Imai et al. The Journal of Headache and Pain (2015) 16:35 DOI 10.1186/s10194-015-0519-3 RESEARCH ARTICLE Open Access Short-lasting unilateral neuralgiform headache attacks with ispilateral facial flushing is a new variant of paroxysmal extreme pain disorder Noboru Imai1*†, Noriko Miyake2†, Yoshiaki Saito3,4, Emiko Kobayashi3, Masako Ikawa5, Shinya Manaka6, Masaaki Shiina7, Kazuhiro Ogata7 and Naomichi Matsumoto2* Abstract Background: We encountered a 5-year-old girl who had short-lasting, severe, unilateral temporal headaches with ipsilateral lacrimation, nasal congestion and rhinorrhoea, and facial flushing after severe attacks. Family history revealed similar short-lasting, severe headaches in an older brother, younger sister, mother, maternal aunt, and maternal grandfather’sbrother. Methods: We performed routine laboratory examinations and electrophysiological and radiological studies for three children, and whole-exome sequencing to determine the genetic causality in this family. Results: Focal hyperperfusion of the right trigeminal root entry zone was seen during a right-sided attack in one child, while left-sided temporal headache attacks were provoked by bilateral electrical stimulation of the upper extremities in another. We identified a novel SCN9A mutation (NM_002977: c.5218G>C, p.Val1740Leu) in all affected family members, but not in any of the unaffected members. SCN9A encodes the voltage-gated sodium-channel type IX alpha subunit known as Nav1.7. Conclusions: Gain-of-function mutations in Nav1.7 are well known to cause paroxysmal extreme pain disorder (PEPD), a painful Na-channelopathy characterized by attacks of excruciating deep burning pain in the rectal, ocular, or jaw areas. The SCN9A mutation suggests that our patients had a phenotype of PEPD with a predominant symptom of short-lasting, severe, unilateral headache. Keywords: Unilateral headache; Facial flushing; SCN9A mutation; Paroxysmal extreme pain disorder; Voltage-gated sodium channel; Focal hyperperfusion Background and sometimes asystole are also common. Attacks of excru- Paroxysmal extreme pain disorder (PEPD) was first de- ciating deep burning pain in the rectal, ocular, or jaw areas scribed in 1959 as a familial disorder characterized by emerge later in affected individuals. These attacks are trig- very brief episodes of excruciating rectal pain associated gered by factors such as defecation, cold wind, eating, and with flushing of the buttocks and legs, ocular pain and emotions. These painful symptoms are completely allevi- flushing of the eyelid and periorbital skin, and submaxillary ated by carbamazepine in most patients [2]. pain [1]. In PEPD, autonomic symptoms of skin flushing, SCN9A encodes the voltage-gated sodium-channel often with a harlequin pattern distribution, emerge during type IX alpha subunit known as Nav1.7, which is mainly the neonatal period. Dramatic syncopes with bradycardia expressed in peripheral sensory neurons of the dorsal root/sympathetic ganglia. Mutations in this gene can cause * Correspondence: [email protected]; [email protected] variable phenotypes with different patterns of inheritance. †Equal contributors Gain-of-function mutations mainly cause primary eryther- 1 Department of Neurology, Japanese Red Cross Shizuoka Hospital, 8-2 malgia [3], PEPD [2], small-fiber neuropathy [4], and Ohtemachi, Aoi-ku, Shizuoka, Shizuoka 420-0853, Japan 2Department of Human Genetics, Yokohama City University Graduate School chronic non-paroxysmal neuropathic pain [5] in an of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan autosomal-dominant manner. SCN9A mutations also result Full list of author information is available at the end of the article © 2015 Imai et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. Imai et al. The Journal of Headache and Pain (2015) 16:35 Page 2 of 9 in some features of Dravet syndrome [6] and febrile convul- S1). Unilateral, mainly right-sided, facial and upper- sions [7]. In addition, loss-of-function mutations in SCN9A extremity flushing (Figure 2) appeared 5–10 min after can lead to indifference to pain [8,9] and hereditary sensory severe attacks and lasted from half an hour to a few and autonomic neuropathy type IID [10] with autosomal- hours. She had undergone repeated medical examina- recessive inheritance. tions, such as routine laboratory investigations, brain Here, we describe familial cases of a painful disorder computed tomography, magnetic resonance imaging showing some clinical features reminiscent of those in (MRI), and electroencephalography (EEG), but no or- PEPD, but with short-lasting, severe, unilateral headache ganic abnormalities