had no evidence of gastrooesophageal reflux. Once extubated on day 8 after birth, the infant had significant apnoeas with desaturation. Polysomnography was performed using an Alice 4 Sleep system. The sleep study comprised 35 % active and 65 % quiet sleep. All but one clinically significant central apnoea (more than 20 s in duration and/or associated with desaturation or bradycardia) occurred during quiet sleep, at a rate of 16 per hour. Respiratory pauses of more than 2 s occurred on average 45 times per hour. During the polysomnography study, the infant’s respiratory rate was 30 breaths per minute and his mean end tidal carbon dioxide (CO2) level was 56 mmHg. An EEG showed no abnormal activity associated with the apnoeas. The results of a brain MRI examination were unremarkable. The infant’s central chemoreceptor sensitivity was assessed by determining his ventilatory response (as indicated by changes in minute volume) to air, 2 and 4 % CO2. The ventilatory response to CO2 was measured using a steadystate technique as described by Rigatto et al. [10]. A nasal mask was placed over the infant’s nose which was connected to a pneumotachograph and a side-sampling capnograph. Respiratory gas was delivered with a bias flow of 4 l/min through a non-return valve to a pneumotachograph attached to either a snugly fitting nasal mask or the endotracheal tube. A side-sampling capnograph provided a continuous readout of both inspired CO2 and end tidal CO2. Each level of CO2 was maintained for 5 min and the mean of the results of the last minute of exposure was calculated. He was assessed while self-ventilating in quiet sleep and also on a ventilator providing synchronised intermittent mandatory ventilation (SIMV), both while he was awake and asleep. During SIMV, his respiratory rate was greater than the backup rate of 25 bpm; hence, we were able to differentiate the infant’s breathing efforts from ventilator inflations. During testing, in no period was there increases in minute volume in response to increasing levels of inspired CO2 (Fig. 1). The PHOX2B mutational analysis was subsequently reported as abnormal; there was a heterozygous increase in alanine repeats confirming the diagnosis of severe CCHS with the 20/ 31 genotype. The infant subsequently underwent a tracheostomy and remained ventilator dependent at 9 months of age.
Discussion We report a detailed CO2 sensitivity study undertaken in a neonate with severe CCHS confirmed by PHOX2B analysis. The 20/31 genotype, which is a relatively rare genotype, in
Eur J Pediatr (2014) 173:1727–1730
1729
Fig. 1 Ventilatory responses (as indicated by the change in minute volume) to increased inspired CO2 levels. The infant with CCHS: blue circle asleep (self ventilating), blue box asleep (synchronised intermittent mandatory ventilation), grey diamond awake (synchronised intermittent mandatory ventilation) and grey triangle a healthy term control with no respiratory problems
association with Hirschsprung disease (which occurs in up to 50 % of cases) comprises Haddad’s syndrome [4]. Since genotyping has been available, reports that included assessments of CO2 sensitivity have been described in individuals with milder genotypes (20/25, 20/27), and in all but one case, the individuals were studied in late childhood or adulthood. In a case report, carbon dioxide levels were assessed and compared to the infant’s respiratory rate [5]. The infant’s respiratory rate remained low (usually less than 20 breaths per minute) despite a severe respiratory acidosis [5]. In addition, techniques used to evaluate CO2 sensitivity were rebreathing or responses to spontaneous hypercapnoea. Those techniques may incorporate a period of CO2 exposure too brief to result in a maximal ventilatory response, unlike the steady-state challenge we have used. A further advantage of the method we used to assess CO2 sensitivity was that we were able to apply it when the infant was awake, asleep, ventilated or spontaneously breathing. On all study occasions, there was no ventilatory response to increasing CO2 levels, reflecting the severity of the infant’s abnormality. The management of CCHS remains supportive, with artificial ventilation required in most cases. Diaphragmatic pacing has been successfully used, but respiratory support may still be required during sleep. Respiratory stimulants such as caffeine or doxapram have been shown to be ineffective in the treatment of CCHS [11]. As these may work via enhanced central chemoreceptor sensitivity, their lack of efficacy may be explained by the “total” disruption of the pathway in severely affected individuals. Medroxyprogesterone was reported to successfully improve the response to carbon dioxide in two
children (aged 1 and 20 months) with hypoventilation syndrome [8]. Neither, however, had genotyping to confirm (or refute) the diagnosis, and we are unaware of subsequent confirmatory studies since that initial report in 1985. Studies in older infants, children and adults have suggested there may be partial preservation on central nervous system networks. Carroll et al. [2] demonstrated graded dysfunction in cardiovascular regulation in association with genotype in 32 infants, children and older adults with CCHS and suggested this could represent differential effects on the autonomic system. In addition, there were also differences between the cases of 15 young adult controls with regard to their cerebrovascular responses to chemosensory challenge which the authors suggested might indicate alteration in cerebral autoregulation [2]. This finding may suggest targets for potential pharmacologic interventions. Genotyping is essential to the diagnosis [12], but CO2 sensitivity studies could be used to facilitate identification of infants with milder phenotypes of CCHS as indicated by a partial response to increased CO2 levels and who may respond to respiratory stimulants. Acknowledgments Conflict of interest None. Funding AG is an NIHR Senior Investigator. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
1730 Contributor statement Dr. Rossor undertook the physiological assessments under Professor Greenough and Dr. Bhat’s guidance. All authors contributed to the writing of the manuscript.
