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Congenital Central Hypoventilation Syndrome and Hypoglycemia.

Farina MI, Scarani R, Po' C, Agosto C, Ottonello G, Benini F.

Acta Paediatr. 2011 Nov 21. doi: 10.1111/j.1651-2227.2011.02533.x. [Epub ahead of

.Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder
typically presenting in infants with an impaired automatic control of breathing,
particularly during sleep, and often associated with variable patterns of
autonomic nervous system dysregulations. We studied three children who had CCHS
associated with episodes of severe hypoglycemia and hyperinsulinemia; we discuss
the possible relationship with impaired dopamine-beta-hydroxylase function.
Conclusion: hypoglycemia and hyperinsulinemia might be suspected in children
with CCHS presenting with seizures and hyperhydrosis, though further studies are
needed to confirm this association.


Late Onset Central Hypoventilation Syndrome due to a Heterozygous Polyalanine
Repeat Expansion Mutation in the PHOX2B Gene.

Al Rashdi I, Al Ghafri M, Al Hanshi S, Al Macki N.

Oman Med J. 2011 Sep;26(5):356-8.

This report describes a 6 year old girl with late onset central hypoventilation
syndrome due to a heterozygous polyalanine repeat expansion mutation in the
PHOX2B gene. This report aims to increase the awareness of this condition among
physicians to allow earlier clinical and genetic diagnosis and management of
cases of unexplained hypoventilation.


Late onset congenital central hypoventilation syndrome after exposure to general

Mahfouz AK, Rashid M, Khan MS, Reddy P.

Can J Anaesth. 2011 Dec;58(12):1105-1109. Epub 2011 Oct 12.

PURPOSE: Prolonged postoperative hypoventilation presents a challenge to
anesthesiologists with regard to assessing etiology and related treatment. We
present a case of recurrent episodes of postoperative hypoventilation in a
previously asymptomatic child after uneventful general anesthesia. In this case,
the child eventually required lifelong ventilatory support during sleep. CLINICAL
FEATURES: A case of postoperative hypoventilation in a previously asymptomatic
six-year-old child was investigated to determine the possible etiology. After
uneventful general anesthesia for dental surgery, the child experienced recurrent
episodes of hypoventilation associated with sleep. The child's lungs were
mechanically ventilated due to failure of all trials of weaning. Clinical
examination was unremarkable and laboratory investigations excluded the
possibility of thyroid, hepatic, renal, and neuromuscular diseases. Computerized
tomography, magnetic resonance imaging, and electroencephalogram studies were
within normal limits. A negative pyridostigmine trial ruled out myasthenia. The
child was finally diagnosed as having "late onset congenital central
hypoventilation syndrome". Genetic testing revealed a PHOX2B mutation consistent
with this diagnosis. The child was discharged home on mechanical ventilatory
support during sleep. CONCLUSION: Congenital central hypoventilation syndrome is
a rare lifelong multisystem disorder which may occur during the neonatal period
as a result of severe genetic mutation in the PHOX2B gene. In mild mutations, a
triggering factor, such as sedation or anesthesia, may be required for the
syndrome to manifest itself. These patients often require lifelong mechanical
ventilatory support, particularly during sleep.


In vitro drug treatments reduce the deleterious effects of aggregates containing
polyAla expanded PHOX2B proteins.

Di Zanni E, Bachetti T, Parodi S, Bocca P, Prigione I, Di Lascio S, Fornasari D,
Ravazzolo R, Ceccherini I.

Neurobiol Dis. 2012 Jan;45(1):508-18. Epub 2011 Sep 21.

