-
- Paroxysmal extreme pain disorder (PEPD) is a
rare autosomal dominant pain disorder linked to
a mutation in the SCN9A gene, which encodes
voltage-gated sodium channel Nav1.7. Abnormal
pain sensitivity occurs because of changes in
the properties of voltage-gated sodium channels.
Different mutations in SCN9A and a spectrum of
clinical expressions have been described.
-
-
- Here we describe a 3-year-old child with a
rare clinical picture of PEPD. Extremely painful
voiding had been present since the child's
birth. The diagnosis was confirmed by the
detection of a heterozygous pathogenic mutation
in the SCN9A gene, c.554G>A (p.Arg185His)
inherited paternally. The same mutation was
also found in the girl's father, who has
occasionally had some pain in his jaw while
yawning since childhood. Significant
reduction of the pain was achieved with
carbamazepine.
-
- The case is interesting because the same
mutation as that found in the girl and her
father has been found in patients with small
fiber sensory neuropathy. These data do not
correlate with the clinical picture of our case
and her father, but intra- and interfamily
phenotypic diversity in symptoms associated with
a gain-of-function variant of Na(V)1.7 are also
described and may explain our case.
-
- Introduction
-
- Paroxysmal extreme pain disorder (PEPD) is a
rare autosomal dominant pain disorder linked to
a mutation in the SCN9A gene, which encodes
voltage-gated sodium channel Nav1.7. Abnormal
pain sensitivity occurs because of changes in
the properties of voltage-gated sodium channels
[1]. Different mutations in SCN9A and a
spectrum of clinical expressions have been
described: congenital insensitivity to pain,
primary erythromelalgia (PE), febrile seizures,
small fiber sensory neuropathy (SFN), and PEPD.
The different effects of mutations (which may
enhance channel activation or impair channel
inactivation) may contribute to the wide
spectrum of symptomatology of these disorders
[2].
-
- Onset of PEPD is in the neonatal period;
most characteristic clinical features are
attacks of excruciating pain that affect various
parts of the body such as the rectum, genitalia,
face, and limbs. Autonomic manifestations
predominate initially, with skin flushing in all
cases and harlequin color changes and tonic
attacks in most. Dramatic syncopes with
bradycardia and sometimes asystole are common.
Later, the disorder is characterized by attacks
of excruciating deep burning pain often in the
rectal, ocular or jaw areas, but also diffuse
pain. Attacks are triggered by factors such as
defecation, cold wind, eating, and emotions
[1]. The case, a 3-year-old child,
described in the article, is interesting because
of the clinical picture of very painful voiding
since birth, without any other autonomic
manifestations.We only found one other article
with a clinical description of painful voiding
of a child with this disease [1], but
this was explained as a perineal symptom, such
as described elsewhere. The diagnosis of PEPD
was confirmed by sequencing of a pathogenic
mutation in the SCN9A gene, and the girl was
successfully treated with carbamazepine.
-
- Case report
-
- A 3-year-old girl was admitted to the
Pediatric Nephrology Department because of her
unusual voiding pattern. Her parents said that
for each voiding, 5&endash;7 times a day, the
girl writhed in pain; she cried, became pale,
and sweated. As soon as she started to urinate,
she looked relieved and stopped crying. Since
birth, the parents had observed sudden attacks
including crying and curled up legs, which had
passed when she began to urinate. Even when
passing stools, which were of normal
consistency, but small in diameter, the girl
occasionally cried. Otherwise, the girl had
normal everyday stools and she was not
constipated. The girl was shy and never as
lively as her three older brothers. Her motor
development was slower than normal; she started
walking at 18 months of age. She had had a few
lower urinary tract infections in the previous 2
years. Ultrasound of the urinary tract was
normal, as well as a voiding cystogram, except
for a backlog of urine after voiding. She was
born with syndactyly, and corrective plastic
surgery was performed in her first year. Her
family history does not include any kidney
disease. The girl's father occasionally had
pain in the jaw while yawning. He did not
remember having any pain attacks in his early
childhood.
-
- When the girl was first seen, her weight was
at the 10th percentile and her height at the
50th percentile for her age; she had a high
forehead, low-placed ears, retrognatia, and a
long nose with a narrow tip. Neither of her
parents had any of these facial features. She
had scars after surgery for syndactyly type 1,
subtype 2 (second/third fingers of the left
hand, third/fourth toes of the left foot).
Neurological examination revealed no focal
neurological deficits, but there was a slight
delay in reaching developmental milestones.
