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mise à jour du
8 juin 2014
Pediatr Nephrol
2014 May
Painful micturition in a small child:
an unusual clinical picture of
paroxysmal extreme pain disorder
Meglic A, Perkovic-Benedik M, Trebus Podkrajsek K, Bertok S.

Chat-logomini

 
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).
 
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.
 
References
 
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2. Drenth JPH, Waxman SG (2007) Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J Clin Invest 117:3603&endash;3609
 
3. Theile JW, Cummins TR (2011) Inhibition of Nav?4 peptidemediated resurgent sodium currents in Nav1.7 channels by carbamazepine, riluzole, and anandamide. Mol Pharmacol 80:724&endash;734
 
4. Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, Dib-Hajj S, Drenth JP, Waxman SG, Merkies IS (2012) Gain of function Na?1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 71:26&endash;39
 
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6. Estacion M, Han C, Choi JS, Hoeijmakers JG, Lauria G, Drenth JP, GerritsMM, Dib-Hajj SD, Faber CG,Merkies IS,Waxman SG (2011) Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV1.7. Mol Pain 7:92
 
7. Goldberg YP, Price N, Namdari R, Cohen CJ, LamersMH,Winters C, Price J, Young CE, Verschoof H, Sherrington R, Pimstone SN, Hayden MR (2012) Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodiumchannel blocker. Pain 153:80&endash;85
 
8. Han C,Hoeijmakers JG, Liu S, GerritsMM, te Morsche RH, Lauria G, Dib-Hajj SD, Drenth JP, Faber CG, Merkies IS, Waxman SG (2012) Functional profiles of SCN9Avariants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy. Brain 135:2613&endash;2628