Adult Identified with Congenital Central Hypoventilation Syndrome–Mutation in PHOX2b Gene and Late-Onset CHS
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《美国医学杂志》
To the Editor:
In light of our recent review of the genetic basis for congenital central hypoventilation syndrome (CCHS) (1), we bring to your attention a 35-year-old adult recently identified as having had late-onset CHS and the CCHS-mutation in PHOX2b.
One year ago this patient presented with a history of snoring "for his whole life," nocturnal gasping, and "stopping breathing and turning blue." During polysomnography he had 46 obstructive events (38 hypopneas, 8 apneas), 16 central apneas, and an apnea–hypopnea index of 77 events/hour, with an SaO2 nadir of 65% in room air and 80% with supplemental oxygen. He temporarily responded to Bi-Pap with supplemental oxygen during sleep, but within 6 months was referred for uvulopalatopharyngoplasty. He was readmitted 48 hours after discharge with intermittent confusion, difficulty staying awake, and respiratory failure (awake arterial PCO2 of 73 mm Hg). His admission hematocrit was 73%, body temperature was 35.5°C, chest X-ray revealed cardiomegaly, and ECG revealed right axis deviation, enlargement, and hypertrophy. He required intubation and mechanical ventilation, then a tracheostomy; however, mechanical ventilation was discontinued. We were contacted by the family when an arterial blood gas assay upon awakening revealed a PCO2 of 129 mm Hg (pH 7.03). Because of his daughter's diagnosis of late-onset CHS 3 years before, and documentation that she is heterozygous for the CCHS-related PHOX2b polyalanine expansion mutation, we conducted the same assay with the father's DNA. Figure 1 demonstrates the identical mutation in the 4-year-old daughter and the father, as well as in the 2-year-old daughter, who also has alveolar hypoventilation (all three have a genotype of 20/25). In retrospect, we learned that the father uses Dexadrine to "stay on task," has symptoms compatible with autonomic nervous system dysregulation (low body temperature, postural hypotension, pinpoint pupils minimally reactive to light, no shortness of breath despite markedly increased carbon dioxide levels), and has awakened with headaches and periods of disorientation for several years.
On the basis of this remarkably late presentation of the alveolar hypoventilation component of CHS, we suggest that adult pulmonologists and intensivists consider the possibility of late-onset CHS, confirmable by PHOX2b assay, when caring for adults with hypercarbia of unknown etiology. From a scientific perspective, this case raises the possibility of a regulatory gene that modifies the expression or activity of PHOX2b, determining the severity of the autonomic dysregulation in late-onset CHS.
Debra E. Weese-Mayer, Elizabeth M. Berry-Kravis and Lili Zhou
Rush University Medical Center Chicago, Illinois
FOOTNOTES
Conflict of Interest Statement: D.E.W.-M. is named on a patent application for the PHOX2b assay but has not received any financial benefit from this application; E.M.B.-K. is named on a patent application for the PHOX2b assay but has not received any financial benefit from this application; L.Z. is named on a patent application for the PHOX2b assay but has not received any financial benefit from this application.
REFERENCES
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.
Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, Marazita ML. 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 2003;123A:267–278.
In light of our recent review of the genetic basis for congenital central hypoventilation syndrome (CCHS) (1), we bring to your attention a 35-year-old adult recently identified as having had late-onset CHS and the CCHS-mutation in PHOX2b.
One year ago this patient presented with a history of snoring "for his whole life," nocturnal gasping, and "stopping breathing and turning blue." During polysomnography he had 46 obstructive events (38 hypopneas, 8 apneas), 16 central apneas, and an apnea–hypopnea index of 77 events/hour, with an SaO2 nadir of 65% in room air and 80% with supplemental oxygen. He temporarily responded to Bi-Pap with supplemental oxygen during sleep, but within 6 months was referred for uvulopalatopharyngoplasty. He was readmitted 48 hours after discharge with intermittent confusion, difficulty staying awake, and respiratory failure (awake arterial PCO2 of 73 mm Hg). His admission hematocrit was 73%, body temperature was 35.5°C, chest X-ray revealed cardiomegaly, and ECG revealed right axis deviation, enlargement, and hypertrophy. He required intubation and mechanical ventilation, then a tracheostomy; however, mechanical ventilation was discontinued. We were contacted by the family when an arterial blood gas assay upon awakening revealed a PCO2 of 129 mm Hg (pH 7.03). Because of his daughter's diagnosis of late-onset CHS 3 years before, and documentation that she is heterozygous for the CCHS-related PHOX2b polyalanine expansion mutation, we conducted the same assay with the father's DNA. Figure 1 demonstrates the identical mutation in the 4-year-old daughter and the father, as well as in the 2-year-old daughter, who also has alveolar hypoventilation (all three have a genotype of 20/25). In retrospect, we learned that the father uses Dexadrine to "stay on task," has symptoms compatible with autonomic nervous system dysregulation (low body temperature, postural hypotension, pinpoint pupils minimally reactive to light, no shortness of breath despite markedly increased carbon dioxide levels), and has awakened with headaches and periods of disorientation for several years.
On the basis of this remarkably late presentation of the alveolar hypoventilation component of CHS, we suggest that adult pulmonologists and intensivists consider the possibility of late-onset CHS, confirmable by PHOX2b assay, when caring for adults with hypercarbia of unknown etiology. From a scientific perspective, this case raises the possibility of a regulatory gene that modifies the expression or activity of PHOX2b, determining the severity of the autonomic dysregulation in late-onset CHS.
Debra E. Weese-Mayer, Elizabeth M. Berry-Kravis and Lili Zhou
Rush University Medical Center Chicago, Illinois
FOOTNOTES
Conflict of Interest Statement: D.E.W.-M. is named on a patent application for the PHOX2b assay but has not received any financial benefit from this application; E.M.B.-K. is named on a patent application for the PHOX2b assay but has not received any financial benefit from this application; L.Z. is named on a patent application for the PHOX2b assay but has not received any financial benefit from this application.
REFERENCES
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.
Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, Marazita ML. 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 2003;123A:267–278.