A 54-year-old woman presented with loss of touch, temperature, position, and vibration sense and taste disorder, and she was insensitive to pain at the body surface since infancy. She also suffered from an autonomic disorder, with symptoms, such as orthostatic hypotension, fluctuation in body temperature, and lack of urge to defecate.
She had normal mental growth and development, although she did not walk until 18 months of age. Her family history was unremarkable; she had a healthy younger sister and her parents were not related (Fig. 1). She had repeated injuries during childhood because of insensitivity to pain, and she was diagnosed with Freiberg disease at 6 years. She experienced frequent fainting episodes and was diagnosed with an autonomic nervous system imbalance at 21 years. Even in cold temperatures, she perspired on her back and reported not needing a snowsuit. She did not have high blood pressure.
After repeated jumping from a squatting position in gym class at 14 years, the sole of her left foot developed severe blisters, and the wounds transitioned into metatarsal osteomyelitis after a few weeks. As a result of the refractory osteomyelitis, a left metatarsal was replaced by an autogenous bone graft when she was 18 years. It took approximately 10 years to recover fully from the wounds.
She had migraine since childhood until she was 20 years and took a painkiller (an antipyrine medication) daily during that time. Although she could feel a toothache/headache, she lacked sensation on the surface of her face, except around the jaw. She showed a “stocking and glove distribution”, and the detection range of sensation varied along a gradient from the periphery to center. She could perceive visceral pain, such as menstrual or gastroenteritis pain, which she controlled with an antipyrine medication. Since 42 years of age, she started using a cane for walking outside.
Although she had known that she was different from others concerning pain perception since childhood, she and her parents had never consulted a doctor regarding the impaired pain sensation until 48 years of age.
At 48 years of age, the patient developed sudden severe pain and swelling in her right joint, and her previous physician diagnosed Charcot arthropathy (X-ray photograms are shown in Fig. 2). At 50 years of age, she was confined to a wheelchair to avoid putting weight on her joints. The pain gradually affected multiple joints over subsequent years. Non-steroidal anti-inflammatory drugs (NSAIDs) improved her joint pain to a limited degree. At 54 years of age, her joint pain became intolerable. NSAIDs were not effective enough for her to resume activities of daily living. Mexiletine hydrochloride treatment was not effective. She experienced side effects of pregabalin and duloxetine. Subsequently, her physician referred her to our multidisciplinary center for pain management. She was diagnosed with HSAN type II using molecular genetic analysis and was prescribed acetaminophen (2400 mg/day), which controlled her pain very well and improved her quality of life.
During our follow-up, she reported: “one day severe ‘electric-shock-like or piercing pain’ occurred, and which made me suffer few times per hour and keeping for months after this episode, and which was naturally decreased.”
Pain-related assessment
Brief Pain Inventory (BPI), including numerical rating scale (NRS) [12, 13], was used to assess pain intensity and interference. Pain-related psychosocial factors were quantitated using the Hospital Anxiety and Depression scale (HADS) [14] and Pain Catastrophizing Scale (PCS) [15]. NRS and pain interference scale of BPI decreased from 6/10 to 3/10 and from 52/70 to 20/70 points, respectively, over 3 months. PCS scores also decreased from 22/52 to 3/52 points. At baseline, HADS indicated normal mental state; both the anxiety and depressive scales of HADS were relatively low (both 5/21 points) despite severe pain. After 3 months, the anxiety and depressive scales of HADS decreased from 5/21 to 3/21 points and from 5/21 to 4/21 points, respectively.
Neurological examination
A neurological examination revealed normal mental status, speech, and comprehension and intact cranial nerve-innervated muscles. Manual muscle testing revealed moderate weakness in the distal parts of the extremities and mild weakness in the proximal parts. Grip strength was significantly reduced (right, 4.0 kg; left, 6.0 kg). Deep tendon reflexes were absent. Plantar responses were flexor on both sides. The sensory examination revealed that the tactile and pinprick sensations were moderately decreased in the face and trunk and severely diminished in the upper and lower distal extremities. Sensations were diminished in a stocking and glove pattern. The vibration sense was reduced till the knees and absent in the ankles. The joint position sense was absent at the hallux. There was no apparent laterality of the sensory disturbance. Pseudoathetosis was observed in the upper limbs, and Romberg’s test was not positive in the seated position. With the exception of abnormal sweating, thermoregulatory failure, and lack of urge to defecate, there were no signs of autonomic dysfunction, such as pupillary responses, dry eyes, or dry mouth. Her blood pressure was 138/85 bpm in the supine position and 126/72 bpm while standing. The head-up tilt test did not reveal any orthostatic intolerance. On electrocardiogram, the coefficient of variation of the R-R intervals (CVR-R) measured at rest was normal. The early and delayed heart-to-mediastinum (H/M) ratio was not decreased on 123I-MIBG myocardial scintigraphy (early: 3.14, delay: 2.97).
Nerve conduction and electromyographic evaluation
The nerve conduction study revealed normal compound muscle action potentials (CMAPs) values, except for a slightly reduced motor nerve conduction velocity of 50.0 m/s, 41.0 m/s, and 39.0 m/s in the median, peroneal, and tibial nerves, respectively. The velocity was in the normal range in the ulnar nerve (>50.5 m/s) and in the tibial and peroneal nerves (>48.0 m/s). The sensory nerve action potentials of the median, ulnar, and sural nerves were not evoked. The electromyography revealed a reduction in recruitment in the distal muscles of the upper and lower limbs. The patient was diagnosed with pure sensory neuropathy.
Pathologic examination
Sural nerve biopsy revealed a severe loss of myelinated and unmyelinated nerve which were observed by light microscopy of the epon section with toluidine blue staining (Fig. 3a, b) and electron microscopy (Fig. 4a, b). Collagen pockets, which were indicative of unmyelinated nerve loss, were observed by electron microscopy (indicated by the arrows in Fig. 4c). Myelinated nerve tissue was completely lost. The density of unmyelinated nerve tissue (7620 per mm2), calculated by electron microscopy, was significantly decreased. Skin biopsy was not performed.
Molecular genetic analysis
Mutation screening was conducted as previously described [16]. Target sequencing with 16 HSAN disease-related genes were conducted using Illumina MiSeq (Illumina Inc., San Diego, CA, USA). The WNK1 mutation observed in this patient was validated by Sanger sequencing. A homozygous frame shift mutation was identified in the WNK1/HSN2 gene c.3237_3238insT (p.Asp1080fsX1; ENST00000537687), which was previously reported as c.1134_1135insT (p.Asp379fsX1; ENST00000574564) [8, 9]. This mutation is absent in 1000 Genomes, ExAC, or HGVD, which comprises exome sequencing of 1208 Japanese individuals (http://www.genome.med.kyoto-u.ac.jp/SnpDB/).