[MIM 209 880]

(Congenital central alveolar hypoventilation)

Very rare: 1/50,000 to 1/200,000 live births. Generally de novo heterozygous mutation of the PHOX2B gene (4p12) (90 % of cases) that causes a more than 20 times repeat of alanine (PARM mutation): the consequences are more severe when the number of repeats increases. A few cases of dominant autosomal transmission with incomplete penetrance and variable expressivity have been observed. The normal genotype is described as 20/20, which indicates the number of alanine repeats in the expansion area of exon 3 on each allele. PARM genotypes vary from 20/24 to 20/33. Forms equal or greater than 20/27 produce the most severe phenotypes (prolonged sinusal pauses that require the insertion of a cardiac pacemaker, association with Hirschprung disease). Other mutations (very rare), which are not caused by repeats of alanine, have been described and are called non-PARM: for example, mutations of the MYO1H and LBX1 genes (autosomal recessive transmission in  consanguineous families). The risk of neuroblastoma is increased in  non-PARM children. In case of less frequent repeats of alanine (between 23 and 25), central hypoventilation begins later (childhood, adulthood). In that situation, it presents as acute respiratory problems (requiring ventilation during sleep, even tracheotomy) in case of enlarged tonsils, or use of sedative or anesthetic agents. The congenital central alveolar hypoventilation is sometimes associated with Hirschsprung's disease (13-26 % of patients), it is then called Haddad syndrome.

Central alveolar hypoventilation is probably due to an anomaly of integration at the level of the central nervous system where different relevant information is received from the chemoreceptors.

Clinical presentation:

-        severe alveolar hypoventilation (hypoxemia and hypercarbia) during spontaneous breathing due to a lack of response to hypercapnia: this hypoventilation manifests itself as a decrease in frequency and amplitude of respiratory movements. It is more severe during sleep, especially during quiet  (non-REM) sleep

-        hypoventilation is permanent until around 6-12 months of age: at that stage, the infant becomes generally able to control their respiratory frequency while awake; however, hypoventilation remains permanent in 10 to 15 % of cases

-        anomalies of the cardiovascular autonomic control (40 %): sinusal pauses, severe bradycardia, sometimes short asystoly requiring the insertion of a pacemaker (indicated if RR interval ≥ 3 sec on ECG); vasovagal syncopes; nocturnal hypertension and diurnal hypotension, orthostatic hypotension.

-        sweating episodes, low blood sugar and body temperature homeostasis disorders

-        flat and squared facies

-        severe gastroesophageal reflux secondary to esophageal dysmotility

-        eye anomalies (66 %): intermittent strabismus, abnormal pupils or iris with impaired pupillary dilation, frequent anisocoria.

There are also acquired forms following a trauma or linked to a brainstem tumor.

According to the disease gravity and the patient's age, some special treatments can be required:

-        nocturnal non-invasive ventilation

-        tracheostomy with nocturnal ventilation

-        negative pressur ventilation ('iron lung')

-        electric stimulation of the phrenic nerves(procedure performed under thoracoscopy and unipulmonary ventilation) to provide nocturnal ventilation

Reference center in France : www.ondinefrance.org

and Hôpital R Debré: ha.trang@rdb.aphp.fr

Anesthetic implications:

recent ECG and echocardiography. Gastroesophageal reflux. Sometimes, midface hypoplasia secondary to the mask applied during childhood for nocturnal non-invasive ventilation. If possible, avoid the use of general anesthetics and opiates with a long duration of action and prefer locoregional anesthesia techniques. A case of complete AVB  associated with a bolus of 3 mg/kg propofol injection has been reported. Keep that diagnosis in mind in case of prolonged awakening from anesthesia or in presence of unexplained apnea following sedation or general anesthesia.

References : 

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  Central hypoventilation syndrome: diagnosis, management, and long-term outcome in thirty-two children. 
  J Pediatr 1992; 120: 381-7.
• Sochala C, Van Deenen D, De Villé A, Govaerts MJM. Heart block following propofol in a child. Paediatr Anaesth 1999; 9: 349-51.
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  Anesthetic implications of undiagnosed late onset central hypoventilation syndrome in a child : from elective tonsillectomy to tracheostomy. 
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• Mahfouz AKM, Rashid M, Khan MS, Reddy P. Late onset central hypoventilation syndrome after exposure to general anesthesia. Can J Anesth 2011; 58: 1105-9.
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• Trang H , Samuels M, Ceccherini I, Frerick M, Maria Angeles Garcia-Teresa MA et al.
  Guidelines for diagnosis and management of congenital central hypoventilation syndrome.
  Orphanet Journal of Rare Diseases. 2020 ; 15:252, doi.org/10.1186/s13023-020-01460-2

Updated: October 2020