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Pediatrics International (2015) 57, 30–36

doi: 10.1111/ped.12538

Review Article

Hereditary sensory and autonomic neuropathy types IV and V
in JapanNobuhiko Haga,1 Masaya Kubota2 and Zenzo Miwa3 on behalf of the Japanese Research Group on Congenital Insensitivity
to Pain1
Department of Rehabilitation Medicine, University of Tokyo, 2Division of Neurology, National Center for Child Health andDevelopment and 3Department of Pediatric Dentistry, Tokyo Medical and Dental University Graduate School, Tokyo, Japan
Abstract

Hereditary sensory and autonomic neuropathy (HSAN) is a group of genetic disorders involving varying sensory andautonomic dysfunction. HSAN types IV and V are characterized by congenital generalized loss of pain and thermal
sensation. HSAN type IV is additionally accompanied by decreased sweating and intellectual disability. From 2010 to2013, we (members of the Japanese Research Group on Congenital Insensitivity to Pain) carried out research on HSAN
types IV and V. Research by this group included epidemiological data, examination of clinical findings, solutions ofdisease etiology, investigation of complications and development of their management. Complications were categorized
into musculoskeletal complications, oral/dental complications, dermal complications, ocular complications, complications resulting from impaired thermal control, anesthetic considerations, other complications possibly related to autonomic dysfunction, and abnormal mental development and behavior. Treatment and care for patients with HSAN types
IV and V require a wide range of knowledge and experience, and a multidisciplinary team approach. Therefore, we
produced the “Guideline of Total Management and Care for Congenital Insensitivity to Pain (Ver.1)” in 2012, to provide
information for medical specialists based on our knowledge and experience. This guideline includes medical issues, aswell as descriptions of social participation and welfare. This review outlines the situation of HSAN types IV and V in
Japan, and the recommendations of treatment and care for patients, mostly based on research conducted by the Japanese
Research Group.

Key words anhidrosis, Charcot’s joint, complications, congenital insensitivity to pain, hereditary sensory and autonomic
neuropathies.

Hereditary sensory and autonomic neuropathy (HSAN) is agroup of genetic disorders involving varying sensory and autonomic dysfunction. Dyck et al. classified HSAN into five types
according to the mode of inheritance and clinical features.1 This
classification has been modified with subtyping, addition of new
types, and discovery of related genes (Table 1).2,3 The degree andnature of sensory and autonomic disturbances differ among eachsubtype, and some of them are accompanied by motor deficit.
HSAN type IV (HSAN-IV) and type V (HSAN-V) are characterized by congenital generalized loss of pain and thermal sensation with autosomal recessive inheritance. HSAN-IV, also
called congenital insensitivity to pain with anhidrosis, is additionally accompanied by decreased sweating and intellectual
disability.
From 2010 to 2013, the Japanese Research Group on Congenital Insensitivity to Pain, consisting of researchers from
related medical fields, carried out research on HSAN-IV and -V.
Correspondence: Nobuhiko Haga, MD PhD, Department of Rehabilitation Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-8655, Japan. Email: hagan-reh@h.u-tokyo.ac.jp
Received 3 September 2014; revised 26 October 2014; accepted 29
October 2014.

© 2014 Japan Pediatric Society

The Medical Examination Gathering, which has been annually
held since 1994 in collaboration with the non-profit organization
Japanese Patients’ and Supporters’ Society for Congenital Insensitivity to Pain with Anhidrosis, “Tomorrow”, has made great
contributions to our research. This review outlines the current
situation of HSAN-IV and -V in Japan, and recommendations oftreatment and care for patients, mostly based on research conducted in Japan.

