Download Genetics

Genetics of CCHS
A genetic test has been
available since 2003 for the
diagnosis of CCHS.
A
mutation of the gene
PHOX2B,
located
on
chromosome
4,
is
responsible
for
the
condition. No genetic test is
currently available
for
diagnosis of ROOHAD
syndrome.
The accessibility of the
genetic test has eased the
diagnosis and may have
improved patient care.
Latest clinical guidelines
state that it is possible to
predict important aspects of
the clinical presentation
according to the type of
mutation, including: 1) the
severity of hypoventilation
and the risk of 24-hour day
mechanical
ventilation
dependence;
2)
the
incidence of neural crests
tumours,
like
neuroblastoma
or
ganglioneuroma; 3) the
incidence of Hirschsprung’s
disease; and 4) the presence
of prolonged sinus pauses, a
possible cause of sudden
death, as an indication for
24-48 hour ECG (Holter)
monitoring in order to
identify patients who need
a cardiac pacemaker.
Knowlege of the PHOX2B
mutation
also
allows
identification of either
asymptomatic
parents
carrying the mutation, who
have an higher risk of
recurrence in subsequent
pregnancies, or adults with
mild hypoventilation, which
has
not
been
previouslyobserved
or
diagnosed.
It is possible to perform
genetic testing of the fetus
during pregnancy to provide
prenatal diagnosis. Every
affected individual has a
50% risk of transmitting the
disorder to each child
according to the principles
of autosomal dominant
inheritance.
As
a
consequence,
a
single
mutation in one of the two
PHOX2B genes is enough
to cause the disease.
Nevertheless some parents
carrying the mutation are
asymptomatic;
this
is
explained
by
the
phenomenum of mosaicism,
where only a proportion of
the bodies cells show the
mutation.
To perform the analysis of
the PHOX2B gene a sample
of blood must be sent to one
of the specialised genetic
laboratories existing in
Europe (link to the map).
Such testing must be
undertaken via a referring
physician in order that all
clinical
information
is
provided.
More
details
PHOX2B Gene
about
PHOX2B gene is located on
the short (p) arm of
chromosome 4 at position
12. The structure of the
gene consists of 3 segments
called exons and numbered
1,2 and 3. The mutations
described so far include:
1) the most common
mutation, found in the 90%
of patients, and located
inside exon 3. It consists of
an expansion of a 20alanine stretch (alanine is
the nucleotide, or building
block of the DNA spiral).
The number of nucleotides
increases from 24 to 39
producing genotypes from
20/24 to 20/39 (the normal
being genotype 20/20); The
longer the expansion of the
alanine tract, the more
severe phenotype (clinical
manifestation) will arise in
the patient. For example,
patients with a 20/25
genotype are unlikely to
present 24 hours a day
hypoventilation,
whereas
individuals carrying longer
mutations
have
severe
hypoventilation even when
awake.
2) the less common
mutation, about 10% of the
patients, located out of exon
3, so called missense
(nonsense) or frame shifts
of the gene.
The presence of the second
type
of
mutation
is
frequently associated with
severe forms of CCHS, with
both Hirschsprung’s disease
(with
extensive
gut
involvement) and tumors of
the neural crest being more
commonly found.
Tumors of neural crest
origin
Individuals carrying the
missense or frame shift
mutation need to be
periodically screened for
tumors of neural crest origin
as they have a high
incidence in these patients.
Cardiac asystole
Only one study has focused
attention on a crucial aspect
of CCHS, that of the risk of
sudden death due to
arrhythmia. CCHS is a
disorder of all the automatic
activities of the body and
this include that affecting
cardiac electrical activity.
The risk of developing long
cardiac pauses is higher in
patients with a longer
amplification of alanine
tract in the exon 3. From
preliminary reports it seems
that patients with 20/25
phenotype are perhaps not
affected by cardiac asystole
while patients with longer
PARMs are.
This is a critical aspect of
the disease and a life
threatening symptom. It
must be early diagnosed in
order to prevent potential
serious complications as it
can be efficaciously treated
with cardiac pacemaker.
Therefore these patients
need to be screened with a
prolonged
holter
ECG
recordings every year in
order to identify the need
for pacing.
It is likely that in the future
genetic studies will offer
new
opportunities
for
CCHS patients, especially if
we consider that nowadays
we know som much more
than 10 years ago.
EU-CHS NETWORK
CCHS in Adulthood
With the introduction of
genetic testing, it has been
possible to diagnose some
adult
patients
with
hypoventilation as a result
of CCHS.
The
medical
literature
reports some adult patients
with
chronic
hypoventilation or late
onset hypoventilation who
have been found to have a
PHOX2B mutation. The
mutation
commonly
reported in such patients is
the (shorter) expansion of 5
alanine with a 20/25
genotype.
The
mild
phenotype associated with
this mutation explains why
the disease presents in
adulthood or remained
unrecognised
before.
Sometimes
precipitating
events like the use of
sedative drugs or acute
respiratory
distress
highlights the onset of
hypoventilation.
Patient & Carer
Information
Leaflet
Genetics of
CCHS