had been identified, and she had over the cranium as the prominent symptom in most af- received no medical treatment. fected family members. We identified a novel SCN9A When the patient sought medical attention from our mutation in this family, suggesting that the family suffers institution, we tentatively diagnosed short-lasting unilateral from a variant of PEPD. Detailed clinical information of neuralgiform headache attacks with cranial autonomic the proband and her siblings, and genetic data of her symptoms (SUNA), in accordance with the criteria of the family, including the results of whole-exome sequencing International Classification of Headache Disorders [11]. (WES), are presented. After initiation of treatment with carbamazepine at 50 mg/ day (3.125 mg/kg/day) at bedtime, the frequency and Case reports intensity of attacks decreased within a couple of weeks, Patient 1 and no adverse drug reactions were seen. An increase The index patient (Patient 1: IV-3 in Figure 1) was a 5- in the carbamazepine dosage to 100 mg/day resulted in year-old girl with a history of recurrent, unilateral temporal complete disappearance of the attacks within 2 weeks. headaches lasting 20–90 s associated with ipsilateral con- When her parents forgot to give her the carbamazepine, junctival injection, lacrimation, nasal congestion, rhinor- the attacks began again. rhea, and facial flushing. Headaches were often triggered Family history revealed similar headaches with auto- by hitting her head or body, taking a bath, experiencing a nomic symptoms in an older brother (Patient 3: IV-2), a temperature change, or sleeping. Her past medical history younger sister (Patient 2: IV-4), her mother (III-2), her included a febrile convulsion at 15 months old. She experi- maternal aunt (III-4), and her maternal grandfather’s enced the first episode of severe headache with thrashing brother (II-3). The headache attacks of her mother, and crying out at 16 months old. Thereafter, the frequency maternal aunt, and maternal grandfather’s brother all of moderate or severe headache attacks gradually increased showed spontaneous remission in adulthood. The aunt to 10–20 times per day. Attacks initially emerged during has experienced episodic burning pain in the legs since sleep, but later predominantly occurred during the daytime adolescence. The maternal grandfather had suffered epi- while the patient was awake. When experiencing a severe lepsy and headache attacks with conjunctival injection. attack, she screamed and thrashed, and bilateral lacrima- Autosomal-dominant inheritance of this disease was in- tion and facial flushing occurred (Additional file 1: Video ferred from the pedigree (Figure 1). Figure 1 Familial pedigree. Autosomal-dominant inheritance is suspected. y, years. For each family member, age at the time Patient 1 first presented for medical attention is shown. Imai et al. The Journal of Headache and Pain (2015) 16:35 Page 3 of 9 Patient 5 (III-4) She had experienced moderate unilateral headaches with ipsilateral conjunctival injection since childhood. Genital pain sometimes occurred during defecation, with enlarge- ment of the external genitalia. She had chronic pain in her extremities that emerged in childhood and worsened in the lower limbs when she was a high school student. Severe pain was occasionally provoked by light touch and warm- ing, and was relieved by cooling. Patient 6 (II-3) Patient 6, a younger brother of the maternal grandfather of Patients 1–3, had moderate to severe unilateral head- aches with ipsilateral conjunctival injection in childhood. He did not remember any further detailed features con- cerning the headaches. Figure 2 Clinical findings. Flushing of (A) the face and (B) arm after a right-sided severe headache attack in Patient 1. Methods Patient 2 (IV-4) In an attempt to identify the background condition of Headaches with similar features to those in her sister the painful disorder and to find any structural or func- emerged at 18 months old and were accompanied by tional abnormalities in the central and peripheral nervous hemi-facial flushing after the severe headache attacks. systems of the family members, Patients 1–3wereadmit- She had the same triggers as her sister, and in addition, ted for further evaluation. We observed and recorded all her headaches were often precipitated by defecation and headache attacks of the three patients in the hospital for associated with external genital pain. She was treated 3 days. We also performed routine laboratory examin- with carbamazepine at 35 mg/day (3.2 mg/kg/day at ation, spinal radiography, brain MRI, brain magnetic res- bedtime),