Epidemiology
The prevalence of HSAN-IV and -V is not well establishedworldwide. Reports from countries other than Japan on more than
10 HSAN-IV patients came only from Israel.4 The only report on
HSAN-V was on a large family from Sweden.5,6 Although there
are many articles on Japanese patients with HSAN-IV and only a
few on HSAN-V, no epidemiological studies on these conditions
have been conducted in Japan.
To collect epidemiological data on Japanese patients, questionnaires were sent to pediatricians, neurologists, orthopedic
surgeons, and dentists.7 We estimated that the number of Japanese patients with HSAN-IV and -V was 130–210 and 30–60,
respectively. We identified no sex differences, and patients with a

HSAN types IV and V in Japan

31

Table 1 Classification of hereditary sensory (and autonomic) neuropathies
Subtype†
HSAN-IA

Gene orlocus
SPTLC1

HeredityAD

HSAN-IB

3p24–p22

AD

HSAN-ICSPTLC2AD

HSN-IDATL1

AD

HSN-IEDNMT1

ADHSN-IF

ATL3

AD

HSAN-IIA

WNK1

AR

HSAN-IIB

FAM134B

AR

HSN-IIC

KIF1A

AR

HSN-IID‡

SCN9A

AR

HSAN-IIIIKBKAPAR

HSAN-IV

NTRK1

AR

HSAN-V

NGFB

AR

HSAN-VI

DST

AR

HSAN-VIISCN11AAD

HSN with spastic
paraplegia

CCT5

AR

Clinical features

Age at onset

OMIM

Loss of pain and temperature sensation; lancinating pain;
ulcerative mutilations; variable distal motor involvement
Sensory loss with cough and gastroesophageal reflux; footulcerations (rare)
Loss of pain and temperature sensation; lancinating pain;
ulcerative mutilations; variable distal motor involvement
Severe distal sensory loss and amyotrophy in the lower limbs;
trophic skin and nail changes; ulcerative mutilations
Loss of all somatosensory modalities; lancinating pain;
ulcerative mutilations; sensorineuronal hearing loss; dementia
Distal sensory loss in the lower limbs; painless ulceration of thefeet; no autonomic involvement
Loss of pain, temperature and touch sensation; mutilation in thehands and feet; acropathy
Impaired nociception and progressive mutilating ulceration ofhands and feet with osteomyelitis and acro-osteolysis
Impaired position and vibration senses; ulcerative mutilation;
minor distal weakness
Loss of pain and temperature sensation; autonomic nervous
dysfunction; hearing loss; hyposmia
No response to painful stimuli and temperature changes;
alacrima; absence of fungiform papillae of the tongue;
vasomotor instability and hyperhidrosis
No (or reduced) response to painful stimuli; reduced thermal
sensation; anhidrosis; episodic fever; intellectual disability
and/or learning deficits; skin and corneal lesions; joint
deformities
Insensitivity to pain; reduced thermal sensation; severe loss ofdeep pain perception; painless fractures; joint deformities
Neonatal hypotonia; joint contractures; alacrima; absent corneal
reflexes; lack of psychomotor development
Insensitivity to pain; painless fractures; self mutilation; mild
muscle weakness and delayed motor development
Loss of all somatosensory modalities; mutilating acropathy;
spastic paraplegia

Mostly adolescence
to adulthood
Adulthood

162400

Mostly adulthood

613640Adulthood613708Adulthood614116Adulthood615632Childhood

201300Childhood613114

Childhood toadolescence
Congenital oradolescence
Congenital

614213243000Congenital

256800Congenital

608654

Congenital

614653Congenital

615548

Early childhood

256840608088223900This table has been modified from Rotthier et al.2 and Yuan et al.3 †Based on the description in OMIM, except for the use of Roman numbers
according to the Dyck et al. original description.1 ‡In OMIM (243000), this subtype is named “channelopathy-associated insensitivity to pain”,
and the clinical features differ among reports. HSAN, hereditary sensory and autonomic neuropathy; HSN, hereditary sensory neuropathy;
OMIM, Online Mendelian Inheritance in Man

family history of the disorder were limited to affected siblings inboth conditions. Most patients with HSAN-IV were 5–40 yearsof age, whereas half of the patients with HSAN-V were ≥40years. We found no significant difference in the prevalence of
HSAN-IV and -V among different regions in Japan (Table 2; N.
Haga, unpubl. data, 2012).