Heterozygous in frame duplications of the PHOX2B gene, leading to polyalanine
(polyAla) expansions ranging from +5 to +13 residues of a 20-alanine stretch,
have been identified in the vast majority of patients affected with Congenital
Central Hypoventilation Syndrome (CCHS), a rare neurocristopathy characterized by
absence of adequate autonomic control of respiration with decreased sensitivity
to hypoxia and hypercapnia. Ventilatory supports such as tracheostomy, nasal mask
or diaphragm pacing represent the only options available for affected. We have
already shown that the severity of the CCHS phenotype correlates with the length
of polyAla expansions, ultimately leading to formation of toxic intracytoplasmic
aggregates and impaired PHOX2B mediated transactivation of target gene promoters,
such as DBH. At present, there is no specific treatment to reduce cell aggregates
and to ameliorate patients' respiration. In this work, we have undertaken in
vitro analyses aimed at assessing the effects of molecules on the cellular
response to polyAla PHOX2B aggregates. In particular, we tested 17-AAG,
ibuprofen, 4-PBA, curcumin, trehalose, congo red and chrysamine G for their
ability to i) recover the nuclear localisation of polyAla expanded PHOX2B, ii)
rescue of PHOX2B mediated transactivation of the DBH promoter, and iii) clearance
of PHOX2B (+13 Ala) aggregates. Our data have suggested that 17-AAG and curcumin
are effective in vitro in both rescuing the nuclear localization and
transactivation activity of PHOX2B carrying the largest expansion of polyAla and
promoting the clearance of aggregates of these mutant proteins inducing molecular
mechanisms such as ubiquitin-proteasome (UPS), autophagy and heat shock protein
(HSP) systems.


Epidemiologic survey of patients with congenital central hypoventilation syndrome
in Japan.

Hasegawa H, Kawasaki K, Inoue H, Umehara M, Takase M; Japanese Society of
Pediatric Pulmonology Working Group (JSPPWG).

Pediatr Int. 2011 Sep 29. doi: 10.1111/j.1442-200X.2011.03484.x. [Epub ahead of

Background: Congenital central hypoventilation syndrome (CCHS) is a rare disease
characterized by hypoventilation during sleep. This study discusses the first
epidemiologic survey of patients with CCHS in Japan. Methods: The first survey
was conducted between September and December 2006 and involved 507 registered
institutes for pediatric training in Japan. The second survey was conducted
between January and April 2007 and involved only those institutes that confirmed
diagnosis of CCHS in the first survey or reported on CCHS at a conference during
the preceding decade. Results: Thirty-seven patients with CCHS were reported
from 23 hospitals. Patient characteristics were as follows: 18 were male, 19 were
female; and age range 4 months to 34 years. Diagnosis was based on clinical
symptoms in 37/37 patients; blood gas analysis in 25/37; ventilatory response to
inhaled CO(2) in 14/37; and genetic analysis (paired-like homeobox gene 2B) in
11/37. Complications included Hirschsprung's disease in 13/37 and central nervous
system disorders in 15/37. Prognoses were as follows: 3/37 died in hospital, 1/37
remained in hospital, 33/37 were on home mechanical ventilation (died 4/33,
survived 29/33), and 0/37 were cured. Ventilation methods included tracheostomy
(21/37), use of a nasal mask (9/37), use of a facemask (5/37), and diaphragmatic
pacing (1/37). Conclusions: There is currently no consensus on the most
appropriate methods for diagnosing and treating patients with CCHS in Japan. More
CCHS-related data need to be collected in the near future in order to enable
appropriate diagnosis and management of patients with CCHS.


Ondine's curse: anesthesia for laparoscopic implantation of a diaphragm pacing
stimulation system.

Niazi AU, Mocon A, Varadi RG, Chan VW, Okrainec A.

Can J Anaesth. 2011 Nov;58(11):1034-8. Epub 2011 Aug 25.

