We would like to highlight three important points from this case. First, this is the second case of WNK/HSN2 gene mutation of HSAN type II reported in a Japanese patient. Second, this is the first reported case of an autonomic disorder in a patient with the WNK/HSN2 gene mutation. Third, the patient’s arthropathy-related pain, despite congenital impairment of pain sensation, was a noteworthy symptom.

The current patient is the second reported case of a patient with WNK1/HSN2 gene mutation in Japan, both of which resulted from the same homozygous mutation, c.3237_3238insT [9]. WNK1/HSN2 with homozygous 1134–1135 ins T mutation was reported in a Japanese patient by Takagi et al. [9], and the same mutation was reported in Korea by Cho et al. [8].

Although an autonomic disorder has never been reported in HSAN type II with the WNK1/HSN2 gene mutation, our patient presented with several symptoms of autonomic disturbances. In particular, the lack of urge to defecate through decreased parasympathetic pelvic nerve activity resulted in serious disruptions in her activities of daily living. Although there have been no reports of hyperhidrosis in patients with HSAN type II, fluctuation in body temperature is one of the most common symptoms of autonomic failure. In the presence of partial hyperhidrosis, there may be peripheral autonomic dysfunction. WNK influences transient receptor potential vanilloid 4 (TRPV4) channel function, which controls osmoregulation at the cellular level and regulates water balance. Therefore, there is an association between WNK1 and severe hypertension as reported previously [17]. However, our patient did not present with hypertension. Although our examination did not reveal autonomic dysfunction, we think that the possibility of autonomic failure cannot be excluded. This is the first reported case of an autonomic disorder in a patient with the WNK/HSN2 gene mutation, and HSAN type II should be carefully considered because symptoms of autonomic dysfunction appeared in our patient.

Recurrent skin ulcers on the tips of the fingers and toes were previously reported [1, 8, 9]. Our patient had a difficult in recovering from injury and an amputated metatarsal due to osteomyelitis, but she did not develop skin ulcers. Except the autonomic disorder, her neurological examination had almost the same clinical features as those of previous patients with HSAN type II with WNK1/HSN2 gene mutations.

NSAIDs are generally more effective than acetaminophen for arthritis with inflammation. However, in our patient, acetaminophen was more effective than NSAIDs for alleviating multiple joint pain. Theoretically, her arthropathy pain was conducted by unmyelinated nerve fibers (C fibers) and was possibly modified by central pain because acetaminophen was very effective for controlling her pain, although she had a reduction in unmyelinated nerve tissue. The antinociceptive mechanism of acetaminophen is still unclear, but the theory of multiple pathways is supportive. Although acetaminophen inhibits cyclooxygenase (COX), anti-inflammatory effect of acetaminophen is weak. Acetaminophen is lipid-soluble, passes through the blood–brain barrier, and has an effect on the central nerve system [18]. Acetaminophen activates 5-hydroxytryptamine 3 receptors in the serotonergic pathways, which are part of the descending pain system, with resulting pain relief [19]. The gamma-aminobutyric acid receptor is associated with acetaminophen [20]. Cannabinoid is one of the key factors of acetaminophen-induced antinociception [21]. Moreover, TRPV1 has an important role in antinociception induced by acetaminophen in the brain [22].

The patient felt non-specific ‘electric shock-like or piercing’ pain suddenly, but she was innately unable to feel sharp pain because of complete demyelination. Her non-specific pain might have been phantom pain, derived from the central nervous system because it was correlated with her strong emotional episode. When she complained about non-specific pain, her father was diagnosed of cancer and reported a pins-and-needles sensation in his fingers due to peripheral nerve disorder, which was caused by anti-cancer chemotherapy. He had complained about the pins-and-needles sensation every day, and she was told that she had empathized with and imagined his pain. We suspect that her non-specific pain was central pain from this emotional episode relating to her father. A previous study reported that empathy for pain may effectively activate pain neural circuits in an individual observing another person’s pain [23]. Consistent with our findings, Danzier et al. reported a 32-year-old woman with HSAN type V who experienced tension-type headaches shortly after the sudden loss of her brother, despite complete absence of physical pain [24].