Pathoetiology
The common and basic manifestations of HSAN-IV and -V are
generalized insensitivity to pain and reduced thermal sensation.

In HSAN-IV, perception thresholds of touch/pressure, vibration,and two-point discrimination are higher and proprioception sensitivity is lower compared with healthy controls.8 Tomioka et al.
reported on a patient with HSAN-IV who complained of itchingas a sequel of Herpes zoster infection, and they suspected that
this itching was a symptom of post-herpetic neuralgia.9 Indo,however, noted that patients with HSAN-IV lack pain anditching sensation because of a lack of nerve growth factor(NGF)-dependent primary afferents.10 In addition, HSAN-IV
manifests reduced sweating, various degrees of intellectual

Table 2 Prevalence of HSAN-IV and -V in Japan

HSAN-IV
HSAN-V

Hokkaido
3.6
1.8

Tohoku
8.3
1.0

Kanto
8.9
2.2

No. patients per 10 000 000 population
Chubu
Kinki
Chugoku
9.6
6.2
5.2
2.3
1.8
1.3

Shikoku
0.0
2.4

Kyushu5.4
2.0

HSAN, hereditary sensory and autonomic neuropathy.

© 2014 Japan Pediatric Society

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N Haga et al.

disability and/or learning deficits, and self-mutilating
behavior.
In HSAN-IV and -V, conventional nerve conduction studies
were apparently normal, and nerve biopsies showed selective lossof unmyelinated and small myelinated fibers.1,11 Patients with
HSAN-IV show loss of innervation of eccrine sweat glands bysympathetic neurons.11
In 1996, Indo et al. reported mutations in the tyrosine kinasedomain of the NTRK1 (TRKA) gene in Japanese and Ecuadorianpatients with HSAN-IV.12 Mutations of NTRK1 have beenreported in patients of various ethnic origins, including additional
Japanese patients13 and Bedouin people in northern Israel.4
NTRK1 encodes tropomyosin-related kinase A (TrkA), a receptor
tyrosine kinase for NGF. Patients with HSAN-IV lack NGFdependent neurons because defects in NGF-TrkA signaltransduction lead to failure of survival of various NGF-dependentneurons.14
Mutations in the NGFB gene encoding nerve growth factorbeta have been reported in a large family from Sweden5,6 and in
a consanguineous Bedouin family with HSAN-V.15 In the former
family, homozygous patients had severe clinical manifestations,
including progressive joint swelling, painless fractures, and progressive arthropathy. Temperature perception was impaired withnormal sweating, and mental retardation was not observed.
Heterozygous patients were mildly affected or not affected. In the
Bedouin family, homozygous patients had multiple painless injuries of varying severity and had mild mental retardation. Thesefindings suggested phenotypic overlap between HSAN-IV and-V because of changes in the NGF-TrkA signaling pathway.

Complications and their management
Musculoskeletal complications

Musculoskeletal complications are frequent in HSAN-IV and -V,
and include repeated fractures and joint dislocations, arthritis andosteomyelitis, avascular necrosis, and Charcot arthropathy,
mainly in the lower extremities.16–19 A review of Japanese patientswith HSAN-IV showed that fractures are frequent between 1 and7 years of age, whereas other complications have no apparent age
relationship.20
Fractures and dislocations develop in HSAN-IV and -V, even
without any apparent trauma or following minor trauma, such as
short falls (Fig. 1).20 Although the reason for these fractures anddislocations has not been clarified, decreased sensation, including deep sensation, intellectual disability, and mutilating behavior, may be related. Video gait analysis for patients with
HSAN-IV and -V has shown that younger patients walk fasterwith a longer stride length and higher heel contact angular velocity than controls.21 This finding may explain the high incidence ofmusculoskeletal trauma in the lower extremities.
Charcot arthropathy may develop following malunion of fractures, avascular necrosis, and unreduced/recurrent dislocations in
the absence of pain sensation (Fig. 2). Kawashima et al. measured grip force and acceleration of a held object in patients with
HSAN-IV and -V.22 They found greater grip force during theobject grasp-lift-holding task and greater fluctuation in accelera© 2014 Japan Pediatric Society