Namely, her gross motor skills were not
appropriate for her age: at 3 years, she was
unable to stand on one foot momentarily, and was
unable to run or jump. Her posture was stooped;
she walked slowly and cautiously. Her voiding,
according to her parents' description of the
state when the girl was trying to begin
urinating was as follows: she would squat on the
toilet seat, crying because of genital pain, her
face became pale and later erythematous, and she
sweated. There was no redness of her hands and
feet and no swelling of the extremities
appeared. Suddenly, voiding occurred and the
girl seemed released. The voiding volume was
small,maximum 40 ml, and the urinary stream was
weak. At admission she had no genital or urinary
tract infection, and her kidney function was
normal. Urodynamic studies were performed. After
installation of only 20 ml of filling volume the
girl started to cry. Intravesical pressure was
between 70 and 160 cm of water. The procedure
was stopped because of the girl's pain.
-
- Neurological examination revealed no focal
neurological deficits. Electroencephalography
between attacks, somatosensory evoked
potentials, and magnetic resonance imaging of
the lumbosacral spine and brain were all normal.
In accordance with the odd clinical course, we
assumed that the girl had an unusual expression
of PEPD, and she was prescribed carbamazepine.
The effect of carbamazepine is attributed to the
inhibition of Nav?4 peptide-mediated resurgent
sodium currents in Nav1.7 channels [3].
In a few weeks the pain attacks became less
invasive and less frequent. The diagnosis of
PEPD was confirmed by detection of a
heterozygous pathogenic mutation in the SCN9A
gene (Fig. 1), a missense mutation in exon 5:
c.554G>A (p.Arg185His). Cytogenetic
evaluation confirmed a normal female karyotype
without structural chromosomal abnormalities.
The samemutationwas also confirmed in the girl's
father (Fig. 2).
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- After a year of carbamazepine therapy, the
pain attacks had almost disappeared. The girl's
motor skills improved significantly and were
appropriate for age: her posture became erect,
she became a playful child able to jump forward
and backward, run, and ride a bike.
-
- getting the genetic analysis results because
it was obvious that the patient was suffering
very much and that her everyday activities were
limited because of overcoming the pain.
Following treatment, the reduction in pain was
obvious, and therefore the positive genetics
result did not come as a surprise&emdash; as
such, we continued with the therapy.
-
- Discussion
-
- The case described is interesting because of
the rare clinical expression of PEPD with pain
triggered by voiding, and clear evidence of
suppressed motor development in a child with
extreme pain attacks&emdash;both motor
development and pain improved after treatment
with carbamazepine. We suppose that past
recurrent urinary tract infections were
associated with painful voiding, which was
dysfunctional, with incomplete bladder emptying.
When pain relief was achieved with treatment,
urinary tract infections also ceased. The girl's
other clinical characteristics remain
unexplained. In the literature, we were unable
to find any description of a patient with
similar clinical features and a mutation in the
SCN9A gene. So far we have been unable to
identify a syndrome simultaneously encompassing
the girl's facial characteristics and her
syndactyly within the available international
databases.
-
- However, the same mutation in SCN9A has also
been described in patients with SFN [4].
Study of the functional importance of this
mutation showed that it increased the firing
frequency of pain-signaling neurons. The role of
Na(V)1.7 mutations in neurological disease in
comparison with studies on rare genetic
syndromes suggests an etiological basis for
idiopathic SFN, whereby expression of
gain-of-function mutant sodium channels in small
diameter peripheral axons may cause these fibers
to degenerate [5]. These data do not
correlate with the clinical picture of either
our case or her father, but intra- and
interfamily phenotypic diversity in the clinical
picture associated with a gain-of-function
variant of Na(V)1.7 have also been described
[6]. Mutation p.Arg185His has been
reported in patients with idiopathic SFN
[4] and in patients with inherited
erythromelalgia [7], but to our
knowledge not in patients with PEPD. Our report
supports existing experience of the variability
of clinical presentations caused by SNC9A
mutations. Functional studies have shown that
p.Arg185His variant channels enhance resurgent
currents within dorsal root ganglion neurons and
render dorsal root ganglion neurons
hyperexcitable, but do not produce detectable
changes within sympathetic neurons of the
superior cervical ganglion, and have no effect
on the excitability of these cells [8].
This suggests that differential effects in
different types of neurons could contribute to
the clinical phenotype and might, together with
additional genetic (modifier genes) and/or
environmental factors, be involved in disease
presentation.Mutation p.Arg185His is located in
a highly conserved amino acid position, as
illustrated in the HGMD database (accession
number CM120566).
-
- Conclusion
-
- The case described is obviously rare in
pediatric nephrology, but her clinical course
and therapy response are interesting. The
precise historical data, good clinical
observations, and collaboration of pediatric
nephrologist, pediatric neurologist, and
genetics team led to the diagnosis, therapy
decision, and relief of symptoms in the
child.
-
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