References 1. Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual L, Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich A, Gaultier C, Lyonnet S (2003) Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHO2B in congenital central hypoventilation syndrome. Nat Genet 33:459–461 2. Carroll MS, Patwari PP, Kenny AS, Brogadir CD, Stewart TM, Weese-Mayer DE (2014) Residual chemosensitivity to ventilatory challenges in genotyped congenital central hypoventilation syndrome. J Appl Physiol 116:439–450 3. Dubreuil V, Ramanantsoa N, Trochet D, Vaubourg V, Amiel J, Gallego J, Brunet JF, Goridis C (2008) A human mutation in Phox2B causes lack of CO2 chemosensitivity, fatal central apnea and specific loss of parafacial neurons. Proc Natl Acad Sci U S A 105:1067–1072 4. Haddad GG, Mazza NM, Defendini R, Blanc WA, Driscoll JM, Epstein MA, Mellins RB (1978) Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore) 57:517–526 5. Lingappa L, Panigrahi NK, Chirla DK, Burton-Jones S, Williams MM (2012) Congenital central hypoventilation syndrome with PHOX2B gene mutation. Indian J Pediatr 79:1526–1528 6. Da L, Rand CM, Zhou L, Berry-Kravis EM, Jennings LJ, Yu M, Weese-Mayer DE (2009) Paired-like homeobox gene 2B (PHOX2B) and congenital central hypoventilation syndrome (CCHS): genotype/ phenotype correlation in cohort of 347 cases. Am J Respir Crit Care Med 179:A6341
Eur J Pediatr (2014) 173:1727–1730 7. Mellins RB, Balfour HH Jr, Turino GM, Winters RW (1970) Failure of automatic control of ventilation (Ondine’s curse). Report of an infant born with this syndrome and review of the literature. Medicine 49:487–504 8. Milerad J, Lagercrantz H, Lofgren O (1985) Alveolar hypoventilation treated with medroxyprogesterone. Arch Dis Child 60:150–155 9. Patwari PP, Carroll MS, Rand CM, Kumar R, Harper R, Weese-Mayer DE (2010) Congenital central hypoventilation syndrome and the PHOX2B gene: a model of respiratory and autonomic dysregulation. Respir Physiol Neurobiol 173:322– 335 10. Rigatto H, Brady JP, de la TorreVerduzco R (1975) Chemoreceptor reflexes in preterm infants: II. The effect of gestational and postnatal age on the ventilatory response to inhaled carbon dioxide. Pediatrics 55:614–620 11. Spengler CM, Gozal D, Shea SA (2001) Chemoreceptive mechanisms elucidated by studies of congenital central hypoventilation syndrome. Respir Physiol 129:247–255 12. Trang H, Dehan M, Beaufils F, Zaccaria I, Amiel J, Gaultier C, French CCHS Working Group (2005) The French congenital central hypoventilation syndrome registry: general data, phenotype, and genotype. Chest 127:72–79 13. Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, Marazita ML (2003) 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 123:267–278 14. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H (2010) An official ATS clinical policy statement: congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med 181: 626–644