Fig. 1 Calcaneal fracture. A male patient with hereditary sensory
and autonomic neuropathy type IV developed calcaneal fracture
without any apparent trauma at 6 years old.

tion of the object. Such impaired motor control ability may leadto overuse and/or misuse of the extremities and cause joint
destruction.
Management of musculoskeletal complications is extremely
difficult. In conservative treatments, such as cast fixation andtraction for fractures and dislocations, maintaining an appropriate
position and avoiding weight bearing are difficult because of lossof pain sensation and intellectual disability. These may also leadto development of pressure sores. Even after surgical treatment,
some patients cannot maintain non-weight bearing status, and the
fixation of fractures or reduction of dislocations can break down.
Because surgical and conservative treatment has drawbacks, prevention of trauma is important in HSAN-IV and-V, although few
comments on injury prevention have appeared in the literature.
The authors recommend that patients wear high-top sneakers
with shoe-inserts of shock-absorbing material and knee pads.
Some parents cover the floor in their house with soft-material
sheets to prevent injuries.
Oral and dental complications

Oral self-mutilation, including autoextraction of teeth and biting
injuries of the tongue, lip, and buccal mucosa, are common inpatients with HSAN-IV (Fig. 3a).23 In infants, trauma of theincisal edge of erupting mandibular primary incisors during
sucking or nursing causes ulcers on the ventral surface of the
tongue. Oral self-mutilation decreases with age and with intellectual, social, and/or emotional development. Treatment andprevention of glossal injuries and tooth luxation include tooth
extraction, elimination of sharp edges of teeth, and use of aprotective plate (Fig. 3b).23

HSAN types IV and V in Japan

a

33

a

b

b

Fig. 3 Oral and dental complications. A female patient with hereditary sensory and autonomic neuropathy type IV aged 1 year 4 months
developed (a) biting injuries of the tongue and lip, and autoextractionof a deciduous tooth. (b) She was using a protective plate at the ageof 2 years.

a normal person. We also observed only a few myelinated fibers
in the dental pulp of patients with HSAN-IV. With regard to oral
sensation of taste, we found that the ability to taste and smell inpatients with HSAN-IV is not impaired (Z. Miwa et al.; unpubl.
data, 2012).
Dermal complications

Fig. 2 (a) Photograph and (b) X-ray of Charcot’s knee joint. A malepatient with hereditary sensory and autonomic neuropathy type IV
aged 10 years developed a Charcot joint with knock-knee deformity
following avascular necrosis in the lateral femoral condyle.

We tested the threshold of pre-pain sensation of dental pulp ofanterior teeth with the electric pulp test in patients with
HSAN-IV and -V. Patients with HSAN-IV did not feel any sensation, but those with HSAN-V felt pre-pain sensation similar to

In HSAN-IV, diminished sweating leads to dry and exfoliatedskin, and sometimes results in palmoplantar keratoderma.24 Baba
et al. measured the degree of hydration in the superficial layers of
the stratum corneum, using the Moisture Checker (MY707S;
Scalar, Tokyo, Japan). The degree of hydration was lower in
HSAN-IV patients compared with normal subjects. Daily use ofa moisturizing agent improved dermal complications (N. Baba
et al.; pers. comm., 2014). In relation to the pathomechanism of
diminished sweating, Nolano et al. demonstrated, on immunohistochemistry, a lack of unmyelinated and small myelinatednerve fibers in the epidermis, and only a few hypotrophic andnon-innervated sweat glands in the dermis.11 In HSAN-V, sweating is reported as normal.6
Multiple skin ulcerations and scars are observed in HSAN-IV
and -V, and these can develop from painless injuries, and sometimes from self-mutilation.25 Self-mutilation typically manifests© 2014 Japan Pediatric Society

34

N Haga et al.

as biting of the lips, tongue, and fingertips. Biting of fingertips
can lead to digital shortening, nail deficiency, and phalangeal
osteomyelitis (Fig. 4).

vaccine (M. Kubota et al.; unpubl. data, 2014). The pathomechanism of the development of acute encephalopathy is still
unclear.

