The American Thoracic Society has released a new official
clinical policy statement on congenital central hypoventilation
syndrome (CCHS), a disorder of respiratory and autonomic nervous
system (ANS) regulation. The ANS regulates reflexive acts,
including heart rate and blood pressure, digestion, body
temperature and pain perception.
The statement appears in the March 15, 2010 issue of the
American Journal of Respiratory and Critical Care
Medicine.
In light of a crucial discovery linking CCHS to mutations in a
single gene, the new guidelines represent a complete overhaul of
the guidelines the ATS last published in 1999. In 2003, a gene
called PHOX2B was found to be the disease-defining gene for CCHS.
The specific manner in which the PHOX2B gene mutates predicts the
severity and form of the disease, making it a rich source of
diagnostic and prognostic information.
"This discovery confirmed what we had long believed to be true:
first, that CCHS is a genetic disorder; second, that the gene
responsible for CCHS has a key role in the early embryology of the
ANS; third, that inheritance of CCHS and the PHOX2B mutation is
autosomal dominant; fourth, that the nature of the PHOX2B mutations
can explain the spectrum of the CCHS phenotype; and so much more,"
explained Debra E. Weese-Mayer, M.D., professor of pediatrics at
Northwestern University Feinberg School of Medicine, who chaired
the committee that wrote the guidelines. "The discovery that PHOX2B
is the gene that defines CCHS offers endless opportunities in terms
of basic science inquiry and clinical care - all with the long-term
goal to improve quality of life for these patients."
By late 2009, collective publications from laboratories in the
United States, France, Italy, Japan, Germany, Taiwan, China, the
Netherlands and the United Kingdom have identified nearly 1,000
cases of PHOX2B mutation-confirmed CCHS.
The first sign of CCHS often appears just after birth, when
affected infants will turn blue when they sleep, as their breathing
becomes very shallow or even stops. Severely affected babies can
also turn blue while awake. But now that CCHS is more widely
recognized, patients are being identified in the newborn period
with greater frequency. Those who were "missed" in early infancy
and who have a milder presentation are now being identified in
later childhood and even into adulthood. "They usually have a
history of turning blue after receiving sedation, anesthesia or
anti-seizure meds," explained Dr. Weese-Mayer. "They also may have
exceptional talent at underwater swimming or breath-holding (due to
an inability to perceive the sensation of asphyxia). Many
later-presenting cases will have unexplained neurocognitive
delay."
Afflicted individuals generally require fastidious medical
supervision to attain the highest quality of life. The opportunity
for PHOX2B clinical testing as soon as the diagnosis of CCHS is
considered has expedited aggressive intervention and management.
Early identification and intervention are critical to maintain
optimal oxygenation and ventilation awake and asleep in these
highly vulnerable, but extraordinarily "normal" children.
"When optimally managed, patients have attended college, married
and held jobs," Dr. Weese-Mayer continued. "The aim is to identify
the patients as early as possible, develop a teamwork approach to
management so that family members, home nurses, pediatric
pulmonologists, pediatricians and the CCHS Center that is treating
the child all work together to maximize the quality of life and
neurocognitive potential for patient - and to minimize the risk for
sudden death from respiratory insufficiency or cardiac pauses. Our
aim is a lifetime of success for the individual with CCHS."
The new guidelines recommend a number of key management options
for CCHS:
- Biannual, then annual, comprehensive in-laboratory and
in-patient evaluations that would last for several days, and which
would include:
- Physiological studies during wakefulness and sleep to assess
ventilatory needs during different activities and sleep to
ascertain safe conditions and ventilatory management
recommendations;
- Endogenous and exogenous gas challenges and autonomic testing
to characterize the extent of compromise and to ascertain safe
conditions;
- 72-hour Holter monitoring of heart rhythm to identify
asystoles, where the heart temporarily stops beating;
- Echocardiograms to screen for effects of low oxygen; and
- Comprehensive neurocognitive testing to measure success of the
management and offer intervention options.
- Barium enema or manometry and/or full thickness rectal biopsy
for patients with a history of constipation to identify
Hirschsprung disease; and
- Imaging for neural crest tumors in individuals at risk based on
their PHOX2B mutation.
Because PHOX2B exerts its influence so early in embryonic
development, no gene therapy yet exists, though this will
undoubtedly be a target of future investigations. Pre-implantation
genetics will be another target. Prenatal testing for families with
a known PHOX2B mutation is already available.
"Most PHOX2B mutations arise spontaneously, as long as neither
parent is affected by CCHS. However, we demonstrated in 2003 that
it is also possible for children to inherit the PHOX2B mutation
from an unaffected parent. An estimated five to 10 percent of
parents of children with CCHS will have mosaicism for the PHOX2B
mutation, meaning that they will have the same mutation as their
child, but in only a subset of their cells. These parents can pass
the mutation on to their offspring with up to a 50-percent risk of
transmission in each pregnancy," said Dr. Weese-Mayer.
Currently, the population incidence of PHOX2B mutations across
all ethnicities is unknown, but future research will be focused on
using the current base of knowledge about CCHS to answer such
questions. Dr. Weese-Mayer points to the section of the new ATS
statement that deals with "future directions" - outlining the need
for prospective studies on large cohorts of children and adults
with CCHS to more clearly define the clinical features by specific
PHOX2B mutation; the development of animal models to study the
mutations and understand their pathology and clinical
manifestations; stem cell research to better understand how each
organ system can be affected by PHOX2B mutations; and collaboration
between clinical physicians, physician-scientists and basic science
researchers to better understand and treat the disease.
SOURCE