PURPOSE: Central alveolar hypoventilation syndrome (CAHS) is a rare disease
characterized by the loss of autonomic control of breathing. This condition
causes hypoventilation and obstruction during sleep. Throughout their lives,
these patients require ventilatory assistance by means of positive pressure
ventilation to their lungs via mask, tracheotomy, or other means, such as phrenic
nerve pacers. The diaphragm pacing stimulation system (DPSS) is a new treatment
where electrodes are implanted into the diaphragm and cause contraction on
stimulation. The DPSS has been used successfully in tetraplegic patients and
patients suffering from amyotrophic lateral sclerosis (ALS). It has been shown to
improve quality of life and to extend survival in patients with advanced
respiratory muscle weakness. In our case, we describe the perioperative
management of an adult patient with acquired CAHS who presented for laparoscopic
DPSS insertion.
CLINICAL FEATURES: Our patient was a 50-yr-old female who developed CAHS at age
thirteen after contracting encephalitis. Since the onset of her disease, she had
been managed with positive pressure ventilation to her lungs via mask. Due to her
longstanding disease, she presented with pulmonary hypertension and cor pulmonale
and was scheduled for laparoscopic DPSS implantation. Our anesthetic technique
included a total intravenous technique with remifentanil and propofol, and her
trachea was intubated without the use of muscle relaxants. The pacemakers were
switched on when the patient emerged from anesthesia, which provided her with
ventilatory support and allowed us to extubate her trachea.
CONCLUSION: We present the successful anesthetic management of an adult patient
with CAHS undergoing laparoscopic DPSS insertion.


Variable human phenotype associated with novel deletions of the PHOX2B gene.

Jennings LJ, Yu M, Rand CM, Kravis N, Berry-Kravis EM, Patwari PP, Weese-Mayer

Pediatr Pulmonol. 2011 Aug 9. doi: 10.1002/ppul.21527. [Epub ahead of print]

BACKGROUND: Clinical testing for PHOX2B mutations is widely used for patients
with any symptoms suggestive of hypoventilation (with/without
anatomic/physiologic autonomic dysregulation), though not necessarily with the
congenital central hypoventilation syndrome (CCHS) phenotype. Consequently, a
multitude of referrals for clinical PHOX2B testing (fragment analysis of the 20
polyalanine repeat region and/or sequencing of entire coding region) have no
identifiable mutation. Whole gene deletions/duplications have recently been
identified as a common disease-causing mechanism, but have not been reported in a
clinical population referred for PHOX2B testing. The objective of this study was
to determine if PHOX2B exon or whole gene deletion/duplication would be
identified in a subset of patients referred for PHOX2B testing. HYPOTHESIS: We
hypothesized that PHOX2B exon or whole gene deletion or duplication would be
identified in a subset of cases who were referred for genetic testing but not
found to have a PHOX2B mutation with currently available clinical PHOX2B testing.
METHODS: Genomic DNA samples from patients that tested negative for PHOX2B
mutations using fragment analysis and/or sequencing, and control samples, were
screened for PHOX2B exon deletions/duplications by multiplex ligation-dependent
probe amplification with confirmation by array comparative genomic hybridization.
RESULTS: Deletions of/in PHOX2B were identified in 4/250 patients and 0/261
controls. The deletions ranged from 6,216 base pairs (involving only PHOX2B exon
3) to 2.6 megabases (involving all of PHOX2B and 12 other genes). The case with
PHOX2B partial exon 3 deletion had a CCHS-compatible phenotype (hypoventilation,
Hirschsprung disease). Phenotypes for the other three cases, all PHOX2B
whole-gene deletions, were varied including: (1) apparent life threatening event,
(2) full CCHS necessitating artificial ventilation with ganglioneuroblastoma, and
(3) hypoventilation during sleep. Family studies of two of the four probands
showed these deletions to be maternally inherited; the mothers also had
phenotypic findings of autonomic dysfunction. CONCLUSIONS: PHOX2B exon or whole
gene deletion should be considered as another mechanism of disease which may
include CCHS, Hirschsprung disease, and/or tumors of neural crest origin,
although the genotype-phenotype relationship requires further clarification.

update: 09/12/2011

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