Ocular complications

Anesthetic considerations

In patients with HSAN-IV, corneal opacity and corneal ulcer
have been reported as ocular manifestations.26 Amano et al.
carried out ophthalmologic examinations in 18 Japanese patientswith HSAN-IV. They observed superficial punctate keratopathy
at the interpalpebral area in 64% and corneal opacity in 8.3% of
the examined eyes. Tear breakup time was below the lower limitof the normal range in all of the examined eyes, and the Schirmer
1 test was above the lower limit of the normal range in most of theexamined eyes.27 Accordingly, they recommended care for dryeye, prevention of corneal infection, and daily observation of theocular surface to maintain good visual function in patients. They
also observed the morphology of corneal cells and the sub-basal
nerve plexus in patients with HSAN-IV or -V on in vivo confocal
microscopy, and found lower superficial epithelial cell density
and a severe decrease in nerve fibers at the central cornea.28

Patients with HSAN sometimes need anesthesia to undergo
surgery or examination, although they do not feel pain. Tomioka
et al. carried out a questionnaire study on 45 surgical procedures
under general anesthesia for 15 Japanese patients with HSAN-IV.
Among them, four patients felt mild headache and nine felt mild
abdominal pain. With appropriate temperature management andsufficient perioperative sedation, problems associated with theuse of muscle relaxants and malignant hyperthermia did notoccur. Two patients experienced postoperative nausea or vomiting, although no patients had clear autonomic nervous systemdysfunction. They recommended consideration of the possible
abnormalities in the autonomic nervous system.30 Rozentsveig
et al. reviewed 40 anesthesia records for 20 patients with HSANIV, and reported that cardiovascular events occurred in 15
patients, with one case of cardiac arrest. They recommended that
attention should be paid to potential cardiovascular events whenmanaging patients with HSAN-IV.31

Complications resulting from impaired thermal control

Impaired temperature perception in HSAN-IV and -V, andreduced sweating in HSAN-IV lead to difficulty in thermal
control. Rosenberg et al. reported that death from hyperpyrexia
occurs within the first 3 years of life in almost 20% of HSAN-IV
patients.29 Among 15 Japanese patients who had HSAN-IV anddied, hyperthermia was recognized in six before death (Y. Awaya,
pers. comm., 2010). We recently encountered an 8-year-old boy
with HSAN-IV (he had the NTRK1 mutation, R548fs) who developed acute encephalopathy with hyperthermia and prolonged
convulsion following injection of diphtheria-tetanus-pertussis

Other complications possibly related toautonomic dysfunction

Kubota carried out a questionnaire study on 23 Japanese patientswith HSAN-IV about sleep-wake rhythm, digestive symptoms,
and development of locomotion. All the patients were noted tohave muscle hypotonic tendency in the early infancy. Sixteen outof 23 patients had frequent nocturnal awakening (fragmented
sleep) and crying at night in infancy, mainly in the summer
season, and 14 had various digestive symptoms. All five patients
who suffered from cyclic vomiting also had nocturnal waking ininfancy, and in four of them, development of crawling wasdelayed.32 Generally, sleep–wake rhythm, sleep stages and antigravity locomotion are controlled, at least in part, by thecholinergic and aminergic neurons of the brainstem.33,34
Sobreviela et al. showed that raphe serotonergic neurons
coexpressed TrkA in the brainstem.35 Miyamoto et al. showedthat integrative function of the serotonergic input to the basal
forebrain/preoptic area via the excitatory action of 5-HT2 receptors plays a critical role in the diurnal regulation of slow wave
sleep and night-dominant locomotor activity.36 We have noted theclinical efficacy of serotonergic modulating drugs including
valproic acid, cyproheptadine or tandospirone for the treatmentof cyclic vomiting in HSAN-IV patients. Together, although theunderlying mechanism in sleep–wake rhythm disturbance, abnormal locomotion and cyclic vomiting is still unclear, somecommon causal system such as a serotonergic one could be
postulated.
Abnormal mental development and behavior

