Paroxysmal Extreme Pain Disorder

A number sign (#) is used with this entry because paroxysmal extreme pain disorder (PEXPD, or PEPD) is caused by heterozygous mutation in the SCN9A gene (603415) on chromosome 2q24.

Description

Paroxysmal extreme pain disorder, formerly known as familial rectal pain, is characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. Onset is usually in the neonatal period or infancy (Fertleman et al., 2006).

Clinical Features

Hayden and Grossman (1959) described a syndrome consisting of very brief, excruciating pain of the submandibular, ocular and rectal areas with flushing of the surrounding skin. Autosomal dominant inheritance with incomplete penetrance of the components was suggested. Submandibular and ocular pain is a more consistent feature than rectal pain. They considered the condition to be a 'dysautonomia.'

Dugan (1972) described affected individuals in 5 generations with male-to-male transmission. 'Intense searing pain' accompanied bowel movements. 'Jaw aches' also were frequent.

Mann and Cree (1972) recorded some observations on another extensively affected family and gave graphic descriptions of the severe rectal pain. They concluded that the disorder is distinct from proctalgia fugax, first described by Thaysen (1935).

Fertleman et al. (2006) noted that PEXPD is a rare autosomal dominant disorder of pain and autonomic dysfunction that presents with 4 types of painful episode: birth crisis, in which babies are born red and stiff; rectal crisis, which is triggered by defecation in infants and young children and by a variety of emotional factors in older children and adults; ocular crisis, which may be provoked but is more usually spontaneous; and mandibular crisis, which is often triggered by eating and yawning. The distinctive features of this condition are paroxysmal episodes of burning pain in the rectal, ocular, and mandibular areas, accompanied by the autonomic manifestations such as skin flushing, reflex asystolic syncopal events, lacrimation, and rhinorrhea. In between episodes, physical examination is normal, and investigations such as imaging or tissue biopsy are normal. Diagnosis therefore relies on the history and either direct observation or video of the episodes.

Fertleman et al. (2007) reported the results of an international consortium that identified a total of 77 patients with PEXPD from 15 families. The earliest age at onset in the series was probably in utero, in which the fetal heart could not be picked up by cardiotocography. The infant was delivered by cesarean section and exhibited painful attacks on the first day of life. Most of the 77 patients presented at birth, likely induced by the pain of delivery. Although most patients reported localization of painful attacks to the rectal, ocular, or jaw area, consistent with previous reports, patients stressed that pain was not confined to these regions and could even involve the entire body. The pain was described as excruciating and the 'worst pain imaginable,' even worse than labor pain. Other phenotypic features of the attacks included skin flushing, harlequin color changes, and nonepileptic tonic seizures, which were more common in infants and young children. These seizures usually included posturing, apnea, bradycardia, and even asystole. Attacks were virtually always provoked by a physical trigger, such as defecation, eating, or crying. The only consistent problem between attacks was constipation, most likely because patients were reluctant to induce a painful attack. There appeared to be a decrease in attacks with age in general, although PEXPD is a lifelong disorder. Carbamazepine was effective in most who tried it, but the response was often incomplete.

Meglic et al. (2014) reported a 3-year-old girl with PEPD confirmed by genetic analysis (R185H; 603415.0026). From birth, she had painful urinary voiding manifest as crying, sweating, and writhing. Similar symptoms occasionally occurred when passing stool. She had no other autonomic manifestations, but had mildly delayed motor development. Treatment with carbamazepine resulted in significant clinical improvement and normal psychomotor development. Family history revealed that her father occasionally had pain in the jaw while yawning, but did not remember pain attacks in his early childhood; the father was found to carry the same heterozygous SCN9A mutation.

Mapping

Fertleman et al. (2006) conducted a genomewide linkage search in 1 large pedigree with PEXPD. The marker D2S2330 on chromosome 2q gave a lod score of 4.99 at theta = 0.0. Haplotype analysis identified critical recombinants at D2S142 and D2S335, defining a 16-cM critical region.

Molecular Genetics

In 11 families and 2 sporadic cases of PEXPD, Fertleman et al. (2006) identified 8 missense mutations in the SCN9A gene (603415), which encodes the Na(v)1.7 voltage-gated sodium channel alpha subunit. Functional analysis in vitro of 3 of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Other mutations in SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (133020). Carbamazepine, a drug that is effective in PEXPD but not in primary erythermalgia, showed selective block of persistent current associated with PEXPD mutants, but did not affect the negative activation threshold of a primary erythermalgia mutant. Fertleman et al. (2006) concluded that PEXPD and primary erythermalgia are allelic disorders with distinct underlying biophysical mechanisms any represent a separate class of peripheral neuronal sodium channelopathy. The finding of mutations in 8 of 13 families suggested that approximately two-thirds of families with PEXPD have mutations in the SCN9A gene and that locus heterogeneity exists, as in other sodium channelopathies.

Nomenclature

Fertleman and Ferrie (2006) discussed the considerations involved in the choice of the term 'paroxysmal extreme pain disorder' to describe this condition.