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PCO2 in index case and first-degree relatives except the father with and without tracheostomy.
Source publication
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of an autonomic nervous disorder that affects breathing. It is characterized by respiratory insufficiency secondary to insensitivity to hypoxemia and hypercarbia, particularly during sleep leading to persistent apnea. We report four individuals across two generations harb...
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Citations
... The first case of congenital central hypoventilation syndrome (CCHS) in an infant was reported in 1970 by Mellins and colleagues under the term Ondine's curse 1 . The name was derived from German folklore, where a human was cursed to forget performing all bodily functions, including breathing, causing him to die. ...
... Central apneas have been commonly reported in patients with CCHS and have been ascribed to a failure of the central respiratory drive from the brainstem respiratory centers (7,8). Obstructive apneas were occasionally reported in case or smallgroup studies (9)(10)(11)(12)(13)(14)(15)(16)(17) and were considered to require management in 50% of patients under 1 year old (18). However, with rare exceptions (19), the study of apneas in CCHS was conducted before the discovery of the disease-causing gene (2,4) and possibly included heterogeneous patient groups. ...
Rationale:
Congenital Central Hypoventilation Syndrome (CCHS) is characterized by life-threatening sleep hypoventilation and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome.
Objectives:
To determine if Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms.
Methods:
Apneas were classified as central, obstructive or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparations.
Measurements and main results:
The median (interquartile range) of obstructive apnea frequency was 2.3/min (1.5-3.3) in Phox2b27Ala/+ pups versus 0.6/min (0.4-1.0) in wildtypes (P < 0.0001). Obstructive apnea duration was 2.7s (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7s (1.1-1.9) in wildtypes (P < 0.0001). Central and mixed apneas presented similar, significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared to wildtype preparations. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal with respect to phrenic activity onset (P < 0.001).
Conclusions:
The Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely due to hypoglossal dysgenesis. These results thus demand attention towards obstructive events in infants with CCHS.
... Central apneas were commonly reported in CCHS patients and they were assigned to failure of central respiratory drive from the brainstem respiratory centers (7,8). Obstructive apneas were occasionally reported in case or small-group studies (9)(10)(11)(12)(13)(14)(15)(16)(17)(18) and were considered to require management in 50% of patients under one year (19). However, with rare exceptions INTRODUCTION 4 Here, we analyzed whether the Phox2b 27Ala/+ mutation caused obstructive apneas in mice. ...
Rationale: Congenital Central Hypoventilation Syndrome is characterized by life-threatening sleep hypoventilation, and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation. Patients require lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome.
Objectives: To determine whether Phox2b27Ala/+ mice, which presented main symptoms of Congenital Central Hypoventilation Syndrome and died within hours after birth, also presented obstructive apneas and investigate potential underlying mechanisms.
Methods: Apneas were classified as central, obstructive or mixed by using an original system combining pneumotachography and laser detection of thoracoabdominal movement immediately after birth. Some respiratory nuclei involved in airway patency were analyzed by immunohistochemistry and electrophysiology in brainstem-spinal cord preparation.
Measurements and Main Results: The median (interquartile range) of obstructive apnea frequency was 2.3/min (1.5-3.3) in Phox2b27Ala/+ pups versus 0.6/min (0.4-1.0) in wildtypes (P < 0.0001). Obstructive apnea duration was 2.7s (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7s (1.1-1.9) in wildtypes (P < 0.0001). Central and mixed apneas presented similar, significant differences. In Phox2b27Ala/+ preparations, hypoglossal nucleus had fewer neurons (P < 0.05) and smaller size (P < 0.01), compared to wildtypes. Importantly, coordination of phrenic and hypoglossal activities was disrupted, as shown by the longer and variable delay of hypoglossal with respect to phrenic onset, compared to wildtypes (P < 0.001).
Conclusions: The Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also obstructive and mixed apneas likely due to hypoglossal dysgenesis. These results call for attention toward obstructive events in infants with Congenital Central Hypoventilation Syndrome.
Background
Congenital central hypoventilation syndrome (CCHS) is a disorder of respiratory and autonomic regulation which presents with hypoventilation. In some patients, CCHS is associated with Hirschsprung disease and as such known as Haddad syndrome.
Case presentation
A preterm was referred to our intensive care unit due to suspicion of meconium ileus after loop-ileostomy at the age of 8 days. The patient presented with recurrent apnea, did not respond to caffeine citrate, and was dependent on ventilation. Furthermore, the patient was unable to pass stool spontaneously. In the course of clinical deterioration, fluoroscopy showed a perforation next to the ileostomy and resection of ileum was conducted. An ileostomy was performed, and several biopsies of the intestines were taken. Neither in the biopsies nor in the resected segment were ganglion cells identified histopathologically. Considering the poor prognosis, life support was withdrawn. Autopsy and histology verified total aganglionosis of the intestines. Genetic testing confirmed a rare pathogenic deletion in the alanine-repeat region in the PHOX2B (c.722-759del; p.Ala241Glyfs*106).
Conclusion
CCHS and intestinal aganglionosis are hints for Haddad syndrome. To confirm the diagnosis, biopsies of the intestines and genetic testing for mutations in the PHOX2B gene should be performed.