Fig. 4 Digital shortening and nail deficiency in an adult patientwith hereditary sensory and autonomic neuropathy type IV.
© 2014 Japan Pediatric SocietyChildren with HSAN-IV are mentally retarded and sometimes
have symptoms of attention-deficit–hyperactivity-disorder(ADHD), whereas mental and cognitive dysfunctions are rare inHSAN types IV and V in Japan
those with HSAN-V. Levy Erez et al. examined 23 Arab Bedouinchildren with HSAN-IV. They found that these children had
lower scores in the intelligence test and the adaptive behavior
scale compared with their healthy siblings. IQ was significantly
higher among children aged up to 7 years than among the older
children.37 In examinations of Japanese children with HSAN-IV,
Shirakawa and Nihei found that development is variable in preschool children, and reduced interest in objects, a lack of communication, speech delay, autistic traits, and ADHD symptoms,
are often observed. At school age, patients have difficulty inlearning the concept of numbers and are weak in arithmetic. In
adolescence, most patients have delayed mental development (K.
Shirakawa and K. Nihei, pers. comm., 2012).

Guidelines of treatment and care
As mentioned here, the treatment and care for patients with
HSAN-IV and -V require a wide range of knowledge and experience, and a multidisciplinary team approach. To provide information for medical specialists based on our knowledge andexperience, our group planned and produced the “Guideline of
Total Management and Care on Congenital Insensitivity to Pain
(Ver.1)” in 2012. This guideline includes not only medical
issues, but also descriptions of social participation andwelfare. This can be downloaded from MHLW Grant System(http://mhlw-grants.niph.go.jp/) with the literature number
201128072B. Our group also collaborated with the JapanesePatients’ and Supporters’ Society to produce a book called “Congenital Insensitivity to Pain with Anhidrosis: Our Care Guide”,
and a DVD called “Congenital Insensitivity to Pain with
Anhidrosis: Understanding this Disease and Support thePatients”, for patients, families, and caregivers.

Acknowledgments
We appreciate the contribution of co-researchers in the Japanese
Research Group on Congenital Insensitivity to Pain, including
Shiro Amano, Yasuhiro Indo, Chizuko Tanaka, Toshiya Tomioka,
Naoko Baba, Kenji Nihei, Kikuko Ikeda, Tomoko Uehara, TetsujiSato, Kumiko Sugimoto, Masakazu Ikeda, Tomoko Kubodera,
Kimiko Shirakawa, Fumiko Hamabe, Noritaka Kawashima,
Makoto Nozaki, Hiroshi Tanaka, Masahiro Iijima, Arito Yozu,
and Yasu Zhang. We also express our sincere appreciation to allof the participants of this study, especially the nationwide
Patients’ and Supporters’ Society for Congenital Insensitivity to
Pain with Anhidrosis “Tomorrow”. We dedicate this article to
Yutaka Awaya, a pediatric neurologist, and Nobuyuki Tanaka, apediatric orthopedic surgeon, both of whom passed away during
the research period, in appreciation of their continued great contribution to the support of patients and our research. This work
was partly supported by Health and Labour Sciences Research
Grants for Research on Intractable Diseases, the Ministry of
Health, Labour and Welfare, and by JSPS KAKENHI, a Grantin-Aid for ScientificResearch on Innovative Areas (Grant
Number 26120008). The authors have no conflicts of interest to
declare.

35

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